CBMTG G-PB versus G-BM Trial
CBMTG Study 0601
Protocol Version: 03-Sep-2008
Version 03-Sep-2008 (Notification of Changes #4)
A Randomized Multicentre Study Comparing G-CSF
Mobilized Peripheral Blood and G-CSF Stimulated Bone
Marrow in Patients Undergoing Matched Sibling
Transplantation for Hematologic Malignancies
(CBMTG 0601)
Summary of Protocol Versions
Version 11-Jul-2006
Version 15-Sep-2006
Amendment 1 (Notification of Changes #1) Version 10-Nov-2006
Amendment 2 (Notification of Changes #2) Version 20-Mar-2007
Amendment 3 Version 24-Sep-2007
Notification of Changes #3 Version 17-Jun-2008
Amendment 4 Version 10-Jul-2008
Notification of Changes #4 Version 03-Sep-2008
Page 1 of 107
CBMTG G-PB versus G-BM Trial
CBMTG Study 0601
Protocol Version: 03-Sep-2008
Study Chair:
Stephen Couban
Queen Elizabeth II Health Sciences Centre
Bethune Building, Room 431
1278 Tower Road
Halifax, Nova Scotia, Canada, B3H 2Y9
Telephone: 902-473-7006
Fax: 902-473-4420
Email: stephen.couban@cdha.nshealth.ca
Study Co-Chair:
Jeffrey H. Lipton
Princess Margaret Hospital
610 University Avenue
Toronto, Ontario, Canada, M5G 2M9
Telephone: 416-946-2268
Fax: 416-946-6585
Email: Jeff.Lipton@uhn.on.ca
Grant Principal Investigator:
Kirk Schultz
British Columbia’s Children’s Hospital
4480 Oak Street
Vancouver, British Columbia, Canada V6H 3V4
Telephone: 604-875-2316
Fax: 604-875-2911
Email: kschultz@interchange.ubc.ca
Page 2 of 107
CBMTG G-PB versus G-BM Trial
CBMTG Study 0601
Protocol Version: 03-Sep-2008
Quality of Life Studies:
Cynthia Toze
Leukemia/BMT Program of British Columbia
Vancouver General Hospital
Gordon and Leslie Diamond Health Care Centre
10th Floor, 2775 Laurel Street
Vancouver, British Columbia, Canada V5Z 1M9
Telephone: 604-875-4863
Fax: 604-875-4763
Email: ctoze@bccancer.bc.ca
Gerald Devins
Toronto General Hospital
9EN-223
200 Elizabeth Street
Toronto, Ontario, Canada M5G 2C4
Telephone: 416-340-3113
Fax: 416-340-3099
Email: gdevins@uhnres.utoronto.ca
Stephanie Lee
Fred Hutchinson Research Centre
1100 Fairview Avenue North, D5-290
P.O. Box 19024
Seattle, Washington, United States 98109
Telephone: 206-667-5160
Fax: 206-667-1034
Email: sjlee@fhcrc.org
Diane Fairclough
University of Colorado Health Sciences Centre
Mail Stop F443, P.O. Box 6508 Aurora
Aurora, Colorado 80045
Telephone: 303-724-1168
Fax: 303-845-9313
Email: diane.fairclough@uchsc.edu
Economic Studies:
Christopher Skedgel
Dalhousie University/Capital Health
DOM Research Office
Centre for Clinical Research, Rm 207
5790 University Avenue
Halifax, Nova Scotia, Canada, B3H 1V7
Telephone: 902-473-6684
Fax: 902-473-6891
Email: chris.skedgel@cdha.nshealth.ca
Study Statistician:
Tony Panzarella
Director, Department of Biostatistics
Princess Margaret Hospital
610 University Avenue
Toronto, Ontario, Canada, M5G 2M9
Telephone: 416-946-4501, ext 4881
Fax: 416-946-2048
Email: tony.panzarella@uhnres.utoronto.ca
Page 3 of 107
CBMTG G-PB versus G-BM Trial
CBMTG Study 0601
Protocol Version: 03-Sep-2008
CBMTG CTN Chair:
Ronan Foley
Molecular Medicine & Pathology
McMaster University
711 Concession Street
Henderson Hospital
2nd Floor Laboratory
Hamilton, Ontario, Canada
Telephone: 905-389-4411
Fax: 905-575-2553
Email: foleyr@hhsc.ca
Study Project Manager:
Holly Kerr
Trial Management Office (CBMTG 0601)
Vancouver General Hospital
Gordon and Leslie Diamond Health Care Centre
10th Floor (Room 10133), 2775 Laurel Street
Vancouver, British Columbia, Canada V5Z 1M9
Telephone: 604-875-4111, ext 63196
Fax: 604-875-5584
Email: hkerr@bccancer.bc.ca
Protocol Steering Committee: Stephen Couban
Gerald Devins
Diane Fairclough
Ronan Foley
Stephanie Lee
Jeffrey Lipton
Holly Kerr
Tony Panzarella
Kirk Schultz
Christopher Skedgel
Clayton Smith
Cynthia Toze
Data Safety and Monitoring
Committee:
Pediatric Blood and Marrow Transplantation Consortium
Data Safety and Monitoring Committee (PBMTC DSMC)
Kamar Godder, MD (Chair)
Pediatric BMT physician, PBMTC Member
Virginia Commonwealth University Health System-MCV
Pediatrics Hematology/Oncology
1101 East Marshall Street, P. O. Box 980121
Richmond, VA 23298-0121
Phone: 804-828-9605
Fax: 804-828-0386
Email: kgodder@vcu.edu
Page 4 of 107
CBMTG G-PB versus G-BM Trial
CBMTG Study 0601
Protocol Version: 03-Sep-2008
Paul J. Martin, MD (Adult BMT physician)
Fred Hutchinson Cancer Research Center
1100 Fairview Avenue N, D2-100
Seattle, WA 98109-4798
Phone: 206-667-4798
Fax: 206-667-5255
Email: pmartin@fhcrc.org
Shaun Tumpane (Patient advocate)
630 NW Alpine Terrace
Portland, OR 97210
Phone: 503-243-4747
Fax: 503-243-3636
Cell: 503-701-7781
Email: stumpane@aol.com
Andrew L. Gilman, MD
(Pediatric BMT physician, PBMTC Member)
University of North Carolina at Chapel Hill
Pediatric Hematology/Oncology
Department of Pediatrics CB# 7220
Chapel Hill, NC 27599-7220
Phone: 919-966-9631
Fax: 919-843-7623
Email: agilman@med.unc.edu
Kimberly A. Schmit-Pokorny,
RN, MSN, OCN (Adult BMT nursing)
University of Nebraska Medical Center
Oncology/Hematology
987680 Nebraska Medical Center
Omaha, Nebraska 68198-7680
Phone: 402-559-4910
Fax: 402-559-3800
Email: kschmit@unmc.edu
Dr. Meenakshi Devidas, PhD (Statistician)
Children's Oncology Group - Data Center (Gaines)
104 North Main Street, Suite 600
Gainesville, FL 32601-3330
Phone: 352-273-0551
Fax: 352-392-8162
Email: mini@cog.ufl.edu
Page 5 of 107
CBMTG G-PB versus G-BM Trial
CBMTG Study 0601
Protocol Version: 03-Sep-2008
Participating Clinical Centers:
BC Children's Hospital
(Study Chair - no patient contribution)
4480 Oak Street
Vancouver, BC, V6H 3V4
Canadian Blood and Marrow Transplantation
Group – Clinical Trials Network
Vancouver Hospital & Health Sciences Centre
950 West 10th Avenue
Vancouver, BC V5Z 4E3
CancerCare Manitoba
675 McDermot Ave., Rm 2083
Winnipeg, MB R3N 1A5
Princess Margaret Hospital
610 University Avenue
Toronto, ON M5G 2M9
Hamilton Health Sciences
1200 Main Street W.
Hamilton, ON L8N 3Z5
The Ottawa Hospital
501 Smyth Road
Ottawa, ON K1H 8L6
London Health Sciences Centre
800 Commissioners Rd. E.
London, ON N6A 4G5
Hôpital Maisonneuve-Rosemont
2nd Floor, Block 4, 5415 boulevard de
l’Assomption
Montréal, QC H1T 2M4
CHA Hôpital Enfant-Jésus
1050, chemin Sainte-Foy
Québec, QC GIS 4L8
Page 6 of 107
Principal Investigator: Dr. Kirk R. Schultz
Phone: 604-875-2316 Fax: 604-875-2911
E-mail: kschultz@interchange.ubc.ca
Chair: Dr. Ronan Foley
Phone: 905-389-4411 x42076 Fax: 905-575-2553
E-mail: foleyr@hhsc.ca
Director: Dr. Clayton Smith
Phone: 604-875-4863; Fax: 604-875-4763
E-mail: clsmith@bccancer.bc.ca
Local Principal Investigator: Dr. Cynthia Toze
Study Coordinator: Holly Kerr
Director: Dr. Matthew Seftel
Phone: 204-787-3594; Fax: 204-787-1345
E-mail: morel.rubinger@cancercare.mb.ca
Local Principal Investigator : Dr. Morel Rubinger
Study Coordinator: Erin Richardson
Director: Dr. Jeffrey H. Lipton
Phone: 416-946-2268; Fax: 416-946-6585
E-mail: Jeff.Lipton@uhn.on.ca
Local Principal Investigator: Dr. Jeffrey H. Lipton
Study Coordinator: Isabel Belen
Director: Dr. Irwin Walker
Phone: 905-521-2100; Fax: 905-521-4971
E-mail: walkeri@mcmaster.ca
Local Principal Investigator: Dr. Irwin Walker
Study Coordinator: Tammy DeGelder
Director: Dr. Lothar Huebsch
Phone: 613-737-8158; Fax: 613-737-8861
E-mail: lhuebsch@ottawahospital.on.ca
Local Principal Investigator: Dr. Lothar Huebsch
Study Coordinator: Melissa Tessier
Director: Dr. Kang Howson-Jan
Phone: 519-685-8500; Fax: 519-685-8477
E-mail: kang.howsonjan@lhsc.on.ca
Local Principal Investigator: Dr. Kang Howson-Jan
Study Coordinator: Darlene Tenhaaf
Director: Dr. Jean Roy
Phone: 514-252-3404; Fax: 514-254-5094
E-mail: jean.roy@ssss.gouv.qc.ca
Local Principal Investigator: Dr. Silvy Lachance
Study Coordinator: Nathalie LaChapelle
Director: Dr. Guy Cantin
Phone: 418-649-5727
Local Principal Investigator: Dr. Robert Delage
Study Coordinator: Chantal Gagné
CBMTG G-PB versus G-BM Trial
CBMTG Study 0601
Protocol Version: 03-Sep-2008
Participating Clinical Centers (continued):
Queen Elizabeth II Health Sciences Centre
Bethune Building, Room 417, 1278 Tower Road
Halifax, NS B3H 2Y9
Fred Hutchinson Cancer Research Centre
P.O. Box 19024
Seattle, Washington 98109-1024
King Faisal Specialist Hospital & Research Center
P.O. Box 3354, MBC-64
Riyadh 11211
Kingdom of Saudi Arabia
Auckland City and Starship Children’s Hospitals
Stem Cell Transplant Program
Auckland City Hospital
2 Park Road
Grafton, Auckland 1023
New Zealand
Royal Melbourne Hospital
c/o Post Office
PARKVILL 3050
Victoria, Australia
Page 7 of 107
Director: Dr. Stephen Couban
Phone: 902-473-7006; Fax: 902-473-4420
E-mail: stephen.couban@cdha.nshealth.ca
Local Principal Investigator: Dr. Stephen Couban
Study Coordinator: Valerie Dorcas
Director: Dr. Frederick Appelbaum
Phone: 204-667-4412
Fax: 206-667-6936
E-mail: fappelba@fhcrc.org
Local Principal Investigator: Dr. Stephanie Lee
Study Coordinator: Katie Laigo
Director (Adult Program): Dr. Mahmoud Aljurf
Phone: 966-1-4423940 Fax: 966-1-4423941
E-mail: maljurf@kfshrc.edu.sa
Local Principal Investigator: Dr. Mahmoud Aljurf
Study Coordinator: Ed Colcol and Merybeth Dingle
Director: Dr. Richard Doocey
Phone: 64-9-307-4949, x 23306
Fax: 64-9-375-7053
E-mail: RDoocey@adhb.govt.nz
Local Principal Investigator: Dr. Richard Doocey
Study Coordinator: Jane Wylie
Director: Dr. Jeffrey Szer
Phone: 61-3-9342-7737 Fax: 61-3-9342-7386
E-mail: jeff.szer@mh.org.au
Local Principal Investigator: Dr. David Curtis
Study Coordinator: Peter Shuttleworth
CBMTG G-PB versus G-BM Trial
CBMTG Study 0601
Protocol Version: 03-Sep-2008
Abstract
Patients will be eligible for this study if they are between 16 to 65 years old, have
a hematologic malignancy and are eligible to undergo matched sibling progenitor
cell transplantation following a myeloablative conditioning regimen. (Acceptable
regimens include busulfan and cyclophosphamide, cyclophosphamide and TBI
OR other myeloablative regimens as approved by the Clinical Study Chair).
The study is designed to evaluate the impact of two different sources of
allogeneic progenitor cells on the incidence and severity of chronic graft versus
host disease (GVHD) following sibling allogeneic progenitor cell transplantation.
Eligible patients will be randomized to receive either G-CSF mobilized allogeneic
peripheral blood (G-PB)(standard arm) or G-CSF stimulated allogeneic bone
marrow (G-BM) (experimental arm). The study will test the hypothesis that use
of G-BM is associated with a longer time to treatment failure (extensive chronic
GVHD, relapse, death) than is the use of G-PB for adult allogeneic
transplantation for hematologic malignancies. The study will also assess the
impact of this novel source of allogeneic progenitor cells on overall survival,
disease-free survival, hematologic recovery, acute GVHD, overall chronic GVHD,
health-related quality of life and economic impact in donors and recipients.
The study is a randomized phase III multicentre trial. All patients will receive a
myeloablative conditioning regimen. Graft versus host disease prophylaxis will
be with methotrexate and cyclosporin. Supportive care will be according to
institutional practice.
Page 8 of 107
CBMTG G-PB versus G-BM Trial
CBMTG Study 0601
Protocol Version: 03-Sep-2008
Table of Contents
Page
1.0
Specific Aims
11
2.0
Overview of Study Design
12
3.0
Background and Rationale
13
4.0
Eligibility and Study Entry
18
5.0
Treatment Plan (Overview)
22
5.2
Administration of G-CSF
22
5.3
Apheresis
23
5.4
Bone Marrow Harvest
24
5.5
Conditioning Regimens
25
5.6.1
Methotrexate
27
5.6.1.2 Dose Reduction for Methotrexate Toxicity
28
5.6.2
Cyclosporin (Including Tapering)
30
5.7
Supportive Care
30
5.8
Graft versus Host Disease Treatment
32
6.0
Required Observations
33
7.0
Evaluation of Outcome
36
8.0
Criteria for Removal from Protocol Therapy and Off Study
Criteria
44
9.0
Statistical Considerations
45
10.0
Laboratory Blood and Marrow Collections
50
11.0
Adverse Events/Serious Adverse Events
54
12.0
Data Safety Monitoring Committee
60
13.0
Records and Reporting
60
14.0
Regulatory Ethics Compliance
62
15.0
Study Monitoring
63
16.0
References
64
Page 9 of 107
CBMTG G-PB versus G-BM Trial
CBMTG Study 0601
Protocol Version: 03-Sep-2008
Appendices
Page
Appendix 1
ECOG Performance Status
68
Appendix 2
Registration and Minimization
69
Appendix 3
Study Forms (Available on the Project Website)
3A: Data Collection Forms
3B: Quality of Life Questionnaires
3C: Health Economics Questionnaires
3D: Chronic GVHD Forms
3E: Safety Reporting
3F: Requisition for Optional Donor Research Samples
74
Appendix 4
Regimen Related Toxicity: Bearman Scale (Stomatitis)
76
Appendix 5
Acute Graft Versus Host Disease Staging and Grading
(Przepiorka et al, 1995)
77
Appendix 6
Chronic Graft Versus Host Disease
Limited versus Extensive (Sullivan et al, 1986)
78
Appendix 7
Consent Templates
7A: Donor Consent Form
7B: Recipient Consent Form
7C: Donor Consent Form for Optional Laboratory
Research
79
Appendix 8
Schedule of Events
103
Page 10 of 107
CBMTG G-PB versus G-BM Trial
CBMTG Study 0601
Protocol Version: 03-Sep-2008
1.0
Specific Aims
Clinical Study
Primary Clinical Hypothesis: The use of G-BM is associated with a longer
time to treatment failure (extensive chronic GVHD, relapse, death) than is the
use of G-PB for adult myeloablative allogeneic transplantation for hematologic
malignancies.
Secondary Clinical Hypotheses:
1. Compared to G-PB, the use of G-BM for sibling allografts will lead to a
comparable hematological recovery and comparable overall survival with
clinically significant reductions in extensive chronic GVHD.
2. Recipients of G-BM will report improved quality of life in association with
decreasing extensive chronic GVHD.
3. Economic impact will be lower in G-BM group than in the G-PB group.
Additional Planned Analyses: To compare the two treatment arms with
respect to:
1. Acute GVHD (incidence, severity)
2. Chronic GVHD (organ involvement, symptomatology and functional
impact)
3. Overall survival
4. Disease-free survival
5. Time to relapse
6. Donor quality of life
7. Cost analysis from a societal perspective
Page 11 of 107
CBMTG G-PB versus G-BM Trial
CBMTG Study 0601
Protocol Version: 03-Sep-2008
2.0
Overview of Study Design
Study Schema
Eligible Recipient
Eligible Donor
Informed Consent
Registration
Minimization
Page 12 of 107
Standard Arm
G-PB Transplant
Experimental Arm
G-BM Transplant
Standard Conditioning
Standard GVHD Prophylaxis
Standard Supportive Care
Standard Conditioning
Standard GVHD Prophylaxis
Standard Supportive Care
Evaluation of Primary
and
Secondary Outcomes
Evaluation of Primary
and
Secondary Outcomes
CBMTG G-PB versus G-BM Trial
CBMTG Study 0601
Protocol Version: 03-Sep-2008
3.0
Background and Rationale
The preferred source of hematopoietic progenitor cells for high dose therapy
and hematopoietic stem cell transplantation has changed in the last two
decades. Traditionally, cells harvested directly from bone marrow in the iliac
crests were used for both autologous and allogeneic transplantation.
Progenitor cells capable of re-establishing hematopoiesis after myeloablative
therapy are present in low concentration in blood but the number of apheresis
procedures required for a satisfactory graft makes collection from unstimulated
blood impractical. However, the concentration of peripheral blood progenitor
cells increases following administration of recombinant growth factors such as
G-CSF or GM-CSF alone or after chemotherapy allowing collection of an
adequate graft with only one or a few apheresis procedures. Autologous
peripheral blood harvesting by apheresis has permitted collection of large
numbers of progenitor cells and Phase 2 studies and randomized studies
(Schmitz et al, 1996; Vose et al, 2002) have demonstrated faster hematologic
recovery compared to marrow autografting. Peripheral blood autografting has
also facilitated graft manipulations such as CD34+ cell selection and tumor cell
purging which had been difficult using the smaller number of progenitor cells
collected by autologous marrow harvesting. For these reasons, peripheral
blood has almost completely replaced marrow in autologous transplantation
with marrow employed only for patients in whom mobilization is poor or those
who cannot tolerate apheresis.
1. Allogeneic Peripheral Blood Transplantation
Peripheral blood as a source of progenitor cells for allografting was initially
overlooked for two major reasons.
First, peripheral blood contains
approximately ten-fold more T-lymphocytes which are the principal mediators of
graft versus host disease (GVHD). In marrow allografting, T-cell depletion
studies had shown a correlation between the number of T-lymphocytes in the
allograft and the extent and severity of GVHD. Second, there were concerns
about the risks to normal donors of both administering recombinant growth
factors and undergoing apheresis, including uncertainty about whether central
venous catheters would be required.
In 1995, three pivotal studies (Korbling et al, 1995; Schmitz et al, 1995;
Bensinger et al, 1995) demonstrated the safety and feasibility of using G-CSF
mobilized peripheral blood allografts. Patients experienced prompt hematologic
recovery with a similar incidence of GVHD as had been described in marrow
recipients. In addition, no serious short-term complications of G-CSF mobilized
peripheral blood harvesting were noted among the normal donors.
A retrospective comparison of 288 HLA-identical sibling peripheral blood
transplants with 536 HLA-identical sibling marrow transplants (Champlin et al,
2000) demonstrated more rapid neutrophil and platelet recovery among
Page 13 of 107
CBMTG G-PB versus G-BM Trial
CBMTG Study 0601
Protocol Version: 03-Sep-2008
peripheral blood recipients. While there was no difference in the incidence of
Grades II-IV acute GVHD, chronic GVHD was more common in peripheral
blood recipients (65% vs 53%; P=0.02). Furthermore, treatment-related
mortality was lower and disease-free survival higher among peripheral blood
recipients who had more advanced disease with no difference among those
with early disease.
2. Randomized Studies of Sibling Allogeneic Peripheral Blood
Transplantation
Direct comparisons of peripheral blood and marrow in allogeneic sibling
transplantation have been reported in 8 randomized trials (Bensinger et al,
2001; Blaise et al, 2000; Couban et al, 2002; Heldal et al, 2000; Mahmoud et al,
199; Powles et al, 2000; Schmitz et al, 2002; Vigorito et al, 1998). The results
from the four largest trials (Bensinger et al 2001; Blaise et al 2000; Couban et al
2002, Schmitz et al 2002) which included 829 evaluable patients may be
summarized as follows:
i. Hematologic Recovery
Neutrophil and platelet recovery was faster among peripheral blood allograft
recipients. In some studies, fewer red cell and platelet transfusions as well as
shorter hospitalizations were also reported.
ii. Acute Graft Versus Host Disease
Three (Bensinger et al, 2001; Blaise et al, 2000; Couban et al, 2002) of the four
studies found no difference in the incidence or severity of acute GVHD among
peripheral blood and marrow recipients. In contrast, the largest trial (Schmitz et
al, 2002) described a statistically significant higher incidence of Grades II-IV
acute GVHD in peripheral blood recipients (52% vs 39%; P=0.013). Patients in
this study did not receive Day +11 methotrexate while those in two of the other
three studies did, which may account for this difference.
iii. Chronic Graft Versus Host Disease
A significant increase in the incidence of overall and extensive chronic GVHD
was demonstrated in recipients of peripheral blood allografts. A meta-analysis
of published reports (Cutler et al, 2001) including randomized trials, registry
data and case series has confirmed this observation. However, although more
chronic GVHD with peripheral blood allografting appears certain, the magnitude
of this observation and its effect on relapse, survival and the recipients’ quality
of life are less clear. Furthermore, chronic GVHD following peripheral blood
allografting may be qualitatively different from chronic GVHD after marrow
allografting and further studies including long-term follow-up of patients in the
randomized trials will be very important.
iv. Survival
Only one trial (Couban et al, 2002) demonstrated a benefit in overall survival
among peripheral blood recipients (68% vs 60% at 30 months, P = 0.04).
Page 14 of 107
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Protocol Version: 03-Sep-2008
Bensinger et al (Bensinger et al, 2001) reported a trend to better overall survival
of similar magnitude among peripheral blood recipients (66% vs 54% at 24
months, P = 0.06) whereas the two European studies (Schmitz et al, 2002;
Blaise et al, 2000) noted no difference in overall survival among marrow and
peripheral blood recipients.
Higher overall survival in the Canadian study (Couban et al, 2002) was due to
lower treatment-related mortality in peripheral blood recipients. Interestingly,
this benefit was realized early (before Day +30) and continued beyond Day
+100. It seems likely that faster hematologic recovery as well as more rapid
and complete early (Lapierre et al, 2001) and later (Storek et al, 2001; Ottinger
et al, 1996) immunologic reconstitution contribute to lower treatment-related
mortality of peripheral blood recipients.
Although subgroup analyses of randomized studies are problematic because of
power limitations and imbalances of prognostic factors between groups, both
North American studies (Bensinger et al, 2001; Couban et al, 2002)
demonstrated a survival benefit of peripheral blood allografting only in patients
with advanced disease (AML beyond first remission, CML beyond first chronic
phase and advanced stage MDS). Such patients with advanced disease may
derive greater benefit from the faster hematologic and immunologic recovery
afforded by peripheral blood transplantation. Alternatively, peripheral blood
allografts may exert a more potent anti-tumor effect benefiting patients with
more advanced disease although this hypothesis remains unsubstantiated.
Both European studies (Blaise et al, 2000; Schmitz et al, 2002) included
predominantly patients with early disease, possibly accounting for the absence
of a survival benefit of peripheral blood allografting in these studies.
v. Differences in Collection Protocols
The dose of G-CSF administered to donors differed significantly among the four
trials (Table 1). G-CSF increases the number of CD34+ progenitor cells in the
peripheral blood but also affects T-lymphocytes, dendritic and natural killer cells
and other cellular constituents of the allograft. G-CSF mobilized peripheral
blood allografts contain substantially more monocytes, natural killer and
dendritic cells than marrow (Ottinger et al, 1996; Arpinati et al, 2000) and GCSF directs T-lymphocytes to a Th2 phenotype secreting interleukin-4 and
interleukin-10 (Pan et al, 1995). Differences in the methodology of progenitor
cell mobilization with G-CSF and peripheral blood collection could have resulted
in substantial quantitative and qualitative differences in the peripheral blood
allograft among studies, not accounted for solely by CD34 + cell and Tlymphocyte quantitation. More sophisticated characterization of peripheral
blood allografts with comparison of different collection strategies may lead to
improved outcomes after peripheral blood allografting. A planned individual
patient data meta-analysis of the randomized studies comparing sibling
peripheral blood and marrow allografting will afford an opportunity to examine
these issues further (B. Djulbegovic, personal communication).
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Protocol Version: 03-Sep-2008
3. Donor Considerations
Marrow harvesting from normal donors is generally safe and well-tolerated with
serious risks limited mainly to the complications of general anesthesia.
Peripheral blood donors must receive a recombinant growth factor for several
days followed by one or more apheresis procedures. Administration of
recombinant growth factors such as G-CSF to normal donors was initially a
major safety concern in peripheral blood allografting. G-CSF causes normal
donors to experience bone pain, myalgias, arthralgias and malaise (Anderlini et
al, 1996). It also leads to leukocytosis, thrombocytopenia and elevations of
alkaline phosphatase, lactate dehydrogenase, uric acid, alanine
aminotransferase, γ-glutamyl transpeptidase, prothrombin, thrombin-antithrombin complexes and D-dimer (Falanga et al, 1999). While these common
effects are usually transient, rare but more serious medical events including
myocardial infarction and stroke (Cavallaro et al, 2000; Anderlini et al, 1997)
have been reported. There have also been reports of spontaneous splenic
rupture requiring emergency splenectomy following G-CSF administration to
normal donors (Becker et al, 1997; Falzetti et al, 1999). Careful follow-up of
normal donors who received G-CSF is essential to determine whether there are
serious long-term effects of this practice. However, recent quality of life data
from the Canadian randomized study comparing marrow with peripheral blood
(Bredeson et al, 2004, in press) has suggested that both types of harvest are
well-tolerated by donors, although the toxicities of marrow and peripheral blood
harvests are different.
4. Allogeneic G-CSF Stimulated Marrow Transplantation
The use of autologous and allogeneic progenitor cells collected from peripheral
blood leads to faster hematologic recovery because greater numbers of CD34 +
cells are obtained with this approach. This approach also leads to the collection
of ten-fold more T-lymphocytes which may explain the higher incidence of
chronic GVHD following peripheral blood allografting. It is possible that
treatment of a donor with G-CSF prior to marrow collection may also allow
collection of more CD34+ progenitor cells compared to unstimulated marrow
without the large number of T-lymphocytes which accompany peripheral blood
collection. Several investigators have demonstrated the safety and feasibility of
this approach (Couban et al, 2000; Isola et al, 2000; Serody et al, 2000). A
randomized comparison of G-CSF mobilized peripheral blood and G-CSF
stimulated marrow allografts closed early because more overall (90% vs 47%;
P<0.02) and extensive 80% vs 22%; P<0.02) chronic GVHD was seen in
peripheral blood compared to G-CSF stimulated marrow recipients (Morton et
al, 2001). No difference in overall survival was observed among the 57
evaluable patients and a definitive trial comparing G-CSF stimulated bone
marrow with G-CSF mobilized peripheral blood is warranted.
5. Quality of Life Considerations for Donors and Recipients
The health care system in Canada presents unique opportunities to perform
comprehensive quality of life evaluations in conjunction with assessment of the
Page 16 of 107
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major biologic end points which may differ between the strategies described
above using G-CSF mobilized blood or marrow as hematopoietic stem cell
source.
Achievement of widespread agreement in the transplant community as to
optimal stem cell source would require consideration of multiple outcomes over
time for both patient and donor. Clearly for the patient, important issues are
'hard' outcomes such as duration of survival and disease-free survival, risk of
death due to the procedure, and risk of relapse. However, the ultimate quality
of recipient life would be expected to impact on treatment choice. G-PB has
been associated with an increased incidence of chronic GVHD. Chronic GVHD
can have a positive impact on outcome via association with a 'graft vs
malignancy' effect, whereby, for some diseases, lower relapse rates are seen
for patients experiencing this complication. However, it may be expected to
have the opposite effect on QOL via increased symptoms, need for medical
attention, and associated complications such as infection, fatigue, and others.
If the potential benefit is small, and the potential cost in terms of decreased
QOL is large, the preferred stem cell source may change. Therefore, it is
important to know about the impact of stem cell collection strategy on broad
aspects of patient QOL to evaluate the decision about whether G-BM or G-PB
may be the best option overall.
For donors, hard outcomes such as complication rate and risk of mortality with
the stem cell collection procedure need to be determined. However, the two
strategies (PB or BM harvesting) differ quite markedly in terms of what is
required from the donor. There may be associated differences in donor QOL,
such as anticipatory anxiety, symptoms, and duration of time lost from work,
etc. To date, few studies have addressed these issues in the donor. If recipients
are found to prefer multiple aspects of a particular strategy, it would be
important to know whether that strategy was disadvantageous to the donor in
any manner. Therefore, the proposed trial, which aims to compare G-BM and
G-PB broadly, will also compare the two different strategies in regard to QOL
for donors. Several previously validated QOL instruments have been applied to
these populations. In the current study, we are interested primarily in assessing
potential differences between the experimental and control arms.
6. Conclusions
The use of G-CSF mobilized peripheral blood allografts is a safe and feasible
alternative to unstimulated marrow. In matched sibling allogeneic
transplantation, peripheral blood allografts lead to faster hematologic recovery
and may result in less blood product use and shorter hospitalizations. Despite
an apparent lack of increased acute GVHD, peripheral blood allografting is
associated with more chronic GVHD and the impact of this on survival, relapse
and the recipients’ quality of life remains to be determined.
In the absence of evidence from randomized trials, bone marrow remains the
standard allograft for unrelated transplantation, although peripheral blood may
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be a reasonable alternative. Further studies of the long-term outcome of
allogeneic peripheral blood transplantation are needed to define the
consequences of increased chronic GVHD. In addition, randomized trials of
mobilized blood allografts in unrelated transplantation and in children as well as
further evaluation of stimulated marrow allografts are required. Finally, as the
components of an allograft are better characterized and understood, it should
be possible to define optimal mobilization, stimulation and collection strategies.
Table 1: Collection protocols, target CD34+ cell dose and CD34+ and Tlymphocyte content (per kg of recipient weight) of peripheral blood (PB)
allografts in four randomized comparisons of allogeneic marrow and peripheral
blood.
Table 1
Number of
Apheresis
Median (range)
Target PB
CD34+
cell dose
Actual PB CD34+
cell dose
Median (range)
Actual PB
T-cell dose
Median (range)
4
1
(1-3)
4x106
5.8 x106
(1.5-68.3)
300.1 x106
(15.6-212.3)
5
4
2
2.5 x106
6.4 x106
(0.7-32)
370 x106
(12.0-3080)
Bensinger et al,
2001
16
5
1
(1-4)
5 x106
7.3 x106
(1.0-29.8)
238 x106
(5.4-347)
Blaise et al,
2000
10
5
2
(1-3)
4 x106
6.6 x106
(1.5-19.2)
356 x106
(131-754)
G-CSF
Dose
g/kg/d
Days of
G-CSF
Schmitz et al,
2002
10
Couban et al,
2002
4.0
Eligibility and Study Entry
4.1
Inclusion Criteria
Recipient must
1. Be between the ages of 16 and 65 years old
2. Have one of the following hematologic malignancies:
 Acute myeloid leukemia (de novo, secondary or therapy
related) in first complete remission or second complete
remission
 Chronic myeloid leukemia in chronic or accelerated phase
(de novo or therapy related)
 Myelodysplasia (de novo or therapy related)
 Other hematologic malignancy (de novo or therapy related)
including but not limited to: ALL (CR 1, CR2 or CR3), CLL,
non-Hodgkin’s Lymphoma, Hodgkin lymphoma disease)
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3. Must be receiving a myeloablative conditioning regimen of
busulfan and cyclophosphamide or TBI and
cyclophosphamide or other myeloablative regimen approved
by the Clinical Study Chair. (Regimens containing ATG are
not allowed.)
4. Have an HLA-identical sibling donor
5. Meet the transplant center’s criteria for myeloablative
allogeneic transplantation
6. Have an ECOG performance status of 0, 1 or 2
7. Have given signed informed consent
8. For the QOL component, be able to communicate in English or
French
Please Note: If a centre is unsure how to categorize a
recipient in terms of disease and disease stage (early versus
late) when completing the Trial Registration/Randomization
form, contact the Project Manager or Clinical Study Chair.
Donor must
1. Be 18 years of age or older. (Upper age limit is at the
discretion of the transplant physician at the collection centre.)
2. Be able to undergo general anesthesia and BM harvest or
peripheral blood collection as per assessment by a transplant
physician. (If an anesthetist assesses a donor after
randomization and determines the donor should not undergo
general anesthesia, then the donor and recipient will be
withdrawn from the study.)
3. Be a sibling of the recipient
4. Be a 6/6 HLA match of the recipient. HLA typing is by
serologic or DNA methodology for A and B and by DNA
methodology for A and B and by DNA methodology for DRB1
(intermediate resolution)
5. Have given signed informed consent
6. For the QOL component, be able to communicate in English or
French
Exclusion Criteria
Recipient
1. The recipient is HIV antibody positive
Please note: Randomization can occur prior to the availability
of HIV test results (as long as results will be available prior to
the start of recipient conditioning). In a situation where a
positive result is not known until after randomization, the
patient and/or donor will be taken off study).
2. For the QOL component, inability to participate due to
cognitive, linguistic or emotional difficulties.
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Donor
1. The donor is unable to undergo general anesthesia, bone
marrow harvest or peripheral blood collection
2. The donor is pregnant or breastfeeding at the time of
progenitor cell collection
3. The donor has a history of malignant disease within the last 5
years or current malignancy other than non-melanomatous in
situ skin carcinoma or cervical carcinoma in situ
4. The donor is HIV antibody positive
Please note: Randomization can occur prior to the availability
of HIV test results (as long as results will be available prior to
the start of recipient conditioning). In a situation where a
positive result is not known until after randomization, the
patient and/or donor will be taken off study).
5. The donor has a known sensitivity to E. coli-derived products
6. The donor and recipient are identical twins
7. For the QOL component, inability to participate due to
cognitive, linguistic or emotional difficulties; must be able to
communicate in English or French
Clarification:
Recipients with AML: If a recipient with AML in CR1 relapses
after randomization but before conditioning, then a subsequent
CR must be achieved in order to continue on the study. Recipient
and donor eligibility must be reconfirmed within 30 days of the
recipient’s conditioning chemotherapy. (A recipient in 3rd CR or
greater is not eligible for this study.) A second registration/
randomization form must be completed and signed by the
investigator (and faxed to the Project Management Office), but
randomization is not repeated.
If a transplant is postponed due to any other reason following
randomization, the recipient/donor can remain on study as long as
the transplant occurs within 42 days of randomization. Recipient
and donor eligibility must be reconfirmed within 30 days of the
recipient’s conditioning chemotherapy. A second registration/
randomization form must be completed and signed by the
investigator (and faxed to the Project Management Office), but
randomization is not repeated.
4.2
Informed Consent
The recipient and/or the recipient’s legally authorized guardian
and the donor and/or the donor’s legally authorized guardian must
acknowledge in writing that consent to become a study subject
has been obtained.
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4.3
Protocol Approval
This protocol must be reviewed and approved by the Institutional
Review Board (IRB) or equivalent at each participating transplant
centre prior to approaching donors and recipients to participate in
the study.
4.4
Registration and Minimization
4.4.1
Registration
Eligible donor and recipient pairs who give informed
consent will be registered with the Project Management
Office. Registration is accomplished by sending a Study
Registration Form (Appendix 2) to the Office. The
Eligibility Criteria Checklist (Appendix 2) must be
submitted with the Study Registration Form.
4.4.2
Minimization
We intend to ensure balance for 4 important factors:
center, type of conditioning regimen (Bu/Cy vs Cy/TBI
vs Other), disease (CML vs. AML vs. MDS vs Other
Hematologic Malignancy), and disease stage (early
disease vs. late disease). These disease characteristics
are important determinants of the benefit of G-PB
transplants, as suggested previously [1]. However,
given the size of the trial, which has four prognostic
factors and over 100 strata, it would be impractical to
use stratified randomization. Thus, we will implement a
method of allocation called minimization. Unlike
stratified randomization with permuted blocks,
minimization considers the individual factor levels
separately from each other and therefore can cope with
more factors [38]. As the name implies, minimization
works toward minimizing the difference in the treatment
group assignments using these a priori identified
prognostic factors. The first patient will have their
treatment randomly allocated. For each subsequent
patient, we will determine which treatment would lead to
better balance between the groups with respect to the
variables of interest. Each patient is then randomized
using a weighting in favor of the treatment that would
minimize the imbalance. A weighting of 4 to 1 will be
used in this study [41]. This means that there will be an
80% chance of each patient getting the treatment that
minimizes imbalance. The weighted randomization is
meant to avoid selection bias, where in some situations
treatment assignments may be predicted with certainty.
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A recent review [42] concluded that minimization is a
highly effective method for achieving balance of
predefined variables across treatment groups. Some
have, in fact, argued that it should be the preferred
method and deserves wider adoption in clinical trials
[43]. In the trial, the study statistician (T. Panzarella) will
prepare two randomization lists using a computer
random number generator before the study begins: (i) a
simple randomization list where both treatments occur
equally often; this list will be used only when the two
treatments have equal sums for the levels of the
prognostic factors; and (ii) a list in which the treatment
with the smaller sum total of patient factor levels occurs
with probability 0.8 while the other treatment occurs with
probability 0.2. Allocation will occur centrally by the
Project Manager or delegate through the Project
Management Office, in consultation with the clinical
coordinator (S. Couban) and statistician (T. Panzarella)
with each randomization.
5.0
Treatment Plan
5.1
Overview of Treatment Plan
Table 2
Day
–7
Day
–6
Day
–5
Day
–4
Day
–3
Day
–2
Day
–1
Myeloablative conditioning regimen1
Patient
Donor G-PB Arm
G-CSF
G-CSF
G-CSF
Day
0
Infusion
G-CSF
(G-CSF)2
(only if 2nd apheresis)
Donor G-BM Arm
G-CSF
G-CSF
G-CSF
Standard Arm (G-PB)
G-CSF
Apheresis
Experimental Arm (G-BM)
Bone Marrow
Harvest
1Greater
2If
detail regarding the conditioning regimens is found in Section 5.5.
required. See Sections 5.2.2
5.2
Administration of G-CSF
5.2.1
Dose of G-CSF
The dose of G-CSF will be approximately 5 g/kg/day and will be
determined according to the donor’s actual body weight as
indicated in Table 3.
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Table 3
Actual Donor Weight
G-CSF
Less than 60 kg
300 g SC OD
60 to 90 kg
480 g SC OD
More than 90 kg
600 g SC OD
G-CSF is administered according to standard practice at the site.
5.2.2 G-CSF and Donors in the G-PBSC Group
G-CSF will be administered to the donor by a single daily
subcutaneous injection for 4 days (Day -4 to Day -1).
Apheresis will occur on Day 0.
If the minimum number or more CD34+ cells are not
collected with the first apheresis, then a second
ahpheresis will be conducted on the following day. The
donor should receive a 5th dose of G-CSF following the
first apheresis and prior to the 2nd apheresis. The exact
time point is at the discretion of the Transplant Physician
at the centre. The second collection of PBSC’s will be
infused on the day of collection (unless cryopreservation
necessary as per Section 5.3). See Section 5.3 for
information related to apheresis procedure and graft
parameters.
5.2.3 G-CSF and Donors in the G-Bone Marrow Group
G-CSF will be administered to the donor by a single daily
subcutaneous injection for 4 days only (Day -4 to Day -1).
Donors will undergo bone marrow harvest on the day
following the fourth (last) dose of G-CSF (Day 0).
See Section 5.4 for information related to the harvest
procedure and graft parameters.
5.3 Apheresis
Donors randomized to the standard arm will undergo apheresis as
described below.
Where possible, the apheresis procedure will be undertaken using
peripheral venous access. If an apheresis procedure cannot be
completed using peripheral venous access, a central venous
apheresis catheter may be placed. Each apheresis procedure may
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be standard volume processed (10L-12L) or large volume
processed (up to 20L) as determined by the transplant centre.
The target collection dose of progenitor cells is at least 2.5 x 106
CD34+ cells/kg actual recipient weight. If this target is achieved
with the first apheresis, a second apheresis will not be undertaken.
If this target is not achieved after two apheresis procedures, the
Study Chair must be notified immediately.
Based on the
circumstances, a decision will be made about whether additional
apheresis procedures or a bone marrow harvest is required.
[Based on the experience from the first CBMTG Study (Couban et
al, 2002) and modifications of the previous collection protocol in the
current study, the requirement for additional collection procedures
beyond two aphereses is very unlikely (<5%)].
The collection from the first day will be infused on the day of
collection (Day 0). If a second collection is required, this will be
infused immediately after the second collection and the timing of
methotrexate will be adjusted accordingly.
Cryopreservation of the apheresis product will be permitted in
situations where scheduling difficulties make it impossible to infuse
the product on the day of collection and/or this is currently the
standard practice at the site.
No manipulation of the G-PB collection is permitted. In the event of
major ABO incompatibility between the donor and the recipient, the
collection will not be red cell-depleted.
5.4 Bone Marrow Harvest
Donors randomized to the experimental arm will undergo bone
marrow harvest as described below.
Donors will undergo bone marrow harvest on the day following the
fourth dose of G-CSF (Day 0). Bone marrow will be aspirated from
the posterior iliac crests under general or regional anesthesia. The
bone marrow harvest will be at least 15 mL/kg actual donor weight
and will not exceed 22 mL/kg actual donor weight. At least 3 x 108
nucleated cells/kg actual recipient weight will be collected within the
donor bone marrow volume parameters noted above.
The volume of bone marrow aspirated at each position in the iliac
crest must not exceed 5 mL. Following aspiration of up to 5 mL
bone marrow, the trochar should be repositioned in the iliac crest.
The following approaches are all acceptable methods of
repositioning:
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i. Insertion or withdrawal of the trochar at the same site.
ii. Turning the trochar (so the bevel is facing a different position
at the site). Four turns of the trochar at a single level is the
maximum recommended.
iii. Inserting the trochar at another site.
(Personal Communication-James Morton to Stephen Couban).
The bone marrow harvest will be infused on the day of collection
(Day 0). (Cryopreservation of the G-BM product is allowed in
situations where scheduling difficulties make it impossible to infuse
the product fresh.)
No manipulation of the bone marrow harvest is permitted, with the
exception of red cell depletion in the event of a major ABO
incompatibility between the donor and recipient and plasma
depletion in the case of a minor ABO incompatibility.
As an
alternative to red cell depletion, centers may undertake recipient
pre-infusion apheresis of the recipient in the event of a major ABO
incompatibility.
5.5 Conditioning Regimens
Recipients will receive a myeloablative conditioning regimen of
either busulfan and cyclophophamide OR cyclophosphamide and
TBI OR other myeloablative regimen approved by the Clinical Study
Chair. The regimen cannot contain Anti-thymocyte globulin (ATG)..
ALL regimens must be submitted to the Project Management Office
and must be reviewed and approved by the Clinical Study Chair.
The weight used to calculate chemotherapy doses should be
adjusted (corrected) according to institutional practice. Participating
sites are required to submit the standard calculation for adjusting
weight that is used at their site. (The calculation will be reviewed by
the Clinical Study Chair and kept on file.)
Intrathecal chemotherapy is allowed according to standard
institutional practice.
5.5.1 Conditioning with Busulfan and Cyclophosphamide
A myeloablative regimen of busulfan and cyclophosphamide
will be administered according to the doses and schedule
utilized by the participating transplant centers in their
standard practice. Participating transplant centers must
submit their standard busulfan and cyclophosphamide doses
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and schedule (for myeloablative transplant) to the Project
Management Office. The Clinical Study Chair must review
and issue a written approval to the PI at the center prior to
the enrollment of study subjects.
The bone marrow or peripheral blood harvest will be infused
at least 48 hours following completion of the
cyclophosphamide.
Phenytoin or lorazepam must be
administered with the busulfan to prevent busulfanassociated seizures. Hyperhydration and/or mesna must be
administered with the cyclophosphamide to prevent
cyclophosphamide-induced hemorrhagic cystitis.
Table 4 Typical Schedule for Busulfan and Cyclophosphamide Conditioning
Day
-7
Day
-6
Day
-5
Day
-4
Day
-3
Day
-2
Busulfan
Busulfan
Busulfan
Busulfan
Cyclophosphamide
Cyclophosphamide
Day
-1
Day
0
Bone marrow
or peripheral
blood infusion
A “rest day” between the end of Busulfan and the start of Cyclophosphamide is acceptable, and
therefore the Busulfan can also be administered on Days -8 to -5 (instead of Days -7 to -4).
5.5.2
Conditioning with TBI and Cyclophosphamide
A myeloablative regimen of fractionated TBI and
cyclophosphamide will be administered according to the
doses and schedule utilized by the participating transplant
centers in their standard practice. Participating transplant
centers must submit their standard TBI and
cyclophosphamide doses and schedule (for myeloablative
transplant) to the Project Management Office. The Clinical
Study Chair must review and issue a written approval to the
PI prior to the enrollment of study subjects.
Radiation sources, dose rates, details of lung shielding,
and sites receiving boost radiation will be defined by the
transplant centre.
The order of administration of cyclophosphamide and TBI
is at the discretion of the transplant centre. Within each
institution, all recipients should receive the same doses of
cyclophosphamide and TBI in the same order.
If
cyclophosphamide is given last, there should be at least a
one-day rest period before the G-BM or G-PB infusion.
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Table 5 Typical Schedule for Cyclophophamide and TBI Conditioning
Day
-7
Day
-6
Day
-5
Day
-4
Day
-3
Day
-2
Day
-1/01
Cy2
Cy
Cy
TBI
TBI
TBI
Bone marrow or
peripheral blood infusion
1BMT
may be performed immediately after the last dose of TBI; in this case Day -1 becomes Day 0.
of days of Cyclophosphamide is specific to each institution. (Standard orders approved
by the Clinical Chair should be followed.)
2Number
5.5.3 Conditioning with Other Regimens
Other myeloablative conditioning regimens can be utilized.
As stated in Section 5.5, the regimen must be submitted to
the Project Management Office and must be reviewed and
approved by the Clinical Study Chair. Regimens containing
Anti-thymocyte globulin (ATG) will not be allowed.
5.6 Graft Versus Host Disease Prophylaxis
Cyclosporin and methotrexate will be used for graft versus host
disease prophylaxis. Participating transplant centers must submit
their standard cyclosporin and methotrexate doses and schedule to
the Project Management Office for review. See section 5.6.1 for
requirements regarding methotrexate administration. See section
5.6.2 for requirements regarding cyclosporine administration.
5.6.1 Methotrexate
All participating sites must follow the methotrexate dose
schedule that is outlined in this section except for King Faisal
Specialist Hospital and Research Center (KFSHRC). For
methotrexate administration at KFSHRC see section 5.6.1.1.
Methotrexate will be administered intravenously on Days +1
(15 mg/m2) and Days +3, +6, +11 (10 mg/m2). The dose of
methotrexate on Day +1 will be administered at least 24
hours after the infusion of bone marrow or peripheral blood.
For patients randomized to peripheral blood who required the
infusion of two apheresis products, the administration of Day
1 methotrexate will be delayed by 24 hours and the timing of
subsequent doses of methotrexate will be adjusted
accordingly. The dose of methotrexate on Days +1, +3, +6
and +11 will be reduced for hepatic and renal dysfunction,
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mucositis and for significant fluid collections (ascites, pleural
effusions) as described below in Section 5.6.1.2. The use of
folinic acid rescue will be according to institutional practice.
5.6.1.1
Methotrexate Administration
Specialist Hospital (KFSHRC)
at
King
Faisal
Pharmacogenomic data on the Arab population
suggests this group is more susceptible to the toxic
effects of methotrexate (possibly related to the
prevalence of MTHFR polymorphisms) (Abu-Amero
et al, 2003). It has also been noted that the Arab
population is less likely to experience graft versus
host disease following myeloablative sibling HSCT
in comparison to the general population. Therefore,
standard gvhd prophylaxis at KFSHRC does not
include a dose of methotrexate on Day +11. For
these reasons, the methotrexate dose schedule for
recipients enrolled in CBMTG 0601 at KFSHRC will
be as follows: Methotrexate on Day +1 [15 mg/m2]
and Days +3, +6 [10 mg/m2].)
5.6.1.2
Dose Reduction for Methotrexate Toxicity
Methotrexate dose adjustments for toxicity will be
according to institutional practice; however, the
following adjustments for renal dysfunction, hepatic
dysfunction
and
pleural
effusions
are
recommended.
5.6.1.2.1 Reduction of Methotrexate Dose for
Hepatic Dysfunction
Table 6
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Direct Bilirubin
(micromoles/litre)
Direct Bilirubin
(mg/dl)
Percent Reduction of
Methotrexate Dose
0-34
35-50
51-100
Greater than 100
0- 2.0
2.0 -2.9
3.0-5.8
Greater than 5.8
0
25
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5.6.1.2.2 Reduction of Methotrexate Dose for
Renal Dysfunction
Table 7
Calculated Creatinine
Clearance (mL/min)1
Greater than 85
65-84
50-64
0-49
Percent Reduction of
Methotrexate Dose
0
25
50
100
1For
males, calculated creatinine clearance = [(140 age in years) x
(Ideal Body Weight) x 60]/[serum creatinine x 50]. For females,
multiply the calculated creatinine clearance for males by 0.85.
5.6.1.2.3 Reduction of Methotrexate Dose for
Mucositis
It is recommended that sites grade
mucositis according to the Bearman
criteria (Table 8) on Days +1, +3, +6 and
+11. It is recommended that the dose of
methotrexate will be reduced for
mucositis as indicated in Table 8.
(See Appendix 4 for Bearman Scale.);
Table 8
Bearman Stomatitis
(Mucositis) Grade
Grade 0, Grade 1, Mild Grade 2
Moderate Grade 2
Severe Grade 2, Grade 3
Percent Reduction of
Methotrexate Dose
0%
25%
100%
5.6.1.2.4 Reduction of Methotrexate Dose for Fluid
Collections
If the patient has a clinically significant
pleural effusion or ascites, it should be
drained if this is feasible. If the clinically
significant fluid collection cannot be
drained, it is strongly recommended that
the dose of methotrexate be held.
Note:
According to the Bearman
Scale, the reductions in methotrexate
dose based on direct bilirubin,
calculated
creatinine
clearance,
mucositis and fluid collections are
additive.
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5.6.2 Cyclosporin
Cyclosporin will be administered orally or intravenously
according to standard practice at the site. The standard
regimen must be approved by the Clinical Chair. The
starting dose will be according to institutional practice.
After initiation of the cyclosporine, the dose will be adjusted
to maintain adequate trough levels according to standard
institutional practice.
Tapering of cyclosporin will be according to institutional
practice. It is essential that the same tapering schedule
is followed for patients on both arms of the study. If a
recipient develops acute graft versus host disease prior to
or during the tapering of cyclosporin, further adjustments of
the cyclosporin dose and decisions about the initiation and
speed of tapering will be according to institutional practice.
5.7 Supportive Care
5.7.1 Veno-occlusive Disease Prophylaxis
The use of agents for veno-occlusive disease prophylaxis
will be according to local institutional practice.
5.7.2 Antibacterial Prophylaxis during the Neutropenic Period
Prophylactic
antibiotics
except
trimethoprimsulfamethoxazole are not required but may be administered
from the start of conditioning until neutrophil recovery
(absolute neutrophil count > 0.5 x 109/L) according to local
institutional practice.
5.7.3 Herpes Simplex Virus (HSV) Prophylaxis
HSV prophylaxis will be according to local institutional
practice.
5.7.4 Antifungal Prophylaxis
Antifungal prophylaxis will be according to local institutional
practice. Antifungal prophylaxis (e.g. fluconazole 400 mg
po/IV OD) is recommended when corticosteroids
(equivalent of prednisone 1 mg/kg/day or greater) are used
to treat graft versus host disease.
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5.7.5 Cytomegalovirus (CMV) Prophylaxis
Monitoring for CMV infection in recipients at risk (recipient
or donor is positive for CMV antibody) will be by CMV
antigenemia, PCR-based assessment of viral load or
surveillance bronchoscopy according to local institutional
practice. Ganciclovir (or equivalent antiviral treatment) will
be initiated based on the results of monitoring for CMV
infection according to local institutional practice.
5.7.6 Pneumocystitis Carinii Prophylaxis
All recipients will receive pneumocystitis carinii prophylaxis
from at least the time of neutrophil recovery (absolute
neutrophil count > 0.5 x 109/L) until at least 6 months posttransplant. This will be trimethoprim-sulfamethoxazole DS
one tablet PO b.i.d. on 2 or 3 days a week. Recipients who
are
allergic
to
or
intolerant
of
trimethoprimsulfamethoxazole will receive alternative pneumocystitis
carinii prophylaxis according to local institutional practice.
5.7.7 Blood Product Support
Irradiated red blood cell and platelet transfusions will be
used. Transfusion thresholds will be according to local
institutional practice.
5.7.8 Administration of Growth Factors Following Bone Marrow
or Peripheral Blood Infusion
Neutrophil recovery is a secondary study endpoint and
growth factors such as G-CSF or GM-CSF will not be
routinely used following the infusion of bone marrow or
peripheral blood.
If a recipient develops primary
engraftment failure (absolute neutrophil count of less than
0.5 x 109/L on Day +28), G-CSF may be administered and
an additional infusion of donor cells with or without
additional conditioning should be strongly considered.
G-CSF may also be used at any time in a recipient’s course
according to the attending physician’s discretion. This will
be recorded.
5.7.9 Prophylactic Intravenous Gammaglobulin
It is recommended that prophylactic intravenous
gammaglobulin not be routinely administered post-
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transplantation; however, if given, it should be administered
according to institutional practice.
5.8 Graft versus Host Disease Treatment
The initial treatment of acute and chronic GVHD will be according to
the study protocol, as follows:
5.8.1
Acute Graft versus Host Disease Treatment
Grades 2-4 acute GVHD, which requires treatment, will be
treated
with
corticosteroids,
either
intravenous
methylprednisolone 1-2 mg/kg/day or oral prednisone 1-2.5
mg/kg/day in single or divided daily doses. The initial
treatment with corticosteroids should be administered for at
least 5 days. After 5 days, tapering of the corticosteroid
can be initiated if the patient’s acute GVHD is improving,
according to local institutional practice.
If tapering of cyclosporin had begun at the onset of Grades
2-4 acute GVHD requiring treatment, the dose of
cyclosporin will be increased to re-establish a therapeutic
cyclosporin level (whole blood trough cyclosporin level of
200-400 micromoles/L). Tapering of cyclosporin may
recommence once the acute GVHD is improving.
If the acute GVHD does not respond or progresses during
the initial treatment with corticosteroids, the dose of
corticosteroids may be increased or additional agents may
be used according to local institutional practice.
All
treatments for acute GVHD will be recorded.
5.8.2
Chronic Graft Versus Host Disease Treatment
Limited and extensive chronic GVHD which requires
systemic treatment will initially be treated according to
institutional practice. Biopsy of involved organs or tissues
is strongly recommended but not required. Limited and
extensive chronic GVHD which requires systemic treatment
will initially be treated with prednisone (0.5-2mg/kg PO
daily in single or divided doses). If cyclosporin had been
tapered or discontinued, it may be restarted either at the
same time as prednisone is started or as second line
therapy, according to the clinician’s judgement. If the
chronic GVHD does not improve with initial therapy
consisting of prednisone with or without cyclosporin, the
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dose of corticosteroids may be increased or additional
agents may be used according to local institutional
practice. All therapies for chronic GVHD will be recorded.
6.0
Required Observations
6.1
Pre-transplant Evaluation – Recipient
The following observations should be made within 53 days prior to
the initiation of conditioning therapy (except as noted otherwise):
6.1.1
6.1.2
6.1.3
6.1.4
History and physical examination;
Height and weight;
ECOG performance status;
CBC, differential, creatinine, total bilirubin, AST, ALT, ALP,
blood group and antibody screen;
6.1.5 Infectious Disease Markers: CMV antibody, Hepatitis B
surface antigen, total antibody to Hep B core antigen,
Hepatitis C antibody, HIV-1 and HIV-2 antibodies, HTLV-1
and HTLV-2 antibodies and VDRL or equivalent testing for
syphilis; West Nile virus testing (according to institutional
practice); testing for HSV antibody is optional. Testing for
infectious disease markers must be done within 30 days of
transplant.
6.1.6 Cardiac evaluation with assessment of ejection fraction by
radionucleotide scan or echocardiogram;
6.1.7 Pulmonary evaluation with spirometry (FEV1) and diffusing
capacity (DLCO);
6.1.8 Renal evaluation with 24 hour urine for measured
creatinine clearance or serum calculated GFR;
6.1.9 Beta-HCG in female recipients of child bearing potential
(within 30 days of transplant);
6.1.10 Bone marrow aspirate and biopsy; cytogenetic analysis is
strongly recommended for recipients with myeloid
malignancies
6.1.11 Quality of Life Assessment: Bradburne Scale, CES-D
Scale, Illness Intrusiveness Ratings Scale, Screening
FACT-BMT, EQ-5D Questionnaire, Socio-demographic
Questionnaire and McGill Pain Questionnaire (Appendix
3B). Any time between signing of consent form and day -8
prior to start of conditioning chemotherapy;
6.1.12 Societal Cost Questionnaire (Appendix 3C). Any time
between signing of consent form and day -8 prior to start of
conditioning chemotherapy.
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6.2
Pretransplant Evaluation – Donor
The following observations should be made within 53 days prior to
the initiation of recipient’s conditioning (except as noted
otherwise):
6.2.1 History and physical examination;
6.2.2 Height and weight;
6.2.3 CBC, differential, creatinine, total bilirubin, AST, ALT, ALP,
blood group and antibody screen;
6.2.4 Infectious Disease Markers: CMV antibody, Hepatitis B
surface antigen, total antibody to Hep B core antigen,
Hepatitis C antibody, HIV-1 and HIV-2 antibodies, HTLV-1
and HTLV-2 antibodies and VDRL or equivalent testing for
syphilis; West Nile virus testing (according to institutional
practice); testing for HSV antibody is optional. Testing for
infectious disease markers must be done within 30 days of
transplant.
6.2.5 Beta-HCG in female donors of child bearing potential;
6.2.6 Quality of Life Assessment: Bradburne Scale, CES-D
Scale, EQ-5D Questionnaire, Socio-demographic
Questionnaire, McGill Pain Questionnaire (Appendix 3B).
Any time between signing of consent form and day -5 prior
to starting G-CSF.
6.3
Donor Assessment During Peripheral Blood or Bone Marrow
Collection
Donors will undergo the following evaluations during G-CSF
administration and peripheral blood or bone marrow collection:
6.3.1 Daily clinical assessment for myalgias, arthralgias, bone
pain and abdominal pain on each day of G-CSF
administration;
6.3.2 CBC and differential on each day of apheresis or on day of
bone marrow harvest;
6.3.3 For bone marrow donors: 20 mL of peripheral blood will be
collected from all donors randomized to the bone marrow
collection arm on the day of collection (prior to the harvest)
(See Section 10.0).
6.3.4 For bone marrow donors: 10 mL of bone marrow to be
taken at time of collection for correlative laboratory studies;
6.3.5 For peripheral blood stem cell donors: 5 mL of product to
be taken from first collection (See Section 10.0).
6.4
Assessment of Hematopoietic Stem Cell Product:
6.4.1 Peripheral Blood Stem Cell Product:
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6.4.1.1 Number of apheresis procedures;
6.4.1.2 Volume of blood processed during each apheresis
procedure;
6.4.1.3 Total volume of product;
6.4.1.4 Total nucleated cell count of product;
6.4.1.5 CD34+ cell count of collection.
6.4.2 Bone Marrow Product
6.4.2.1
6.4.2.2
6.4.2.3
6.5
Total volume of product;
Total nucleated cell count of product;
CD34+ cell count of collection.
Post-Collection Evaluation – Donor
The following observations will be made of the donor following the
collection of peripheral blood or bone marrow:
6.5.1 McGill Pain Questionnaire:
 PB donors: Following the first apheresis (same day)
 BM donors: On the day following harvest
6.5.2 Quality of Life Assessment: Bradburne Scale, CES-D
Scale, EQ-5D Questionnaire, Socio-demographic
Questionnaire and McGill Pain Questionnaire at 1
month and 1 years post-transplant.
6.6
Post-Transplant Evaluation – Recipient
The following observations will be made of the recipient from the
start of conditioning until the recipient is no longer in the study:
6.6.1 CBC and differential and platelet count: daily until
neutrophil and platelet recovery;
6.6.2 Direct bilirubin and serum creatinine on Days +1, +3, +6
and +11;
6.6.3 Assessment of mucositis according to the Bearman
Toxicity Scale (Appendix 4) on Days +1, +3, +6, +11;
6.6.4 Acute GVHD: Recipients will be assessed daily while in
hospital and then regularly to Day +100 for the presence
and severity of acute GVHD;
6.6.5 The highest grade of acute GVHD from Day 0 to Day +30
to be assessed using the Przepiorka Critiera (Appendix
5). (Grade to be documented.);
6.6.6 The highest grade of acute GVHD from Day +0 to Day
+100 to be assessed using the Przepiorka Criteria
(Appendix 5) (Grade to be documented in site source
documents);
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6.6.7 Chronic GVHD: Transplant physician or RN with
specialized training in GVHD assessment will classify and
document chronic GVHD in the recipient using the Sullivan
Grading Criteria (Appendix 6) every 3 months starting at
Month 6 until 1 year post-transplant then every 6 months
until 4 years post-transplant (Grade to be documented in
site source documents);
6.6.8 The Data Collection Form for Diagnosis and Scoring of
Chronic GVHD According to the NIH Consensus
Guidelines (Appendix 3D) is to be completed at 1 year
and 3 years post transplant (by either a Transplant
Physician or RN with specialized training in GVHD
assessment).
6.6.9 Chronic GVHD: The recipient will complete the Patient
Chronic GVHD Severity Scoring Table (Part B)
(Appendix 3D) every 3 months starting at Month 6 until 1
year post-transplant then every 6 months until 4 years posttransplant. This can be completed over the telephone with
the study coordinator or directly by the recipient;
6.6.10 Quality of Life Assessment: Bradburne Scale, CES-D
Scale, Illness Intrusiveness Ratings Scale, FACT-BMT
(Year 1 and 3), EQ-5D Questionnaire, Socio-demographic
Questionnaire, McGill Pain Questionnaire (Appendix 3B) at
1 year and 3 years post-transplant;
6.6.11 Societal Cost Questionnaire (Appendix 3C) at 1 year and
3 years post-transplant;
6.6.12 Health Care Questionnaire (Appendix 3C) will be
completed at month 1, 2 and 3 post transplant (Part A) and
then every 3 months from month 6 up to 2 years posttransplant (Part B);
6.6.13 Clinical assessment regularly as per standard of care;
6.6.14 Frequency of bone marrow evaluations post-transplant will
be according to standard institutional practice.
See Schedule of Events for a summary of all study
Evaluations (Appendix 8).
7.0 Evaluation of Outcomes
7.1
Primary Outcome:
Time to failure (extensive chronic GVHD, relapse, death): This is
defined as the time to the earliest of 3 events after the transplant:

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First onset of extensive chronic GVHD: Defined as either:
(i) Generalized skin involvement, or
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(ii) Localized skin involvement and/or hepatic dysfunction


7.2
Secondary Outcomes:

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due to chronic GVHD plus:
 Liver histology showing chronic aggressive
hepatitis, bridging necrosis, or cirrhosis, or
 Involvement of eye (Schirmer’s test with < 5
mm wetting), or
 Involvement of minor salivary glands or oral
mucosa demonstrated on labial biopsy, or
 Involvement of any other target organ
Relapse from the underlying malignancy: This is defined
as persistence or recurrence of the original malignancy based
on standard pathology testing for myeloid malignancies and
progression or recurrence of the original malignancy based on
standard pathology or radiology testing for lymphoid
malignancies. The day of relapse is the day of the first
diagnostic test demonstrating relapse. Evidence of minimal
residual disease by molecular testing in the absence of other
data will not be considered relapse.
Death from any cause: Deaths will be classified as either
due to relapse of the original disease (relapse deaths) or
deaths without evidence of relapse of the original disease
(non-relapse deaths).
Hematologic recovery:
 Time to Neutrophil Recovery. This is defined as the time
from transplant (Day 0) to the first day of achieving an
absolute neutrophil count of greater than 0.5 x 10 9/L for 3
consecutive measurements on different days.
 Primary Graft Failure. This is defined as the absence of
neutrophil recovery (absolute neutrophil count less than 0.5
x 109/L) in patients surviving until at least Day +28 posttransplant.
 Platelet Recovery. This is defined as the time from
transplant (Day 0) to the first day of achieving a platelet
count of greater than 20x109/L for 3 consecutive
measurements on different days without requiring platelet
transfusions in the previous 7 days.

Overall survival.

Quality of life. See Section 7.4.1.
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7.3
Additional endpoints of interest:
 Time to acute GVHD. Acute GVHD is graded according to the
Przepiorka Criteria (Appendix 5). This endpoint will be
evaluated from Day 0 (transplant) to Day +100 (i.e. 100 days
post-transplant). Grades II-IV and grades III-IV will be
reported.
 Time to chronic GVHD. Chronic GVHD will be graded
according to the Sullivan Criteria [36] (Appendix 6). The
cumulative incidence of chronic GVHD will be calculated
considering death as a competing risk. Patients who survive to
day +100 will be considered eligible for this endpoint. Any
chronic GVHD and extensive chronic GVHD will be reported.
 Chronic GVHD detail. Additional information will be collected
on specific chronic GVHD organ manifestations, overall
severity, and medical management. For example, case report
forms will collect detailed data on organ involvement, overall
clinical
impression
(limited
vs
extensive),
and
immunosuppressive regimens.
 Chronic GVHD NIH consensus grading. A comprehensive
data collection form (Data Collection Form for the Diagnosis
and Scoring of Chronic GVHD According to the NIH
Consensus Guidelines) will be completed at Year 1 and Year
3. The data collected will allow the study team to categorize,
and score chronic GVHD according to the NIH consensus
guidelines (Filipovich et al, 2005) Biology of Blood and Marrow
Transplantation 11:945-955 (2005)
 Costs. See below.
 Detailed donor and patient self-reported outcomes,
including pain and symptoms, psychosocial outcomes, return
to work and impact of illness on lifestyle. See below.
7.4
Subject-reported Outcomes/Quality of Life Evaluations (QOL) and
Health Economics
7.4.1 Data collection:
See Schedule of Events for timing of assessments
(Appendix 8).
7.4.2 Justification for instruments:
A spectrum of previously validated instruments will be
utilized to ensure that all relevant patient-reported
outcomes are measured:

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Socio-demographic Questionnaire: Ten questions
will assess race (White, Black, Asian, American Indian,
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etc.), age, sex, education, work status and family
income. This questionnaire is to be administered by the
study coordinator.
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
Patient Chronic GVHD Severity Scoring Table: The
30 item cGVHD symptom scale will measure degree of
bother of cGVHD manifestations in skin, energy, lung,
nutrition, psychological, eye and mouth. Responses are
captured on a five-point Likert scale (“no symptoms, or
not bothered at all”, “slightly bothered,” “moderately
bothered,” “bothered quite a bit,” or “extremely
bothered”). Scores for each domain are converted to a
0-100 scale where higher scores indicate more bother.
Mean (SD) was 12 (9) for patients with mild (N=55), 18
(13) for patients with moderate (N=39), and 34 (13) for
patients with severe (N=13). In a previous study,
although the SF-36 and FACT-BMT were sensitive to
changes in overall health, only the chronic GVHD
symptom scale was sensitive to changes in patientperceived chronic GVHD severity [56]. A single item
asks respondents to grade their chronic GVHD as mild,
moderate or severe.

Bradburn Affect Balance Scale: The Bradburn Affect
Balance Scale has been included as an indicator of
psychological well-being [44].

CES-D Scale: The Center for Epidemiologic Studies
Depression (CES-D) Scale will be used to measure
depressive symptomatology (emotional distress) [48,
49].

Illness Intrusiveness Ratings Scale: Subjective wellbeing will also be assessed with regards to illnessinduced disruptions to lifestyles, activities, and interests
using the Illness Intrusiveness Ratings Scale. This 13
item scale evaluates illness and treatment related
disruptions to valued activities and interests. It has
been previously used in patients with chronic illness
such as renal failure [50] and both autologous [51] and
allogeneic BMT patients [52]. Psychometric testing of
the Illness Intrusiveness Ratings Scale in a variety of
chronic illness populations indicates high levels of
reliability and validity [53].

EQ-5D Questionnaire: A standardized non-diseasespecific instrument for describing and valuing health-
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related quality of life. This instrument is also useful with
respect to economic evaluation. The EQ-5D has been
specifically designed to complement other quality of life
measurements.
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
FACT-BMT: The Functional Assessment of Cancer
Therapy-Bone Marrow Transplant Scale (FACT-BMT)
was specifically designed to measure aspects of QOL in
relation to bone marrow transplantation, and consists of
the general Functional Assessment of Cancer Therapy
(FACT-G) and a Bone Marrow Transplantation
Subscale (BMTS), which assess specific BMT-related
concerns. The FACT system will assess the effects of
therapy in four major areas: physical well being,
social/family well being, emotional well-being, and
functional well being. It has site-specific and symptom
specific subscales in addition to the BMT subscale [55]
(see Appendix 3B). The FACT-BMT is sensitive to
changes in overall health status in patients with chronic
GVHD [56].

McGill Pain Questionnaire: Will be used to assess
pain which is an important component of quality of life
evaluations. This scale is a standardized list of 15
types of pain using a scale of “None”, “Mild”, “Moderate”
and “Severe”. This instrument is appropriate for use in
both transplant patients and healthy individuals.

Societal Cost Questionnaire: A brief questionnaire will
assess medical care that occurs away from the
transplant center, current prescription medications,
care-giver time, and out-of-pocket expenses.

Health Care Questionnaire: A one page questionnaire
will track number of visits to the hospital and/or
physician/specialist. Medications taken within a week of
the questionnaire date will also be recorded. This
questionnaire will be completed once per month for the
first 3 months post transplant and then every 3 months
up until 2 years post- transplant). A clinician, nurse or
data coordinator will complete this questionnaire with
the patient in person or by telephone. If the patient is
too ill to participate, then the information required may
be obtained from the medical chart (or other clinical
sources). The questionnaire should be completed +/one week of the due date.
The Health Care
Questionnaire is not administered to recipients who
have relapsed.
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Recipient Instruments: Recipients will be asked to
complete all the instruments described in Section 7.4.2.
Donor Instruments:
Donors will be asked to complete the following instruments:
Socio-demographics; Bradburn Affect Balance Scale; CESD; EQ-5D; McGill Pain Questionnaire.
7.4.3
Administration of QOL Instruments:
Prior to transplantation, patients (recipients) will complete
their initial QOL questionnaires prior to beginning
conditioning chemotherapy. Patients are followed closely
post stem cell transplant (post-BMT) in the transplant
centers.
Donors will complete their initial QOL
questionnaires prior to commencing G-CSF. Patients will
complete the QOL instruments when they present for their
routine medical follow-up but before their visits with the
physician. The battery of surveys will contain ~94-156
items and will take an estimated 20-30 minutes to
complete. It is anticipated that missing data will be minimal,
as these data are collected in-person coincident with
ongoing medical care. Patients typically stay within a 1
hour drive of the transplant centers until after the 100 day
post-transplant date, and then continue to return to the
transplant center for ongoing follow up at regular intervals.
Assessments will be conducted +/- one week for the 1
month assessment (donor), and +/- one month for the 1
year (donor and recipient) and 3 year (recipient)
assessments. (Donors will also complete the McGill Pain
Questionnaire following their stem cell collection (as
described in Section 6.5.1).
If a patient is not scheduled to be seen at the transplant
center within that time period, the research assistant will
call the patient to collect the data by reading the
questionnaires verbatim over the telephone. QOL
information will be collected until a patient’s death
(when appropriate). Relapsed patients are eligible for
ongoing QOL assessments.
Donors will complete the baseline instruments in person or
over the telephone any time after consent and prior to the
start of G-CSF. The follow-up assessments at 1 month and
1 year will be conducted by mail or phone.
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Recipients or donors who are unable to communicate in
English or French will not be included in the QOL and
Health Economics components of the study.
In situations where the recipient dies within one year, the
transplant centre is to use their discretion with respect to
contacting the donor regarding the completion of further
questionnaires.
QOL data will be reviewed to ensure that no items are
accidentally missing. The CES-D will be scored as in
Section 7.4.4. The written patient or interviewer
questionnaire will be transmitted to the CBMTG 0601
Project Management Office for data entry.
7.4.4 Risk and protections for study subjects and conditions that
will lead to breach of confidentiality:
In order to identify at-risk patients in an ethical and timely
manner, the CES-D will be scored by Dr. Devins in a timely
manner following the interview with the patient. The study
Project Manger will ensure that Dr. Devins has returned
this assessment. Recommendation for referral to
“psychosocial services” or psychiatry will be done to the
caring physician if the total score exceeds 15; this is the
routine cut-off indicating an intensity of distress consistent
with that observed among depressed psychiatric patients.
Study subjects will be notified that they and/or their
physicians will be contacted if anything on their QOL
surveys indicates they are a danger to themselves or
others. In addition, study subjects will be told they may skip
over any questions they wish. Previous experience
suggests that most participants will be open and willing to
complete QOL instruments.
7.4.5 Economic Analysis:
The economic impact both of the use of allogeneic G-PB
and of the increased incidence of chronic GVHD
associated with the use of G-PB has not been studied. The
large randomized trial proposed herein provides a unique
opportunity to compare the economic impact of G-PB
allografts
(standard
arm)
with
G-BM
allografts
(experimental arm).
The cost analysis will take a societal perspective to
calculate the direct costs associated with BMT to the
recipient and donor, as well as to caregivers. As costs are
the product of unit prices and quantity, the cost analysis of
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the study will track the utilization of healthcare resources
and assign a unit cost based on wages, billings or
acquisition costs. The analysis will consider healthcare
utilization in three timeframes: short-term costs associated
with the BMT procedure itself, from the time of initial
hospital admission to BMT Day +100; medium-term
utilization, from Day +100 to 1 year post-BMT; and longerterm utilization from 1 year to 2 years post-BMT. Relevant
costs in each timeframe will include physician fees, hospital
days, blood products, G-CSF and non-prophylactic
antibiotics and other drug utilization. Healthcare utilization
will be identified via chart review, discharge abstracts and
case report forms completed on all patients on an on-going
basis.
The cost of utilization will be standardized based on
Ontario unit prices. Physician fees will be taken from the
Ontario schedule of fees and benefits. The cost of hospital
admissions will be derived from Ontario Case Costing
Initiative (OCCI) case cost estimates. OCCI data provides a
fully-allocated average case cost for hospital admissions by
primary diagnosis or procedure code. OCCI cost estimates
categorize costs by functional center, allowing analysis of
costs attributed to nursing, laboratory, diagnostic imaging
and pharmacy. In-patient drug utilization, including G-CSF
and non-prophylactic antibiotics will be captured in these
case cost estimates.
OCCI data is collected by the Ontario Ministry of Health
and Long-term Care using a standardized case costing
methodology and covers 17 acute care and 5 specialty
hospitals [57]. It is the most comprehensive estimate of
hospital case costs available in a Canadian setting and is a
dramatic improvement over traditional per diem cost
estimates. As blood products are provided to hospitals
without charge, unit prices for blood products will be
derived from Canadian Blood Services cost data. Other
non-hospital drug utilization will be based on a survey of
retail pharmacies in Ontario. Caregiver time will be derived
from patient case report forms and costs will be based on
the rates of national home care providers; the time of
unpaid caregivers will be valued at the same rates. Much of
the utilization data will be collected concurrently with the
clinical trial, but information on unit costs will be sought
only in the event that there is no significant difference in the
primary endpoint of time to failure (chronic GVHD, relapse,
death).
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Given the existence of a societal time preference that
emphasizes costs incurred in the present over costs
occurring in the future, and the fact that the costs
associated with transplantation may be spread over a
significant period of time, long term costs will be reported in
both current and present value terms. Discounting adjusts
for time preference and allows future costs to be
considered on the same basis as current costs [58, 59]. A
rate of 3% will be used in this analysis, and will be varied in
a sensitivity analysis.
If the clinical trial demonstrates the superiority of G-PB, the
economic analysis will report the net costs in both groups.
However, if G-BM is shown to be equivalent or superior to
G-PB, the economic analysis will combine information on
treatment costs with the survival and QOL data captured by
other aspects of the study within the framework of a costeffectiveness analysis (CEA). The first stage of the CEA will
provide a quantitative description of expected costs and
outcomes for each treatment modality. Outcomes data will
be converted to quality-adjusted life years (QALYs) by
weighting survival time by utilities derived from the EQ-5D
questionnaires administered during the study. If one stem
cell collection modality is found to be ‘dominant’—that is,
both more effective in terms of QALYs gained and less
costly—this result will be highlighted. If no alternative is
dominant, the analysis will move to the second stage and
calculate an incremental cost effectiveness ratio (ICER) on
the basis of incremental cost per QALY gained. If the
outcomes of both treatment modalities are equivalent, the
analysis will collapse to a cost-minimization analysis and
the lowest cost alternative will be highlighted.
8.0 Criteria for Removal from Protocol Therapy and Off Study Criteria
All recipients will be followed from registration until death or at least 4
years from the day of transplant. All donors will be followed from
registration until at least 1 year from the first day of G-CSF
administration. Recipients and donors will be considered off study if:



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They withdraw their consent to continue participating in the
study
They are lost to follow-up
They die
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9.0
Statistical Considerations
9.1 Data Management
Information will be collected and recorded on Data Collection Forms
(Appendix 3A). These will be completed at study entry (registration
and randomization), peripheral blood or bone marrow collection,
Day +30, Day +100, every 3 months to 1 year post-transplant and
every 6 months to 4 years post-transplant. Copies of the completed
Data Collection Forms are to be sent to the Project Management
Office within 30 days of each assessment. The original Data
Collection Forms, Questionnaires and source documentation will be
stored at each site.
9.2 Definition of an Event for the Primary Endpoint (Time to failure)
Recipients will be considered to have had an event when any of the
following occurs:
9.2.1 First onset of extensive chronic GVHD;
9.2.2 Death from any cause;
9.2.3 Relapse of the underlying malignancy.
This composite endpoint was selected because the study treatment
is likely related to each of these causes of failure. Furthermore,
each of these endpoints is a competing risk with respect to the
study patient. The occurrence of death would, of course, preclude
the occurrence of extensive chronic GVHD while the occurrence of
relapse would fundamentally alter the probability of observing
extensive chronic GVHD. Thus, use of extensive chronic GVHD
alone as the primary endpoint would have to incorporate the
complication of competing risks, which we wanted to avoid. The
primary endpoint, as defined above, is clinically meaningful and has
the added advantage of allowing us to utilize traditional approaches
to the design and analysis of time-to-failure endpoints.
9.3 Registration and Minimization
We intend to ensure balance for 4 important factors: center, disease
(CML vs. AML vs. MDS vs Other Hematologic Malignancy), type of
conditioning regimen (Bu/Cy vs Cy/TBI vs Other) and disease stage
(early disease vs. late disease). These disease characteristics are
important determinants of the benefit of G-PB transplants, as
suggested previously [1]. However, given the size of the trial, which
has four prognostic factors and over 100 strata, it would be
impractical to use stratified randomization. Thus, we will implement
a method of allocation called minimization. Unlike stratified
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randomization with permuted blocks, minimization considers the
individual factor levels separately from each other and therefore can
cope with more factors [38]. As the name implies, minimization
works toward minimizing the difference in the treatment group
assignments using these a priori identified prognostic factors. The
first patient will have their treatment randomly allocated. For each
subsequent patient, we will determine which treatment would lead
to better balance between the groups with respect to the variables
of interest. Each patient is then randomized using a weighting in
favor of the treatment that would minimize the imbalance. A
weighting of 4 to 1 will be used in this study [41]. This means that
there will be an 80% chance of each patient getting the treatment
that minimizes imbalance. The weighted randomization is meant to
avoid selection bias, where in some situations treatment
assignments may be predicted with certainty.
A recent review [42] concluded that minimization is a highly
effective method of achieving balance of predefined variables
across treatment groups. Some have, in fact, argued that it should
be the preferred method and deserves wider adoption in clinical
trials [43]. In the proposed trial, the study statistician (T. Panzarella)
will prepare two randomization lists using a computer random
number generator before the study begins: (i) a simple
randomization list where both treatments occur equally often; this
list will be used only when the two treatments have equal sums for
the levels of the prognostic factors; and (ii) a list in which the
treatment with the smaller sum total of patient factor levels occurs
with probability 0.8 while the other treatment occurs with probability
0.2. Allocation will occur centrally by the Project Manager or
delegate through the Project Management Office, in consultation
with the Clinical Chair (S. Couban) and statistician (T. Panzarella)
with each randomization.
9.4 Sample Size
The primary objective of the study is to compare time to treatment
failure, defined as extensive chronic-GVHD, relapse or death,
between the two treatment arms using an intent-to-treat analysis.
Based on our previous CBMTG study (published in Blood, 1
September 2002, Vol. 100, No. 5, pp. 1525-1531) , we anticipate
that the probability of experiencing extensive chronic GVHD-free
survival at 12 months post-transplant in the G-PB group will be 0.46.
We consider a 30% relative increase in the probability of extensive
chronic-GVHD-free survival as the smallest clinically significant
difference required to adopt G-BM as standard of care. In order to
detect a 30% relative difference in extensive chronic GVHD-free
survival at 12 months between G-PB and G-BM (i.e. 0.46 for G-PB
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vs. 0.60 for G-BM) with 80% power, using a 2-tailed alpha level of
0.05, a total of 192 events would be required (EAST v3.1, Cytel
Software, Cambridge, MA 2003). Assuming a 5% loss to follow-up
with an accrual time of 3.5 years (including 0.25 years for IRB
approval) and a follow-up time of 2.0 years a total of 230 patients
will need to be accrued in order to meet our target number of events.
Owing to the approximately 5.0-5.5-year duration of the study, and
given that assumptions made for the sample size calculation may
not hold, an interim check conducted on the blinded data will occur
after 25% of the anticipated events have occurred. If it reveals that
the event rates are not as assumed then a revised sample size will
be calculated using suitably modified assumptions. These changes
will be documented in a protocol amendment.
9.5 Interim Analyses
The trial will be monitored for both efficacy and futility. Two interim
analyses using the primary endpoint are scheduled. As our outcome
is a time to failure endpoint, the pertinent information is in the
number of events. The interim analyses will be conducted after onethird and two-thirds of the total number of anticipated events has
occurred. A Lan-DeMets spending function approach [66] using the
O’Brien-Fleming stopping boundary [60] will be implemented.
Stopping will be considered for one of two reasons: superiority (or
inferiority) of the experimental treatment or futility. Stopping
boundaries for rejecting the null hypothesis and rejecting the
alternative hypothesis are listed in the table below. The interim
analyses will also review the donor and patient safety profile of each
graft source. During interim analyses, arms will be labeled “A” and
“B” to keep the DSMB blinded as to treatment assignment.
Table 9
Analysis Number of
number
events
1
2
3
64
128
192
Alpha
spent
0.0002
0.0120
0.0501
Stopping boundary
for rejecting H0
 3.7103
 2.5110
 1.9593
Beta
spent
0.009
0.088
0.200
Stopping
boundary for
rejecting H1
 0.0428
 0.9457
 1.9593
9.6 Problems with Compliance and the Likely Rate of Loss to Follow-up
In a similar multicenter randomized study, the CBMTG Centers
have been able to demonstrate a high level of compliance. Based
on that study, we anticipate 100% compliance both with the
preparative regimen and with administration of the GVHD
prophylaxis. These are the primary areas in which compliance
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problems might be expected. Since BMT is a medically intensive
intervention and requires follow-up by the BMT center frequently
within the first 1-2 years post-BMT, the possibility of loss to followup is very low. This was not an issue in the previous CBMTG study
[3; see Appended Paper], in which only 1 of 228 patients was lost to
follow-up. In this study, we anticipate that we will lose ≤5% of
patients to follow-up.
9.7 Details of the Planned Analyses
9.7.1 Clinical outcomes:
As the primary outcome alone was based on a priori
considerations of statistical power, only treatment comparisons
based on it would be considered confirmatory. Comparisons
of treatment groups for secondary endpoints should be
considered exploratory and hypothesis-generating.
Analysis of outcomes will be performed on an intent-to-treat
basis regardless of product ultimately used with factors used in
the minimization [61] included in the analysis. As a result, a
Cox proportional hazards model, adjusted for the variables of
center, conditioning regimen, disease and disease stage, will
be used to compare the effect of PB and BM from G-CSF
treated donors for extensive chronic-GVHD-free, malignancyfree
survival
following
allogeneic
progenitor
cell
transplantation. Kalish and Begg [62] agree that factors used
in the allocation procedure ought to be accounted for in the
analysis, and also concede that a simple unadjusted analysis
with demonstration of good balance of important factors is
likely more compelling to scientific audiences. Thus, we will
also report on this treatment difference using the unadjusted
log-rank test. Time to neutrophil and platelet recovery, chronic
GVHD, the incidence of acute GVHD, and time to relapse will
be analyzed as time to failure endpoints. Given the presence
of competing risks, probabilities will be summarized using the
cumulative incidence approach [63], while treatment group
comparisons will be performed using the Cox proportional
hazards regression model. The severity of acute GVHD will be
compared between treatment groups using a chi-square test
for trend, which accounts for the natural ordering of severity
(grade I-grade IV).
The probability of overall survival and disease-free survival
(disease relapse or death) will be calculated using the method
of Kaplan and Meier. Differences in overall survival and
disease-free survival will be compared using the Cox
proportional hazards model, adjusted for the effects of center,
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conditioning regimen, disease and disease stage. The number
of days in hospital from the day of transplant (Day 0) to first
hospital discharge, number of days in hospital in the first 100
days and first year post-transplant, and the number of days on
non-prophylactic antibiotics in the first 100 days posttransplant will be compared between treatment groups using,
where appropriate, a two-sample t-test; if assumptions do not
hold, we will use the non-parametric equivalent, the MannWhitney test. Differences between treatment groups will be
reported using 2-sided p-values and 95% confidence intervals.
9.7.2 QOL outcomes:
Statistical analysis will make the following comparisons:
(i) Comparison of donor QOL measured pre-transplant
and at 1 month and 1 year post harvest between
donor groups (G-BM vs G-PB);
(ii) Comparison of recipient QOL measured pretransplant and at 1 year and 3 years post-transplant
between recipient groups (G-BM vs G-PB).
Each instrument will be scored according to convention or the
specifications of the developers. Most instruments allow
scoring of subscales as long as 50% of more of items are
answered. Differences in donor and recipient QOL between
the 2 treatment groups will be tested for each instrument
using a linear mixed model [64]. The linear mixed model
incorporates the correlation between QOL measurements
within the same patient in the estimation of regression
coefficients. Treatment group (G-BM vs. G-PB) will be tested,
adjusted for the effects of baseline covariates including pretreatment QOL. A treatment by time interaction will also be
tested to investigate if a treatment difference in QOL is
dependent on time. P-values will be reported without
adjustment for multiple testing, although appropriate caveats
will be included in any interpretation.
9.7.3
Planned Subgroup Analyses:
There is some evidence that G-PB stem cells yield superior
results for patients with advanced disease, but perhaps not for
those with early disease. Similarly, different malignant
diseases appear to have different sensitivities to the ‘graft vs.
malignancy’ effect (i.e. CML is more sensitive than is AML,
MDS or other hematologic malignancy). Therefore, it is
possible that one type of stem cell source may have specific
benefit for patients with a given disease. Both of these
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situations describe a statistical interaction, where the effect of
treatment on outcome depends on the value of another
variable. Thus, separate significance tests for an interaction
using the Cox proportional hazards model will be performed.
One interaction will test whether the effect of treatment on
outcome varies by the disease state and the other will test
whether the effect of treatment on outcome is different among
the 4 disease types. The outcomes to be considered include
extensive chronic GVHD-free survival, overall survival, time to
relapse, and time to acute GVHD. If an interaction test is
highly statistically significant (i.e., p<0.001), then separate
significance tests within the relevant subgroups will be
calculated.
This approach will account for multiple statistical comparisons
(i.e., multiple subgroups with multiple outcomes) but will
increase the probability of a Type I error: that is, attributing a
difference to an intervention when chance is the more likely
explanation. In this study, no formal adjustment of significance
tests will occur. In addition to compromising the Type I error
rate, the subgroup analyses will also compromise the Type II
error rate. Thus, there will be limited power to detect
statistically significant differences. Results of treatment
comparisons within subgroups and for secondary endpoints
will be interpreted cautiously and will be considered
hypothesis-generating exploratory analyses.
9.8 Handling of Missing Data:
Missing values represent a potential source of bias in a clinical
trial. As stated in the International Conference on Harmonization
guideline on statistical methodology [65], no universally applicable
methods of handling missing values can be recommended.
Multiple imputation is a strategy for handling missing data that
attempts to incorporate missing data uncertainty, and so will be
utilized in this study.
10.0
Laboratory Blood and Marrow Collections
Donors will be asked to donate a small volume of the stem cell product
that is collected. (Bone marrow donors will also be asked to donate a
small amount of peripheral blood on the day of bone marrow harvest).
10.1
Primary Biology Hypothesis:
Measurable differences in the numbers and functional properties
of immunological cells in the donor graft will explain and predict
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differences in the in vivo development of chronic GVHD in
recipients of allografts of peripheral blood stem cells versus bone
marrow cells from G-CSF pretreated donors.
10.2
Secondary Biology Hypotheses:
The lower rate of chronic GVHD associated with G-BM is due to:
(i) Differences in maturity and activation of B cells;
(ii) An altered number and function of plasmacytoid dendritic cells;
(iii) An increased number of regulatory (Treg) and Tr1 cells in
G-BM;
(iv) A shift in Th1 and Th2 function.
10.3
Primary Outcome:
To determine if the presence of differences of immune populations
between G-PB and G-BM donor grafts correlate with time to
development of GVHD.
10.4
Secondary Outcomes:
To evaluate the numbers and functional properties of the following
populations of cells between G-BM and G-PB: B cells; myeloid
and plasmacytoid dendritic cells; CD4+CD25+ Treg cells and TR1
cells; and Th/c1, Th/c2 cells.
10.5
Sample Collection:
10.5.1 G-CSF Mobilized Peripheral Blood Donors
Each donor will be asked to donate 5 mL of the apheresis
product on the first day of collection. The sample will be
collected into a 14 mL BD sterile Polypropylene Falcon
collection tube. (This tube will be supplied by the Schultz
Laboratory.) This sample is to be taken immediately
following the collection.
It is up to the discretion of the apheresis physician
whether to collect 5 mL of product or a lesser amount.
10.5.2 G-CSF Stimulated Bone Marrow Donors
Each donor will be asked to donate 10 mL of the bone
marrow collection. The sample should be taken from the
bone marrow collection bag at the end of the harvest.
(The anti-coagulant in the bone marrow collection bag will
prevent the specimen from clotting.) This sample will be
collected into a 14 mL BD sterile Polypropylene Falcon
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collection tube. (This tube will be supplied by the Schultz
Laboratory.) Bone marrow donors will also be asked to
donate 20 mL of peripheral blood on the same day as
their bone marrow harvest prior to the harvest. This
sample will be collected into heparinized (Sodium
heparin) collection tubes. Each tube should only be filled
to half its capacity. (eg, For a 7 mL collection tube only
3.5 mL of blood should be collected into the tube.) The
reason is to prevent clotting of the specimen. Sites are to
use standard clinical sodium heparin collection tubes
(size 7 or 10 mL).
10.6
Shipping of Samples (Canadian and US Sites)
All samples are to be shipped fresh on the day of collection to the
Schultz Laboratory. (There will be no processing of samples on
site.) Samples can be sent from the study site Monday –
Thursday (no shipping on Friday). (Optional blood and marrow
samples will not be drawn on Fridays.)
The Schultz Laboratory is to be notified at least 48 hours prior to
shipment of the samples at (604) 875-2454. The shipping
address for samples is:
Dr. Kirk Schultz
Child and Family Research Institute
950 West 28th Avenue, Rm 217
Vancouver, BC
Canada V5Z 4H4
Phone number: (604) 875-2454; Fax number: (604) 875-3597
(Instructions for courier: Buzz # 2454 for access after 3:00 pm)
Attention: Soudabeh Aslanian
10.7
Sample Processing and Shipping (Outside Canada and the US)
Collection of optional donor samples will occur on a “site-by-site”
basis for transplant centres outside of Canada and the US. For
those sites participating in the collection of donor samples, the
samples will be processed and frozen on site. The samples will
be sent in batches on an annual basis to the Schultz Laboratory.
(Dr. Schultz will provide a Standard Operating Procedure for the
processing, freezing and shipping of samples to sites outside
Canada and the US.)
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10.8
Additional Research
Donors will also be asked to give their permission for banking of
any cells left over after the studies described above have been
completed. This is identified as “Option B” in the Optional
Laboratory Research consent template.
Samples will be banked for up to 10 years from the start of
patient enrollment. Access to the study data bank for future
research will not be available after 10 years from the start of
enrollment.
A log will be kept which links the donor ID number to the code
number on their sample(s) and to information regarding which
optional laboratory research the donor has consented to. The
subject’s name will not be used (and will never be made available
to future researchers).
Only a small group of trained study personnel will have access to
this log. This group includes: The Project Manager and
designated research assistant(s) at the Project Management
Office. The log will be managed by the Project Management
Office located at the Leukemia/BMT administrative office,
Vancouver General Hospital, Vancouver, British Columbia. The
Project Management Office will be responsible for ensuring
patient confidentiality is maintained.
All future research projects must have the approval of an
institutional review ethics board.
The Project Manager (or delegate) will maintain a copy of all IRB
approval certificates for future research projects and a system of
record keeping.
The Project Management Office will be
responsible for confirming that a subject has consented to Option
B (sample banking) and that a specific project has IRB approval
before any samples are released.
10.9
Research Results
Donors participating in the optional laboratory research will not
have access to any of the results. This includes future as yet
undetermined research.
10.10 Withdrawal from the Optional Laboratory Studies
Donors can withdraw their consent from the optional laboratory
research at any time. If a donor wishes to withdraw their consent
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for participation in the optional studies, they must notify the study
doctor at their site. The study doctor will then notify the Project
Management Office (located in Vancouver, BC). All remaining
samples will be destroyed. There will be no further access to the
study database.
Any information that has been gathered from the samples prior to
notification of withdrawal will not be destroyed.
11.0
Adverse Events and Serious Adverse Events
11.1
Definitions
11.1.2 Definition of Adverse Event
The ICH definition of an adverse event is: Any untoward
medical occurrence in a patient or clinical investigation
subject administered a pharmaceutical product and which
does not necessarily have a causal relationship with this
treatment. An adverse event (AE) can therefore be any
unfavourable and unintended sign (including an abnormal
laboratory finding, for example), symptom, or disease
temporally associated with the use of a medicinal
(investigational) product, whether or not related to the
medicinal (investigational) product.
(Definition per
International Conference on Harmonization [ICH].
For the purposes of this study, the G-BM product is the
“investigational” product; the G-BM harvest is considered
an “investigational” procedure.
11.1.3 Definition of Serious Adverse Event (SAE)
The ICH definition of a Serious Adverse Event is any
untoward medical occurrence that:





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Results in death
Is life-threatening
Requires inpatient hospitalization or prolongation of
existing hospitalization (or admission to ICU)
Results in persistent or significant disability/incapacity,
or
Results in a congenital anomaly/birth defect.
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11.1.4 Definition of Unexpected Adverse Reactions
According to the ICH Guidelines: An unexpected adverse
reaction is one in which the nature or severity is not
consistent with the applicable product information (e.g.
Investigator’s Brochure).
11.1.4.1
Unexpected Adverse Reactions and Recipients
For the purposes of this study, an unexpected
adverse reaction with respect to the recipient, is
one that would not be expected with a standard
Peripheral Blood Stem Cell graft or standard
bone marrow graft.
11.1.4.2 Unexpected Adverse Reaction and Donors
For the purposes of this study, an unexpected
adverse reaction with respect to the donor, is
one that would not be expected with the
standard Peripheral Blood Stem Cell collection
or a standard bone marrow harvest.
11.1.5 Attribution of Causality and Definitions
Investigators are required to assess the relationship, if
any, of each AE (that meets the criteria for reporting) to
either the G-BM product in the case of recipients or the
G-BM harvest in the case of the donors. Clinical judgment
is to be used to determine the degree of certainty with
which an AE can be attributed to either the G-BM product
(recipient AE) or the G-BM harvest (donor AE). Causality
criteria are defined as follows:
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
Not related: There is another obvious cause of the AE.

Doubtful: There is another more likely cause of the
AE.

Possible: The AE could have been due to the G-BM
product (recipient AE) or G-BM harvest (donor AE).

Probable: The AE is probably attributable to the G-BM
product (recipient AE) or G-BM harvest (donor AE).

Very likely: The AE is most likely attributable to the GBM product (recipient AE) or G-BM harvest (donor AE).
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11.2
Adverse Event Monitoring and Source Documentation
All recipients are to be assessed for adverse events according
to institutional practice following standard hematopoietic stem cell
transplant (HSCT) except where additional assessment is
required per protocol. Source documentation of adverse events
should be according to institutional practice, except in cases were
additional information is required to be documented by the
protocol.
All donors are to be assessed for adverse events according to
standard institutional practice with respect to the follow-up of
donors except where additional assessment is required per
protocol. It is recommended that donors be contacted either by
phone or seen in the clinic on Day 30 to review AE’s experienced
up to that time point. Source documentation of adverse events
should be according to standard clinical practice, except in cases
were additional information is required to be documented by the
protocol.
11.3
Adverse Event Reporting
Adverse events will be reported in the Data Collection Forms for
recipients and donors on both study arms according to the criteria
in the following sections.
11.3.1 Adverse Event Reporting and Recipients
Adverse event reporting for both G-PB and G-BM
recipients should begin on the day that conditioning
chemotherapy commences.
There are several mild to moderate toxicities that are
expected and common with HSCT, both during the
conditioning period and in the period following the
transplant; therefore, adverse events less than grade 3 do
not need to be recorded in the “Adverse Event Data
Collection Form”. All adverse events (grade 3 or greater)
must be recorded up until Day 30 post transplant (for
Adverse Event reporting after Day 30, see Section 11.6.)
The start date of the event must be recorded in the
“Adverse Event Data Collection” form. The start date is
defined as the date the adverse event first meets the
criteria for grade 3 or greater. (Stop dates do not need to
be recorded.)
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Abnormal laboratory results do not need to be recorded
unless considered by the investigator to be relevant in
terms of subject or trial safety (or in relation to a serious
adverse event that is being reported).
11.3.2 Adverse Event Reporting and Donors
Adverse event recording for both G-PB and G-BM
donors should begin on the first day of G-CSF.
Minor toxicity is expected and common with respect to
G-CSF as well as in association with apheresis and bone
marrow harvest; therefore, adverse events less than
grade 3 do not need to be recorded in the “Adverse
Event Data Collection Form”. All adverse events of
grade 3 or greater (for both G-PB and G-BM donors)
must be recorded in the “Adverse Event Data Collection”
form up until Day 30 post collection.
The start date of the event must be recorded in the
“Adverse Event Data Collection” form. The start date is
defined as the date that the adverse event first meets the
criteria for grade 3 or greater. (Stop dates do not need
to be recorded.) Abnormal laboratory results do not
need to be recorded unless considered by the
investigator to be relevant in terms of subject or trial
safety (or in relation to a serious adverse event that is
being reported).
11.4 Grading of Adverse Events
The NCI Common Toxicity Criteria (CTC) Version 3 will be used to
grade adverse events that recipients and donors experience. (A
copy of version 3 of the CTC can be downloaded from the CTEP
home page [http://ctep.info.nih.gov]. Additionally, if assistance is
needed the NCI has an Index to the CTC that provides help for
classifying and locating terms. )
11.5 Serious Adverse Event Reporting Criteria to Day 30
11.5.1 Recipients
Any serious adverse event that occurs between the
start of the conditioning regimen up to 30 days after
HSCT must be reported to the Project Management
Office within 24 hours except as noted below:
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Exceptions:
The following serious adverse events do NOT require
expedited reporting for this protocol for recipients
because they are common and expected events in
patients undergoing transplant:
Grade 3 hemoglobinemia, leukopenia, neutropenia
or thrombocytopenia with hospitalization
Grade 3 infection with hospitalization
Grade 3 mucositis with hospitalization
Grade 3 fever/neutropenia with hospitalization
Grade 3 transfusion with hospitalization
Grade 3 diarrhea or gastritis with hospitalization
Grade 4 fever/neutropenia +/- hospitalization
Grade 4 hemoglobinemia, leukopenia, neutropenia
or thrombocytopenia +/- hospitalization
(These exceptions are subject to all other adverse
event reporting requirements described in Section 11.)
Serious adverse events that meet the criteria for
expedited reporting should be reported using the
“Recipient Expedited Report” form (Appendix 3E).
This form should be faxed to the Project
Management Office at: (604) 875-5584. Serious
adverse events should also be recorded in the
“Adverse Event Data Collection” form.
11.5.2 Donors
Any serious adverse event that occurs between the
first day of G-CSF up to 30 days after stem cell
collection must be reported to the Project
Management Office within 24 hours.
Serious adverse events should be reported using
the “Donor Expedited Report” form (Appendix 3E).
This form should be faxed to the Project
Management Office at: (604) 875-5584.
Serious adverse events should also be recorded in
the “Adverse Event Data Collection” form.
11.6
AE and SAE Reporting after Day 30
Reporting of adverse events and serious adverse events
after Day 30 is not required for recipients or donors except
as noted:
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Recipients: In the time period between Day +31 and the
end of study follow-up (up to 4 years post HSCT), if a
serious adverse event occurs that is unexpected in
standard G-PB or BM HSCT and is felt to be related to the
G-BM product, then this event should be reported to the
Project Management Office within 24 hours using the
Recipient Expedited Report Form (Appendix 3E).
Donors: In the time period between Day +31 and the end
of study follow-up (up to 1 year post collection), if a serious
adverse event occurs that is unexpected with a standard
collection process and is felt to be related to the G-BM
harvest or G-CSF, then this event should be reported to the
Project Management Office with 24 hours using the
Recipient Expedited Report Form (Appendix 3E).
11.7
Reporting of Secondary Malignancies
If a subject develops a secondary malignancy at any time
during study follow-up (4 years for recipients; 1 year for
donors), and it is felt to be possibly, probably or definitely
related to G-CSF (donors) or the G-BM graft, (recipients)
then this must be reported to the Project Manager within 15
days from the time the transplant centre becomes aware
(for review by the Study Clinical Chair).
11.8
Pregnancies
Pregnancies occurring during study follow-up (4 years for
recipients; 1 year for donors) must be reported by the
investigational staff within 1 working day of their knowledge
of the event using the Pregnancy Notification Form
(Appendix 3E).
Follow-up information regarding the
outcome of the pregnancy any postnatal sequelae in the
infant will be required. Pregnancies in partners of male
subjects included in the study must also be reported.
11.9
Reporting of Serious Adverse Events to Health Canada
The Sponsor (CBMTG) or delegate will be responsible for
reporting of Serious Adverse Events to Health Canada
according to Health Canada Guidelines. Recipient deaths
that are “expected” and “not related” to G-BM will not be
submitted to Health Canada (unless the DSMC and/or
Study Steering Committee conclude the death constitutes a
safety concern).
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11.10 Safety Reports
SAE reports received by the Project Management Office
will be distributed to participating sites (in the form of
“Safety Reports”) according to the recommendations of the
Steering Committee, DSMB and the regulations of
participating countries.
11.11 Reporting of Safety Reports to Institutional
Review Boards
Sites will follow the guidelines of their local IRB with
respect to the submission of SAE’s that occur at the site as
well as reports of SAE’s that occur at other sites.
12.0
Data Safety Monitoring Committee
During the course of the study, an independent Data Safety Monitoring
Committee (DSMC) will review efficacy and safety data. As described in
Section 9.5, two interim analyses are planned. The DSMB will convene
on a yearly basis.
Additional meetings/conferences calls will be
conducted as necessary.
13.0
Records and Reporting
13.1 The CBMTG 0601 Project Management Office (located in
Vancouver, BC, Canada) will perform the randomization, data
collection and management, site audits, administration, meeting
support, and statistical support. A centralized database will be
utilized and housed on a secure server with daily backup. The
project manager will communicate with data management and
clinical research personnel in each of the participating institutions.
13.2 Data Entry, Confidentiality and Security
Data Collection Forms and Quality of Life Forms will be faxed to
the Project Management Office at the pre-specified registration and
at follow-up time points. Data will be identified by code initials and
a randomly generated number only. Data will be entered (by staff
at the Project Management Office) into the database using a Visyx
web based electronic data capture system (developed by ICM
Corporation). The server for the database will be located in the
Leukemia/BMT Program of BC administrative office (in Vancouver,
BC). Appropriate security measures will be in place such that
current Canadian privacy laws are adhered to with respect to
security and confidentiality of data, electronic data transmission,
data storage and data access. A secure ID and password will be
necessary to access the system. Audit trails of entries will be
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provided. The Project Manager and delegate will be the only
individuals that can edit data.
During the course of the study, web based data entry may be
expanded to participating sites.
Site staff will only have
authorization to enter and view data for subjects at their site. Site
staff will not be able to edit data once they have submitted it. (See
previous paragraph regarding confidentiality and security
measures.)
13.3 Access to Database and Statistical Analysis
The Project Manager (and delegate) will be the only individuals who
have authorization to transfer data to the statistician for study
analysis. Statistical analysis will be carried out using SPSS and
SAS software.
13.4 Clinical Trials Agreement (NIH/NCI Requirements)
1. For a clinical protocol where there is an investigational Agent
used in combination with (an)other investigational Agent(s), each
the subject of different CTAs or CRADAs , the access to and use of
data by each Collaborator shall be as follows (data pertaining to
such combination use shall hereinafter be referred to as "Multi-Party
Data.):
a. NCI must provide all Collaborators with written notice
regarding the existence and nature of any agreements
governing their collaboration with NIH, the design of the
proposed combination protocol, and the existence of any
obligations that would tend to restrict NCI's participation in
the proposed combination protocol.
b. Each Collaborator shall agree to permit use of the MultiParty Data from the clinical trial by any other Collaborator
to the extent necessary to allow said other Collaborator to
develop, obtain regulatory approval or commercialize its
own investigational Agent.
c. Any Collaborator having the right to use the Multi-Party
Data from these trials must agree in writing prior to the
commencement of the trials that it will use the Multi-Party
Data solely for development, regulatory approval, and
commercialization of its own investigational Agent.
2. The NCI encourages investigators to make data from clinical
trials fully available to Collaborator(s) for review at the appropriate
time (see #5). The NCI expects that clinical trial data developed
under a CTA or CRADA will be made available exclusively to
Collaborator(s), and not to other parties.
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3. When a Collaborator wishes to initiate a data request, the
request should first be sent to the NCI, who will then notify the
appropriate investigators (Group Chair for cooperative group
studies, or PI for other studies) of Collaborator's wish to contact
them.
4. Any data provided to Collaborator(s) must be in accordance
with the guidelines and policies of the responsible Data Monitoring
Committee (DMC), if there is a DMC for this clinical trial.
5. Any manuscripts reporting the results of this clinical trial
should be provided to CTEP for immediate delivery to
Collaborator(s) for advisory review and comment prior to
submission for publication. Collaborator(s) will have 30 days from
the date of receipt for review. An additional 30 days may be
requested in order to ensure that confidential and proprietary data,
in addition to Collaborator(s) intellectual property rights, are
protected.
Copies of abstracts should be provided to
Collaborator(s) for courtesy review following submission, but prior
to presentation at the meeting or publication in the proceedings.
Copies of any manuscript and/or abstract should be sent to:
Regulatory Affairs Branch, CTEP, DCTD, NCI
Executive Plaza North, Room 7111
Bethesda, Maryland 20892
FAX 301-402-158
The Regulatory Affairs Branch will then distribute them to
Collaborator(s).
14.0
Regulatory Ethics Compliance
14.1
Investigator Responsibilities
The investigator at each site is responsible for ensuring that the
clinical study is performed in accordance with the protocol, current
ICH Guidelines on Good Clinical Practice (GCP), and applicable
regulatory requirements.
GCP is an international ethical and scientific quality standard for
designing, conducting, recording, and reporting studies that
involve participation of human subjects. Compliance with this
standard provides public assurance that the rights, safety, and
well being of study subjects are protected, consistent with the
principles that originated in the Declaration of Helsinki, and that
the clinical study data are credible.
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14.2
Independent Ethics Committee or Institutional Review Board
This study will be undertaken at a site only after IEC/IRB has
given full approval of the final protocol, amendments (if any), the
informed consent form(s), applicable recruiting materials, and the
study management center has received a copy of this approval.
This approval letter must be dated and must clearly identify the
documents being approved. The study management center will
require a copy of all IEC/IRB documents.
14.3 Serious Adverse Event Reporting (Site Responsibilities)
Serious Adverse Events that occur at a site must be reported to
the local IEC/IRB of that site according to the criteria of the local
IEC/IRB.
15.0
Study Monitoring
The project manager will review the protocol and Data Collection Forms
with the investigator and study staff before study initiation at the site
initiation visit or the investigator's meeting.
A monitor will visit the site one or two times throughout the duration of
the study (or more frequently if necessary) to audit the following:

Completeness of patient records,

Verification of consent,

Accuracy of entries on the Data Collection Forms,

Adherence to the protocol and to GCP,

Verification of subject eligibility,

Administration of G-CSF according to the protocol.
The monitor will also review all regulatory study documents at regular
time points throughout the duration of the study. The investigator and
key study personnel must be available to assist the monitor as required.
The investigator must give the monitor access to relevant hospital or
clinical records to confirm their consistency with the Data Collection
Form entries. No information in these records about the identity of the
patients will leave the study center. Monitoring standards require full
verification for the presence of informed consent, adherence to the
inclusion/exclusion criteria, documentation of all adverse events required
as per protocol and the recording of primary efficacy and safety
variables.
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16.0 References
1. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A et al. The
European Organization for Research and Treatment of Cancer QLQ-C30: A
Quality-of-Life Instrument for Use in International Clinical Trials in Oncology.
J Natl Cancer Inst 1993; 85: 365-376.
2. Anderlini P, Körbling M, Dale D, et al.
Allogeneic blood stem cell
transplantation: considerations for donors. Blood 1997; 90:903-8.
3. Anderlini P, Przepiorka D, Champlin R, et al. Biologic and clinical effects of
granulocyte colony stimulating factor in normal individuals. Blood 1996;
88:2819-25.
4. Arpinati M, Green C, Heimfeld S, Heuser JE, Anasetti C. Granulocytecolony stimulating factor mobilizes T helper 2-inducing dendritic cells. Blood
2000; 95:2484.
5. Becker PS, Wagle M, Matous S, et al. Spontaneous splenic rupture
following administration of granulocyte colony stimulating factor (G-CSF):
occurrence in an allogeneic donor of peripheral blood stem cells. Biol Blood
Marrow Transplant 1997; 3:45-9.
6. Bender R and S Lange Multiple test procedures other than Bonferroni’s
deserve wider use BMJ 1999;318:600.
7. Bensinger WI, Martin PJ, Storer B, et al. Transplantation of bone marrow as
compared with peripheral blood cells from HLA-identical relatives in patients
with hematologic cancers. N Engl J Med 2001;344:175-81.
8. Bensinger WI, Weaver CH, Appelbaum FR, et al. Transplantation of
allogeneic peripheral blood stem cells mobilized by recombinant human
granulocyte colony-stimulating factor. Blood 1995; 85:1655-1658.
9. Blaise D, Kuentz M, Fortanier C, et al. Randomized trial of bone marrow
versus lenograstim-primed blood cell allogeneic transplantation in patients
with early-stage leukemia: a report from the Société Française de Greffe de
Moelle. J Clin Oncol 2000; 18:537-546.
10. Bradburn NM. The structure of psychological well-being. 1 ed. Chicago:
Aldine, 1969. Cavallaro AM, Lilleby IT, Majolino I, et al. Three to six year
follow-up of normal donors who received recombinant human granulocyte
colony stimulating factor. Bone Marrow Transplant 2000; 5:85-89.
11. Bredeson C, Leger C, Couban S et al. An Evaluation of the Donor
Experience in the Canadian Multicenter Randomized Trial of Bone Marrow
Versus Peripheral Blood Allografting Biol Blood Marrow Transplant 2004
(Manuscript in press)
12. Cavallaro AM, Lilleby IT, Majolino I, et al. Three to six year follow-up of
normal donors who received recombinant human granulocyte colony
stimulating factor. Bone Marrow Transplant 2000; 5:85-89.
13. Cella DF, Tulsky DS, Gray G, Sarafian B, Linn E, Bonomi A et al. The
functional assessment of cancer therapy scale: Development and validation
of the general measure. J Clin Oncol 1993; 11:570-579.
14. Champlin RE, Schmitz N, Horowitz MM, et al. Blood stem cells compared
with bone marrow as a source of hematopoietic cells for allogeneic
transplantation. Blood 2000; 95:3702-3709.
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15. Couban S, Messner HA, Andreou P, et al.
Bone Marrow Mobilized with
Granulocyte Colony-Stimulating Factor in Related Allogeneic Transplant
Recipients: A Study of 29 Patients. Biol Blood Marrow Transplant 2000;
422-427.
16. Couban S, Simpson DR, Barnett MJ, et al. A randomized multicenter
comparison of bone marrow and peripheral blood in recipients of matched
sibling allogeneic transplants for myeloid malignancies. Blood 2002;
100:1525-1531.
17. Cutler C, Giri S, Jeyapalan S, Paniagua D, Viswanathan A, Antin JH. Acute
and chronic graft-versus-hose disease after allogeneic peripheral blood
stem cell and bone marrow transplantation: a meta-analysis. J Clin Oncol
2001;19:3685-91.
18. Devins GM, Binik YM, Hutchinson TA, Hollomby DJ, Barre PE, Guttmann
RD. The emotional impact of end-stage renal disease: Importance of
patients' perceptions of intrusiveness and control. Int J Psychiat Med 1983;
13:327-343.
19. Devins GM, Dion R, Pelletier LG, Shapiro CM, Abbey SE, Raiz L et al. The
structure of lifestyle disruptions in chronic disease: A confirmatory factor
analysis of the illness intrusiveness ratings scale. Med Care 2001; 39:10971104.
20. Devins GM, Mandin H, Hons RB, Burgess ED, Klassen J, Taub K et al.
Illness intrusiveness and quality of life in end-stage renal disease:
Comparison and stability across treatment modalities. Health Psychol 1990;
9:117-142.
21. Devins GM, Orme CM, Costello CG, Binik YM, Frizzell B, Stam HJ et al.
Measuring depressive symptoms in illness populations: Psychometric
properties of the Center for Epidemiologic Studies Depression (CES-D)
scale. Psychol Health 1988; 2:139-156.
22. Falanga A, Marchetti M, Evangelista V, et al. Neutrophil activation and
hemostatic changes in healthy donors receiving granulocyte colony
stimulating factor. Blood 1999; 93:2506-14.
23. Falzetti F, Aversa F, Minelli O, Tabilio A. Spontaneous rupture of spleen
during peripheral blood stem cell mobilisation in a healthy donor (Research
Letter). Lancet 1999; 353:55.
24. Heldal D, Tjonnfjord GE, Brinch L, et al. A randomized study of allogeneic
transplantation with stem cells from blood or bone marrow. Bone Marrow
Transplant 2000; 25:1129-1136.
25. Isola L, Scigliano E, Fruchtman S. Long-Term Follow-Up After Allogeneic
Granulocyte
Colony-Stimulating
Factor-Primed
Bone
Marrow
Transplantation. Biol Blood Marrow Transplant. 2000; 6:428-433.
26. Korbling M, Przepiorka D, Huh YO, et al. Allogeneic blood stem cell
transplantation for refractory leukemia and lymphoma: potential advantage
of blood over marrow allografts. Blood 1995; 85:1659-1665.
27. Lewis JA, 1999. ICH Harmonized Tripartite Guideline: Statistical Principles
for Clinical Trials Statistics in Medicine 18, 1905-1942
28. Lapierre V, Oubouzar N, Aupérin A, et al. Influence of the hematopoietic
stem cell source on early immunohematologic reconstitution after allogeneic
transplantation. Blood 2001; 97:2580-2586.
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29. Mahmoud HK, Fahmy OA, Kamel A, Kamel M, El-Haddad A, El-Kadi D.
Peripheral blood vs. bone marrow as a source for allogeneic hematopoietic
stem cell transplantation. Bone Marrow Transplant 1999; 24:355-58.
30. Maunsell E, Brisson J, Deschenes L. Psychological distress after initial
treatment of breast cancer: Assessment of potential risk factors. Cancer
1992; 70:120-125.
31. McQuellon RP, Russel GB, Cella DF, Craven BL, Brady M, Bonomi A, Hurd
DD.
Quality of life measurement in bone marrow transplantation:
development of the Functional Assessment of Cancer Therapy-Bone
Marrow Transplant (FACT-BMT) scal. Bone Marrow Transplant. 1997;
19:357-68.
32. Morton J, Hutchins C, Durrant S. Granulocyte-colony-stimulating factor (GCSF)-primed allogeneic bone marrow: significantly less graft-versus-host
disease and comparable engraftment to G-CSF-mobilized peripheral blood
stem cells. Blood 2001; 98:3186-3191.
33. O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials.
Biometrics 1979; 35:549-556.
34. Ottinger HD, Beelen DW, Scheulen B, Schaefer UW, Grosse-Wilde H.
Improved immune reconstitution after allotransplantation of peripheral blood
stem cells instead of bone marrow. Blood 1997; 89:3891-3.
35. Pan L, Delmonte J Jr, Jalonen CK, Ferrara JL. Pretreatment of donor mice
with granulocyte colony-stimulating factor polarizes donor T lymphocytes
toward type-2 cytokine production and reduces severity of experimental
graft-versus-host disease. Blood. 1995;86:4422-4429
36. PASS 2000 User’s Guide. 2000 J. Hintze, Kaysville Utah.
37. Powles R, Mehta J, Kulkarni S, et al. Allogeneic blood and bone marrow
stem-cell transplantation in haematological malignant diseases: a
randomized trial. Lancet 2000; 355:1231-37.
38. Perneger TV What’s wrong with Bonferroni adjustments BMJ
1998;316:1236-1238
39. Radloff LS. The CES-D scale: A self-report depression scale for research in
the general population. App Psychol Meas 1977; 3:385-401.
40. Remberger M, Ringden O, Blau IW, et al. No difference in graft-versus-host
disease, relapse and survival comparing peripheral blood stem cells to bone
marrow using unrelated donors. Blood 2001; 98:1739-45.
41. Ringden O, Remberger M, Runde V, et al. Peripheral blood stem cell
transplantation from unrelated donors: a comparison with marrow
transplantation. Blood 1999; 94:455-64.
42. Rubin DB, 1987. Multiple imputation for nonresponse in surveys. New York:
John Wiley
43. Schmitz N, Beksac M, Hasenclever D, et al. Transplantation of mobilized
peripheral blood cells to HLA-identical siblings with standard-risk leukemia.
Blood 2002; 100:761-767.
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44. Schmitz N, Dreger P, Suttorp M, et al. Primary transplantation of allogeneic
peripheral blood progenitor cells mobilized by filgrastim (granulcyte colonystimulating factor). Blood 1995;85:1666-1672.
45. Schmitz N, Linch DC, Dreger P, et al. Randomised trial of filgrastimmobilised peripheral blood progenitor cell transplantation versus autologous
bone-marrow transplantation in lymphoma patients.
Lancet 1996;
347(8998):353-357.
46. Schimmer AD, Elliott ME, Abbey SE, Raiz L, Keating A, Beanlands HJ et al.
Illness intrusiveness in survivors of autologous bone and marrow
transplantation. Cancer 2001; 92:3147-3154.
47. Serody JS, Sparks SD, Lin Y, et al. Comparison of Granulocyte ColonyStimulating Factor(G-CSF)-Mobilized Peripheral Blood Progenitor Cells and
G-CSF-Stimulated Bone Marrow as a Source of Stem Cells in HLA-Matched
Sibling Transplantation. Biol Blood Marrow Transplant 2000; 6:434-440.
48. Storek J, Dawson MA, Storer B, et al.
Immune reconstitution after
allogeneic marrow transplantation compared with blood stem cell
transplantation. Blood 2001; 91:3380-3389.
49. Sullivan K. Acute and Chronic Graft versus Host Disease in Man. Int J Cell
Cloning 1986; 4:42-93 (Suppl 1)
50. Vigorito AC, Azevedo WM, Marques JF, et al. A randomized prospective
comparison of allogeneic bone marrow and peripheral blood progenitor cell
transplantation in the treatment haematological malignancies. Bone Marrow
Transplant 1998; 22:1145-1151.
51. Vose JM, Sharp G, Chan WC, et al. Autologous Transplantation for
Aggressive Non-Hodgkin’s Lymphoma: Results of a Randomized Trial
Evaluating Graft Source and Minimal Residual Disease. J Clin Oncol 2002;
20:2344-2352.
52. Abu-Amero KK, Wyngaard CA, Dzimiri N.
Prevalence and Role of
Methylenetetrahydrofolate Reductase 677 C→T and 1298 A→C
Polymorphisms in Coronary Artery Disease in Arabs. Arch Pathol Lab Med
2003;Vol 127:1349-13
53. Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health
Consensus Development Project on Criteria for Clinical Trials in Chronic
Graft-versus-Host Disease: I. Diagnosis and Staging Working Group
Report. Biology of Blood and Marrow Transplantation 11:945-955
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Appendix 1: ECOG Performance Status
Grade 0:
Fully active, able to carry on all pre-disease performance without
restriction.
Grade 1:
Restricted in physically strenuous activity but ambulatory and able
to carry out work of a light or sedentary nature.
Grade 2:
Ambulatory and capable of all self-care but unable to carry out
any work activities. Up and about more than 50% of waking
hours.
Grade 3:
Capable of only limited self-care, confined to bed or chair more
than 50% of waking hours.
Grade 4:
Completely disabled. Cannot carry on any self-care. Totally
confined to bed or chair.
Grade 5:
Dead
Reference:
Oken et al. Toxicity and response criteria of the Eastern
Cooperative Oncology Group. Am J Clin Oncol. (CCT) 1982;
5:649-655.
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Appendix 2
Registration and Minimization (Randomization)
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SECTION 1: REGISTRATION & ASSESSMENT OF ELIGIBILITY
When a donor and recipient who may be eligible to participate in this study are identified, and the IRB-approved
informed consent forms have been completed, this form should be completed and faxed to the CBMTG 0601 Project
Management Office (Fax: 604-875-5584). (Shaded areas to be completed by the Project Management Office.)
1.1 Registration:
Recipient’s Initials: |__|__|__|
Recipient’s Date of Birth: |__|__||__|__|__| |__|__|__|__|
DD
Donor’s Initials:
|__|__|__|
Donor’s Date of Birth:
MMM
YYYY
|__|__| |__|__|__| |__|__|__|__|
DD
MMM
YYYY
1.2 Participating Centre (please circle one):
Vancouver
Saskatoon
Winnipeg
London
Ottawa
Hamilton
Toronto
Montreal-McGill
Montreal-Maisonneuve
Halifax
Quebec City
Other: _________
1.3 Assessment of Eligibility:
Recipient must:








Be between 16 and 65 years old
Have one of the following hematologic malignancies: chronic myeloid leukemia in
chronic or accelerated phase, acute myeloid leukemia in complete remission,
myelodysplasia, or other hematologic malignancy
Be receiving a myeloablative conditioning regimen of Busulfan and Cyclophosphamide OR
Cyclophosphamide and TBI OR other myeloablative conditioning regimen approved by the
Clinical Chair
Have an HLA-identical sibling donor
Meet the transplant centre’s criteria for myeloablative allogeneic transplantation
Be able to give informed consent
Have an ECOG performance status of 0, 1 or 2
Not be positive for the HIV antibody
Donor must:









Be 18 years of age or older.
Be able to undergo general anesthesia, bone marrow or peripheral blood harvest
Be a sibling of the recipient
Be a 6/6 HLA match of the recipient. HLA typing is by serologic or DNA methodology for A and
B and by DNA methodology for DRB1 (intermediate resolution)
Not be pregnant or breastfeeding at the time of the progenitor cell collection
Not have a history of malignant disease within the last 5 years or current malignancy other than
non-melanomatous in situ skin carcinoma or cervical carcinoma in situ
Not be positive for HIV antibody
Not have a known sensitivity to E. coli-derived products
Not be an identical twin of the recipient
1.4 Do the recipient and the donor fulfill all of the eligibility criteria?
|__| Yes – Please complete SECTION 2: RANDOMIZATION
|__| No – DO NOT RANDOMIZE
Page 1 of 4
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SECTION 2: MINIMIZATION (RANDOMIZATION)
Upon completion of this form, fax to the CBMTG 0601 Project Management Office (Fax: 604-875-5584). The
CBMTG 0601 Project Management Office will assign a study number to the recipient and the donor. This study
number should be used on all subsequent data forms for this donor-recipient pair.
Recipient Initials: |__|__|__|
Donor Initials:
|__|__|__|
Recipient Study #: |__|__|__|__|
Donor Study #:
|__|__|__|__|
2.1 Recipient Diagnosis (please circle one disease and if applicable one sub type):
Please consult with the Project Manager in situations where it is unclear how to classify the
recipient’s disease. This is important for the statistical analysis of the data.
Chronic Myeloid Leukemia
First Chronic Phase
Second Chronic Phase
Accelerated Phase
Acute Myeloid Leukemia
First Complete Remission
Second Complete Remission
Myelodysplasia
Refractory Anemia
Refractory Anemia with Ringed Sideroblasts
Refractory Anemia with Excess Blasts-I
Refractory Anemia with Excess Blasts-II
Chronic Myelomonocytic Leukemia
Other Hematologic Malignancy
Indolent Non-Hodgkin’s Lymphoma
Aggressive Histology Non-Hodgkin’s Lymphoma
Chronic Lymphocytic Leukemia
Hodgkin’s Lymphoma
Myelofibrosis
Other: Specify______________________________
2.2 Is the malignancy “de novo”, “therapy related” or “secondary” (AML only)?
(Please circle one only):
De novo
Therapy Related
Page 2 of 4
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Recipient’s Initials: |__|__|__|
Donor’s Initials: |__|__|__|
SECTION 2: MINIMIZATION (RANDOMIZATION) (continued)
Recipient Disease Stage (Early or Late)
Please identify whether the patient has early stage disease or late stage disease:
Early Stage Disease: First chronic phase CML, first remission AML, refractory anemia, refractory anemia with
ringed sideroblasts, chronic lymphocytic leukemia in first remission, non-hodgkin’s lymphoma in first remission,
hodgkin’s lymphoma in first remission.
Late Stage Disease: Accelerated phase CML, second chronic phase CML, second remission AML, refractory
anemia with excess blasts-I, refractory anemia with excess blasts-II, chronic lymphocytic leukemia beyond first
remission, non-hodgkin’s lymphoma beyond first remission, hodgkin’s lymphoma beyond first remission.
2.3
Recipient has (please circle one only):
Early Stage Disease
2.4
Late Stage Disease
Conditioning Regimen (please circle one only):
Busulfan and Cyclophosphamide
Cyclophosphamide and TBI
Other: _________________
2.5
Conditioning regimen(s) used at Transplant Centre has been approved by the Study
Clinical Chair (please circle one only):
Yes
2.6
No
Prospective Bone Marrow Transplant Date:
|__|__| |__|__|__| |__|__|__|__|
DD
2.7
Date recipient signed informed consent:
Date donor signed informed consent:
MMM
YYYY
|__|__| |__|__|__| |__|__|__|__|
DD
2.9
YYYY
|__|__| |__|__|__| |__|__|__|__|
DD
2.8
MMM
MMM
YYYY
Date of donor consent for optional laboratory samples:
|__|__| |__|__|__| |__|__|__|__|
DD
MMM
YYYY
□ Not applicable (donor did not consent)
2.10 Which laboratory sample option(s) did the donor consent to? (circle all that apply):
Sample(s) can
be used for 0601
Leftover cells can be
stored for future research
Not Applicable
This form must be signed and dated by the Investigator or Co-Investigator on page 4 before the
form is faxed to the Project Management Office.
Page 3 of 4
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I verify that this patient meets the eligibility criteria for this study and all other patient
information (pages 1- 3) is correct.
______________________
Investigator’s Signature
______________________
Investigator’s Printed Name
__________________
Date
The CBMTG 0601 Project Management Office will assign a treatment arm once the required
registration and randomization data are submitted. Fax the completed form to the CBMTG 601
Project Management Office at: 604-875-5584. The study arm assignment and recipient-donor
study numbers will be returned to the Study Centre by fax and an email notice.
2.11 Date of Minimization (Randomization):
|__|__| |__|__|__| |__|__|__|__|
DD
MMM
YYYY
2.12 Treatment Arm Assigned: (To be completed by the CBMTG 0601 Project Management Office)
G-CSF Mobilized Peripheral Blood
G-CSF Stimulated Bone Marrow
Signature of person completing the randomization: ______________________________
Page 4 of 4
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Appendix 3
Study Forms
Study forms are available on the project website
The project website is located at: http://cbmtgprotocol601.org
This is an open website. User ID and password are not required.
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3A: Data Collection Forms
 Section 3: Donor Assessment
 Section 4: Recipient Pre-Transplant Information
 Section 5: G-CSF Mobilized Peripheral Blood Collection
 Section 6: G-CSF Stimulated Bone Marrow Collection
 Section 7: Recipient Day 30 Information
 Section 8: Recipient Day 100 Information
 Section 9: Recipient Follow-Up (Month 6 to Month 48)
 Section 10: Hospitalizations
 Section 11: Cause of Death
 Investigator Statement Page
 G-PB Recipient and Donor Adverse Events Form
 G-BM Recipient and Donor Adverse Events Form
3B: Quality of Life Questionnaires
 Bradburn Scale
 CES-D Scale
 Illness Intrusiveness Ratings Scale
 Screening FACT-BMT Questionnaire
 Year 1 and 3 FACT-BMT Questionnaire
 EQ-5D Questionnaire
 Socio-demographic Questionnaire
 McGill Pain Questionnaire
3C: Health Economics Questionnaires
 Societal Cost Questionnaire
 Health Care Questionnaire (Part A)
 Health Care Questionnaire (Part B)
3D: Chronic GVHD Forms
 Patient Chronic GVHD Severity Scoring Table (Part B)
 Data Collection Form for Diagnosis and Scoring of Chronic GVHD According to
the NIH Consensus Guidelines
3E: Safety Reporting
 Expedited Report Form (for SAE reporting) for Donors
 Expedited Report Form (for SAE reporting) for Recipients
 Pregnancy Notification Form
3F: Requisition for Optional Donor Research Samples
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Appendix 4
Regimen Related Toxicity: Bearman Toxicity
Criteria Stomatitis (Mucositis)
Stomatitis
Toxicity
Page 76 of 107
Grade I
Grade II
Grade III



Pain and/or
ulceration not
requiring a
continuous IV
narcotic drug
Pain and/or ulceration
requiring a continuous IV
narcotic (morphine drip)

Severe ulceration and/or
mucositis requiring preventative
intubation
Severe ulceration – resulting in
documented aspiration
pneumonia with or without
intubation
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Appendix 5
Acute Graft Versus Host Disease Staging and Grading (Przepiorka Criteria)
Step 1: Perform staging of individual organ systems for acute GVHD
(a)
Skin Stage:
+ 1 Maculopapular eruption involving less than 25% of the body surface
+ 2 Maculopapular eruption involving 25%-50% of the body surface
+ 3 Maculopapular rash > 50% of the body surface
+ 4 Generalized erythoderma with bullous formation and often with desquamation
(b)
Liver Stage*
+ 1 Bilirubin 35-50 µmol/L
+ 2 Bilirubin 51-100 µmol/L
+ 3 Bilirubin 101-255 µmol/L
+ 4 Bilirubin > 255 µmol/L
*If patient has documented GVHD of the liver and documented alternative cause of
hyperbilirubinemia (i.e. veno-occlusive disease) then downstage liver GVHD by 1 stage
(c)
Gut Stage**
Severity is categorized according to volume of diarrhea (average of two consecutive days) or
the presence of nausea/vomiting
+ 1 Diarrhea volume = 500-900 mL/day or persistent nausea (+ vomiting) with
histological proof of GVHD within the gut
+ 2 Diarrhea volume = 1000-1500 mL/day
+ 3 Diarrhea volume > 1500 mL/day
+ 4 Severe abdominal pain or ileus
**If patient has documented GVHD of the gut and alternative cause of diarrhea (i.e. severe
mucosists, CMV enteritis, or C.difficile infection), then downstage gut by 1 stage
Step 2: Add organ staging together to determine overall clinical grade.
Clinical Grading of Severity of Acute Graft-Versus-Host Disease
GRADE
SKIN
LIVER
GUT
0 (none)
0
0
0
I (mild)
+1 to +2
0
0
II (moderate)
0 to +3*
+1 and/or
+1
III (severe)
-
+2 t0 +3 and/or
+2 to +4
IV (life threatening)**
+4
+4
-
*Skin stage 3 alone is also considered overall grade II
**Severe decrease in performance status due to GVHD should be considered
grade IV irrespective of the organ stages
From Przepiorka et al, Consensus conference on acute GVHD grading. Bone Marrow Transplant 15:325, 1995
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Appendix 6:
Chronic Graft Versus Host Disease Assessment
Limited Chronic GVHD
Either or both:
1.
Localized skin involvement
2.
Hepatic dysfunction
Extensive Chronic GVHD
Either:
1.
Generalized skin involvement or
2.
Generalized skin involvement and/or hepatic dysfunction plus
i.
ii.
iii.
iv.
Liver histology showing aggressive hepatitis, bridging necrosis or cirrhosis
or
Involvement of eye: Schirmer’s test with <5 mm wetting
or
Involvement of minor salivary glands or oral mucous demonstrated on labial biopsy
specimen
or
Involvement of any target organ e.g. esophageal abnormalities, polymyositis
Reference: Sullivan K. Acute and Chronic Graft versus Host Disease in Man. Int J Cell Cloning
1986; 4:42-93 (Suppl 1)
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Appendix 7
Consent Templates



Page 79 of 107
Appendix 7A: Donor Consent Form
Appendix 7B: Recipient Consent Form
Appendix 7C: Donor Consent Form for Optional
Laboratory Research
CBMTG G-PB versus G-BM Trial
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Protocol Version: 03-Sep-2008
Donor Consent Form
{Insert Name of Institution}
{Insert Address of Institution}
STUDY TITLE: A Randomized Multicentre Study Comparing G-CSF Mobilized Peripheral
Blood and G-CSF Stimulated Bone Marrow in Patients Undergoing
Matched Sibling Transplantation for Hematologic Malignancies
Principal Investigator:
{Insert Name, Address and Contact Information for Principal
Investigator}
Associate Investigators:
{Insert Name, Address and Contact Information for Associate
Investigators}
Study Sponsor:
Canadian Blood and Marrow Transplant Group
Introduction:
You are invited to take part in a research study at the {Insert Institution}. Taking part in this study
is voluntary. The quality of your health care will not be affected by whether you participate or not.
Participating in the study might not benefit you, but information might be gained that will benefit
others. You may withdraw from the study at any time without affecting your care. The study is
described below. This description tells you about the risks, inconvenience, or discomfort that you
might experience. You should discuss any questions you have about this study with the people
who explain it to you.
Purpose of the Study:
WHY IS THIS STUDY BEING DONE?
Your doctors have explained that your brother or sister has cancer of the blood and they have
recommended that he/she receives a bone marrow transplant using cells collected from you.
Usually, cells for this type of transplant are collected in the following way. You are given a
medication called G-CSF for 4 or 5 days and then special cells called stem cells are collected
from your bloodstream, using a machine called an apheresis machine. These cells are then
given to your brother or sister after they have received very high doses of chemotherapy. This
type of transplant is called a “G-CSF mobilized peripheral blood transplant”.
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Please note that although the use of G-CSF for mobilization of stem cells in healthy donors (for
the purpose of allogeneic stem cell transplant) is considered standard care, G-CSF is not actually
approved by Health Canada for this use. (G-CSF is currently approved for use by Health
Canada for cancer patients receiving chemotherapy that decreases the white blood cells, and for
the mobilization of stem cells in cancer patients who will undergo autologous transplant following
chemotherapy.)
In this study, the investigators are studying a new way to collect stem cells. The new way to
collect stem cells is called a “G-CSF stimulated bone marrow transplant”. In this type of
transplant, you are given the medication called G-CSF for 4 days then stem cells are collected
directly from your bone marrow in a procedure called a bone marrow harvest. The cells collected
from your bone marrow are given to your brother or sister after they have received very high
doses of chemotherapy.
The purpose of this study is to compare the effects G-CSF mobilized peripheral blood transplant
and the G-CSF stimulated bone marrow transplant on you and your brother or sister to whom
you are donating these stem cells. The G-CSF stimulated bone marrow transplant contains a
smaller number of special immune cells called “T-lymphocytes” compared to the G-CSF
mobilized peripheral blood transplant. T-lymphocytes cause a condition called “graft versus host
disease”. The purpose of this study is to see if using G-CSF stimulated bone marrow instead of
G-CSF mobilized peripheral blood will cause the person receiving the bone marrow transplant to
experience less graft versus host disease.
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY
About 230 patients and their donors from Canada will take part in this study. It will take about 3.5
years to enroll all the patients/donors for this study. Donors will be followed for up to one year.
WHAT IS INVOLVED IN THE STUDY?
Randomization (assignment to a group):
If you decide to participate, you will be “randomized” into one of the study groups described
below. Randomization means that you are put into a group by chance. It is like flipping a coin.
A central statistical office will be called which will assign one of the treatments to you. Neither
you nor your doctor can choose what group you will be in. You will have an equal chance of
being placed in either group.
Randomization will happen once at the beginning of the study.
You will be told which treatment you are to get in each case.
If you agree to take part in this study, you will be assigned to one of the following groups:
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Group 1: G-CSF mobilized peripheral blood transplant (Standard Treatment)
You will receive G-CSF for 4 or 5 days. Stem cells will then be collected from your
bloodstream using a machine called an apheresis machine. Most donors need to undergo
one or two apheresis procedures. Each process usually takes 4 to 6 hours. A needle is
inserted into each of your arms and blood is removed from your body, processed through the
apheresis machine and returned to your body.
Most donors tolerate the G-CSF and apheresis very well. While receiving the G-CSF, you
may experience bone and joint aches and pains. During the apheresis, you may experience
numbness or tingling. Your blood pressure may fall but this will be monitored.
Once collected, these cells will be infused into your brother or sister.
Group 2: G-CSF stimulated bone marrow transplant (Experimental Treatment)
You will receive G-CSF for 4 days. Stem cells will then be collected from your bone marrow
directly using a procedure called a bone marrow harvest. For the bone marrow harvest, you
will usually be put to sleep using a general anaesthetic. You will then be laid on your
stomach. Small incisions will be made over your pelvic bones and approximately 1L of bone
marrow will be removed multiple needle punctures.
Most donors tolerate the G-CSF and bone marrow harvest very well. While receiving the GCSF, you may experience bone and joint aches and pains. After the bone marrow harvest,
you will experience pain and discomfort in the pelvic bones and lower back. There is a small
risk (<5%) that you may develop infection or bleeding at the harvest site. There is a very
small risk (<1%) that you may require a transfusion of blood.
Once collected, these cells will be infused into your brother or sister.
WHO CAN PARTICIPATE IN THIS STUDY?
You may take part in the study if you:





Are either brother or sister to the patient identified as the recipient
Are 18 years of age or older
Are a full match for your brother or sister (6/6 HLA match)
Are able to receive a general anaesthetic and undergo a bone marrow harvest or peripheral
blood collection
Are not pregnant or breastfeeding
You may not take part in the study if you:
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




Have had cancer in the last 5 years (except for certain types of skin cancer and cervical
cancer). Please discuss any history of cancer with the study doctor prior to signing this
consent form.
Are an identical twin of your brother or sister who has been identified as the recipient.
Are HIV-positive
Known sensitivity to E. coli-derived products
Have active infectious hepatitis
These will be discussed in detail with you.
Contraception:
The study doctor has explained that the effects of G-CSF and bone marrow harvest or peripheral
blood collection on the unborn child are unknown. Therefore women who are pregnant, nursing
or planning to become pregnant cannot be in the study, and men should not father children while
participating in the study.
Abstinence will be considered an acceptable method of birth control for this study. However, if
you are female and of child bearing potential who chooses to be sexually active, or a male who
chooses to be sexually active during the course of this study, you must agree to use a proven
method of birth control throughout the study, (for example: previous tubal ligation, vasectomy, or
current oral, injectable or implantable contraceptives, condoms, foam, or IUD).
If you become pregnant while taking part in this study, you should not take the study drug and
should contact your doctor immediately. You will be immediately withdrawn from the study and
referred to your family physician for obstetric care. You will be asked for permission to access
your health records relating to your pregnancy, as well as the health records of your infant at the
time your pregnancy is confirmed.
Screening For Your Participation:
The hematologist for your brother or sister who is the recipient will notify the study coordinator
that you may be eligible to participate in this study. Both the hematologist and the study
coordinator will review your case. If you are eligible to take part, the hematologist will mention
the study to you and if you are interested, the study coordinator will discuss the study with you in
more detail.
Procedures of the Study:
Collection of stem cells for transplantation is a major medical procedure. As part of the normal
standard of care, you will need to undergo the following tests and procedures. These will be
done to see if it possible to proceed with your donation of stem cells.


Physical exam
Blood tests
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

Pregnancy test
Visual inspection of your veins prior to apheresis
As well as the tests and procedure described above, the following tests are being doing only for
the purposes of this study:

Sample of Bone Marrow Harvest or Peripheral Blood Collection.
A small sample of the bone marrow or peripheral blood collected from you will be tested as a
result of your participation in this study. In the bone marrow group, the sample (10mL, 2
teaspoons) represents approximately 1% of the total volume of the harvest. In the peripheral
blood group, the sample (10mL, 2 teaspoons) represents approximately 2.5% of the harvest.
If you are randomized to the bone marrow group you will also be asked to donate a sample of
blood as well as bone marrow for research purposes (50 mL, 4 tablespoons). This will be
collected on the day that the bone marrow is collected. The sample will be collected at the
same time you have blood drawn for standard clinical assessments.

Quality of Life and Economic Analysis Questionnaires
You will be asked to fill out some questionnaires related to quality of life and pain at the
following time points: before starting the G-CSF; following stem cell collection; at 1 month
after stem cell collection; and 1 year after stem cell collection. The questionnaires take
approximately 20-30 minutes to complete at each time point. The forms can be mailed to
you if you live out-of-town, and then once completed you will be asked to mail them back to
the study coordinator.
Some of the questions are personal; You can refuse to answer these if you wish. The
information you provide is for research purposes only and will remain strictly confidential. The
individuals (e.g. doctors, nurses, etc) directly involved in your care will not usually see your
responses to these questions. If you wish them to know this information, please bring it to
their attention.
Your name will not be put on these questionnaires. Instead you will be identified by a code
number and code initials. Once questionnaires are completed they will be faxed to the
Project Management Office (in Vancouver, BC).
HOW LONG WILL I BE IN THE STUDY?
You will be followed for at least 1 year after your donation as part of this study. You can refuse
to participate in this study or stop participating at any time and your doctor will continue to treat
you with the best means available. If you decide to stop participating in the study, we encourage
you to talk to your doctor first.
Even if you stop participating early, we would like to keep track of your medical condition for the
rest of your life to look at the long-term effects of the study treatments.
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Possible Harms and Discomforts:
 The G-CSF stimulated bone marrow harvest may cause you to experience more pain and
discomfort than the G-CSF mobilized peripheral blood collection.
 The G-CSF stimulated bone marrow harvest may cause your brother or sister to experience
more graft versus host disease.
 The G-CSF stimulated bone marrow harvest may cause your brother or sister’s blood counts
to recover more slowly.
 You may find the interviews and questionnaires you receive during the course of the study
upsetting or distressing. You may not like all the questions that you will be asked. You do
not have to answer those questions you find too distressing.
 There is a small (about 1 in 10,000) risk of pain and bleeding from the spleen. Normal
healthy individuals receiving G-CSF (filgrastim) may experience transient swelling of the
spleen. This swelling appears to resolve 3-4 days after G-CSF injections have finished. In
rare cases internal bleeding from rupture of the spleen has been described. Symptoms of
this serious side effect include pain in the upper left side of the abdomen just below the rib
cage, fatigue and weakness or loss of consciousness from low blood pressure. Rupture of
the spleen is a medical emergency and may require blood transfusions or surgery to control
bleeding. In some instances splenic rupture will require surgical removal of the spleen
(splenectomy). It is suggested that subjects abstain from rigorous activities and contact
sports for at least two weeks after treatment is completed.
Possible Benefits:
There is no guarantee you will benefit personally by taking part in this study; your physical
condition and/or that of your brother or sister who is the recipient may even worsen. However,
information may be gained that will help in the treatment of patients with similar disease in the
future.
Alternative Treatments Or What If I Don’t Enter This Study?
You do not have to participate in this study to donate cells for transplant for your brother or sister.
If you do not wish to take part, you will receive the normal standard of care. The normal standard
of care is to donate your cells in the standard way using a G-CSF mobilized peripheral blood
collection.
Compensation:
No costs will be charged to you for being in this study, nor will you be paid for participating in the
study. You will not be charged for any research procedures
Research-Related Injury:
If you become ill or injured as a direct result of participating in this study, necessary medical
treatment will be available at no additional cost to you.
Your signature on this form only indicates that you have understood to your satisfaction the
information regarding your participation in the study and agree to participate as a subject. In no
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way does this waive your legal rights nor release the investigator, the research doctor, the study
sponsor or involved institutions from their legal and professional responsibilities.
Confidentiality:
You will not be identified as a study participant in any reports or publications of this research.
Your records will be kept in a secure area such as a locked file cabinet. Only the staff involved in
the research study or the regulatory agencies (such as Health Canada) will see them.
Data (information about you) collected throughout the study will be entered into a study database
using a web based data capture system. Data will not be identified by your name or any
personal numbers (such as your Social Insurance Number or Hospital Number). A study number
and coded initials only will be used to identify the data. Security measures are in place that
comply with current Canadian Privacy Laws.
With your permission, your family doctor will also be informed of your participation in this
research study. This consent form will be placed in your Health Chart.
Declaration of Financial Interest:
Neither the Investigator nor the institution has a financial interest or a proprietary interest in the
drug, procedure or device under study.
Withdrawal from the Study:
If you choose to participate and later decide to change your mind, you can say no and stop the
research at any time. A decision to stop being in the study will not affect your health care. Your
physician or the study sponsor may stop your participation at any time, without your consent, if
they feel it is in your best interest. You may be taken out of the study, if you do not follow your
doctor’s instructions, if you experience a side effect that needs medical treatment, or if the
sponsor stops the study for any reason.
Other Pertinent Information:
Throughout the research study, you will be told about any new information that might affect your
decision about being in this research study. In particular, you will be told of any unforeseen risks
that may be identified.
You will be provided with a signed copy of this consent form for your own records.
Questions or Problems:
If you have any questions about the study, you should contact: {Insert Name and Contact
Information for Principal Investigator}. The 24-hour contact number is {Insert Number for on call
physician}. If you have any questions about your rights as a research participant, you may
contact the principal investigator, {insert name of Principal Investigator} or the Patient
Representative at {Insert name of appropriate person and their contact number}.
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Signatures:
I have read the explanation about this study “A Randomized Multicentre Study Comparing
G-CSF Mobilized Peripheral Blood and G-CSF Stimulated Bone Marrow in Patients
Undergoing Matched Sibling Transplantation for Hematologic Malignancies”. I have been
given the opportunity to discuss it and my questions have been answered to my
satisfaction. I hereby consent to take part in this study.
________________________________
________________________________
Signature of Participant
Printed Name
Date Signed
________________________________
________________________
_____
Signature of Person Conducting
Printed Name
Date Signed
Consent Discussion
_______________________________
________________________
_____
Signature of Witness
Printed Name
Date Signed
________________________________
________________________
_____
Signature of Investigator
Printed Name
Date Signed
It is possible the researchers may be interested in following your health status after the 1
year follow-up period for this study. Do you agree to be contacted in the future regarding
extended follow-up?
If yes, please initial __________
I have been given a copy of this signed consent form to keep.
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Recipient Consent Form
{Insert Name of Institution}
{Insert Address of Institution}
STUDY TITLE: A Randomized Multicentre Study Comparing G-CSF Mobilized
Peripheral Blood and G-CSF Stimulated Bone Marrow in Patients
Undergoing Matched Sibling Transplantation for Hematologic
Malignancies
Principal Investigator:
{Insert Name and Address of Principal Investigator}
Associate Investigators:
{Insert Names of Associate Investigators}
Study Sponsor:
Canadian Blood and Marrow Transplant Group
Introduction:
You are invited to take part in a research study at the {insert name of institution}. Taking
part in this study is voluntary. The quality of your health care will not be affected by
whether you participate or not. Participating in the study might not benefit you, but
information might be gained that will benefit others. You may withdraw from the study at
any time without affecting your care. The study is described below. This description tells
you about the risks, inconvenience, or discomfort that you might experience. You should
discuss any questions you have about this study with the people who explain it to you.
Purpose of the Study:
WHY IS THIS STUDY BEING DONE?
Your doctors have explained that you have cancer of the blood and they have
recommended that you receive a bone marrow transplant from your brother or sister.
Usually, cells for this type of transplant are collected in the following way. Your donor is
given a medication called G-CSF for 4 or 5 days and then special cells called stem cells
are collected from his or her bloodstream, using a machine called an apheresis machine.
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These cells are then given to you after you have received very high doses of
chemotherapy. This type of transplant is called a “G-CSF mobilized peripheral blood
transplant”.
Please note that although the use of G-CSF for mobilization of stem cells in healthy donors
(for the purpose of allogeneic stem cell transplant) is considered standard care, G-CSF is
not actually approved by Health Canada for this use. (G-CSF is currently approved for use
by Health Canada for use in situations where an individual has an infection and a low white
blood cell count.)
In this study, the investigators are studying a new way to collect stem cells. The new way
to collect stem cells is called a “G-CSF stimulated bone marrow transplant”. In this type of
transplant, your donor is given the medication called G-CSF for 4 days then stem cells are
collected directly from the bone marrow in a procedure called a bone marrow harvest. The
cells collected from the bone marrow are given to you after you have received very high
doses of chemotherapy.
The purpose of this study is to compare the effects G-CSF mobilized peripheral blood
transplant and the G-CSF stimulated bone marrow transplant on you and your donor. The
G-CSF stimulated bone marrow transplant contains a smaller number of special immune
cells called “T-lymphocytes” compared to the G-CSF mobilized peripheral blood transplant.
T-lymphocytes cause a condition called “graft versus host disease”. The purpose of this
study is to see if using G-CSF stimulated bone marrow instead of G-CSF mobilized
peripheral blood will cause you to experience less graft versus host disease after the
transplant.
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY
About 230 patients and their donors from Canada will take part in this study. It will take
about 3.5 years to enroll and the patients and donors. If you agree to participate, you will
be followed for up to 4 years post transplant.
WHAT IS INVOLVED IN THE STUDY?
Randomization (assignment to a group):
If you decide to participate, you will be “randomized” into one of the study groups
described below. Randomization means that you are put into a group by chance. It is like
flipping a coin. A central statistical office will be called which will assign one of the
treatments to you. Neither you nor your doctor can choose what group you will be in. You
will have an equal chance of being placed in either group.
Randomization will happen once at the beginning of the study.
You will be told which treatment you are to get in each case.
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If you agree to take part in this study, you will be assigned to one of the following groups:
Group 1: G-CSF mobilized peripheral blood transplant (Standard Treatment)
Your donor will receive G-CSF for 4 or 5 days. Stem cells will then be collected
from his or her bloodstream using a machine called an apheresis machine. Once
collected, these cells will be infused into your body.
Group 2: G-CSF stimulated bone marrow transplant (Experimental Treatment)
Your donor will receive G-CSF for 4 days. Stem cells will then be collected from his
or her bone marrow directly using a procedure called a bone marrow harvest. Once
collected, these cells will be infused into your body.
WHO CAN PARTICIPATE IN THIS STUDY?
You may take part in the study if you:
 Are between the ages of 16 and 65 years old
 Have a brother or sister who is a match (6/6 HLA-match)
 Have one of the following types of cancer of the blood:
-acute myeloid leukemia in first or second complete remission
-chronic myeloid leukemia in chronic or accelerated phase
-myelodysplasia
-other blood cancer
 Your doctor recommends a matched sibling allogeneic transplant for you
You may not take part in the study if you:
 Have serious problems with your heart, lungs or kidneys
 Are HIV-positive
These will be discussed in detail with you.
Contraception:
The study doctor has explained that the effect of G-CSF and bone marrow transplantation
on the unborn child is unknown. Therefore women who are pregnant, nursing or planning
to become pregnant cannot be in the study, and men should not father children while
participating in the study.
Abstinence will be considered an acceptable method of birth control for this study.
However, if you are female and of child bearing potential who chooses to be sexually
active, or a male who chooses to be sexually active during the course of this study, you
must agree to use a proven method of birth control throughout the study, (for example:
previous tubal ligation, vasectomy, or current oral, injectable or implantable contraceptives,
condoms, foam, or IUD).
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If you become pregnant while taking part in this study, you should not take the study drug
and should contact your doctor immediately. You will be immediately withdrawn from the
study and referred to your family physician for obstetric care. You will be asked for
permission to access your health records relating to your pregnancy, as well as the health
records of your infant at the time your pregnancy is confirmed.
Screening For Your Participation:
Your hematologist will notify the study coordinator that you may be eligible to participate in
this study. Both the hematologist and the study coordinator will review your case. If you
are eligible to take part, your hematologist will mention the study to you and if you are
interested, the study coordinator will discuss the study with you in more detail.
Procedures of the Study:
Bone marrow transplantation is a major medical procedure. As part of the normal standard
of care, you will need to undergo the following tests and procedures. These will be done to
see if it possible to proceed with your bone marrow transplantation. Many of these tests
will also be repeated after the bone marrow transplant.






Physical exams
Blood tests
Bone marrow aspiration and biopsy
Tissue biopsy (if needed, to confirm graft versus host disease)
Pregnancy test
Quality of Life and Economic Analysis Questionnaires
More Information about the Study Questionnaires
The questionnaires will involve questions about your quality of life, pain experience and
costs related to the transplant process. You will be asked to complete the questionnaires
when you are at the transplant centre for clinic visits that are part of standard transplant
care. Your name will not be put on these questionnaires. Instead you will be identified by
a code number and code initials. Once the questionnaires are completed, they will be
faxed to the Project Management Office (located in Vancouver, BC).
If you do not need to visit the transplant centre at a time when questionnaires are
scheduled as part of the study, then these questionnaires will be mailed or faxed to you.
You can complete them at home and mail or fax them back to the transplant centre.
You will be asked to complete 8 different questionnaires prior to starting conditioning
therapy for your transplant and then again at 1 and 3 years after your transplant. It will
take you approximately 35 minutes to complete the 8 questionnaires (which equals a total
of approximately 2 hours for the 3 different times that you will be asked to complete them).
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In addition to the questionnaires described above, you will also be asked to complete a
questionnaire to determine the number of visits you have to medical clinics or hospitals
and which medications you are taking. This questionnaire will be given to you at the
following time points: One, two and three months after your transplant, and then every 3
months up until 2 years after your transplant. This questionnaire takes approximately 5
minutes to complete.
There will also be a questionnaire that involves a list of known symptoms of graft versus
host disease. You will be asked to complete this questionnaire every 3 months starting 3
months after your transplant until one year after your transplant, and then every 6 months
until 4 years after your transplant. This questionnaire takes approximately 5 minutes to
complete. (In total you will spend about 1.5 hours completing this questionnaire.)
Some of the questions are personal. You can refuse to answer any questions that may
make you feel uncomfortable. The information you provide is for research purposes only
and will remain strictly confidential. The individuals (e.g. doctors, nurses, etc) directly
involved in your care will not usually see your responses to these questions – if you wish
them to know this information, please bring it to their attention.
The total amount of time that you could potentially spend with respect to questionnaires
related to this study is approximately 5 hours (over the course of 4 years).
Please ask your study doctor or study nurse if you would like to have more information
about the questionnaires.
HOW LONG WILL I BE IN THE STUDY?
You will be followed for 4 years after your transplant as part of this study.
The researchers may take you off the study for reasons such as:

The treatment does not work for you and your cancer gets worse.

You are unable to tolerate the treatment

New information becomes available that indicates the study treatment is no
longer in your best interest.

Your doctor no longer feels the treatment you are receiving is the best for you.
You can refuse to participate in this study or stop participating at any time and your doctor
will continue to treat you with the best means available. If you decide to stop participating
in the study, we encourage you to talk to your doctor first.
Even if you stop participating early, we would like to keep track of your medical condition
for the rest of your life to look at the long-term effects of the study treatments.
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Possible Harms and Discomforts:
 It is possible that the G-CSF stimulated bone marrow transplant may cause you
to have more graft versus host disease.
 It is possible that the G-CSF stimulated bone marrow transplant may cause your
blood counts to recover more slowly.
 You may experience some temporary discomfort when the additional blood
samples are taken. There is a small risk of bruising, infection or swelling at the
site where the needle is inserted; and some people may feel faint and dizzy.
 You may experience some temporary discomfort when the additional bone
marrow samples are taken.
 You may find the interviews and questionnaires you receive during the course of
the study upsetting or distressing. You may not like all the questions that you
will be asked. You do not have to answer those questions you find too
distressing.
Possible Benefits:
There is no guarantee you will benefit personally by taking part in this study; your condition
may even worsen. However, information may be gained that will help in the treatment of
patients with similar disease in the future.
Alternative Treatments Or What If I Don’t Enter This Study?:
You do not have to participate in this study to receive treatment for your disease. If you do
not wish to take part, you would receive the normal standard of care. Your options would
include:



Standard bone marrow transplant using G-CSF mobilized peripheral blood
Various non-transplant treatments which your physician can discuss with you
further
No further treatment
Compensation:
No costs will be charged to you for being in this study, nor will you be paid for participating
in the study. You will not be charged for the research drugs or any research procedures
Research-Related Injury:
If you become ill or injured as a direct result of participating in this study, necessary
medical treatment will be available at no additional cost to you.
Your signature on this form only indicates that you have understood to your satisfaction the
information regarding your participation in the study and agree to participate as a subject.
In no way does this waive your legal rights nor release the investigator, the research
doctor, the study sponsor or involved institutions from their legal and professional
responsibilities.
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Confidentiality:
You will not be identified as a study participant in any reports or publications of this
research. Your records will be kept in a secure area such as a locked file cabinet. Only
the staff involved in the research study will see them.
Data (information about you) collected throughout the study will be entered into a study
database using a web based data capture system. Data will not be identified by your
name or any personal numbers (such as your Social Insurance Number or Hospital
Number). A study number and coded initials only will be used to identify the data.
Security measures are in place that comply with current Canadian Privacy Laws.
With your permission, your family doctor will also be informed of your participation in this
research study. This consent form will be placed in your Health Chart.
Declaration of Financial Interest:
Neither the Investigator nor the institution has a financial interest or a proprietary interest in
the drug, procedure or device under study.
Withdrawal From The Study:
If you choose to participate and later decide to change your mind, you can say no and stop
the research at any time. A decision to stop being in the study will not affect your health
care. Your physician or the study sponsor may stop your participation at any time, without
your consent, if they feel it is in your best interest. You may be taken out of the study, if
you do not follow your doctor’s instructions, if you experience a side effect that needs
medical treatment, or if the sponsor stops the study for any reason.
Other Pertinent Information:
Throughout the research study, you will be told about any new information that might affect
your decision about being in this research study. In particular, you will be told of any
unforeseen risks that may be identified.
You will be provided with a signed copy of this consent form for your own records.
Questions or Problems:
If you have any questions about the study, you should contact: {Insert name and contact
information for Principal Investigator}. The 24-hour contact number is {insert appropriate
contact number}. If you have any questions about your rights as a research participant,
you may contact the principal investigator, {insert name of Principal Investigator} or the
Patient Representative at {insert name of appropriate person and contact information}.
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Signatures:
I have read the explanation about this study “A Randomized Multicentre Study Comparing
G-CSF Mobilized Peripheral Blood and G-CSF Stimulated Bone Marrow in Patients
Undergoing Matched Sibling Transplantation for Hematologic Malignancies”. I have been
given the opportunity to discuss it and my questions have been answered to my
satisfaction. I hereby consent to take part in this study.
________________________________
________________________________
Signature of Participant
Printed Name
Date Signed
________________________________
________________________
_____
Signature of Person Conducting
Printed Name
Date Signed
Consent Discussion
_______________________________
________________________
_____
Signature of Witness
Printed Name
Date Signed
________________________________
________________________
_____
Signature of Investigator
Printed Name
Date Signed
It is possible the researchers may be interested in following your health status after the 4
year follow-up period for this study. Do you agree to be contacted in the future regarding
extended follow-up? If yes, please initial _________.
I have been given a copy of this signed consent form to keep.
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{Insert Name of Institution}
{Insert Address of Institution}
Consent for Optional Laboratory Research
For Donors
STUDY TITLE: A Randomized Multicentre Study Comparing G-CSF Mobilized
Peripheral Blood and G-CSF Stimulated Bone Marrow in Patients
Undergoing Matched Sibling Transplantation for Hematologic
Malignancies
Principal Investigator:
Dr. Kirk Schultz
British Columbia Children’s Hospital
UBC Department of Pediatrics
4480 Oak Street, Rm A119
Vancouver, British Columbia
Canada V6H 3V4
Associate Investigator:
Dr. Megan Levings
UBC Department of Surgery
Jack Bell Research Centre
Room 444, 2660 Oak Street
Vancouver, British Columbia
Canada V6H 3Z6
Study Sponsor:
Canadian Blood and Marrow Transplant Group
(Supported by NCI/NIH Grant – R01 CA108652-01A2)
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1. BACKGROUND
Laboratory analysis of the cells collected from donors for blood and marrow transplantation
is an important part of understanding how to improve clinical outcomes in transplantation.
For this reason, an optional laboratory component was developed as part of the clinical
trial: A Randomized Multicentre Study Comparing G-CSF Mobilized Peripheral Blood and
G-CSF Stimulated Bone Marrow in Patients Undergoing Matched Sibling Transplantation
for Hematologic Malignancies.
2. WHAT IS THE PURPOSE OF THE OPTIONAL LABORATORY STUDIES?
You have already agreed to take part in the main research study which will compare the
effects of G-CSF mobilized peripheral blood transplant versus G-CSF stimulated bone
marrow on both the donor and recipient.
With this form, you are being invited to take part in an extra part of the study. The extra
part of the study involves the analysis of the donor product (either peripheral blood stem
cells collected through apheresis or bone marrow) to learn more about the effect of G-CSF
on the cells you donate and also more about all the cells that you donate.
Because research continues to improve and new research questions become important,
the researchers are also seeking your permission to keep the samples collected from you
for up to 10 years or until they are used up. The samples will be used for research
purposes only and will not be sold.
Please take time to read the following information carefully and to discuss it with your
family, friends and doctor before you decide whether or not to participate.
3. YOUR PARTICIPATION IS VOLUNTARY
You are free to not take part in the optional laboratory sample research and still participate
in the main study that you have already agreed to participate in. There will be no change
in your care (or the care of the recipient) if you choose not to give samples for research
purposes.
You can also take part in all or some of the options that will be described to you in this
consent form. At the end of this consent form (Section 16) you will be asked to
indicate which options you agree to participate in.
4. WHAT ARE THE ALTERNATIVES TO PARTICIPATING?
If you choose not to participate in this study, the only alternative is not to participate. It is
important to discuss all the options with your study doctor prior to making your decision. (If
you do not wish to participate in any of the optional research studies then you should not
sign this consent form.)
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5. WHO IS CONDUCTING THE STUDY?
The main research study was developed by Blood and Marrow Transplantation doctors in
Canada as part of a Canadian Blood and Marrow Transplant Group (CBMTG) study. The
CBMTG includes all BMT centres in Canada.
The optional laboratory studies described in this consent were also developed by
transplant doctors who are part of the CBMTG. Any future research involving the samples
collected will have to be approved by an Ethics Review Board.
6. WHO CAN PARTICIPATE IN THESE OPTIONAL LABORATORY STUDIES?
Any donor who is eligible for the main study can participate in the optional laboratory
component described in this consent form.
7. WHAT TYPE OF SAMPLES DO THE RESEARCHERS WANT TO COLLECT?
If you are a donor that has been randomized to donate blood stem cells using
apheresis:
We are inviting you to donate a teaspoon (5 mL) of the graft product that is collected. .
Donating these cells will not involve any additional needle pokes. The research sample
will be taken from the bag that the cells are collected into. Taking this small sample will
not affect how the cells grow (engraft) in the recipient.
If you are a donor that has been randomized to donate bone marrow:
We are inviting you to donate 2 teaspoons (10 mL) of the bone marrow that is collected.
Donating this bone marrow will not involve any additional needle pokes. Taking this small
sample will not affect how the cells grow (engraft) in the recipient.
You are also being asked to donate 4 teaspoons (20 mL) of blood on the day of your bone
marrow harvest (prior to the harvest). Donating this blood will not involve any additional
needle pokes as it will be drawn at the same time clinical blood samples are being
collected. (“Clinical samples” are samples that are collected as part of your routine
medical care as a donor.)
8. WHAT WILL HAPPEN WITH MY SAMPLES?
Once your samples are collected all identifying information about you will be removed and
this will be replaced with a code number. Then your sample(s) will be shipped to the
Schultz Laboratory at the Child and Family Research Institute at the BC Children’s
Hospital (in Vancouver, BC). Once your samples arrive at the Laboratory they will be
processed and frozen (until the research studies are conducted).
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It is important that you understand that in this consent form, you are being asked for
permission for two separate uses of your cells. These two different options are identified
as “Option A” and “Option B”. At the end of this consent form (on the Signature Page –
Section 16) you will be asked to indicate which option(s) you agree to participate in. You
may decide not to participate at all. In this case you should not sign the consent form.
OPTION (A): You are being asked to give your permission for the researchers to use your
cells in association with the main study to gain a greater understanding of G-CSF and its
effect on the donor cells and more about the immune function of the cells in general.
OPTION (B): You are being asked to give your permission so that any leftover cells can
be stored for future research related to stem cell transplant and the function of immune
cells (with the exception of genetic testing). Your cells will be identified by a code number
only. Future researchers will not have access to any identifying information about you.
With this option, you are also giving your permission for future researchers to access
information about you in the study bank. This information will be identified by a code
number only. You will not be contacted about this future research.
All future researchers who wish to use your leftover cells will have to submit their research
proposal to an Ethics Review Board and receive approval for their project before they can
obtain your cells for research.
9. WHAT ARE THE POSSIBLE RISKS OF HARM AND SIDE EFFECTS OF
PARTICIPATING?
There are no additional risks specifically associated with obtaining this specimen as no
additional procedures are necessary to obtain the samples.
Experts in the field do not feel that the volume of peripheral blood stem cells or bone
marrow that will be collected will in any way effect the ability of your cells to engraft (grow)
successfully in the recipient.
10. WHAT ARE THE BENEFITS OF PARTICIPATING?
Although there will be no direct benefit to you by participating in this part of the study,
society may benefit from increased knowledge about how G-CSF affects blood cells.
Acceptance or rejection of your participation in this study will in no way affect any aspect of
your treatment or the recipient’s treatment.
11. AFTER THE STUDY IS FINISHED
You (and your study doctor) will not be notified of any results related to your samples.
At the end of 10 years, any remaining cells in storage will be discarded.
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12. WHAT WILL THE STUDY COST ME?
It will not cost you any money to participate in this research.
13. CONFIDENTIALITY
Your confidentiality will be respected. No information that discloses your identity will be
released or published without your specific consent. Your identity will not be used in any
reports about the study. All information associated with this study will be kept behind
locked doors or in a database. Security measures are in place that comply with current
Canadian Privacy Laws.
Your donor cells (and blood if applicable) will be labeled with a unique code. This code
does not contain any information that could identify you. You will not be identified by your
name in any published reports involving your research samples and/or information in the
study data bank.
Reports about any research done with your samples will not be given to you or your
doctor. These reports will not be put in your medical records. The research using your
samples will not affect your care.
Your rights to privacy are legally protected and guaranteed by federal and provincial laws
that require safeguards to insure that your privacy is respected and also give you the right
of access to the information about you that has been provided to the sponsor and, if need
be, an opportunity to correct any errors in this information. Further details about these
laws are available on request to your study doctor or at the {insert name of site IRB}.
14. WHAT HAPPENS IF I DECIDE TO WITHDRAW MY CONSENT TO
PARTICIPATE?
Your participation in this research is entirely voluntary. You may withdraw from this study
at any time and request that the research samples that have been collected be destroyed
(and no further information about you will be accessed in the study data bank.)
If you decide to do this, there will be no penalty or loss of benefits to which you are
otherwise entitled, and your future medical care will not be affected.
In order to withdraw from this research you must notify your study doctor {insert name and
phone number}. Your study doctor will notify the Project Management Office (In
Vancouver, BC).
Please be aware that any information that has been gathered from your samples prior to
notification of withdrawal will not be destroyed.
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15. WHO DO I CONTACT IF I HAVE QUESTIONS ABOUT THE STUDY DURING MY
PARTICIPATION?
If you have any questions regarding:
 your rights as a research subject and/or your experiences while participating in this
study, contact the {insert appropriate independent organization/department responsible
for the protection of research subjects at your institution}.
 study-related injury, please contact your hematologist who is one of the co-investigators
of the study at {insert phone number} (Daytime) or {insert phone number} (Evenings and
Weekends).

your participation in this study, and or the collection, use and disclosure of your
personal information, please contact {Insert site PI} at {insert phone number} (Daytime)
or {insert phone number} (Evenings and Weekends).
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16. SUBJECT CONSENT TO PARTICIPATE
I understand that participation is entirely voluntary. I have read through this consent form and understand that
I am being asked to consent to various options. I understand that I may choose all or some of these options,
and that I may also choose not to participate at all. I am aware that I can withdraw my permission regarding the
options I originally consent to at any time in the future. If I withdraw permission to use my samples they will be
destroyed. Although I cannot have access to test results directly related to my tissue samples, I may ask
questions about the type of research being done. I will receive a signed copy of this consent form including all
attachments, for my own records.
Please indicate the options that you consent to (or do not consent to) by ticking the appropriate box:
OPTION (A): I agree that a sample of the stem cell product (and blood if applicable) that I donate can be
used for the laboratory research related to the main study (as described in this consent form):
□ I agree
□ I do not agree
Subject Initials _______
OPTION (B): I agree that any leftover cells can be stored for future research related to stem cell
transplant and the function of immune cells (with the exception of genetic testing.) I am aware my
cells will be identified by a code number only. With this option I also agree that future researchers
may have access to information about me in the study bank. This information will be identified by a
code number only. (I will not be contacted in the future regarding this research.)
□ I agree
□ I do not agree
Subject Initials _______
SIGNATURES (All signatories must personally date their own signature)
Printed name of subject
Signature
Date
Printed name of witness
Signature
Date
SITE
I confirm that I have explained the purpose, duration etc of this clinical study, as well as any potential risks and
benefits, to the subject.
Printed name of principal investigator/
designated representative
Study Role:
Signature
Date
__________________________
If this consent process has been done in a language other than that on this written form, with the assistance
of a translator, please indicate:
Language: _____________________________
______________________________
____________________
Name of translator
Signature
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Appendix 8: Schedule of Events
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Schedule of Events: DONORS (Screening to 1 year) (Day 0 = HSCT)
INITIAL PROCEDURES
ID prospective subject
Consent1
Randomization2
Book Marrow OR Stem Cell Collection
Day - 60 to Day - 8
X
X
X
X
STUDY PROCEDURES
Day -60 to Day -8
History
Physical Exam, Ht and Wt
CBC,diff
Chemistry3
Blood group
Antibody screen
Infectious disease b/w4
Beta-HCG in females of child bearing potential
Bradburne Scale
CES-D Scale
EQ-5D Questionnaire
Socio-demographic Questionnaire
McGill Pain Questionnaire (PB donor)
McGill Pain Questionnaire (BM donor)
G-CSF (5 mcg/kg/day)6
Assess G-CSF S&S7
Volume of blood processed per apheresis
Total volume of collection
Total nucleated cell count of collection
CD 34+ cell count of collection
10 mL BM or 5 mL apheresis prod8
20 mL peripheral blood (Lab Studies)9
AE assessment
X
X
X
X
X
X
X
X
X5
X5
X5
X5
X5
X5
1Consent
Day -4 to
Day -1/0
Day(s) of
Collection
Post last
PB Collec
Day 1
Day 1 to 30
Day 30
1 year post
transplant
X
X
X
X
X
X
X
X
X
X
X
X
X
X6
X7
X
X
X
X
X
X8
Adverse events assessed/recorded as per protocol (from consent until Day +30 and then prn)
must be signed prior to questionnaires and randomization; however, the remaining screening evaluations are standard of care: results dating prior to signing
of consent (but still within screening period) can be used for screening.
2The following conditions must be met prior to randomization: Consent must be signed (donor and recipient); All Inclusion & Exclusion criteria have been met (donor
and recipient).
3Chemistry includes: creatinine; total bilirubin; AST, ALT, ALP.
4Infectious disease panel includes: CMV antibody; Hepatitis B surface antigen; total antibody to Hep B core antigen ; Hepatitis C antibody; HIV-1 and HIV-2 antibodies;
HTLV-1 and HTLV-2; and VDRL or equivalent testing for syphilis; West Nile Virus Antibody (according to institutional practice); Testing for HSV antibody is optional.
Infectious disease markers must be done within 30 days of transplant (as per Health Canada). Repeat as necessary.
5 Questionnaires (Bradburne Scale, CES-D Scale, EQ-5D Questionnaire, Socio-demographic Questionnaire and McGill Pain Questionnaire): To be done any time
between signing of consent and prior to Day -5 (for donors). (Can be completed prior to randomization as long as consent has been signed.) (Questionnaires
should be faxed to the Data Management Office the same day they are completed.)
6A single daily SC injection for 4, or if required, 5 consecutive days.
7Daily clinical assessment for myalgias, arthralgias, bone pain and abdominal pain (study coordinator – can be done as a telephone assessment).
8PBSC donors: 5 mL of the product will be collected for research from the first collection. (Consent for the “Optional Laboratory Research” for donors must be signed).
9Bone marrow donors only: To be collected on the day of bone marrow harvest, prior to the harvest – Consent for “Optional Lab Research must be signed.
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Schedule of Events: RECIPIENTS (Screening to Day +100) (Day 0 = HSCT)
INITIAL PROCEDURES
Day -60
to Day -8
ID prospective subject
Consent1
Randomization2
Book Harvest OR Apheresis
STUDY PROCEDURES
History
Physical Exam
Ht and Wt
ECOG
X
X
X
Day -60
to Day -8
X
X
X
X
Day -7
X
X
CBC,diff
3
Chemistry
Blood Group
Antibody screen
Infectious disease b/w4
Beta-HCG in females5
MUGA/Echocardiogram
PFT's
X
X
X
X
X
X
X
24 hour urine for creat cl
X
BM Biopsy6
Bradburne Scale7
CES-D Scale7
Illness Intrusiveness Ratings Scale7
Screening FACT-BMT 7
EQ-5D Questionnaire7
Socio-demographic Questionnaire7
McGill Pain Questionnaire7
Societal Cost Questionnaire7
Health Care Questionnaire (Part A)
Example of Schedule (Bu/Cy)8
Example of Schedule (Cy/TBI)8
Creat & Direct Bilirubin
Mucositis assessment9
X
X
X
X
X
X
X
X
X
aGVHD Appendix 510
AE assessment11
See next page for referenced items.
Page 105 of 107
Day -6
Day -5
Day -4
Day -3
Day -2
Day -1
Day +1
to Day +11
Day 0
Day +30
(mo 1)
Day +60
(mo 2)
Day +100
(mo 3)
As per institutional practice
X
X
X
X
X
X
X
OD until neutrophil & platelet recovery then prn
Frequency as per standard practice at institution
X
Bu
Bu
Cy
Bu
Cy
Bu
Cy
Cy
TBI
Cy
TBI
X
X
Rest
TBI
Day +1, +3, +6, +11
Day +1, +3, +6, +11
Document highest grade of aGVHD between Day 0 & Day +30
and Day +0 & Day +100 (and post Day +100 as applicable)
Adverse events assessed/recorded as per protocol (from start of conditioning until Day +30 and then prn as per protocol)
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Schedule of Events: RECIPIENTS (Screening to Day +100) (Day 0 = HSCT) Referenced Items
1
Consent must be signed prior to questionnaires and minimization (randomization); however, the remaining screening evaluations are
standard of care: results dating prior to signing of consent can be used for screening.
2
The following conditions must be met prior to minimization (randomization):
(1) Consent must be signed (both donor and recipient); (2) All Inclusion & Exclusion criteria have been met (donor and recipient).
3
Chemistry includes: creatinine; total bilirubin; AST, ALT, ALP.
4
Infectious disease panel includes: CMV antibody; Hepatitis B surface antigen; total antibody to Hep B core antigen ; Hepatitis C
antibody; HIV-1 and HIV-2 antibodies; HTLV-1 and HTLV-2; and VDRL or equivalent testing for syphilis; West Nile Virus Antibody
(according to institutional practice);Testing for HSV antibody is optional. Infectious disease markers must be done within 30 days of
transplant (as per Health Canada). Repeat as necessary.
5
Beta-HCG in females of child bearing potential to be done within 30 days of transplant.
6
Bone marrow biopsy: Cytogenetic analysis is strongly recommended for recipients with myeloid malignancies.
7
Questionnaires (Bradburne Scale, CES-D Scale, Illness Intrusiveness Ratings Scale, Screening FACT-BMT, Socio-demographic
Questionnaire, EQ-5D Questionnaire and McGill Pain Questionnaire): To be done any time between signing of consent and prior to Day 8 (recipients). (Can be completed prior to randomization as long as consent has been signed.) (Questionnaires should be faxed to the
Data Management Office the same day they are completed.)
8
Recipients receive a myeloablative regimen of either Busulfan and Cyclophosphamide OR Cyclophosphamide and TBI OR Other
myeloablative regimen that has been approved by the Clinical Study Chair. See section 5.5 of the protocol for details. .
9
Mucositis assessment according to Bearman Toxicity scale (Appendix 4).
10
At Day +30 physician to note (in clinic or progress note) the highest grade of acute GVHD according to the Przepiorka Criteria (Appendix
5) between Day 0 and Day +30. At Day +100 physician to note (in clinic or progress note) the highest grade of acute GVHD between
Day 0 and Day +100. Highest grade of acute GVHD after Day +100 to be documented as applicable.
11
Adverse events to be collected starting from time consent signed until Day +30 as per protocol and then prn as per protocol.
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CBMTG G-PB versus G-BM Trial
CBMTG Study 0601
Protocol Version: 03-Sep-2008
Schedule of Events: RECIPIENTS (Day +100 to end of follow-up) (Day 0 = HSCT)
STUDY PROCEDURES
Month post transplant
6
9
12
15
History
Physical Exam
Ht and Wt
ECOG
CBC,diff
Chemistry
PFT's
BM Biopsy
Bradburne Scale1
CES-D Scale1
Illness Intrusiveness Ratings Scale1
FACT-BMT (Year 1 and 3)1
EQ-5D Questionnaire1
McGill Pain Questionnaire1
Societal Cost Questionnaire1
Health Care Questionnaire (Part B)
Chronic GVHD Appendix 62
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
(Limited vs Extensive, Sullivan)
Data Collection Form for NIH Consensus
(chronic GVHD) 3
Chronic GVHD Appendix 3D4
X
X
X
(Patient self assessment)
AE assessment
X
18
21
X
X
X
24
X
X
X
X
X
X
27
30
33
36
X
X
X
X
X
X
X
as per institutional practice
as per institutional practice
as per institutional practice
as per institutional practice
X
X
X
X
39
42
45
48
X
X
X
X
X
X
X
X
X
X
Relapse
Death
X
X
X
X
X
X
X
X
X
X
X
X
X
X
As necessary as per protocol
X
X
X
X
X
1Questionnaires
at 1 and 3 years post transplant (recipients): Bradburn Scale, CES-D Scale; Illness Intrusiveness Ratings Scale, FACT-BMT (Year 1 and 3), EQ-5D
Questionnaire, McGill Pain Questionnaire, Societal Cost Questionnaire. (Questionnaires should be faxed to the Data Management Office the same day they are
completed.)
2Appendix
6: Sullivan Criteria is to be used to assess and grade Chronic GVHD. Physician to note whether patient has experienced limited or extensive chronic GVHDand
which organs involved (every 3 months to year 1and then every 6 months to end of year 4 (or until withdrawal from study).
3Appendix
3D: Data Collection Form for Diagnosis and Scoring of Chronic GVHD According to the NIH Consensus Guidelines (available on project website). This form is
to be completed at 1 year and 3 years post transplant.
4Appendix
3D: Patient Chronic GVHD Severity Scoring Table (Part B) (available on the project website) can be completed over the telephone (or patient can complete at
home and mail copy to centre.) To be done every 3 months to year 1 and then every 6 months to end of year 4 (or until withdrawal from study).
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