Not for publication or presentation
AGENDA
CIBMTR WORKING COMMITTEE FOR ACUTE LEUKEMIA
San Diego, CA
Friday, February 13, 2015, 12:15 – 2:15 pm
Co-Chair:
Co-Chair:
Co-Chair:
Statisticians:
Scientific Director:
Assistant Scientific
Director:
1.
Steven Devine, MD, The Ohio State University, Columbus, OH;
Telephone: 614-293-5655; Fax: 614-293-7526; E-mail: steven.devine@osumc.edu
Marcos de Lima, MD, University Hospitals Case Medical Center, Cleveland, OH;
Telephone: 216-286-6869; Fax: 216-201-5451; E-mail: marcos.delima@uhhospitals.org
Brenda Sandmaier, MD, Fred Hutchinson Cancer Research Center, Seattle, WA;
Telephone: 206-667-4961; Fax: 206-667-6124; E-mail: bsandmai@fredhutch.org
Mei-Jie Zhang, PhD, CIBMTR Statistical Center, Milwaukee, WI;
Telephone: 414-456-8375; Fax: 414-456-6513; E-mail: meijie@mcw.edu
Hai-Lin Wang, MPH, CIBMTR Statistical Center, Milwaukee, WI;
Telephone: 414-805-0647; Fax: 414-805-0714; E-mail: hwang@mcw.edu
Daniel J. Weisdorf, MD, University of Minnesota Medical Center, Minneapolis, MN;
Telephone: 612-624-3101; Fax: 612-625-6919; E-mail: weisd001@umn.edu
Wael Saber, MD, MS, CIBMTR Statistical Center, Milwaukee, WI;
Telephone: 414-805-0700; Fax: 414-807-0714; E-mail: wsaber@mcw.edu
Introduction
a. Minutes and Overview Plan from February 2014 meeting (Attachment 1)
b. Introduction of incoming Co-Chair: Hanna Khoury, MD; Emory University Hospital; Atlanta, GA;
E-mail: hkhoury@emory.edu
2.
Accrual Summary (Attachment 2)
3.
Presentations, published or submitted papers
a.
LK04-01 Holter Chakrabarty JL, Rubinger M, Le-Rademacher J, Wang HL, Grigg A, Selby GB, Szer J, Rowe
JM, Weisdorf DJ, Tallman MS. Autologous is superior to allogeneic hematopoietic cell
transplantation for Acute Promyelocytic Leukemia in second complete remission. Biol Blood Marrow
Transplant, 2014 Jul;20(7):1021-5.
b. LK07-03c McClune BL, Ahn KW, Wang HL, Antin JH, Artz AS, Cahn JY, Deol A, Freytes CO, Hamadani
M, Holmberg LA, Jagasia MH, Jakubowski AA,Kharfan-Dabaja MA, Lazarus HM, Miller AM, Olsson
R, Pedersen TL, Pidala J, Pulsipher MA, Rowe JM, Saber W, van Besien KW, Waller EK, Aljurf MD, Akpek
G, Bacher U, Chao NJ, Chen YB, Cooper BW, Dehn J, de Lima MJ, Hsu JW, Lewis ID, Marks DI, McGuirk
J,Cairo MS, Schouten HC, Szer J, Ramanathan M, Savani BN, Seftel M, Socie G, Vij R, Warlick
ED, Weisdorf DJ. Allotransplantation for patients age ≥40 years with non-Hodgkin Lymphoma:
Encouraging progression-free survival. Biol Blood Marrow Transplant, 2014 Jul;20(7):960-8.
1
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c.
LK12-03 Bejanyan N, Weisdorf DJ, Logan BR, Wang HL, Devine SM, de Lima M, Bunjes DW, Zhang MJ.
Survival of AML patients relapsing after allogeneic hematopoietic cell transplantation: a CIBMTR study.
Biol Blood Marrow Transplant. 2014 [Epub ahead of print].
d. LK11-01 Goyal SD, Zhang MJ, Wang HL, Akpek G, Copelan EA, Freytes C, Gale RP, Hamadani M,
Inamoto Y, Kamble RT, Lazarus HM, Marks DI, Nishihori T, Olsson RF, Reshef R, Ritchie DS, Saber W,
Savani BN, Seber A, Shea TC, Tallman MS, Wirk B, Bunjes DW, Devine SM, de Lima M, Weisdorf DJ, Uy
GL. Allogeneic hematopoietic cell transplant for acute myeloid leukemia: no impact of pretransplant
extramedullary disease on outcome. Submitted.
4.
e.
LK12-01 Seftel MD, Neuberg D, Zhang MJ, Wang HL, Bergeron J, Couban S, DeAngelo DJ, de Lima M,
Devine SM, Eapen M, Horowitz M, Pasquini M, Rizzo D, Saber W, Sallan S, Sandmaier BM, Weisdorf DJ.
Superiority Of Pediatric Chemotherapy Over Allogeneic Hematopoietic Cell Transplantation for
Philadelphia Chromosome Negative Adult ALL in First Complete Remission: A Combined Analysis of
Dana-Farber ALL Consortium And CIBMTR Cohorts. Presentation at annual ASH meeting in San
Francisco, CA, December 2014. Manuscript in preparation.
f.
LK12-02 Deol A, Sengsayadeth S, Jagasia M, Ahn KW, Wang HL, Sandmaier BM, Devine SM, de Lima M,
Weisdorf DJ, Saber W. FLT3 Mutation Increases Relapse Risk After Allogeneic Hematopoietic Cell
Transplant for Acute Myeloid Leukemia in First or Second Complete Remission: A CIBMTR Analysis.
Presentation at annual ASH meeting in San Francisco, CA, December 2014. Manuscript in
preparation.
g.
LK13-03 Munker R, Wang HL, Brazauskas R, Saber W, Weisdorf DJ. Allogeneic transplant for acute
biphenotypic leukemia: characteristics and outcome in the CIBMTR database. Presentation at annual
ASBMT meeting in San Diego, CA, February 2015.
Studies in progress (Attachment 3)
a.
LK09-02 Monosomal Karyotype and chromo 7 abnormality in allo HCT for
AML/MDS (M Pasquini/ M Battiwala)
b. LK12-01 Chemo vs. AlloHCT for Ph- ALL (M Seftel/ D Neuberg)
c. LK12-02 Allotx for FLT3/ITD positive AML in CR1 (A Deol/ S Sengsayadeth/
Jagasia M)
d. LK13-01 Outcomes after RIC AlloHCT in older adult ALL (A Rosko/ M de
Lima/ M Mohty/ V Bachanova)
e. LK13-02 Impact of cytogenetic abnormalities in AlloHCT for Ph- ALL in CR1
(A Lazaryan/ V Bachanova/ D Weisdorf)
f. LK13-03 Outcomes after allogeneic transplants for ABiL (R Munker)
g. LK14-01 Effect of post-remission consolidation chemotherapy prior to
alloHCT for ALL in CR1 (N Bejanyan/ A Lazaryan/ D Weisdorf)
h. LK14-02 Prognostic factors in patients ≥60 years undergoing alloHCT for
AML in CR1/CR2 (F Michelis/ V Gupta)
i. LK14-03 Auto vs. ATO in relapsed APL (C Ganzel / M Tallman)
j
LK15-01 AlloHCT vs. other consolidation therapies per Alliance protocols in
older AML in CR1 (A Artz / C Ustun)
Manuscript Prep
Manuscript Prep
Manuscript Prep
Analysis
Protocol Development
Analysis
Protocol Development
Protocol Development
Analysis
Protocol Development
2
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5.
Future/proposed studies
a.
PROP 1410-04/1411-60 Comparison of Outcomes between Conditioning Regimens using Reduced
Intensity conditioning of Fludarabine plus Melphalan and Myeloablative Regimens Using IV Busulfan
plus Fludarabine or IV Busulfan plus Cyclophosphamide in AML and MDS. (DA Hutcherson / HT Liu/ A
Nooka / A Langston / M Bishop)(Attachment 4)
b. PROP 1411-03 Outcomes of allogeneic transplant for core binding factor leukemias in second or
subsequent complete remission. (L Costa / A Saad / S Mineishi) (Attachment 5)
c. PROP 1411-20 Effect of in vivo T cell depletion on transplant outcomes in CMV seropositive and
seronegative recipients with acute myeloid leukemia. (M Shanavas / D Kim) (Attachment 6)
d. PROP 1411-49/1311-34 Impact of GVHD on outcome after allogeneic hematopoietic cell
transplantation for acute lymphocytic leukemia: a retrospective registry study (M Yeshurun / JM Rowe
/ MS Tallman / V Bachanova) (Attachment 7)
e. PROP 1411-69 Comparison of outcomes of older adolescents and young adults with Philadelphiachromosome/BCR-ABL1-negative acute lymphoblastic leukemia receiving post-remission consolidation
chemotherapy with pediatric-inspired chemotherapy on CALGB 10403 or myeloablative allogeneic
hematopoietic cell transplantation. (M Wieduwilt / W Stock) (Attachment 8)
f. PROP 1411-71 Prognostic risk factors of patients undergoing allogeneic stem cell transplantation for
acute erythroleukemia. (J Cerny / R Nath / Z Zhou) (Attachment 9)
g. PROP 1411-74 Comparison of outcomes post allogeneic hematopoietic cell transplant between
patients with de novo and secondary acute myeloid leukemia in first complete remission. (F Michelis /
H Messner) (Attachment 10)
h. PROP 1411-77/1312-09 Comparison of total body irradiation (TBI)-based with intravenous (i.v.)
busulfan (Bu) containing chemotherapy-only myeloablative transplant conditioning regimens in adult
patients with acute lymphoblastic leukemia (ALL) (P Kebriaei / I Aldoss / V Pullarkat / C Anasetti / D
Marks) (Attachment 11)
i. PROP 1411-85 Allogeneic (allo) stem cell transplant (SCT) for AML: A comparison of three different
reduced intensity conditioning (RIC) regimens in the CIBMTR data base. (R Nath / Z Zhou / J Cerny)
(Attachment 12)
6.
Other Business
3
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Attachment 1
MINUTES AND OVERVIEW PLAN
CIBMTR WORKING COMMITTEE FOR ACUTE LEUKEMIA
Grapevine, TX
Saturday, March 1, 2014, 2:45 pm - 4:45 pm
Co-Chair:
Co-Chair:
Co-Chair:
Statisticians:
Scientific Director:
Donald Bunjes, MD, University Hospital Ulm, Ulm, Germany
Telephone: +49-731-500-45532; Fax: +49-731-500-45655;
E-mail: donald.bunjes@uniklinik.ulm.de
Steven Devine, MD, Ohio State Medical Center - James Cancer Center, Columbus,
OH; Telephone: 614-293-9868; Fax: 614-293-6690;
E-mail: steven.devine@osumc.edu
John F. DiPersio, MD, PhD, Washington University School of Medicine,
St. Louis, MO
Telephone: 314-454-8491; Fax: 314-454-8315; E-mail: dipersi@im.wustl.edu
Hailin Wang, MPH, CIBMTR Statistical Center, Milwaukee, WI
Telephone: 414-805-0647; Fax: 414-805-0714; E-mail: hwang@mcw.edu
Mei-Jie Zhang, PhD, CIBMTR Statistical Center, Milwaukee, WI
Telephone: 414-456-8375; Fax: 414-456-6530; E-mail: meijie@mcw.edu
Daniel Weisdorf, MD, University of Minnesota, Minneapolis, MN
Telephone: 612-624-3101; Fax: 612-625-6919; E-mail: weisd001@umn.edu
1. Introduction
The CIBMTR Acute Leukemia Working Committee was called to order at 2:45 pm on Saturday,
March 1st, 2014, by Dr. Daniel Weisdorf. The chairs, scientific director and statisticians were
presented. Attendees were asked to have their name badges scanned for attendance purposes and
to maintain committee membership, and to fill out the Working Committee evaluations and voting
sheets for proposals. The CIBMTR guidelines for voting on proposals were discussed. The guidelines
are based on a scale from 1 to 9; 1= high scientific impact, 9= low scientific impact. The meeting was
limited to presentation and discussion of proposals. Dr. Donald Bunjes briefly introduced
committee’s accomplishments for the past year and progress of ongoing studies. Each proposal
presentation was limited to 4 minutes (maximum 4 slides) to allow for adequate time for discussion
(5-7 minutes). The minutes of the February 2013 meeting were approved without modifications.
Dr. Daniel Weisdorf welcomed Dr. Brenda Sandmaier as newly appointed ALWC chair starting from
March 2014 and presented a souvenir to departing chair Dr. Donald Bunjes.
2. Accrual summary
Due to the full agenda, the accrual summary of registration and research cases between 1995 and
2013 were not presented to the committee but were available as part of the Working Committee
attachments:
4
Not for publication or presentation
Attachment 1
AML allogeneic
ALL allogeneic
AML autologous
ALL autologous
Research level
16733
9544
1402
222
3. Published/submitted papers and presentations
Due to the full agenda, the 2013 presentations and published papers were mentioned, but not
presented. Five papers were published, two submitted, one ASH presentation and one ASBMT
tandem presentations were given during the past year. These include:
a.
LK08-02 Koreth J, Pidala J, Perez WS, Deeg HJ, Garcia-Manero G, Malcovati L, Cazzola M, Park S,
Itzykson R, Ades L, Fenaux P, Jadersten M, Hellstrom-Lindberg E, Gale RP, Beach CL, Lee SJ,
Horowitz MM, Greenberg PL, Tallman MS, DiPersio JF, Bunjes D, Weisdorf DJ, Cutler C. Role of
reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation in older
patients with de novo myelodysplastic syndromes: an international collaborative decision
analysis. J Clin Oncol. 2013; 31(21):2662-70.
b. LK02-05 Foran JM, Pavletic SZ, Logan BR, Agovi-Johnson MA, Perez WS, Bolwell BJ, Bornhauser
M, Bredeson CN, Cairo MS, Camitta BM, Copelan EA, Dehn J, Gale RP, George B, Gupta V, Hale
GA, Lazarus HM, Litzow MR, Maharaj D, Marks DI, Martino R, Maziarz RT, Rowe JM, Rowlings
PA, Savani BN, Savoie ML, Szer J, Waller EK, Wiernik PH, Weisdorf DJ. Unrelated Donor
Allogeneic Transplantation After Failure of Autologous Transplantation for Acute Myeloid
Leukemia: A Study from the CIBMTR. Biol Blood Marrow Transplant. 2013; 19(7):1102-8.
c.
LK08-01 Lee SJ, Storer B, Wang H, Lazarus HM, Waller EK, Isola LM, Klumpp TR, Umejiego JB,
Savani BN, Loren AW, Cairo MS, Camitta BM, Cutler CS, George B, Khoury HJ, Marks DI, Rizzieri
DA, Copelan EA, Gupta V, Liesveld JL, Litzow MR, Miller AM, Schouten HC, Gale RP, Cahn JY,
Weisdorf DJ. Providing Personalized Prognostic Information For Adult Leukemia Survivors.
Biol Blood Marrow Transplant. 2013; 19(11):1600-7.
d. LK10-03 Bachanova V, Marks DI, Zhang MJ, Wang H, de Lima M, Aljurf MD, Arellano M, Artz AS,
Bacher U, Cahn JY, Chen YB, Copelan EA, Drobyski WR, Gale RP, Greer JP, Gupta V, Hale GA,
Kebriaei P, Lazarus HM, Lewis ID, Lewis VA, Liesveld JL, Litzow MR, Loren AW, Miller AM, Norkin
M, Oran B, Pidala J, Rowe JM, Savani BN, Saber W, Vij R, Waller EK, Wiernik PH, Weisdorf DJ.
Ph+ ALL patients in first complete remission have similar survival after reduced intensity and
myeloablative allogeneic transplantation: Impact of tyrosine kinase inhibitor and minimal
residual disease. Leukemia 2013, Epub ahead of print.
e.
LK10-02 Warlick ED, Paulson K, Brazauskas R, Zhong X, Miller AM, Camitta BM, George B, Savani
BN, Ustun C, Marks DI, Waller EK, Baron F, Freytes CO, Socie G, Akpek G, Schouten HC, Lazarus
HM, Horwitz EM, Koreth J, Cahn JY, Bornhauser M, Seftel M, Cairo MS, Laughlin MJ, Sabloff M,
Ringdén O, Gale RP, Kamble RT, Vij R, Gergis U, Mathews V, Saber W, Chen YB, Liesveld JL,
Cutler CS, Ghobadi A, Uy GL, Eapen M, Weisdorf DJ, Litzow MR. Effect of Postremission Therapy
before Reduced-Intensity Conditioning Allogeneic Transplantation for Acute Myeloid Leukemia
in First Complete Remission. Biol Blood Marrow Transplant 2013, Epub ahead of print.
5
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Attachment 1
f.
LK04-01 Holter-Chakrabarty JL, Rubinger M, Le-Rademacher J, Wang HL, Grigg A, Selby GB, Szer
J, Rowe JM, Weisdorf DJ, Tallman MS. Autologous is Superior to Allogeneic Hematopoietic Cell
Transplantation for Acute Promyelocytic Leukemia in Second Complete Remission. Submitted.
g.
LK07-03c McClune BL, Ahn KW, Wang HL, Antin JH, Artz AS, Cahn JY, Deol A, Freytes CO,
Hamadani M, Holmberg LA, Jagasia MH, Jakubowski AA, Kharfan-Dabaja MA, Lazarus HM, Miller
AM, Olsson R, Pedersen TL, Pidala J, Pulsipher MA, Rowe JM, Saber W, van Besien KW, Waller
EK, Weisdorf DJ. Reduced-Intensity and Non-Myeloablative Hematopoietic Cell Transplantation
in Older Patients with Non-Hodgkin Lymphoma (NHL): Encouraging Survival even in Advanced
Age. Biol Blood Marrow Transplant 2014, Epub ahead of print.
h. LK12-03 Bejanyan N, Weisdorf DJ, Logan B, Wang HL, Devine S, de Lima M, Bunjes D, Zhang MJ.
Survival of AML patients Relapsing after Allogeneic Stem Cell Transplantation. Presentation at
ASH meeting in New Orleans, LA, December 2013. Manuscript in preparation.
i.
LK11-01 Goyal S, Zhang MJ, Wang HL, Weisdorf DJ, Uy G. Extramedullary Involvement does not
Affect the Outcome of Allogeneic Transplantation for Acute Myeloid Leukemia: a CIBMTR
Analysis. Presentation at BMT Tandem meeting in Grapevine, Tx, February 2014. Manuscript
in preparation.
4. Studies in progress
The studies which made progress during the past year were not presented in order to provide
reasonable time to the new proposals for presentation and discussion. A summary of the progress
was provided as an attachment to the committee members. These were:
LK09-02: Impact of monosomal karyotype in the outcome of hematopoietic cell transplantation for
Acute Myeloid Leukemia and Myelodysplasia (M Pasquini/ M Battiwala): The purpose of this study
is to identify the impact of high risk cytogenetic subsets: specifically chromosome 7 abnormalities
(either monosomy7 or del(7q)) and monosomal karyotype in outcomes for AML and MDS after
allogeneic HCT and to evaluate the impact of conditioning intensity in the outcome of patients with
AML and monosomal karyotype. Analysis is completed and draft manuscript is being prepared by
PI.
LK11-01: Impact of extramedullary disease on the outcome of allogeneic HCT in AML (S Goyal/ G Uy):
The purpose of this proposal is (1) to describe the outcome of patients undergoing alloHSCT for
AML with extramedullary involvement and (2) to assess patient, disease and transplant related
factors which influence the outcome of alloHSCT in AML. There are 935 AML patients ≥18 years of
age with extramedullary disease prior to HCT reported to the CIBMTR between 1995 and 2010.
Analysis is completed and draft manuscript is being prepared by PI.
LK12-01: Chemotherapy versus Allogeneic Hematopoietic Cell Transplantation in Philadelphia
negative chromosome negative adult ALL (M Seftel): The purpose of the study is to compare HSCT
outcomes of younger adults with Philadelphia chromosome negative (Ph-) Acute Lymphoblastic
Leukemia (ALL) in first complete remission (CR1) treated with either allogeneic hematopoietic cell
transplantation (alloHCT) or with a pediatric style chemotherapy regimen. Draft protocol has been
circulated within Working Committee. Protocol finalization and data file preparation is underway.
LK12-02: FLT3/ITD mutation in acute myeloid leukemia remains a poor prognostic factor compared
to conventional cytogenetics with increased risk of relapse and decreased overall survival after
6
Not for publication or presentation
Attachment 1
allogeneic stem cell transplantation in first complete remission (S Sengsayadeth): The purpose of this
study is to (1) To study the prognostic significance of FLT3/ITD mutation in AML in patients receiving
allo-HSCT in CR1 and (2) To study the impact of FLT3/ITD mutation on incidence of relapse, diseasefree survival (DFS), overall survival (OS) after allo-SCT in CR1. Protocol has been finalized and data
file preparation is underway.
LK12-03: Survival of AML patients relapsing after allogeneic stem cell transplantation (N Bejanyan/ D
Weisdorf/ MJ Zhang): The purpose of this study is to (1) study the clinical outcomes including overall
survival (OS) after post-transplant relapse among allogeneic transplant recipients with AML and (2)
to identify prognostic factors for survival after post-transplant relapse. Analysis is completed and
draft manuscript is being prepared by PI.
LK13-01: Allogeneic Transplantation for older patients with Acute Lymphoblastic Leukemia reported
to the CIBMTR and EBMT: Impact of age on transplant outcomes (A Rosko/ M de Lima/ M Mohty/ V
Bachanova): The purpose of this study is to (1) To analyze outcomes of allogeneic donor
transplantation for older patients with acute lymphoblastic leukemia ages 55 years and older who
underwent reduced intensity conditioning (2) To define the prognostic factors (patient, disease and
transplant related) that impact mortality, relapse and survival. Protocol development is underway.
LK13-02: Prognostic significance of cytogenetic abnormalities in patients with Philadelphia-negative
ALL undergoing allogeneic Hematopoietic Stem Cell Transplantation in complete remission (A
Lazaryan/ V Bachanova): The purpose of this study is to (1) To develop allo-HCT specific cytogenetic
classification of Ph-negative ALL for prognostication of relapse and survival outcomes following alloHCT (2) To validate within the CIBMTR database the prognostic significance of existing cytogenetic
classifications of Ph-negative ALL in the context of the allo-HCT (3) To compare the performance of
both CIBMTR-based and existing classifications of Ph-negative ALL treated with allo-HCT. Protocol
development is underway.
LK13-03: Allogeneic transplantation for Acute Biphenotypic Leukemia (ABiL): Disease characteristics,
complications and outcomes (R Munker): The purpose of this study is to (1) Describe frequency of
allogeneic transplant for ABiL, demographics and disease characteristics before transplant (2) Assess
patient-, disease- and transplant- related factors which influence the outcome of allogeneic
transplant for ABiL. Protocol development is underway.
5. Future/ Proposed studies
Drs. Devine, de Lima and Bunjes led this section. The proposals were the following:
a. PROP 1310-07 Outcome of allogeneic hematopoietic cell transplantation in patients with acute
myeloid leukemia with antecedent history of Philadelphia-negative myeloproliferative Neoplasm
(V Gupta)
Dr. Gupta presented the proposal. The purpose of this study is to study the outcome of HCT in
patients with leukemic transformation from Philadelphia-negative MPN and identify patient,
disease and transplant related factors associated with outcome. There are 164 adult patients
underwent 1st allo HCT for AML transformed from Ph- MPN between 1996 and 2012. There were
comments about the analyzability of cases and completeness of cytogenetic information.
b. PROP 1310-19 Allogeneic transplantation to treat secondary AML diagnosed after autologous
transplant (L Metheny, M de Lima, H Mohty)
7
Not for publication or presentation
Attachment 1
Dr. Metheny presented the proposal. The main purpose of this study is to evaluate overall
survival of adult allogeneic HSCT patients with secondary AML following autologous transplant.
There were 55 cases who received 1st allo HCT for AML/MDS between 2000 and 2011 after auto
HCT for multiple myeloma/HD/NHL. Concern was raised regarding the selection bias of few
patients who made through to receive allo HCT after developing secondary leukemia.
c. PROP 1311-50 Outcome of umbilical cord blood transplantation (CBT) in adults with high risk
acute myeloid leukemia (I Lewis)
Dr. Lewis presented the proposal. The purpose of this study is to look at the prognostic
significance of high risk cytogenetic or molecular markers in AML compared to other
conventional prognostic markers in patients receiving CBT. There were 841 adult patients who
received 1st UCB graft allo HCT for AML between 2001 and 2011. Issues regarding the
heterogeneity of high risk group were mentioned and incompleteness of cytogenetic and
molecular data was brought up.
d. PROP 1311-56 Prognostic factors in patients ≥60 years undergoing allogeneic hematopoietic cell
transplantation for acute myeloid leukemia in first and second complete remission (FV Michelis,
V Gupta)
Dr. Michelis presented the proposal. The purpose of this study is to identify patient, disease,
and transplant related characteristics associated with outcomes for older patients in particular
(≥60 years) with AML undergoing allogeneic hematopoietic cell transplantation (HCT) in CR1 and
CR2. There were 4396 adult patients receiving 1st BM/PB graft allo HCT for AML between 1999
and 2011 in CR1 and CR2. No major comments were received.
e. PROP 1310-02/1310-04/1312-01 Risk index for Acute Leukemia Patients Receiving Allogeneic
Hematopoietic Cell Transplantation (F Anwer, YX Hu, H Huang, R Krishnadasan, C Ustun, D
Weisdorf, A Yeager)
Dr. Anwer presented the proposal. The main purpose of this study is to create a risk index for
acute leukemia patients (AL-RI) receiving allo transplant. There were 8282 adult patients
receiving 1st allo HCT in complete remission for AML/ALL between 2001 to 2012. It was
suggested that AML and ALL cases to be studied separately due to heterogeneity.
f.
PROP 1311-34 The graft versus leukemia effect following reduced intensity allotransplant for
acute lymphoblastic leukemia (V Bachanova)
Dr. Bachanova presented the protocol. The purpose of this study is to identify a graft vs.
leukemia (GVL) effect after reduced intensity (RIC) HCT for T and B-ALL by comparing leukemia
recurrence in patients with and without acute and/or chronic GVHD. There were 297 adult
patients receiving 1st reduced intensity/non-myeloablative conditioning allo HCT in CR1/CR2 for
ALL between 1998 and 2011. The issue of limited DLI and TKI information was brought up.
g. PROP 1311-43 Effect of post-remission consolidation chemotherapy prior to allogeneic
transplantation for acute lymphocytic leukemia in first complete remission: A Center for
International Blood and Marrow Transplant Research Study (N Bejanyan, A Lazaryan, D Weisdorf)
Dr. Bejanyan presented the proposal. The main purpose of this study is to study overall survival
of ALL patients in first complete remission receiving 0 vs. 1 vs. ≥2 post-remission consolidation
cycles prior to allo HCT. There were 379 adult patients receiving 1st bone marrow / peripheral
blood graft allo HCT in CR1 for ALL between 2008 and 2011. It was suggested that consolidation
drugs to be reviewed extensively.
8
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Attachment 1
h. PROP 1312-09 Comparison of total body irradiation (TBI)-based with intravenous (i.v.) busulfan
(Bu) containing chemotherapy-only myeloablative transplant conditioning regimens in patients
with acute lymphoblastic leukemia (P Kebriaei, D Marks)
Dr. Kebriaei presented the proposal. The purpose of this study is to Compare transplant
outcomes in patients receiving myeloablative TBI-based transplant conditioning with a
chemotherapy-only regimen consisting of i.v. Bu and nucleoside analogue therapy. There were
611 adult patients receiving TBI/ivBu based conditioning 1st allo HCT for non-L3 ALL between
2005 and 2012 reported to CIBMTR, and 94 patients receiving ivBu+Clofarabine based
conditioning 1st allo HCT from MDACC. Questions were raised regarding different HCT time
period in 2 cohorts and relatively short follow-up in MDACC cohort. Also current sample size
might not have enough statistical power to prove the hypothesis.
i.
PROP 1311-05 Second Allogeneic Transplantation using a Reduced Intensity Conditioning
Preparative Regimen in the Case of Relapse or Graft Failure in Patients with Acute Leukemia (R
Salit, C Delaney, T Gooley)
Dr. Milano presented the proposal on behalf of Dr. Salit. The purpose of this study is to examine
the early outcomes of patients receiving a second HCT with reduced intensity conditioning for
graft failure or relapse of acute leukemia or MDS following their initial allogeneic transplant.
There were 267 patients receiving 2nd allo HCT between 2000 and 2011 after graft failure or
relapsed 1st allo HCT for AML/ALL/MDS.
Nine additional proposals were submitted to the committee, but not presented as stated below:
a. PROP 1310-16 Autologous Peripheral Blood Stem Cell Transplantation in Philadelphia-positive
Acute Lymphoblastic Leukemia: An Option for Patients with No HLA-match Sibling Donor (G
Akpek): insufficient number of autologous transplant cases.
b. PROP 1311-38 Effect of Post-transplant Cyclophosphamide on Chronic Severe Graft vs. Host
Disease and Relapse in Acute Leukemia (O Ramirez): incomplete documentation and insufficient
number of cases (n=92) receiving post-transplant Cyclophosphamide
c. PROP 1312-05 Dynamic Bayes Model Averaging for Improved Estimates of BMT/SCT Survival
Benefit (P Chaudhary, T Triche, G Ramsingh): complexity of required data and lack of priority.
d. PROP 1312-02 Allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia
and myelodysplastic syndrome with t(6;9) (H Huang, HY Xian): insufficient number of cases with
t(6;9) abnormality (n=46)
e. PROP 1311-80 Standard cytotoxic induction vs. induction without cytotoxic chemotherapy prior
to allogeneic stem cell transplant for acute myelogenous leukemia (A Hall, M Juckett):
insufficient detailed information about the details of induction
f.
PROP 1311-42 Outcome of Intermediate-risk acute myeloid leukemia patients following
matched related and unrelated allogeneic hematopoietic stem cell transplantation in first
complete remission compared with second complete remission, stratified by age and
comorbidities (F Cheema, R Munker, R Koshy): insufficient scientific impact
9
Not for publication or presentation
Attachment 1
g. PROP 1311-44 Do patients with relapsed core binding factor Acute Myeloid Leukemia benefit
from salvage allogeneic stem cell transplantation (G Hobbs, MA Perales, E Stein): insufficient
scientific impact
h. PROP 1311-11/1311-58 Impact of pre-transplant cytogenetic or molecular minimal residual
disease on outcomes of allogeneic hematopoietic cell transplantation for acute myeloid
leukemia in CR1 or CR2 (B Wirk, M Wieduwilt): insufficient molecular information
6. Other business
After the new proposals were presented, each participant in the meeting had the opportunity to
rate each proposal using paper ballots. Based on the voting results, current scientific merit and the
impact of the study on the field, the following studies will move forward as the committee’s
research portfolio for the upcoming year:
a. PROP 1311-56 Prognostic factors in patients ≥60 years undergoing allogeneic hematopoietic cell
transplantation for acute myeloid leukemia in first and second complete remission
b. PROP 1311-43 Effect of post-remission consolidation chemotherapy prior to allogeneic
transplantation for acute lymphocytic leukemia in first complete remission: A Center for
International Blood and Marrow Transplant Research Study
Dr. Daniel Weisdorf expressed gratitude to the Committee members for their active role and valuable
support to the Committee.
Without additional comments, the meeting was adjourned at 4:30 pm.
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Attachment 1
Working Committee Overview Plan for 2014-2015
a. LK09-02: Impact of monosomal karyotype in the outcome of hematopoietic cell transplantation
for Acute Myeloid Leukemia and Myelodysplasia. Analyses completed and manuscript is under
preparation. Submission is anticipated by June 2015.
b. LK11-01: Impact of extramedullary disease on the outcome of allogeneic HCT in AML.
Manuscript preparation is underway. Submission of paper is expected by June 2014.
c. LK12-01: Chemotherapy versus Allogeneic Hematopoietic Cell Transplantation in Philadelphia
negative chromosome negative adult ALL. Data file preparation is underway. We plan to finish
analysis by June 2014 and submit paper by June 2015.
d. LK12-02: FLT3/ITD mutation in acute myeloid leukemia remains a poor prognostic factor
compared to conventional cytogenetics with increased risk of relapse and decreased overall
survival after allogeneic stem cell transplantation in first complete remission. Data file
preparation is completed. We plan to finish analysis by June 2014 and submit paper by June
2015.
e. LK13-01: Evaluating outcomes of reduced intensity conditioning allogeneic SCT in older adult
lymphoblastic leukemia patients reported to the CIBMTR and EBMT. Protocol development is
underway and we plan to move to data file preparation by June 2014.
f.
LK13-02:
Prognostic significance of cytogenetic abnormalities in patients with Philadelphianegative acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplant
ation in complete remission. Protocol development and request of cytogenetics information is
underway and we plan to move to data file preparation by June 2014 and finish analysis by June
2015.
g. LK13-03: Allogeneic transplantation for Acute Biphenotypic Leukemia: Disease characteristics,
complications and outcomes. Protocol development and request of patient forms is underway
and we plan to move to data file preparation by June 2014 and finish analysis by June 2015.
h. LK14-01: Effect of post-remission consolidation chemotherapy prior to allogeneic
transplantation for acute lymphocytic leukemia in first complete remission: A Center for
International Blood and Marrow Transplant Research Study. We anticipate developing the study
protocol after July 2014 and move to data file preparation by June 2015.
i.
LK14-02: Prognostic factors in patients ≥60 years undergoing allogeneic hematopoietic cell
transplantation for acute myeloid leukemia in first and second complete remission. We
anticipate developing the study protocol after July 2014 and move to data file preparation by
June 2015.
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Attachment 1
Oversight Assignments for Working Committee Leadership (March 2014)
Daniel Weisdorf
LK12-01: Chemotherapy versus Allogeneic Hematopoietic Cell
Transplantation in Philadelphia negative chromosome negative adult
ALL
LK13-02: Prognostic significance of cytogenetic abnormalities in patients
with Philadelphia‐negative acute lymphoblastic leukemia undergoing
allogeneic hematopoietic stem cell transplantation in complete
remission
Wael Saber
LK12-02: FLT3/ITD mutation in acute myeloid leukemia remains a poor
prognostic factor compared to conventional cytogenetics with increased
risk of relapse and decreased overall survival after allogeneic stem cell
transplantation in first complete remission
LK13-01: Evaluating outcomes of reduced intensity conditioning
allogeneic SCT in older adult lymphoblastic leukemia patients reported
to the CIBMTR and EBMT
Marcos de Lima
LK09-02: Impact of monosomal karyotype in the outcome of
hematopoietic cell transplantation for Acute Myeloid Leukemia and
Myelodysplasia
LK11-01: Impact of extramedullary disease on the outcome of allogeneic
HCT in AML
Steven Devine
LK14-01: Effect of post-remission consolidation chemotherapy prior to
allogeneic transplantation for acute lymphocytic leukemia in first
complete remission: A Center for International Blood and Marrow
Transplant Research Study
LK14-02: Prognostic factors in patients ≥60 years undergoing allogeneic
hematopoietic cell transplantation for acute myeloid leukemia in first
and second complete remission
Brenda Sandmaier
LK13-03: Allogeneic transplantation for Acute Biphenotypic Leukemia:
Disease characteristics, complications and outcomes
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Attachment 2
Accrual Summary for the Acute Leukemia Working Committee
Characteristics of recipients of allogeneic transplants for AML and ALL reporteda to the CIBMTR
between 1995 and 2014
Variable
AML
ALL
Number of patients
17318
9420
Number of centers
376
361
Age in decades
Median (range)
42 (<1-83)
20 (<1-75)
<10
1613 (9)
2373 (25)
10-19
1813 (10)
2320 (25)
20-29
2135 (12)
1676 (18)
30-39
2490 (14)
1236 (13)
40-49
3382 (20)
1036 (11)
50-59
3647 (21)
612 (6)
60-69
2021 (12)
164 (2)
>=70
217 (1)
3 (<1)
Gender
Male
9130 (53)
5779 (61)
Female
8186 (47)
3639 (39)
Missing
2 (<1)
2 (<1)
HCT-CI
0
2693 (16)
1236 (13)
1
655 (4)
227 (2)
2
509 (3)
144 (2)
3+
1412 (8)
309 (3)
N/A, earlier than 2007
11984 (69)
7487 (79)
Missing
65 (<1)
17 (<1)
Disease status prior to HCT
Primary induction failure
2305 (13)
326 (3)
CR1
8197 (47)
3718 (39)
CR2
3668 (21)
3301 (35)
>=CR3
296 (2)
853 (9)
Relapse
2799 (16)
1212 (13)
Missing
53 (<1)
10 (<1)
Time from diagnosis to HCT
Median (range)
6 (<1-607)
12 (<1-499)
<6 months
8224 (47)
2584 (27)
6 - 12 months
4335 (25)
2149 (23)
>12 months
4739 (27)
4683 (50)
Missing
20 (<1)
4 (<1)
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Variable
AML
Conditioning regimen intensity
Myeloablative
13180 (76)
RIC
2937 (17)
NMA
494 (3)
TBD
530 (3)
Missing
177 (1)
Graft type
Bone marrow
6133 (35)
Peripheral blood
9200 (53)
Umbilical cord blood
1978 (11)
Missing
7 (<1)
Type of donor
HLA-identical sibling
5970 (34)
Identical twin
77 (<1)
Other relative
862 (5)
Unrelated
8384 (48)
Cord blood
1978 (11)
Missing
47 (<1)
Year of HCT
1995-1996
1639 (9)
1997-1998
1441 (8)
1999-2000
1410 (8)
2001-2002
1775 (10)
2003-2004
2085 (12)
2005-2006
2522 (15)
2007-2008
2372 (14)
2009-2010
2056 (12)
2011-2012b
848 (5)
b
2013-2014
1170 (7)
Median follow-up of survivors (range), months
71 (1-223)
a
Patients
have
available
comprehensive
research
form
and
consented
for
research
b
Cases continue to be reported in this interval
Attachment 2
ALL
8703 (92)
441 (5)
58 (<1)
134 (1)
84 (<1)
4591 (49)
3218 (34)
1607 (17)
4 (<1)
2781 (30)
52 (<1)
516 (5)
4446 (47)
1607 (17)
18 (<1)
1296 (14)
1122 (12)
1056 (11)
1099 (12)
1115 (12)
1248 (13)
1051 (11)
621 (7)
411 (4)
401 (4)
73 (<1-223)
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Attachment 2
Accrual Summary for Acute Leukemia Working Committee
Characteristics of recipients of autologous transplants for AML and ALL reporteda to the CIBMTR
between 1995 and 2014
Variable
AML
ALL
Number of patients
963
154
Number of centers
176
57
Age in decades
Median (range)
44 (<1-78)
29 (1-66)
<10
61 (6)
16 (10)
10-19
68 (7)
25 (16)
20-29
118 (12)
38 (25)
30-39
166 (17)
19 (12)
40-49
179 (19)
27 (18)
50-59
210 (22)
22 (14)
60-69
153 (16)
7 (5)
>=70
8 (<1)
0
Gender
Male
486 (50)
96 (62)
Female
477 (50)
58 (38)
Disease status prior to HCT
Primary induction failure
10 (1)
2 (1)
CR1
629 (65)
98 (64)
CR2
241 (25)
43 (28)
>=CR3
14 (1)
6 (4)
Relapse
66 (7)
5 (3)
Missing
3 (<1)
0
Time from diagnosis to HCT
Median (range)
7 (<1-584)
9 (2-153)
<6 months
405 (42)
22 (14)
6 - 12 months
261 (27)
72 (47)
>12 months
297 (31)
60 (39)
Conditioning regimen intensity
Myeloablative
784 (81)
148 (96)
NMA
4 (<1)
1 (<1)
TBD
172 (18)
5 (3)
Missing
3 (<1)
0
Graft type
Bone marrow
168 (17)
25 (16)
Peripheral blood
792 (82)
128 (83)
Missing
3 (<1)
1 (<1)
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Variable
AML
Year of HCT
1995-1996
267 (28)
1997-1998
222 (23)
1999-2000
107 (11)
2001-2002
89 (9)
2003-2004
65 (7)
2005-2006
86 (9)
2007-2008
99 (10)
2009-2010
17 (2)
b
2011-2012
4 (<1)
b
2013-2014
7 (<1)
Median follow-up of survivors (range), months
87 (1-226)
a
Patients
have
available
comprehensive
research
form
and
consented
for
research
b
Cases continue to be reported in this interval
Attachment 2
ALL
55 (36)
45 (29)
16 (10)
12 (8)
5 (3)
9 (6)
10 (6)
1 (<1)
0
1 (<1)
121 (2-217)
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Attachment 3
TO:
Acute Leukemia Working Committee Members
FROM:
Daniel J. Weisdorf, MD; Scientific Director and Wael Saber, MD, MS; Assistant Scientific
Director for the Acute Leukemia Working Committee
RE:
Studies in Progress Summary
LK09-02: Impact of monosomal karyotype in the outcome of hematopoietic cell transplantation for
Acute Myeloid Leukemia and Myelodysplasia (M Pasquini/ M Battiwalla) The purpose of this study is to
identify the impact of high risk cytogenetic subsets: specifically chromosome 7 abnormalities (either
monosomy7 or del(7q)) and monosomal karyotype in outcomes for AML and MDS after allogeneic HCT
and to evaluate the impact of conditioning intensity in the outcome of patients with AML and
monosomal karyotype. Analysis is completed and draft manuscript is being prepared by PI.
LK12-01: Chemotherapy versus Allogeneic Hematopoietic Cell Transplantation in Philadelphia negative
chromosome negative adult ALL (M Seftel) The purpose of the study is to compare HSCT outcomes of
younger adults with Philadelphia chromosome negative (Ph-) Acute Lymphoblastic Leukemia (ALL) in
first complete remission (CR1) treated with either allogeneic hematopoietic cell transplantation
(alloHCT) or with a pediatric style chemotherapy regimen. Analysis is completed and 1st draft
manuscript is available.
LK12-02: FLT3/ITD mutation in acute myeloid leukemia remains a poor prognostic factor compared to
conventional cytogenetics with increased risk of relapse and decreased overall survival after allogeneic
stem cell transplantation in first complete remission (S Sengsayadeth) The purpose of this study is to (1)
To study the prognostic significance of FLT3/ITD mutation in AML in patients receiving allo-HSCT in CR1
and (2) To study the impact of FLT3/ITD mutation on incidence of relapse, disease-free survival (DFS),
overall survival (OS) after allo-SCT in CR1. Analysis is completed and 1st draft manuscript is available.
LK13-01: Allogeneic Transplantation for older patients with Acute Lymphoblastic Leukemia reported to
the CIBMTR and EBMT: Impact of age on transplant outcomes (A Rosko/ M de Lima/ M Mohty/ V
Bachanova) The purpose of this study is to (1) To analyze outcomes of allogeneic donor transplantation
for older patients with acute lymphoblastic leukemia ages 55 years and older who underwent reduced
intensity conditioning (2) To define the prognostic factors (patient, disease and transplant related) that
impact mortality, relapse and survival. Analysis is underway.
LK13-02: Prognostic significance of cytogenetic abnormalities in patients with Philadelphia-negative ALL
undergoing allogeneic Hematopoietic Stem Cell Transplantation in complete remission (A Lazaryan/ V
Bachanova) The purpose of this study is to (1) To develop allo-HCT specific cytogenetic classification of
Ph-negative ALL for prognostication of relapse and survival outcomes following allo-HCT (2) To validate
within the CIBMTR database the prognostic significance of existing cytogenetic classifications of Phnegative ALL in the context of the allo-HCT (3) To compare the performance of both CIBMTR-based and
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Attachment 3
existing classifications of Ph-negative ALL treated with allo-HCT. Protocol development and cytogenetic
data review is underway.
LK13-03: Allogeneic transplantation for Acute Biphenotypic Leukemia (ABiL): Disease characteristics,
complications and outcomes (R Munker) The purpose of this study is to (1) Describe frequency of
allogeneic transplant for ABiL, demographics and disease characteristics before transplant (2) Assess
patient-, disease- and transplant- related factors which influence the outcome of allogeneic transplant
for ABiL. Analysis is underway.
LK14-01: Effect of post-remission consolidation chemotherapy prior to allogeneic transplantation for
acute lymphocytic leukemia in first complete remission (N Bejanyan/ A Lazaryan/ D Weisdorf) The
purpose of this study is to (1) To study relapse, TRM and survival outcomes of ALL patients in CR1
receiving 0 vs. 1 vs. ≥2 post-remission consolidation cycles prior to allo-HCT. (2) To study relapse, TRM
and survival outcomes in subgroup of ALL patients with MRD positivity who receive 0 vs. 1 vs. ≥2 postremission consolidation cycles prior to allo-HCT. Protocol development is underway.
LK14-02: Prognostic factors in patients ≥60 years undergoing allogeneic hematopoietic cell
transplantation for acute myeloid leukemia in first and second complete remission (F Michelis/ V Gupta)
The purpose of this study is to (1)To identify patient, disease, and transplant related characteristics
associated with outcomes for older patients in particular (≥60 years) with AML undergoing allo-HCT in
CR1 and CR2. (2) To compare outcomes between patients within different age (<60 yrs vs. ≥60 yrs) or
remission status (CR1 vs. CR2) group. (3) To assess the impact of HCT-CI (0-2 vs. ≥3) on outcomes in all
patients with HCT-CI available and a subgroup of CR2 patients only. Protocol development is underway.
LK14-03: Autologous transplant vs. arsenic trioxide in relapsed Acute Promyelocytic Leukemia (C Ganzel
/ M Tallman) The purpose of this study is to compare between the 2 treatment groups for
demographics, details of disease presentation, frontline treatment and outcomes including disease free
survival and overall survival. Analysis is under way.
LK15-01: Comparison of Allogeneic Hematopoietic Cell Transplantation (AlloHCT) with Other
Consolidation Therapies Per Alliance Protocols in Older (≥60 years) AML Patients in First Complete
Remission (CR1) (A Artz / C Ustun) The purpose of this study is to (1) To compare DFS and TRM between
alloHCT and non-alloHCT consolidations (2) To find the frequency of acute and chronic graft-versus-host
disease (GVHD) in the alloHCT cohort (3) To identify patient or disease characteristics (age, cytogenetic
risk group, etc.) which preferentially benefit patients receiving alloHCT vs. non-alloHCT consolidation
therapy. Data preparation and protocol review is underway.
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Attachment 4
Study Proposal 1410-04/1411-60
Study Title:
Comparison of Outcomes between Conditioning Regimens using Reduced Intensity conditioning of
Fludarabine plus Melphalan and Myeloablative Regimens Using IV Busulfan plus Fludarabine or IV
Busulfan plus Cyclophosphamide in AML and MDS
Donald A Hutcherson, RPh, Pharmacy BS, Emory University Hospital/Winship Cancer Institute,
Don.Hutcherson@emoryhealthcare.org
Hongtao Liu, MD, Ph.D., The University of Chicago Medical Center, hliu2@medicine.bsd.uchicago.edu
Ajay Nooka, Doctor of Medicine, Emory University Hospital/Winship Cancer Institute,
anooka@emory.edu
Amelia Langston, Doctor of Medicine, Emory University Hospital/Winship Cancer Institute,
Amelia.Langston@emoryhealthcare.org
Michael Bishop, MD, The University of Chicago Medical Center, mbishop@medicine.bsd.uchicago.edu
Hypothesis:
Busulfan plus cyclophosphamide (Bu/Cy) provides superior disease free survival in younger patients
compared to either fludarabine plus melphalan (Flu/Mel) or busulfan plus fludarabine (Bu/Flu) while
Bu/Flu and Flu/Mel produce less TRM in older patients and comparable overall survival.
Specific Aims:
This study will compare short term outcomes of engraftment rates, reported infections prior to day 100,
sinusoidal obstruction syndrome (SOS), survival at day 100, non-relapse mortality, regimen related
toxicities, best response to transplant and aGVHD for site and overall grade. Long term outcomes will
include incidence of cGVHD, cause of death, disease-free and overall survival. Multivariate analysis will
be performed to compare outcomes by disease (AML or MDS), disease status, age, sex, race, transplant
type, product type, degree of match, GVHD prophylaxis (tacrolimus, cyclosporine, sirolimus,
methotrexate dosing, mycophenolate, anti-lymphocyte globulin, other), recipient and donor CMV
status, comorbidity scores, busulfan dose, busulfan frequency (Q 24h vs. q6h) and drug timing of
administration (if available, Bu/Flu sequential vs concurrent and Cy/Bu vs Bu/Cy).
Scientific Justification:
Few randomized clinical trials have been performed to compare myeloablative transplantation using
Bu/Cy to Bu/Flu or either of these against reduced intensity Flu/Mel in AML/MDS. Several reports have
found the busulfan regimens had similar long term outcomes. Liu, et al report the results of allogeneic
transplant study for Bu/Cy vs Bu/Flu in 108 patients with a median age 30.5 (12 – 54) with AML in first
CR. While the Bu/Flu provided lower incidence of grade III-IV regimen related toxicity than Bu/Cy, there
was no difference seen in treatment related mortality, incidence of relapse, overall or disease-free
survival at 5 years [1]. Lee, et al studied leukemia and MDS patients aged 17 to 59 treated in a
randomized Phase III trial with either Bu/Cy or Bu/Flu. This trial demonstrated better overall, relapsefree and event-free survival for Bu/Cy at 2 years [2]. As part of a subset analysis of study CIBMTR SC0901, Bredeson, et al compared outcomes of 601 Bu/Cy vs. 424 Bu/Flu transplants for AML, MDS and CML.
While the groups were not well balanced for age, performance status and other factors, in this large
series no difference could be seen in mortality, treatment failure, relapse, treatment related mortality
and VOD[3].
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Attachment 4
With regards to Flu/Mel, several retrospective registry analyses compared the outcomes after RIC and
MA SCT in older AML patients. Two separate analyses using EBMT data compared RIC and MA SCT using
matched related donor (MRD) or matched unrelated donor (MUD). Not surprisingly, these two studies
reached similar conclusion. Both RIC MRD and MUD transplant recipients more than 50 years had
reduced adjusted non-relapse mortality, but higher cumulative incidence of relapse resulting in similar
leukemia-free survival compared to patients who had MAC MRD or MUD transplant [4,5]. Similar results
were found in patients with MDS or secondary AML who received RIC vs MA MRD SCT with increased
relapse rate, but decrease NRM in RIC SCT, and comparable PFS and OS in the older patients [6].
Recently, Luger et al published so far the largest retrospective comparison of MA (3731 patients) with
RIC/NMA (non-myeloablative) (1448 patients) regimens in AML/MDS patients using the CIBMTR data
between 1997 and 2004. NMA conditioning resulted in inferior DFS and OS, but there was no difference
in DFS and OS between RIC and MA regimens with adjusted OS at 5 years was 34, 33 and 26% for MA,
RIC and NMA transplants, respectively [7]. The findings from these retrospective studies were further
confirmed by so far the only prospective, open-label randomized phase III trial to compare RIC and
standard MA conditioning in patients with acute myeloid leukemia in first complete remission [8]. One
hundred ninety-five Patients aged 18–60 years with intermediate-risk or high-risk AML in CR1 were
randomly assigned to receive RIC or standard conditioning. RIC SCT results in a similar incidence of nonrelapse mortality and reduced toxic effects compared with standard conditioning without affecting
survival outcomes [8]. These studies established the role of RIC in the allo-SCT of acute leukemia
patients, especially for older patients or patients with co-morbidities not suitable for MA regimens.
All these retrospective and prospective studies compared mixed myeloablative regimens; mainly TBI
based regimen, Busulfan/cyclophosphamide (Bu/Cy) and mixed RIC regimens, mainly
fludarabine/melphalan. While TBI-based regimen might still provide marginal survival benefit for ALL
patients, due to the poor tolerability of older patients to TBI based regimen, and comparable outcomes
between TBI/Cy vs Bu/Cy have been demonstrated in allo-SCT for acute leukemia; although Bu/Cy and
Bu/Flu might not be completely same [2]; Flu/Bu has been more widely used as a myeloablative regimen
in elderly patients. On the other hand, Flu/Mel was one of most commonly used RIC regimens for
AML/MDS. While Bu/Flu is usually chosen for ALL patients due to the results from Moffitt cancer center
[9]; the option between Bu/Flu and Flu/Mel for AML and high risk MDS is still unclear. So far, there is no
direct comparison between Bu/Flu (IV) and Flu/Mel regimen in allo-SCT for acute leukemia, except a
small early study to compare the kinetics of myeloablation between Bu/Flu and Flu/Mel in allogeneic
peripheral blood stem cell transplantation [10]. Thus, one approach is to give Bu/Flu if it is felt that the
patient could tolerate without increased risk of VOD for patients with AML/high risk MDS, and Flu/Mel if
not candidate for Bu/Flu. For the patients with better performance status, one must consider whether
Bu/Cy may give better disease control than other regimens allowing for improved overall survival.
While the desire to find better tolerated conditioning regimens, especially for older patients, has
increased the substitution of fludarabine for cyclophosphamide, Flu/Mel has remained a widely used
reduced intensity regimen. Using data from the CIBMTR database, we hope to determine whether one
of these regimens might provide a better platform for transplanting specific patient populations and if
the most common selections in GVHD prophylaxis alter patient outcomes for these regimens.
Patient Eligibility:
 AML or MDS
 Ages > 18
 Related or unrelated donor (Related haploidentical donor or UCB transplants excluded)
 Myeloablative dosing of IV Bu/Cy, IV Bu/Flu or RIC Flu/Mel
 Transplantation dates 2002 through 2012
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Attachment 4
Data Requirements: This project’s goal is to use existing data in the database.
Sample Requirements from Data repository: None
Study Design (Scientific Plan):
All AML and high risk MDS patients received allo-SCT in CR1 and beyond who were conditioned with
fludarabine/Busulfan (IV, >=8mg/kg), cyclophosphamide/Busulfan (IV, >8mg/kg), or
fludarabine/melphalan (<=140mg/m2) with information available in the designated time period will be
included in the analysis. Descriptive tables of patient-, disease-, and transplant related factors will be
prepared. The tables will list median and range for continuous variables and percent of total for
categorical variables. Characteristics of patients will be compared using the chi-square test for
categorical variables and the Wilcoxon two-sample test for continuous variables. Outcomes will be
defined as above. Comparing the outcomes between the Bu regimens and Flu/Mel transplant groups
will require adjustment for baseline patient characteristics. To adjust for differences in the baseline
characteristics, Cox proportional hazards regression will be used. Probability of DFS and OS will be
calculated using the Kaplan-Meier estimator. Comparison of survival curves will be done using the logrank test.
References:
1.
H. Liu, X. Zhai, Z. Song, et al., Busulfan plus fludarabine as a myeloablative conditioning regimen compared
with busulfan plus cyclophosphamide for acute myeloid leukemia in first complete remission undergoing
allogeneic hematopoietic stem cell transplantation: a prospective and multicenter study, J Hematol Oncol, 6
(2013), p. 15.
2. J. Lee, J Young-Don, et al. Randomized Trial of Myeloablative Conditioning Regimens: Busulfan Plus
Cyclophosphamide Versus Busulfan Plus Fludarabine. JCO 31, Feb 20, 2013, p. 701.
3. Prospective cohort study comparing intravenous busulfan to total body irradiation in hematopoietic cell
transplantation. Christopher Bredeson, et al. Blood Dec 2013, 122 (24) 3871-3878.
4. Ringden, O., et al., Reduced intensity conditioning compared with myeloablative conditioning using unrelated
donor transplants in patients with acute myeloid leukemia. J Clin Oncol, 2009. 27(27): p. 4570-7.
5. Aoudjhane, M., et al., Comparative outcome of reduced intensity and myeloablative conditioning regimen in
HLA identical sibling allogeneic haematopoietic stem cell transplantation for patients older than 50 years of
age with acute myeloblastic leukaemia: a retrospective survey from the Acute Leukemia Working Party (ALWP)
of the European group for Blood and Marrow Transplantation (EBMT). Leukemia, 2005. 19(12): p. 2304-12.
6. Martino, R., et al., Retrospective comparison of reduced-intensity conditioning and conventional high-dose
conditioning for allogeneic hematopoietic stem cell transplantation using HLA-identical sibling donors in
myelodysplastic syndromes. Blood, 2006. 108(3): p. 836-46.
7. Luger, S.M., et al., Similar outcomes using myeloablative vs reduced-intensity allogeneic transplant
preparative regimens for AML or MDS. Bone Marrow Transplant. 47(2): p. 203-11.
8. Bornhauser, M., et al., Reduced-intensity conditioning versus standard conditioning before allogeneic
haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: a
prospective, open-label randomised phase 3 trial. Lancet Oncol.
9. Santarone, S., et al., Fludarabine and pharmacokinetic-targeted busulfan before allografting for adults with
acute lymphoid leukemia. Biol Blood Marrow Transplant, 2011. 17(10): p. 1505-11.
10. Chunduri, S., et al., Comparable kinetics of myeloablation between fludarabine/full-dose busulfan and
fludarabine/melphalan conditioning regimens in allogeneic peripheral blood stem cell transplantation. Bone
Marrow Transplant, 2006. 38(7): p. 477-82.
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Attachment 4
Characteristics of Study Population
Variable
Number of patients
Number of centers
Age in decades
Median (range)
18-29
30-39
40-49
50-59
60-69
>=70
Karnofsky score
<90%
>=90%
Missing
White blood count at diagnosis (x10^9/L)
Median (range)
<= 10
10 - 100
> 100
Missing
Disease
AML
MDS
Disease status prior to HCT
Primary induction failure
CR1
CR2
>=CR3
Relapse
Disease status prior to HCT for MDS
MDS early
MDS advanced
MDS Other
Conditioning regimen
Bu+Cy
Bu+Cy+Arac
Bu+Cy+VP16
Bu+Cy+Thio
Bu+Cy+other
MAC IVBu+Cy MAC IVBu+Flu
1569
1466
134
97
RIC
Flu+Mel
885
96
48 (18-71)
228 (15)
224 (14)
448 (29)
544 (35)
122 (8)
3 (<1)
53 (19-75)
149 (10)
161 (11)
307 (21)
543 (37)
297 (20)
9 (<1)
59 (18-75)
33 (4)
39 (4)
105 (12)
286 (32)
388 (44)
34 (4)
512 (33)
984 (63)
73 (5)
517 (35)
835 (57)
114 (8)
347 (39)
510 (58)
28 (3)
6 (<1-2247)
844 (54)
461 (29)
102 (7)
162 (10)
5 (<1-5500)
797 (54)
379 (26)
80 (5)
210 (14)
4 (<1-9973)
489 (55)
205 (23)
45 (5)
146 (16)
1201 (77)
368 (23)
1056 (72)
410 (28)
606 (68)
279 (32)
196 (12)
595 (38)
234 (15)
17 (1)
159 (10)
150 (10)
532 (36)
205 (14)
13 (<1)
156 (11)
145 (16)
246 (28)
91 (10)
3 (<1)
121 (14)
105 (7)
250 (16)
13 (<1)
154 (11)
249 (17)
7 (<1)
84 (9)
181 (20)
14 (2)
1450 (92)
46 (3)
36 (2)
11 (<1)
26 (2)
0
0
0
0
0
0
0
0
0
0
22
Not for publication or presentation
Variable
Bu+Flu
Bu+Flu+Mel
Bu+Flu+TBI
Bu+Flu+Thio
Bu+Flu+other
Flu+Mel
Flu+Mel+BCNU
Flu+Mel+other
Time from diagnosis to HCT
Median (range)
<6 months
6 - 12 months
>12 months
Missing
GVHD prophylaxis
No GVHD prophylaxis
Ex-vivo T-cell depletion
CD34 selection
Post-tx cy
FK506 + MMF +- others
FK506 + MTX +- others
FK506 + others
FK506 alone
CSA + MMF +- others
CSA + MTX +- others
CSA + others
CSA alone
Other GVHD prophylaxis
Missing
ATG/Campath
ATG + CAMPATH
ATG alone
CAMPATH alone
No ATG or CAMPATH
Missing
Type of donor
HLA-identical sibling
Well-matched unrelated
Partially matched unrelated
Mismatched unrelated
Attachment 4
MAC IVBu+Cy MAC IVBu+Flu
0
1295 (88)
0
73 (5)
0
69 (5)
0
7 (<1)
0
22 (2)
0
0
0
0
0
0
RIC
Flu+Mel
0
0
0
0
0
713 (81)
129 (15)
43 (5)
6 (<1-607)
844 (54)
350 (22)
374 (24)
1 (<1)
7 (<1-173)
635 (43)
426 (29)
404 (28)
1 (<1)
7 (<1-275)
378 (43)
265 (30)
242 (27)
0
11 (<1)
28 (2)
6 (<1)
27 (2)
107 (7)
927 (59)
42 (3)
41 (3)
45 (3)
263 (17)
17 (1)
37 (2)
17 (1)
1 (<1)
14 (<1)
47 (3)
26 (2)
15 (1)
321 (22)
805 (55)
58 (4)
44 (3)
23 (2)
75 (5)
6 (<1)
16 (1)
8 (<1)
8 (<1)
20 (2)
3 (<1)
3 (<1)
1 (<1)
165 (19)
225 (25)
55 (6)
54 (6)
134 (15)
120 (14)
63 (7)
33 (4)
7 (<1)
2 (<1)
0
303 (19)
14 (<1)
1230 (78)
22 (1)
0
678 (46)
35 (2)
699 (48)
54 (4)
1 (<1)
241 (27)
159 (18)
434 (49)
50 (6)
555 (35)
718 (46)
194 (12)
33 (2)
402 (27)
746 (51)
232 (16)
25 (2)
203 (23)
434 (49)
146 (16)
33 (4)
23
Not for publication or presentation
Variable
Unrelated TBD
Graft type
Bone marrow
Peripheral blood
Year of HCT
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
Median follow-up of survivors (range), months
Attachment 4
MAC IVBu+Cy MAC IVBu+Flu
69 (4)
61 (4)
RIC
Flu+Mel
69 (8)
405 (26)
1164 (74)
259 (18)
1207 (82)
131 (15)
754 (85)
28 (2)
67 (4)
157 (10)
191 (12)
184 (12)
172 (11)
231 (15)
212 (14)
229 (15)
45 (3)
53 (3)
58 (3-143)
31 (2)
56 (4)
58 (4)
122 (8)
140 (10)
161 (11)
185 (13)
259 (18)
193 (13)
130 (9)
131 (9)
51 (3-127)
51 (6)
83 (9)
100 (11)
128 (14)
110 (12)
101 (11)
84 (9)
67 (8)
18 (2)
55 (6)
88 (10)
60 (3-124)
Selection criteria:
st
1 HCT for adult AML/MDS between 2002 and 2012 after CAP modeling
Myeloablative conditioning of IV Bu/Cy, IV Bu/Flu or RIC Flu/Mel
Bone marrow or peripheral blood graft
Excluding identical twin and haploidentical donor
Complete research form
Patient consent
24
Not for publication or presentation
Attachment 5
Study Proposal 1411-03
Study Title:
Outcomes of autologous and allogeneic transplant for core binding factor leukemias in second or
subsequent complete remission
Luciano J. Costa, MD, PhD, University of Alabama at Birmingham, AL, ljcosta@uabmc.edu
Ayman Saad, MD, University of Alabama at Birmingham, AL, asaad@uabmc.edu
Shin Mineishi, MD, University of Alabama at Birmingham, AL, smineishi@uabmc.edu
Hypothesis:
Patients with core binding factor (CBF) leukemias in second or subsequent remission have outcomes
with autologous HCT (auto-HCT) that are comparable to outcomes with allogeneic HCT (allo-HCT).
Specific Aims:
1. To describe outcomes of auto-HCT and allo-HCT in patients with CBF leukemia in second or
subsequent remission
2. To compare leukemia free survival (LFS), overall survival (OS) and non-relapse mortality (NRM)
between auto-HCT and allo-HCT in the above setting adjusting for co-variables that may
independent affect outcomes.
Scientific Justification:
Acute myelogenous leukemia with inv(16), t(16;16) or t(8;21) (CBF AML) account for approximately 15%
of cases of AML1,2, typically present in younger patients and have a relatively favorable prognosis when
compared to other cytogenetic subtypes of AML. Conventional cytotoxic chemotherapy containing high
doses of cytarabine is currently the preferred post-remission therapy and HCT is not typically pursued in
CR13. Even though the initial remission rate is approximately 90%1-3 , up to 50% of patients in CR will
experience relapse1,2. Nevertheless, the 5-year survival is above 50%1,2, indicating that many patients
will experience leukemia relapse but benefit from subsequent therapy that, in most cases, will include
HCT.
The vast majority of HCT performed for AML are allogeneic transplants, aiming at the proven benefit of
graft-versus-leukemia (GVL) effect. The benefit of GVL is at least partially overcome by the risk of graft
versus host disease (GVHD). Although the balance of GVL/GVHD clearly favors allo-HCT in intermediate
and high risk leukemias, this is less clear in CBF-AML where the risk of relapse is lower4. In fact,
outcomes of auto-HCT in CBF leukemia have been reported to be similar to allo-HCT in a large US
intergroup study3. A large retrospective European study also identified near “identical” outcomes
between auto-HCT and genoidentical allo-HCT for patients in CR15. Very similar outcomes were also
seen in a large Japanese study6 and in a German individual patient data meta-analysis7. Much less is
known about the outcomes of patients in CR2+ with auto-HCT and with alternative donor
transplantation8.
Patient Eligibility Population:
 Diagnosis of AML with inv (16), t(16;16) or t(8;21)
 Second or subsequent complete remission at time of transplant
 First HCT of any type
 No age restriction.
 Data available at least to day+100.
25
Not for publication or presentation

Attachment 5
Transplant between 1992 and 2012
Data Requirements: No supplemental data collection is required.
Sample Requirements: No samples required.
Study Design:
Variables to be analyzed:
Patient related:
 Age
 Sex
 HCT-CI prior to transplant
 KPS prior to transplant
 Race/ethnicity
Disease related:
 Presence of kit mutation9, if known
 Number of lines of therapy prior to transplant.
 CR2 vs CR3+
Transplant related:
 Auto-HCT vs. Allo-HCT (main effect)
 Conditioning regimen (MA vs. RIC vs. NMA)
 Mobilization regimen (for auto-HCT)
 Donor source (MRD, MMRD, MUD, MMUD).
 Graft type (peripheral blood, bone marrow, cord blood).
 Time from diagnosis to transplant
 Calendar year of transplant
Outcomes:
 Engraftment kinetics
 Rate and severity of acute and chronic GVHD.
 Duration of follow up and survival status.
 Occurrence and timing of relapse.
 Cause of death
 Occurrence of second transplant (timing and type)
Analysis plan:
LFS, OS, NRM and cumulative incidence of relapse (CIR) will be described for both auto-HCT and alloHCT. Relapse and non-relapse death will be treated as competing events. If numbers allow, outcomes of
allo-HCT will be described for different donor types (MRD, MMRD, MUD/MUD, cord blood).
A multivariate analysis (MVA) including patient-related, disease-related and transplant-related variables
will be performed to identify factors associated with the main endpoints of LFS and OS. Type of HCT
(auto-HCT or allo-HCT), the main interest of the study, will be “forced” into each of the multivariate
models.
If the number of patients allows we will perform propensity score matching prior to comparing
transplant strategies (as an alternative to MVA).
26
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Attachment 5
References:
1. Grimwade D, Hills RK, Moorman AV, et al: Refinement of cytogenetic classification in acute myeloid
leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities
among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials.
Blood 116:354-65, 2010
2. Byrd JC, Mrozek K, Dodge RK, et al: Pretreatment cytogenetic abnormalities are predictive of
induction success, cumulative incidence of relapse, and overall survival in adult patients with de
novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood
100:4325-36, 2002
3. Slovak ML, Kopecky KJ, Cassileth PA, et al: Karyotypic analysis predicts outcome of preremission and
postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern
Cooperative Oncology Group Study. Blood 96:4075-83, 2000
4. Burnett AK, Goldstone AH, Stevens RM, et al: Randomised comparison of addition of autologous
bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first
remission: results of MRC AML 10 trial. UK Medical Research Council Adult and Children's Leukaemia
Working Parties. Lancet 351:700-8, 1998
5. Gorin NC, Labopin M, Frassoni F, et al: Identical outcome after autologous or allogeneic
genoidentical hematopoietic stem-cell transplantation in first remission of acute myelocytic
leukemia carrying inversion 16 or t(8;21): a retrospective study from the European Cooperative
Group for Blood and Marrow Transplantation. J Clin Oncol 26:3183-8, 2008
6. Kuwatsuka Y, Miyamura K, Suzuki R, et al: Hematopoietic stem cell transplantation for core binding
factor acute myeloid leukemia: t(8;21) and inv(16) represent different clinical outcomes. Blood
113:2096-103, 2009
7. Schlenk RF, Benner A, Krauter J, et al: Individual patient data-based meta-analysis of patients aged
16 to 60 years with core binding factor acute myeloid leukemia: a survey of the German Acute
Myeloid Leukemia Intergroup. J Clin Oncol 22:3741-50, 2004
8. Hospital MA, Prebet T, Bertoli S, et al: Core-binding factor acute myeloid leukemia in first relapse: a
retrospective study from the French AML Intergroup. Blood 124:1312-9, 2014
9. Paschka P, Marcucci G, Ruppert AS, et al: Adverse prognostic significance of KIT mutations in adult
acute myeloid leukemia with inv(16) and t(8;21): a Cancer and Leukemia Group B Study. J Clin Oncol
24:3904-11, 2006
27
Not for publication or presentation
Attachment 5
Characteristics of Study Population
Variable
Number of patients
Number of centers
Age in decades
Median (range)
<10
10-19
20-29
30-39
40-49
50-59
60-69
>=70
Gender
Male
Female
Recipient race
Caucasian
African-American
Asian
Pacific islander
Native American
Other
Unknown
Karnofsky score
<90%
>=90%
Missing
White blood count at diagnosis
Median (range)
<= 10
10 - 100
> 100
Missing
HCT-CI
0
1
2
3+
N/A, earlier than 2007
CR2
421
143
>=CR3
28
19
34 (2-75)
49 (12)
60 (14)
73 (17)
63 (15)
85 (20)
67 (16)
19 (5)
5 (1)
43 (5-67)
1 (4)
1 (4)
6 (21)
4 (14)
6 (21)
5 (18)
5 (18)
0
243 (58)
178 (42)
16 (57)
12 (43)
345 (82)
22 (5)
39 (9)
1 (<1)
2 (<1)
2 (<1)
10 (2)
18 (64)
5 (18)
2 (7)
1 (4)
0
0
2 (7)
74 (18)
325 (77)
22 (5)
3 (11)
22 (79)
3 (11)
30 (<1-462)
107 (25)
195 (46)
56 (13)
63 (15)
17 (1-158)
6 (21)
12 (43)
2 (7)
8 (29)
118 (28)
18 (4)
12 (3)
46 (11)
225 (53)
9 (32)
1 (4)
2 (7)
4 (14)
12 (43)
28
Not for publication or presentation
Variable
Missing
Conditioning regimen intensity
Myeloablative
RIC
NMA
TBD
Missing
Time from diagnosis to HCT
Median (range)
<6 months
6 - 12 months
>12 months
Graft type
Bone marrow
Peripheral blood
Umbilical cord blood
Type of donor
HLA-identical sibling
Other related
Well-matched unrelated
Partially matched unrelated
Mismatched unrelated
Unrelated TBD
Cord blood
Donor/Recipient sex match
M/M
M/F
F/M
F/F
TBD
Donor/Recipient CMV match
-/-/+
+/+/+
TBD
GVHD prophylaxis
No GVHD prophylaxis
Ex-vivo T-cell depletion
CD34 selection
Attachment 5
CR2
2 (<1)
>=CR3
0
344 (82)
68 (16)
5 (1)
3 (<1)
1 (<1)
20 (71)
5 (18)
2 (7)
1 (4)
0
17 (2-95)
7 (2)
47 (11)
367 (87)
24 (15-59)
0
0
28
118 (28)
217 (52)
86 (20)
7 (25)
11 (39)
10 (36)
101 (24)
17 (4)
126 (30)
50 (12)
13 (3)
28 (7)
86 (20)
1 (4)
1 (4)
10 (36)
5 (18)
1 (4)
0
10 (36)
148 (35)
103 (24)
94 (22)
73 (17)
3 (<1)
10 (36)
5 (18)
6 (21)
7 (25)
0
98 (23)
118 (28)
42 (10)
126 (30)
37 (9)
2 (7)
11 (39)
4 (14)
11 (39)
0
3 (<1)
19 (5)
8 (2)
0
1 (4)
1 (4)
29
Not for publication or presentation
Variable
Post-tx cy
FK506 + MMF +- others
FK506 + MTX +- others
FK506 + others
FK506 alone
CSA + MMF +- others
CSA + MTX +- others
CSA + others
CSA alone
Other GVHD prophylaxis
Missing
Year of HCT
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
Median follow-up of survivors (range), months
Attachment 5
CR2
1 (<1)
28 (7)
138 (33)
18 (4)
11 (3)
66 (16)
99 (24)
13 (3)
12 (3)
4 (<1)
1 (<1)
>=CR3
0
7 (25)
10 (36)
0
1 (4)
5 (18)
2 (7)
0
1 (4)
0
0
21 (5)
24 (6)
24 (6)
30 (7)
39 (9)
32 (8)
24 (6)
31 (7)
51 (12)
58 (14)
36 (9)
20 (5)
31 (7)
61 (3-168)
0
0
1 (4)
3 (11)
5 (18)
2 (7)
0
1 (4)
2 (7)
2 (7)
7 (25)
2 (7)
3 (11)
46 (3-98)
Hailin comments:
468 cases selected for allo HCT in >=CR2 with CBF
10 cases selected for auto HCT in >=CR2 with CBF (36 if including all disease status)
Selection:
st
nd
1 allo HCT for CBF AML in 2 or subsequent CR between 2000 and 2012 after CAP modeling
Excluding syngeneic twin donor
Complete research form
Patient consent
30
Not for publication or presentation
Attachment 6
Study Proposal 1411-20
Study Title:
Effect of in vivo T cell depletion on transplant outcomes in CMV seropositive and seronegative recipients
with acute myeloid leukemia
Mohamed Shanavas, MD, FRACP, FRCPA, Princess Margaret Cancer Centre, University of Toronto, ON
Canada, Mohamed.shanavas@uhn.ca
Dennis Kim MD, PhD, Princess Margaret Cancer Centre, University of Toronto, ON Canada,
dr.dennis.kim@uhn.ca
Hypothesis:
There is likely an interaction (effect modification) between T-Cell depletion (TCD) and recipient CMV
serostatus in allogeneic hematopoietic cell transplantation (allo-HCT). In vivo TCD may result in higher
relapse rate and inferior overall survival in CMV seropositive but not in CMV seronegative recipients
undergoing allo-HCT for acute myeloid leukemia (AML).
Specific Aim:
To assess the effect of in vivo TCD on transplant outcomes in AML by stratified analysis based on CMV
serostatus of recipients.
Exploratory Aims:
To explore whether this effect of T cell depletion varies between alemtuzumab and ATG
To explore the effect of donor CMV serostatus on these outcomes
To explore the effect of CMV reactivation in these outcomes
Outcomes of interest are:
 Cumulative Incidence of Relapse (CIR)
 Non-relapse mortality (NRM)
 Overall survival (OS)
 Leukemia-free survival (LFS)
 Acute Graft versus host disease (acute GVHD)
 Chronic Graft versus host disease (chronic GVHD)
Scientific Justification:
A number of studies have reported an association between CMV reactivation / seropositivity and
reduced relapse risk after allogeneic HCT for acute myeloid leukemia.1-3 However, this finding was not
reproduced in cohorts with significant proportion of T cell depleted transplants.4, 5 This may suggest an
interaction between the effects CMV and T cell depletion in this setting. In a single institution
retrospective study we have observed that in CMV seropositive recipients low relapse rate was seen
only in non-TCD transplants; whereas CMV seropositive recipients undergoing TCD with in vivo
alemtuzumab actually had a paradoxically increased relapse rate (unpublished data, manuscript under
review, and in available on request).6 In the same study we also observed that TCD did not result in
increased relapse risk in CMV seronegative recipients.
The above findings can be explained by opposing actions of CMV on tumor immunity. On one hand,
CMV reactivation has an immune stimulating effect by facilitating maturation of NK and T cells;7-9 on the
31
Not for publication or presentation
Attachment 6
other hand, latent CMV infection has an immunosuppressive effect by increasing the concentrations of
TGF-β and cellular IL-10 in the tumor microenvironment.10 It is possible that the net effect of this
complex interaction may favor antileukimic effect in the presence of competent immune effectors;
whereas in T/NK cell depleted patients the overall effect may be reversed towards the direction of
decreased tumor immunity.
This finding raises a potential safety concern with in vivo T-cell depletion in CMV seropositive patients.
However, this needs to be confirmed in a larger database. Similarly it needs to be seen whether this is
specific for alemtuzumab or not? The effect of CMV reactivation and donor CMV status also need to be
explored if sample size is sufficiently large for stratified analysis. The large size of the CIBMTR registry
should provide an opportunity to explore these in a well-powered study.
Patient Eligibility Population:
Inclusion criteria (should meet all the criteria):
 Diagnosis of AML
 First allogeneic HCT
 Year of HCT between 2000 and 2011
 Age 18 years and older at the time of HCT
 Transplant in complete remission or leukemia free status
 Transplant from matched related or 10/10 unrelated donor
 Peripheral blood or bone marrow graft
Exclusion criteria:
 Syngeneic transplants
 Cord-blood transplants
 Haplo-identical transplants
 Transplant with partially matched donors
 Transplant for leukemia not in remission
 Ex vivo T cell depletion or manipulation
 Post transplant DLI prior to relapse
 Post transplant tumor vaccination
 Prior history of CLL (possibility of prior alemtuzumab)
 Prior history of treatment for aplastic anemia (possibility of ATG)
Data Requirement:
CIBMTR Data Collection forms needed:
 Recipient baseline Data; Form 2000
 Infectious Disease Markers; Form 2004
 AML pre-HCT data; Form 2010
 100 day post HCT data; Form 2100
 6 months – 2 year post HCT data; Form 2200
 Yearly follow up for greater than 2 years Data; Form 2300
 Pre-transplant Essential Data; Form 2400
 Post transplant Essential Data; Form 2450
 Recipient Death Data; Form 2900
Other data requirements:
 Supplemental data requirement: None
32
Not for publication or presentation

Attachment 6
Non –CIBMTR data used: None
Study Design:
Variables to be analyzed:
Patient related:
 Age at HCT
 Gender
 Karnofsky Performance Score: <90 vs. >90 (if available)
 Donor related
 Gender
 CMV serostatus
 Donor type: Matched related vs. matched unrelated
Disease related:
 Type of AML: Denovo AML vs. secondary AML vs. therapy related AML
 Cytogenetics: good risk vs. intermediate vs. poor risk vs. not available (defined according to
SWOG/ECOG definition11)
 Status at HCT: CR1 vs. CR2
Transplant related:
 Year of transplant: 2000-2005 vs. 2006-2011
 Conditioning regimen MAC vs. RIC vs. NMA (as defined by CIBMTR12)
 TBI vs. No TBI with dose of TBI if available
 Type of in vivo T cell depletion: ATG vs. Alemtuzumab vs. none
 Type of ATG if available: horse vs. rabbit
 Total dose of alemtuzumab if available
 GVHD prophylaxis: Calcineurin inhibitor (CNI) + MTX vs. CNI + MMF vs. others
 Source of stem cells: Bone marrow vs. Peripheral blood
Outcome variables:
 Time from HCT to death
 Time from HCT to relapse
 Onset of acute GVHD
 Maximum grade of acute GVHD
 Onset of chronic GVHD
 Maximum grade of chronic GVHD (if available)
 Type of chronic GVHD (extensive vs. limited)
 CMV reactivation
 Onset
 Treatment
 Biological Sample Requirements: None
Effect of T Cell depletion on Transplant outcomes will be analyzed separately for CMV seropositive and
seronegative recipients. Kaplan Meir method and log rank test will be used for time to event endpoints
without competing risks, and cumulative incidence method and Gray’s tests for time to event endpoints
with competing risks.
33
Not for publication or presentation
Attachment 6
Test for interaction between T cell depleted status and recipient CMV serostatus will be performed in
the multivariable analysis of relapse. If interaction is confirmed, further analysis of risk factors for
relapse, NRM, OS, LFS, acute GVHD, and chronic GVHD will be performed by stratified multivariable
analysis (stratified by recipient CMV serostatus)
Graft versus host disease will be used as a time dependent covariable in multivariable analysis if
information about the time of onset in available in sufficient proportion of patients. Further plan will be
developed depending on sample size after discussion with statistical team at CIBMTR.
References:
1. Green ML, Leisenring WM, Xie H, Walter RB, Mielcarek M, Sandmaier BM, et al. CMV reactivation
after allogeneic HCT and relapse risk: evidence for early protection in acute myeloid leukemia. Blood
2013; 122: 1316-1324.
2. Manjappa S, Bhamidipati PK, Stokerl-Goldstein KE, DiPersio JF, Uy GL, Westervelt P, et al. Protective
effect of cytomegalovirus reactivation on relapse after allogeneic hematopoietic cell transplantation
in acute myeloid leukemia patients is influenced by conditioning regimen. Biol Blood Marrow
Transplant 2014; 20: 46-52.
3. Elmaagacli AH, Steckel NK, Koldehoff M, Hegerfeldt Y, Trenschel R, Ditschkowski M, et al. Early
human cytomegalovirus replication after transplantation is associated with a decreased relapse risk:
evidence for a putative virus-versus-leukemia effect in acute myeloid leukemia patients. Blood 2011;
118: 1402-1412.
4. Schmidt-Hieber M, Labopin M, Beelen D, Volin L, Ehninger G, Finke J, et al. CMV serostatus still has
an important prognostic impact in de novo acute leukemia patients after allogeneic stem cell
transplantation: a report from the Acute Leukemia Working Party of EBMT. Blood 2013; 122: 33593364.
5. Ljungman P, Brand R, Einsele H, Frassoni F, Niederwieser D, Cordonnier C. Donor CMV serologic
status and outcome of CMV-seropositive recipients after unrelated donor stem cell transplantation:
an EBMT megafile analysis. Blood 2003; 102: 4255-4260.
6. Shanavas M, Uhm J, Alam N, Gupta V, Kuruvilla J, Lipton H. Protective Effect Of CMV In Myeloid
Malignancies Undergoing HCT Is Altered In The Presence Of Alemtuzumab; Evidence For Effect
Modification. Unpublished article, Manuscript under review
7. Scheper W, van Dorp S, Kersting S, Pietersma F, Lindemans C, Hol S, et al. γδT cells elicited by CMV
reactivation after allo-SCT cross-recognize CMV and leukemia. Leukemia 2013; 27: 1328-1338.
8. Gumá M, Budt M, Sáez A, Brckalo T, Hengel H, Angulo A, et al. Expansion of CD94/NKG2C+ NK cells
in response to human cytomegalovirus-infected fibroblasts. Blood 2006; 107: 3624-3631.
9. Chiesa MD, Falco M, Bertaina A, Muccio L, Alicata C, Frassoni F, et al. Human Cytomegalovirus
Infection Promotes Rapid Maturation of NK Cells Expressing Activating Killer Ig–like Receptor in
Patients Transplanted with NKG2C−/− Umbilical Cord Blood. The Journal of Immunology 2014; 192:
1471-1479.
10. Mason GM, Poole E, Sissons JGP, Wills MR, Sinclair JH. Human cytomegalovirus latency alters the
cellular secretome, inducing cluster of differentiation (CD)4+ T-cell migration and suppression of
effector function. Proceedings of the National Academy of Sciences 2012; 109: 14538-14543.
11. Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A, et al. Karyotypic analysis
predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a
Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 2000; 96: 4075-4083.
12. Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V, et al. Defining the intensity of conditioning
regimens: working definitions. Biol Blood Marrow Transplant 2009; 15: 1628-1633.
34
Not for publication or presentation
Attachment 6
35
Not for publication or presentation
Attachment 6
The plots on the right hand side show increased relapse and inferior OS in CMV with TCD in CMV
seropositive recipients. This effect was not seen in CMV seronegative recipients.
Characteristics of Study Population
Variable
Number of patients
Number of centers
Age in decades
Median (range)
18-29
30-39
40-49
50-59
60-69
>=70
Gender
Male
Female
Karnofsky score
<90%
>=90%
Missing
White blood count at diagnosis
Median (range)
<= 10
10 - 100
> 100
Missing
Type of AML
De-novo
Transformed from MDS/MPS
Therapy linked
Cytogenetics scoring
Normal
Favorable
Intermediate
Poor
Missing
Disease status prior to HCT
CR1
CR2
Conditioning regimen intensity
Myeloablative
RIC
NMA
TBD
Missing
TCD CMV- TCD CMV+
335
611
96
121
noTCD CMV- noTCD CMV+
1102
1954
150
184
52 (18-74)
50 (15)
41 (12)
55 (16)
107 (32)
76 (23)
6 (2)
54 (18-78)
61 (10)
60 (10)
122 (20)
202 (33)
152 (25)
14 (2)
47 (18-74)
190 (17)
171 (16)
287 (26)
333 (30)
112 (10)
9 (<1)
47 (18-75)
303 (16)
328 (17)
515 (26)
552 (28)
234 (12)
22 (1)
196 (59)
139 (41)
317 (52)
294 (48)
631 (57)
471 (43)
957 (49)
997 (51)
87 (26)
232 (69)
16 (5)
169 (28)
405 (66)
37 (6)
288 (26)
756 (69)
58 (5)
512 (26)
1353 (69)
89 (5)
7 (<1-322)
169 (50)
107 (32)
13 (4)
46 (14)
7 (<1-1300)
306 (50)
185 (30)
47 (8)
73 (12)
9 (<1-1048)
508 (46)
391 (35)
79 (7)
124 (11)
10 (<1-999)
850 (44)
689 (35)
175 (9)
240 (12)
249 (74)
18 (5)
68 (20)
462 (76)
40 (7)
109 (18)
887 (80)
71 (6)
144 (13)
1566 (80)
99 (5)
289 (15)
78 (23)
26 (8)
80 (24)
69 (21)
82 (24)
173 (28)
42 (7)
134 (22)
124 (20)
138 (23)
316 (29)
91 (8)
232 (21)
250 (23)
213 (19)
634 (32)
183 (9)
427 (22)
378 (19)
332 (17)
243 (73)
92 (27)
469 (77)
142 (23)
829 (75)
273 (25)
1410 (72)
544 (28)
175 (52)
135 (40)
19 (6)
4 (1)
2 (<1)
288 (47)
273 (45)
27 (4)
23 (4)
0
887 (80)
144 (13)
58 (5)
13 (1)
0
1496 (77)
307 (16)
118 (6)
33 (2)
0
36
Not for publication or presentation
Variable
TBI
No
Yes
ATG/Campath
ATG + CAMPATH
ATG alone
CAMPATH alone
No ATG or CAMPATH
GVHD prophylaxis
Post-tx cy
FK506 + MMF +- others
FK506 + MTX +- others
FK506 + others
FK506 alone
CSA + MMF +- others
CSA + MTX +- others
CSA + others
CSA alone
Other GVHD prophylaxis
Graft type
Bone marrow
Peripheral blood
Type of donor
HLA-identical sibling
Well-matched unrelated
Donor/Recipient CMV match
-/-/+
+/+/+
Donor/Recipient sex match
M/M
M/F
F/M
F/F
Year of HCT
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
Attachment 6
TCD CMV- TCD CMV+
noTCD CMV- noTCD CMV+
278 (83)
57 (17)
538 (88)
73 (12)
600 (54)
502 (46)
1172 (60)
782 (40)
0
302 (90)
33 (10)
0
1 (<1)
532 (87)
78 (13)
0
0
0
0
1102
0
0
0
1954
1 (<1)
50 (15)
137 (41)
6 (2)
15 (4)
31 (9)
64 (19)
13 (4)
12 (4)
6 (2)
1 (<1)
81 (13)
243 (40)
17 (3)
42 (7)
63 (10)
107 (18)
16 (3)
33 (5)
8 (1)
11 (<1)
143 (13)
457 (41)
48 (4)
16 (1)
75 (7)
313 (28)
11 (<1)
22 (2)
6 (<1)
7 (<1)
204 (10)
724 (37)
82 (4)
32 (2)
165 (8)
640 (33)
16 (<1)
71 (4)
13 (<1)
59 (18)
276 (82)
117 (19)
494 (81)
220 (20)
882 (80)
406 (21)
1548 (79)
74 (22)
261 (78)
188 (31)
423 (69)
564 (51)
538 (49)
1207 (62)
747 (38)
238 (71)
0
97 (29)
0
0
322 (53)
0
289 (47)
768 (70)
0
334 (30)
0
0
828 (42)
0
1126 (58)
135 (40)
89 (27)
61 (18)
50 (15)
217 (36)
181 (30)
100 (16)
113 (18)
422 (38)
277 (25)
209 (19)
194 (18)
610 (31)
584 (30)
347 (18)
413 (21)
12 (4)
11 (3)
19 (6)
24 (7)
29 (9)
30 (9)
39 (12)
37 (11)
52 (16)
40 (12)
22 (7)
20 (3)
24 (4)
37 (6)
43 (7)
48 (8)
84 (14)
73 (12)
64 (10)
73 (12)
63 (10)
49 (8)
59 (5)
60 (5)
54 (5)
54 (5)
99 (9)
137 (12)
114 (10)
114 (10)
129 (12)
130 (12)
119 (11)
99 (5)
108 (6)
152 (8)
141 (7)
226 (12)
219 (11)
201 (10)
163 (8)
194 (10)
214 (11)
176 (9)
37
Not for publication or presentation
Variable
2011
Median follow-up of survivors (range), months
Attachment 6
TCD CMV- TCD CMV+
20 (6)
33 (5)
70 (3-169) 70 (2-172)
noTCD CMV- noTCD CMV+
33 (3)
61 (3)
70 (1-171) 68 (1-168)
Selection:
st
1 allo HCT for adult AML in CR1/CR2 between 2000 and 2011 after CAP modeling
HLA-identical sibling or well-matched unrelated donor
excluding ex-vivo TCD
excluding prior history of CLL or aplastic anemia
complete research form
patient consent
38
Not for publication or presentation
Attachment 7
Study Proposal 1411-49/1311-34
Study Title:
Impact of GVHD on outcome after allogeneic hematopoietic cell transplantation for acute lymphocytic
leukemia: a retrospective registry study
Moshe Yeshurun, MD, BMT unit, Institute of hematology, Rabin Medical Center, Petach-Tikva, Israel,
moshe.yeshurun@gmail.com
Jacob M. Rowe, MD, Department of hematology, Shaare Zedek Medical Center, Jerusalem, Israel,
rowe@rambam.health.gov.il
Martin S. Tallman, MD, Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, N.Y.,
USA, TallmanM@mskcc.org
Veronika Bachanova, MD, PhD, Division of Hematology, Oncology and Transplantation, University of
Hypothesis:
The graft-versus-leukemia (GVL) effect and the graft-versus-host disease (GVHD) are closely associated.
However, the strength of this association has been shown to differ significantly between different
hematological malignancies. The increased non-relapse mortality (NRM) associated with GVHD,
particularly in its severe forms, may potentially outweigh the favorable GVL effect on disease relapse.
Nevertheless, there are no sound data on the net impact of acute and chronic GVHD on survival of
patients with acute lymphocytic leukemia (ALL) after allogeneic hematopoietic cell transplantation
(alloHCT).
Specific Aims:
1. Identify any differential GVHD-associated GVL influences after alloHCT for ALL, using either
myeloablative or reduced intensity conditioning regimens.
2. Study the impact of acute and chronic GVHD and its extent on relapse, NRM, DFS and OS rates after
alloHCT for ALL.
Scientific Justification:
The GVL effect following alloHCT is the single most potent antileukemic strategy for adult patients with
ALL as reflected by a significantly reduced relapse rate post alloHCT compared to relapse rates with
standard chemotherapy or after autologous stem cell transplantation (1). While the GVL effect may
occur in the absence of clinical GVHD (2), there are ample of data suggesting that acute and chronic
GVHD are associated with an augmented GVL effect (3). Nevertheless, GVHD affecting more than 50% of
transplanted patients, remains a major cause of morbidity and mortality after allogeneic
transplantation. Hence, the increased non-relapse mortality (NRM) associated with GVHD, particularly in
its severe forms, may potentially offset the favorable GVL effect on disease relapse, thus resulting in a
non-favorable net impact on survival.
Indeed, in a recent retrospective analysis on behalf the CIBMTR, GVHD did not prove to have a beneficial
impact on the overall survival (OS) of AML patients in the myeloablative conditioning (MAC) setting (4).
In fact, acute GVHD emerged as an adverse prognostic factor on OS. Lacking any protective effect
against relapse, acute GVHD had a detrimental effect on NRM, which translated into inferior survival of
patients with acute GVHD compared to patients without any GVHD (HR 1.71, p<0.0001). As for chronic
GVHD, despite its favorable protective effect against relapse (HR 0.68, p< 0.0001), this influence was
offset by increased NRM (HR 2.24, p< 0.0001) and consequently by comparable OS. In the RIC setting,
39
Not for publication or presentation
Attachment 7
acute GVHD had actually a protective effect against relapse (HR 0.63, P<0.0001); nevertheless, it was
offset by increased NRM (HR 3.66, p<0.0001), thus resulting in comparable OS rates in patients with
acute GVHD and in patients without any GVHD. However, the chronic GVHD-associated protective effect
against relapse (HR 0.53, p<0.0001) was only partially offset by increased NRM (HR 2.1, P<0.0001),
which translated into superior survival of patients with chronic GVHD compared to patients without any
GVHD (0.74, p=0.007) after RIC alloHCT. These results are in contrast to a recent report of the Seattle
group arguing that even after RIC alloHCT any potential benefit associated with chronic GVHD is
outweighed by increased NRM and thus does not translate into a better survival (5).
In a recent EBMT megafile analysis, the strength of the GVHD / GVL association has been shown to differ
significantly between hematological malignancies (6). AML appeared relatively insensitive to
development of acute GVHD and limited chronic GVHD; nevertheless, relevant reductions in relapse risk
have been reported in patients experiencing extensive chronic GVHD. ALL however proved to be highly
sensitive to acute and chronic GVHD, comparably to CML. The higher sensitivity of ALL to GVHD
compared to AML had previously been shown by Weiden et al (7). Also, patients with ALL and AML may
differ in their vulnerability to GVHD, which may translate into different NRM rates. Accordingly, the net
impact of acute and chronic GVHD on survival may differ between patients with AML and ALL.
Furthermore, the net impact of GVHD on OS of ALL patients may vary after MAC and RIC alloHCT.
Thus, the objective of the current retrospective study is to assess the impact of the different variants of
GVHD (i.e. acute or chronic, limited or extensive) on transplant outcomes of ALL patients after alloHCT.
Patient Eligibility Population:
Inclusion criteria:
1. Patients with ALL 16 years or older
2. Any disease status at transplantation
3. Transplanted between the years 1993 and 2012
4. MAC or RIC preparative regimens (8)
5. First transplantation only
6. Peripheral blood, bone marrow and cord blood grafts
Exclusion criteria:
1. Ex-vivo T cell depleted grafts
2. Haploidentical transplants
3. Patients who failed to engraft or who died before engraftment
4. Patients who received pre-emptive DLI
Outcomes:
 Acute and chronic GVHD: Occurrence of grade II, III, and/or IV skin, gastrointestinal or liver
abnormalities fulfilling the Consensus criteria of acute GVHD, and limited and extensive chronic
GVHD.
 Non-relapse mortality: death without relapse or progression, where relapse or progression are
competing risks. Those who survive without recurrence or progression are censored at the time of
last contact.
 Relapse/progression: progressive disease or recurrence of disease are counted as events. Treatment
related death, defined as death without relapse or progression, is the competing event. Those who
survive without recurrence or progression are censored at the time of last contact.
40
Not for publication or presentation


Attachment 7
Progression-free survival (PFS): survival without recurrence or tumor progression. Recurrence of
progression of disease and death are counted as events. Those who survive without recurrence or
progression are censored at the time of last contact.
Overall survival: time to death. Death from any cause will be considered an event. Surviving
patients will be censored at the time of last follow-up.
Data Requirements: None
Sample Requirements: None
Variables to be analyzed:
Time dependent acute (Grade II-IV) and chronic GVHD (limited and extensive)
Patient-related:
 Age at transplant (decades)
 Gender: male vs. female
 Karnofsky performance status transplant: <90% vs. ≥90%
 Co-morbidity index 0-2 vs. ≥3
Disease-related:
 B vs. T cell origin
 Cytogenetics: t(9:22) vs. other high risk (hypoploidity, t(4:11)) vs. intermediate risk
 WBCx109/L: <30 vs. >30 for B-ALL , <100 vs. >100 for T-ALL
 Extramedullary disease at diagnosis: CNS (yes/no), other (yes/no)
 Time to achieve CR1: <4 weeks vs. 4-8 weeks vs. >8 weeks
 Disease status at transplantation: CR1 vs. CR2 vs. CR≥3 vs. no remission
Transplant-related:
 Time from diagnosis to transplant
 Time from remission to transplant
 Conditioning regimen intensity: MAC vs. RIC/NMA
 TBI based vs. non TBI based conditioning
 Type of donor: HLA-identical sibling vs. other related vs. well-matched unrelated (8/8) vs.
partially matched unrelated (7/8) vs. mismatched unrelated donor (7/8>) vs. cord blood
 Donor-recipient gender match: F-M vs. all other donor-recipient gender combinations.
 Donor age : continuous, median (range)
 Donor-recipient CMV status: -/- vs. others
 Source of stem cells: BM vs. PBSC vs. UCB
 Year of transplant: by decades
 GVHD prophylaxis: CSA-based vs Tacro-based vs. other
 In-vivo T cell depletion (ATG, Campath) yes vs. no
Study Design:
This is a retrospective registry study on behalf of the CIBMTR.
Patients will be stratified according to conditioning regimen intensity (MAC vs. RIC). Variables related to
patients, disease, and transplantation will be compared using the chi-square test for categorical
variables and the Mann-Whitney test for continuous variables.
Patients will be divided into 4 groups:
41
Not for publication or presentation
Attachment 7
(1) those without any GVHD, (2) those with acute GVHD only, (3) those with chronic GVHD only, (4)
those with acute GVHD and chronic GVHD.
We will consider only GVHD which occurred before relapse. Time to onset of GVHD will be determined
as time to onset to acute GVHD or chronic GVHD, whichever came first. Acute and chronic GVHD will be
treated as time dependent covariates.
To examine the influence of acute GVHD and chronic GVHD on NRM, relapse, DFS and OS, separate
analyses will be conducted for recipients of MAC and RIC regimens. Cox regression models will be built
to adjust for effects of other patient, disease, and treatment variables. The results of multivariate
analysis will be expressed as hazard ratio with the 95% confidence interval. The probabilities of NRM
and relapse will be calculated using cumulative incidence. Data on patients without an event will be
censored at last follow-up. Probability of DFS and OS will be calculated with the Kaplan-Meier estimator.
We will also perform a landmark analysis for relapse and OS for all patients who survived at least 30
days and 1 year disease-free after their transplantation.
References:
1. Glodstone AH, Richards SM, Lazarus HM, et al. In adults with standard-risk acute lymphoblastic
leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in
first complete remission, and an autologous transplantation is less effective than conventional
consolidation/maintenance chemotherapy in all patients: final results of the international ALL
trial (MRC UKALL XII/ECOG E2993). Blood. 2008; 111: 18271833.
2. Horowitz MM, Gale RP, Sondel PM, et al. Graft-versus-leukemia reactions after bone marrow
transplantation. Blood. 1990; 555-562.
3. Passweg JR, Tiberghien P, Cahn JY, et al. Graft-versus-leukemia effects in T lineage and B lineage
acute lymphoblastic leukemia. Bone Marrow Transplant. 1998; 21: 153-158.
4. Weisdorf D, Zhang MJ, Arora M, et al. Graft-versus-host disease induced graft-versus-leukemia
effect: greater impact on relapse and disease-free survival after reduced intensity conditioning.
Biol Blood Marrow Transpl. 2012; 18: 1727-1733.
5. Storb R, Gyurkocza B, Storer BE, et al. Graft-versus-tumor effects after allogeneic hematapoietic
cell transplantation. J Clin Oncol. 2013; 31: 1530-1538.
6. Stern M, de Wreede LC, Brand R, et al. Sensitivity of hematological malignancies to graft-versushost effects: an EBMT megafile analysis. Leukemia. 2014; 28: 2235-2240.
7. Weiden PL, Flournoy N, Thomas ED, et al. Antileukemic effects of graft versus host disease in
human recipients of allogeneic marrow grafts. N Engl J Med. 1979; 300: 1068-1070.
8. Bacigalupo A, Ballen K, Rizzo D, et al. Defining the intensity of conditioning regimens: working
definitions. Biol Blood Marrow Transpl. 2009; 15: 1628-1633.
42
Not for publication or presentation
Attachment 7
Characteristics of Study Population
Variable
Number of patients
Number of centers
Age in decades
Median (range)
18-29
30-39
40-49
50-59
60-69
>=70
Gender
Male
Female
Karnofsky score
<90%
>=90%
Missing
White blood count at diagnosis
Median (range)
<= 10
10 - 100
> 100
Missing
HCT-CI
0
1
2
3+
N/A, earlier than 2007
Missing
Philadelphia positive
No
Yes
FAB classification
T-cell
B-cell
Unspecified
Extramedullary disease at diagnosis
N (%)
3334
256
33 (16-72)
1433 (43)
710 (21)
633 (19)
441 (13)
116 (3)
1 (<1)
2005 (60)
1329 (40)
959 (29)
2218 (67)
157 (5)
13 (<1-2000)
1188 (36)
1032 (31)
405 (12)
709 (21)
513 (15)
125 (4)
79 (2)
165 (5)
2444 (73)
8 (<1)
2665 (80)
669 (20)
513 (15)
1996 (60)
825 (25)
43
Not for publication or presentation
Variable
No
Yes
Missing
EMD at CNS at diagnosis
No
Yes
Missing
EMD at other site at diagnosis
No
Yes
Missing
Disease status prior to HCT
Primary induction failure
CR1
CR2
>=CR3
Relapse
Time from diagnosis to HCT
Median (range)
<6 months
6 - 12 months
>12 months
Conditioning regimen intensity
Myeloablative
RIC
NMA
TBD
Missing
TBI
No
Yes
Graft type
Bone marrow
Peripheral blood
Umbilical cord blood
Type of donor
HLA-identical sibling
Well-matched unrelated
Partially matched unrelated
Mismatched unrelated
Attachment 7
N (%)
2784 (84)
435 (13)
115 (3)
2996 (90)
223 (7)
115 (3)
2976 (89)
243 (7)
115 (3)
147 (4)
1699 (51)
861 (26)
175 (5)
452 (14)
8 (<1-279)
1198 (36)
912 (27)
1224 (37)
2947 (88)
265 (8)
41 (1)
40 (1)
41 (1)
690 (21)
2644 (79)
965 (29)
1966 (59)
403 (12)
1092 (33)
1027 (31)
484 (15)
145 (4)
44
Not for publication or presentation
Variable
Unrelated TBD
Cord blood
Donor/Recipient sex match
M/M
M/F
F/M
F/F
TBD
Donor/Recipient CMV match
-/-/+
+/+/+
TBD
GVHD prophylaxis
No GVHD prophylaxis
Post-tx cy
FK506 + MMF +- others
FK506 + MTX +- others
FK506 + others
FK506 alone
CSA + MMF +- others
CSA + MTX +- others
CSA + others
CSA alone
Other GVHD prophylaxis
Missing
In-vivo TCD
No
Yes
Missing
GVHD occurance
AGVHD + cGVHD before relapse
AGVHD before relapse
CGVHD before relapse
No GVHD before relapse
GVHD occured but time unknown
Year of HCT
2000
2001
Attachment 7
N (%)
183 (5)
403 (12)
1282 (38)
757 (23)
713 (21)
565 (17)
17 (<1)
774 (23)
832 (25)
365 (11)
1091 (33)
272 (8)
42 (1)
9 (<1)
346 (10)
1070 (32)
149 (4)
54 (2)
307 (9)
1120 (34)
114 (3)
80 (2)
26 (<1)
17 (<1)
2423 (73)
712 (21)
199 (6)
613 (18)
690 (21)
680 (20)
1255 (38)
96 (3)
232 (7)
274 (8)
45
Not for publication or presentation
Variable
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
Median follow-up of survivors (range), months
Attachment 7
N (%)
301 (9)
266 (8)
338 (10)
369 (11)
367 (11)
297 (9)
298 (9)
210 (6)
132 (4)
139 (4)
111 (3)
70 (1-173)
Selection Criteria:
st
1 HCT for ALL between 2000 and 2012 after CAP modeling
Age >=16
Excluding identical twin or haploidentical donor
Excluding post-HCT pre-emptive DLI
Excluding engraftment failure cases
Complete research form
Patient consent
46
Not for publication or presentation
Attachment 8
Study Proposal 1411-69
Study Title:
Comparison of outcomes of older adolescents and young adults with Philadelphia-chromosome/BCRABL1-negative acute lymphoblastic leukemia receiving post-remission consolidation chemotherapy with
pediatric-inspired chemotherapy on CALGB 10403 or myeloablative allogeneic hematopoietic cell
transplantation
Matthew Joseph Wieduwilt, MD, PhD, UC San Diego Moores Cancer Center, CA, mwieduwilt@ucsd.edu
Wendy Stock, MD, PhD, University of Chicago, IL, wstock@medicine.bsd.uchicago.edu
Hypothesis:
Post-remission consolidation with pediatric-inspired chemotherapy as administered on CALGB 10403
improves overall survival, leukemia-free survival, relapse, and non-relapse mortality compared with
myeloablative allogeneic hematopoietic cell transplantation (HCT) in adult Philadelphiachromosome/BCR-ABL1 negative acute lymphoblastic leukemia patients aged 16-39 years.
Specific Aims:
1. Compare overall survival between older adolescent and young adults aged 16-39 years with Ph/BCRABL1 negative acute lymphoblastic leukemia in first complete remission receiving consolidation
therapy with pediatric-inspired chemotherapy or myeloablative allogeneic hematopoietic cell
transplantation
2. Compare relapse-free survival in the same populations
3. Compare non-relapse mortality in the same populations
4. Compare CNS relapse rate in the same populations
5. Determine patient and disease factors influencing outcomes of consolidation with pediatric-inspired
chemotherapy versus allogeneic hematopoietic cell transplantation
Scientific Justification:
The optimal post-remission treatment strategy for younger patients with Philadelphia-chromosome
negative acute lymphoblastic leukemia in first complete remission has not been well established,
especially in the era of pediatric-inspired chemotherapy regimens consisting of more intensive
consolidation than administered in traditional adult protocols. Previous studies comparing allogeneic
HCT to chemotherapy suggested superiority of consolidation with allogeneic HCT to chemotherapy
including autologous HCT. MRC UK ALL XII/E2993 compared an adult chemotherapy backbone or
autologous HCT to myeloablative allogeneic HCT in Ph-negative ALL patients aged 15-59 years. An
overall survival benefit was seen in standard-risk ALL patients with a donor primarily due to higher rate
of relapse in the no donor group that combined chemotherapy with autologous HCT1. However, studies
comparing only allogeneic HCT to chemotherapy alone without inclusion of autologous transplant have
shown no clear benefit of transplant2. A metanalysis of 13 trials comparing allogeneic HCT to
chemotherapy with or without autologous HCT concluded that the benefit of allogeneic HCT in first CR
Ph-negative ALL was limited to patients under the age of 352, within the same age group that is currently
being recommended for treatment with pediatric-inspired chemotherapy by the NCCN and other
groups.
The application of pediatric-inspired chemotherapy with its more intensive consolidation appears to
have improved outcomes for older adolescents and young adults with Ph-negative ALL. A meta-analysis
of 11 clinical trials showed superior all-cause mortality, event-free survival, and relapse rates in
47
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Attachment 8
adolescents and younger adults, principally under the age of 25 years, treated with pediatric-inspired
chemotherapy relative to conventional adult chemotherapy3. Whether this benefit will be seen in Phnegative ALL patients older than 20-21 years remains to be seen, but current NCCN guidelines
recommend the use of a pediatric-inspired regimen based on retrospective data and results of singlearm phase II trials. The DFCI Adult ALL Consortium recently reported the results of 74 Ph-negative ALL
aged 18-50 treated with pediatric-inspired chemotherapy4. A 4-year EFS of 62% was observed in Ph- ALL
similar to outcomes with the GRAALL-2003 regimen. The small numbers of Ph- ALL patients treated on
this study and the participation of only 13 centers in the northeastern US and Canada limits
interpretation and generalizability of this study, however.
A recent national, large, single-arm, prospective Intergroup study led by the Alliance for Clinical Trials in
Oncology (Study CALGB 10403) studied the safety, tolerability, and efficacy of applying the COG AALL
0232 Standard-risk arm regimen to older adolescents and young adults aged 16-39 years with
Philadelphia-chromosome negative ALL5. The study opened in November 2007 and completed
enrollment with 318 patients in August 2012. The 2-year EFS rate is 66% with a 2-year OS rate of 78%.
Age > 20 years and initial WBC count >30,000/microliter were significantly associated with inferior EFS
and OS. The study now has a median of 30 months follow-up. Given the large size of the study and its
representative sampling of patients from all areas of the US, it serves as an excellent study to compare
outcomes of pediatric-inspired post-remission therapy to myeloablative allogeneic HCT.
A major limitation of individual allogeneic HCT trials as well as meta-analyses is that the comparator
chemotherapy regimens are of relatively low intensity in consolidation compared with modern
pediatric-inspired chemotherapy regimens. Pediatric-inspired post-remission chemotherapy may
improve relapse rates conceivably leading to superior survival with chemotherapy relative to allogeneic
HCT with lower non-relapse mortality and lower morbidity. This study is designed to compare overall
survival, leukemia-free survival, relapse, and non-relapse mortality in Ph-negative ALL patients aged 1639 years undergoing post-remission therapy with pediatric-inspired chemotherapy on CALGB 10403
versus myeloablative allogeneic HCT. Results from this study could further inform the ongoing debate on
the role of allogeneic HCT for Ph-negative ALL in first remission.
Patient Eligibility Population:
Patients age 16-39 with a diagnosis of Philadelphia-chromosome/BCR-ABL1 negative acute
lymphoblastic leukemia undergoing post-remission chemotherapy on CALGB C10403 or allogeneic
hematopoietic cell transplantation in CR1 from 11/1/2007 through 8/31/2012 (enrollment period of
CALGB C10403) and 11/1/2002-10/31/2007.
Excluded are Philadelphia-chromosome/BCR-ABL1 positive ALL, ALL with t(8;14)/Burkitt leukemia (FAB
L3), biphenotypic leukemia, and patients with Down syndrome.
Data Requirements:
Variables to be described:
Chemotherapy and transplant populations
Patient-related:
 Number of patients
 Number of centers
 Age, years: continuous/range
 Age, years: 16-19, 20-29, 30-39, ≤35, >35 years
 Gender: male, female
 Race: non-Hispanic white vs. Hispanic white vs. Black
48
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Attachment 8
 Body mass: Obese vs. non-obese
 Karnofsky performance score: < 90, ≥90
Disease-related:
 Lineage: T-lineage vs. B-lineage ALL
 WBC at diagnosis, B-lineage ALL (x109/L): continuous and <30, ≥30
 WBC at diagnosis, T-lineage ALL (x109/L): continuous and <100, ≥100
 Cytogenetics risk group at diagnosis: Poor (hypodiploid (<44 chromosomes), MLL
rearranged, complex (>4 abnormalities) vs. other
 Extramedullary disease at diagnosis: yes vs. no
 CNS disease at diagnosis: yes vs no
 Testicular disease at diagnosis: yes vs. no
 Time to documentation of CR1: ≤4 weeks, >4-8 weeks, >8 weeks
 Cycles of chemotherapy prior to transplantation: 1,2,3, >3
Transplant population
Transplant-related:
 Graft source: peripheral blood , bone marrow
 Conditioning regimen intensity: myeloablative, reduced intensity, NMA
 Conditioning regimen
 GVHD prophylaxis: FK506 + MTX +- others vs. CSA + MTX +- others vs. ex vivo T-cell
depletion vs. others
 Type of donor: Matched related donor, well-matched unrelated donor, partially matched
unrelated donor, mismatched unrelated donor, unrelated donor match unknown,
mismatched related donor
 Donor age: continuous
 Sex match: M-M, M-F, F-M, F-F
 D/R CMV status: +/+, +/-, -/+, -/ Years of transplant: 11/1/2007-8/31/2012 or 11/1/2002-10/31/2007
 Median follow up: months
 Duration of CR1: <6 months, 6-12 months, >12 months, not available
Variables to be analyzed:
Main effect:
 Post-remission therapy: post-remission chemotherapy on CALGB 10403 vs. myeloablative
allogeneic HCT in CIBMTR
Patient-related:
 Age, years: 16-19, 20-29, 30-39
 Age, years: ≤35, >35 years
 Karnofsky performance score (%): < 90 vs. 90-100
 Gender: Male vs. female
 Body mass: Obese vs. non-obese
 Race: non-Hispanic white vs. Hispanic white vs. Black
Disease-related:
 Lineage: T-lineage vs. B-lineage ALL
 WBC at diagnosis, B-lineage ALL (x109/L): continuous and <30, ≥30
 WBC at diagnosis, T-lineage ALL (x109/L): continuous and <100, ≥100
49
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Attachment 8

Cytogenetics risk group at diagnosis: Poor (hypodiploid (<44 chromosomes), MLL rearranged,
complex (>4 abnormalities) vs. other
 Extramedullary disease at diagnosis: yes vs. no
 CNS disease at diagnosis: yes vs no
 Testicular disease at diagnosis: yes vs. no
 Time to documentation of CR1: ≤4 weeks, >4-8 weeks, >8 weeks
 Cycles of chemotherapy prior to transplantation: 1,2,3, >3
Transplant-related:
 Donor type: Matched related donor, vs. matched unrelated donor vs. mismatched unrelated
donor
 Conditioning regimen intensity: myeloablative, reduced intensity, NMA
 Conditioning regimen: TBI-based vs. no
 In vivo T-cell depletion with ATG, Campath: yes vs no
 Graft source: Peripheral blood vs. bone marrow
 Years of transplant: 11/1/2007-8/31/2012 or 11/1/2002-10/31/2007
 GVHD prophylaxis: FK506 + MTX +- others vs. CSA + MTX +- others vs. ex vivo T-cell depletion vs.
others
 Sex match: F-M vs other
 D/R CMV status: -/- vs. other
Outcomes and definitions:
 Overall survival (OS): Time from documentation of CR1 to death from any cause. Surviving patients
censored at last time reported alive.
 Leukemia-free survival (LFS): Time from documentation of CR1 to leukemia relapse or death from
any cause. Surviving patients censored at last time reported alive and leukemia-free.
 Relapse: Relapse after documentation of CR1 is the event. Death in remission is the competing risk.
 Non-relapse mortality (NRM): Death in the first 28 days post-transplant or death in continuous
remission. Relapse is the competing risk.
Study Design:
Patient, disease and treatment-related factors will be compared between pre-conditioning
cytogenetically normal and abnormal patients using Chi-square test for categorical and Mann-Whitney
test for continuous variables.
Probabilities of overall survival and leukemia-free survival will be calculated using the Kaplan-Meier
estimator. Log-rank testing will be used to compare survival curves. Cumulative incidence curves will be
made to present relapse and non-relapse mortality with time to relapse and time to NRM as competing
risks. Differences between curves in setting of competing risks will be tested using the Gray method6.
Prognostic factors for OS, LFS, relapse, and NRM will be analyzed using the proportional hazards model
with the competing-risk regression model7.
Further development of design pending assessment of feasibility.
References:
1. Goldstone AH, Richards SM, Lazarus HM, et al. In adults with standard-risk acute lymphoblastic
leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first
complete remission, and an autologous transplantation is less effective than conventional
50
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2.
3.
4.
5.
6.
7.
Attachment 8
consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial
(MRC UKALL XII/ECOG E2993).Blood. 2008 Feb 15;111(4):1827-33.
Gupta V, Richards S, and Rowe J. Allogeneic, but not autologous, hematopoietic cell transplantation
improves survival only among younger adults with acute lymphoblastic leukemia in first remission:
an individual patient data meta-analysis. Blood. 2013 Jan 10;121(2):339-50.
Ram, R, Wolach, O, Vidal, L, et al. Adolescents and young adults with acute lymphoblastic leukemia
have a better outcome when treated with pediatric-inspired regimens: systematic review and metaanalysis. Am J Hematol. 2012 May;87(5):472-8.
DeAngelo, DJ, Stevenson, KE, Dahlberg, SE, et al.Long-term outcome of a pediatric-inspired regimen
used for adults aged 18-50 years with newly diagnosed acute lymphoblastic leukemia. Leukemia.
2014 Jul 31. doi: 10.1038/leu.2014.229. [Epub ahead of print].
Stock, W, Luger, SM, Advani, AS, et al. Favorable Outcomes for Older Adolescents and Young Adults
(AYA) with Acute Lymphoblastic Leukemia (ALL): Early Results of U.S. Intergroup Trial C10403. 56th
ASH Annual Meeting and Exposition, Abstract 796, 2014.
Gray R. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann
Stat 16:1140-1154 (1988).
Fine J, Gray R. A proportional hazards model for the subdistribution of a competing risk. J Am Stat
Assoc 94:496-509 (1999).
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Attachment 8
Characteristics of Study Population
Variable
N (%)
Number of patients
470
Number of centers
134
Age in decades
Median (range)
26 (16-40)
16-19
105 (22)
20-29
203 (43)
20-39
162 (34)
Male
318 (68)
Female
152 (32)
Gender
Recipient race
Caucasian
386 (82)
African-American
18 (4)
Asian
43 (9)
Pacific islander
2 (<1)
Native American
1 (<1)
Other
Unknown
9 (2)
11 (2)
Obese
No
367 (78)
Yes
96 (20)
Missing
7 (1)
Karnofsky score
<90%
87 (19)
>=90%
358 (76)
Missing
25 (5)
White blood count at diagnosis
Median (range)
15 (<1-1410)
<= 10
167 (36)
10 - 100
155 (33)
> 100
70 (15)
Missing
78 (17)
FAB classification
T-cell
109 (23)
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Variable
Attachment 8
N (%)
B-cell
229 (49)
Unspecified
132 (28)
Cytogenetics scoring
Normal
155 (33)
Poor
69 (15)
Other
62 (13)
TBD (needs review)
Not tested
Missing
101 (21)
21 (4)
62 (13)
Extramedullary disease at diagnosis
No
372 (79)
Yes
72 (15)
Missing
26 (6)
EMD at CNS at diagnosis
No
417 (89)
Yes
27 (6)
Missing
26 (6)
EMD at other site at diagnosis
No
396 (84)
Yes
48 (10)
Missing
26 (6)
Time to achieve CR1
Median (range)
7 (<1-113)
<=4 weeks
69 (15)
4-8 weeks
184 (39)
>8 weeks
184 (39)
Missing
33 (7)
Time from CR1 to HCT
Median (range)
3 (<1-35)
<6 months
363 (77)
6-12 months
65 (14)
>12 months
10 (2)
Missing
32 (7)
Total cycles of induction for CR1 cases
1
42 (9)
2
25 (5)
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Variable
Attachment 8
N (%)
3
14 (3)
4
22 (5)
N/A, earlier than 2007
Missing
277 (59)
90 (19)
Conditioning regimen intensity
Myeloablative
450 (96)
RIC
11 (2)
NMA
1 (<1)
TBD
1 (<1)
Missing
7 (1)
Graft type
Bone marrow
166 (35)
Peripheral blood
304 (65)
Type of donor
HLA-identical sibling
227 (48)
Well-matched unrelated
135 (29)
Partially matched unrelated
63 (13)
Mismatched unrelated
12 (3)
Unrelated TBD
33 (7)
Donor/Recipient sex match
M/M
210 (45)
M/F
85 (18)
F/M
107 (23)
F/F
67 (14)
TBD
1 (<1)
Donor/Recipient CMV match
-/-
125 (27)
-/+
92 (20)
+/-
63 (13)
+/+
180 (38)
TBD
10 (2)
GVHD prophylaxis
No GVHD prophylaxis
6 (1)
Ex-vivo T-cell depletion
8 (2)
CD34 selection
9 (2)
FK506 + MMF +- others
28 (6)
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Variable
FK506 + MTX +- others
FK506 + others
FK506 alone
CSA + MMF +- others
CSA + MTX +- others
CSA + others
Attachment 8
N (%)
148 (31)
20 (4)
6 (1)
10 (2)
211 (45)
6 (1)
CSA alone
13 (3)
Other GVHD prophylaxis
4 (<1)
Missing
1 (<1)
Year of HCT
2003
71 (15)
2004
63 (13)
2005
74 (16)
2006
69 (15)
2007
54 (11)
2008
43 (9)
2009
35 (7)
2010
14 (3)
2011
24 (5)
2012
23 (5)
Median follow-up of survivors (range), months
61 (2-122)
Selection:
st
1 allo HCT for Ph- ALL in CR1 between 2003 and 2012 after CAP modeling
Age 16-40 years old
HLA-identical sibling or unrelated donor
Bone marrow or peripheral blood graft
Complete research form
Patient consent
55
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Attachment 9
Study Proposal 1411-71
Study Title:
Prognostic risk factors of patients undergoing allogeneic stem cell transplantation for acute
erythroleukemia
Jan Cerny , MD, PhD, FACP, University of Massachusetts Medical Center, MA,
jan.cerny@umassmemorial.org
Rajneesh Nath, MD, University of Massachusetts Medical Center, MA,
rajneesh.nath@umassmemorial.org
Zheng (Frank) Zhou, MD, PhD, University of Massachusetts Medical Center, MA,
zheng.zhou@umassmemorial.org
Hypothesis:
Treatment with allogeneic transplant improves survival of patients with AEL. Karyotype is the strongest
prognostic factor for overall survival (OS) and cumulative incidence of relapse (RFS) of transplanted
patients.
Specific Aims:
To evaluate:
1. OS
2. relapse free survival (RFS)
3. Nonrelapse mortality (NRM)
4. rates of aGVHD and cGVHD
Of patients with AEL undergoing allogeneic transplantation and how are they effected by:
- cytogenetics
- transplant conditioning (intensity- ablative vs nonabalative)
- pretranslant treatment (chemotherapy vs hypomethylating agents)
- disease status or response at transplant
- other clinical characteristics (age at SCT, sex, CMV, level of matching, ABO compatibility, donor type)
We expect to see that younger patients (<60) and patients with high risk cytogenetics will receive
induction chemotherapy and will be more likely to receive myeloablative conditioning. On the contrary,
older patients (>=60) and patients with normal cytogenetics will be more likely to be treated with
nonmyeloablative approaches and more likely to receive hypomethylating agent as induction therapy.
Scientific Justification:
Acute erythroleukemia (AEL) is a rare subtype of AML with a poor prognosis. Allogeneic stem cell
transplant (alloSCT) improves the outcomes of AEL, 1,2 however only a small percentage of patients are
typically able to receive alloSCT and studies prior to 2008 WHO reclassification included patients with
>30%.1
Cytogenetics is a known prognostic factor for survival while single gene mutations are rather rare.1 What
is not known are other clinical characteristics that impact postransplant outcome such as intensity of
transplant conditioning, best GVHD prophylaxis and risk of CMV reactivation. Pretransplant therapy
impacts outcome with 7+3 being used as induction chemotherapy. AEL patients achieved high rates of
responses (~60%) with hypomethylating agent treatment alone.3 In our experience (data submitted for
Tandem meeting 2015) patients who were able to undergo an alloSCT had a superior OS of 33 months
56
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Attachment 9
compared to 7 months without transplant (p=0.036).2 Patients with high risk karyotype received
induction chemotherapy while patients with normal karyotype responded to hypomethylating agent.
Patient Eligibility Population:
All patients who have undergone an allogeneic stem cell transplant for AEL (previously AML M6)
between January 2000 and December 2013.
Data Requirements:
- Age
- Gender
- Cytogenetics risk category
- Molecular genetics (where available)
- Type of induction (chemo vs hypomethylating agent)
- Best response and its duration
- Karnofsky
- HSCT-comorbidity index
- Disease Status at SCT
- Time from diagnosis to SCT
- Bone marrow blast percentage
- Stem cell source (BM, PBSC, Cord blood)
- Donor age
- Donor-Recipient Sex Match
- Donor recipient CMV status
- Conditioning regimen used
- Documented organ toxicity
- GVHD prophylaxis regimen
- T cell antibody use
- Date of SCT
- Time to Neutrophil engraftment time
- Time to Platelet engraftment time
- Immune recovery (objective measures, including CD4 counts recovery, …)
- Mixed chimerism at 30 days, 6 months and 1 year
- Post-transplant infection (bacteria, fungal and/or viral)
- Acute GVHD, organ involved and grade
- Chronic GVHD, organ involved and grade
- Relapse-free survival at different time points (day 100, 1 year, 3 and 5 years)
- Overall survival at different time points (day 100, 1 year, 3 and 5 years)
Sample Requirements: N/A
Study Design:
Retrospective analysis of adult AEL patients in the CIBMTR database, who underwent allogeneic stem
cell transplantation
Study endpoints:
Primary endpoints:
- Overall survival (OS) at Day +100, 1 year and 3 years
57
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Attachment 9
Secondary endpoints:
- Time to engraftment (neutrophil, platelet and immunorecovery)
- NRM at Day +100, 1 year and 3 years
- RFS at Day+100, 1 year and 3 years
- Incidence and severity of GVHD (acute and chronic)
- Mixed Chimerism (%) at day 30, 6 months and 1 year
Outcomes:
 NRM is defined as death during continuous disease remission after transplant;
 Relapse is defined as clinical or hematological recurrence;
 RFS are clinical or hematological relapses or deaths from any cause;
 OS is death from any cause
 Surviving patients will be censored at the time of last clinic follow-up or the date of last contact,
whichever is later
Methods of analysis:
Comparison will be made for myeloablative vs nonmyeloablative conditioning regimens with respect to
the study endpoints listed above.
Survival Analysis
Multivariate Cox proportional hazard regression will be used with adjustment for patient baseline
clinical and disease characteristics to determine significance of difference in outcomes related to the
condition regimens and pretransplant therapy intensity (chemo vs hypomethylating agents). Hazard
ratio with 95% confidence interval (CI) will be obtained.
Cumulative incidence and Competing risk
Rates of relapse, NRM, success in engraftment (neutrophil, platelet and CD4) and GVHD (acute and
chronic) will be estimated using cumulative incidence approach.
In the analysis of the cumulative incidence of engraftments, early mortality will be considered as
competing risk;
In the analysis of GVHD, relapse and mortality will be considered a competing risk.
Kaplan-Meier Curves
OS, NRM and RFS will be compared with stratification by condition regimens and pretransplant therapy
intensity (chemo vs hypomethylating agents) using Kaplan-Meier curves.
References:
1.
2.
3.
Hasserjian RP, Zuo Z, Garcia C, Tang G, Kasyan A, Luthra R, Abruzzo LV, Kantarjian HM, Medeiros LJ, Wang SA.
Acute erythroid leukemia: a reassessment using criteria refined in the 2008 WHO classification. Blood. 2010
Mar 11;115(10):1985-92.
Kodali S, Tipirneni E, Zhou Z, Ramanathan M, Nath R, Cerny J. Allogeneic stem cell transplant improves the
outcome of patients with acute erythroleukemia: single center analysis. (submitted for Tandem Meeting 2015)
Vigil C, Cortes J, Kantarjian HM, Garcia-Manero G, Lancet JE, List AF. Hypomethylating therapy for the
treatment of acute erythroleukemia patients. Program and abstracts of the 51st American Society of
Hematology Annual Meeting and Exposition; December 5-8, 2009; New Orleans, Louisiana. Abstract 2069.
58
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Attachment 9
Characteristics of Study Population
Variable
N (%)
Number of patients
379
Number of centers
139
Age in decades
Median (range)
49 (<1-73)
<10
26 (7)
10-19
23 (6)
20-29
32 (8)
30-39
41 (11)
40-49
75 (20)
50-59
105 (28)
60-69
73 (19)
>=70
4 (1)
Male
232 (61)
Female
147 (39)
Gender
Karnofsky score
<90%
127 (34)
>=90%
234 (62)
Missing
18 (5)
White blood count at diagnosis
Median (range)
<= 10
3 (<1-333)
300 (79)
10 - 100
33 (9)
> 100
3 (<1)
Missing
43 (11)
0
61 (16)
1
18 (5)
2
19 (5)
3+
24 (6)
HCT-CI
N/A, earlier than 2007
Missing
253 (67)
4 (1)
Disease status prior to HCT
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Variable
Primary induction failure
Attachment 9
N (%)
60 (16)
CR1
216 (57)
CR2
35 (9)
>=CR3
1 (<1)
Relapse
67 (18)
Cytogenetics scoring
Normal
Favorable
Intermediate
Poor
TBD (needs review)
Not tested
Missing
93 (25)
1 (<1)
58 (15)
136 (36)
18 (5)
7 (2)
66 (17)
Time from diagnosis to HCT
Median (range)
<6 months
5 (1-115)
222 (59)
6 - 12 months
98 (26)
>12 months
59 (16)
Conditioning regimen intensity
Myeloablative
RIC
252 (66)
94 (25)
NMA
17 (4)
TBD
14 (4)
Missing
2 (<1)
Graft type
Bone marrow
Peripheral blood
Umbilical cord blood
83 (22)
253 (67)
43 (11)
Type of donor
HLA-identical sibling
Other related
Well-matched unrelated
Partially matched unrelated
117 (31)
18 (5)
129 (34)
47 (12)
Mismatched unrelated
12 (3)
Unrelated TBD
13 (3)
Cord blood
43 (11)
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Variable
Attachment 9
N (%)
Donor/Recipient CMV match
-/-
81 (21)
-/+
107 (28)
+/-
43 (11)
+/+
120 (32)
TBD
28 (7)
Donor/Recipient sex match
M/M
151 (40)
M/F
90 (24)
F/M
81 (21)
F/F
56 (15)
TBD
1 (<1)
GVHD prophylaxis
No GVHD prophylaxis
4 (1)
Ex-vivo T-cell depletion
9 (2)
CD34 selection
15 (4)
Post-tx cy
2 (<1)
FK506 + MMF +- others
54 (14)
FK506 + MTX +- others
111 (29)
FK506 + others
11 (3)
FK506 alone
12 (3)
CSA + MMF +- others
32 (8)
CSA + MTX +- others
82 (22)
CSA + others
18 (5)
CSA alone
22 (6)
Other GVHD prophylaxis
Missing
5 (1)
2 (<1)
Year of HCT
2000
19 (5)
2001
33 (9)
2002
27 (7)
2003
30 (8)
2004
34 (9)
2005
32 (8)
2006
40 (11)
2007
38 (10)
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Variable
Attachment 9
N (%)
2008
41 (11)
2009
39 (10)
2010
20 (5)
2011
18 (5)
2012
8 (2)
Median follow-up of survivors (range), months
64 (3-144)
Selection:
st
1 allo HCT for AEL between 2000 and 2012 after CAP modeling
Excluding syngeneic twin donor
Complete research form
Patient consent
62
Not for publication or presentation
Attachment 10
Study Proposal 1411-74
Study Title:
Comparison of outcomes post allogeneic hematopoietic cell transplant between patients with de novo
and secondary acute myeloid leukemia in first complete remission.
Fotios Vasilios Michelis, MD, PhD, Allogeneic Blood and Marrow Transplant Program, Princess Margaret
Cancer Centre, Toronto, Canada, Fotios.Michelis@uhn.ca
Hans A. Messner, MD, PhD, Allogeneic Blood and Marrow Transplant Program, Princess Margaret Cancer
Centre, Toronto, Canada, Hans.Messner@uhn.ca
Specific Aim:
To compare the outcomes of patients with de novo AML and AML secondary to a previous malignancy
(hematological and solid tumor) undergoing allogeneic hematopoietic cell transplantation (HCT) in first
complete remission (CR1).
Outcomes of interest:
a. Overall survival (OS)
b. Leukemia-free survival (LFS)
c. Cumulative Incidence of Relapse (CIR)
d. Non-relapse mortality (NRM)
Scientific Justification:
The development of AML may occur de novo or subsequent to a previous diagnosis of solid tumors,
hematopoietic malignancies or myelodysplasia.1-4 The occurrence of AML following a previous
malignancy may be the consequence of cytoreductive therapy for the primary disease, and thus can be
considered treatment related (tAML). However, AML may also develop without cytotoxic management
as for instance reported for cases where primary solid tumors were treated with surgery alone3,5,
reflecting different mechanisms (non-tAML) such as genetic instability that already may have been
associated with the development of the primary malignancy. The concept of progression to AML in the
absence of cytotoxic measures is well accepted for myelodysplastic syndrome (MDS) and other
hematopoietic malignancies.
Past studies have often merged patients of both categories (secondary tAML and secondary non-tAML),
characterizing them all as secondary AML (sAML).5-8 Treated conservatively, a worse prognosis was
commonly reported for patients with sAML compared to de novo AML.4,9-14 It remains debated whether
or not the decreased rate of survival reflects biological differences in the disease process, differences in
the frequency of well recognized high risk factors such as unfavorable karyotype, or differences in
management. In contrast to de novo AML, the role of allogeneic hematopoietic cell transplantation
(HCT) as part of the management of sAML is not well established and the effect on the above described
subtypes of sAML (secondary tAML and secondary non-tAML) is relatively unknown. In our own
experience at Princess Margaret Cancer Centre, we recently submitted a retrospective analysis
comparing the outcomes of 180 patients with de novo and 84 patients with sAML post allogeneic HCT in
first complete remission (CR1)(manuscript revision re-submitted to Bone Marrow Transplantation on
October 29, 2014, available on request).15 The study showed that the outcomes for both AML subtypes
post HCT are comparable, as was demonstrated in univariate (Appendix 1), multivariable and propensity
score matched analysis (Appendix 2). Also, a separate subgroup analysis was performed for sAML
patients with primary solid tumors, primary MDS and other primary hematopoietic malignancies that
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have emerged with or without exposure to cytotoxic therapies, and this also demonstrated no
significant difference between these subgroups. One of the limitations of our single-centre study was
the relatively small number of patients involved.
Large-scale studies to investigate the role of allo-HCT in sAML are not available, and information in the
literature is largely derived from subset analyses. For this reason we would like to use a larger database
to compare outcomes between de novo and sAML post-HCT. The large size of the CIBMTR registry
provides an opportunity to investigate these subgroups in a well powered study.
The data from this study will provide useful information as below:
a. Verification of the results from our previously published study demonstrating the comparable
outcomes between de novo and sAML undergoing HCT in CR1. This is significant because it
would stress the need for patients with sAML, who are considered high-risk for relapse, to
undergo HCT in CR1 (provided a suitable donor is available), and thus improve the referral of
these patients to transplant centers.
b. Comparison of outcomes post-HCT for subtypes of sAML such as those arising from previously
treated solid tumors, previously treated hematological malignancies and hematological
malignancies progressing to sAML without previous cytotoxic treatment. Our previously
published work demonstrated comparable outcomes.
c. Patient counseling concerning the risks and benefits of allogeneic HCT in sAML
d. Design of future clinical trials comparing allogeneic and non-allogeneic treatment options for
sAML.
Patient Eligibility Population:
Using the CIBMTR database, patients with AML who underwent HCT between 1999 and 2013 and meet
the following criteria will be identified.
Eligible patients:
Inclusion criteria (should meet all the criteria):
 Age 18 years and older at the time of HCT
 First allogeneic transplant
 Diagnosis of AML, either de novo or sAML (subdivided into therapy-related and secondary to
previous haematological malignancy)
 Patients undergoing HCT in CR1
 Transplant from either a matched related donor or unrelated donor (9/10 or 10/10)
Exclusion criteria:
 Syngeneic transplants
 In vitro T cell depletion
 Cord-blood transplants
 Haplo-identical transplants
 Acute promyelocytic leukemia
 Previous allogeneic transplant
Variables to be analyzed:
Patient-related:
 Age at HCT
 Gender
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 Karnofsky Performance scores: <90 vs ≥90
 Hematopoietic cell transplant-comorbidity index16(HCT-CI)(depending on availability of data)
Disease-related:
 Type of AML: de-novo versus therapy related versus secondary AML with previous diagnosis of
MDS/MPD
 Previous autologous transplant (yes/no)
 Cytogenetics: good risk vs. intermediate vs. poor risk vs. unknown/not available (defined
according to SWOG/ECOG definition17)
 Time from diagnosis of AML to transplant
 Number of courses of chemotherapy to CR1
Transplant related:
 Conditioning regimen: MAC vs. RIC vs. NMA as defined by CIBMTR18
 TBI in conditioning regimen: no TBI versus TBI with dose in cGY included
 Donor age
 Donor type: MSD vs. 9/10 MUD vs 10/10 MUD
 Donor-recipient gender: M-M vs. M-F vs. F-M vs. F-F
 CMV status of donor and recipient: +/+ vs. +/- vs. -/+ vs. -/ ABO incompatibility: none vs. minor vs. major vs. bidirectional
 Source of hematopoietic cells: BM vs. PBSC
 Median CD34 cell dose, x 106/kg
 Date of transplant
 GVHD prophylaxis: Calcineurin inhibitor (CNI) + MTX vs. CNI + MMF vs. others
 Received Serotherapy with either campath or ATG: yes/no
Outcomes of interest:
 Hematopoietic recovery (neutrophil and platelet recovery)
 Acute GVHD
 Chronic GVHD
 Cumulative incidence of Relapse
 Cumulative incidence of NRM
 LFS
 OS
Statistical analysis:
This is a retrospective study of CIBMTR data between 1999 and 2013.
The purpose of the proposed study is to compare the outcomes of patients undergoing allo-HCT for de
novo AML vs sAML in CR1. Moreover, post-HCT outcomes would be investigated for subgroups of sAML,
such as therapy related versus secondary AML with previous diagnosis of MDS/MPD. Patient, disease
and transplant related variables will be compared between the groups using chi-square test for
categorical variables and Mann-Whitney test for continuous variables. Statistical endpoints will be
calculated using Kaplan-Meier Method and will be compared using log-rank test for overall survival,
while non-relapse mortality (NRM), cumulative incidence of relapse (CIR) and GVHD incidence will be
calculated using the cumulative incidence method considering competing risks and will be compared
using Gray method. Multivariate analysis will also be performed using Cox’s proportional hazard model
for overall survival, and using Fine-Gray method for NRM, CIR and GVHD incidence. All variables with a
p-value <0.1 in the univariate analysis will be considered for entry into multivariate analysis, in which all
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p-values will be tested as two-sided and p-value <0.05 will be used as statistically significant. A
propensity score matched analysis may also be performed,19-20 which would involve the generation of
matched pairs of patients between the de novo and sAML groups, and the subsequent comparison of
the matched subgroups. Further plan will be developed depending on sample size after discussion with
statistical team at CIBMTR.
References:
1. Leone G, Mele L, Pulsoni A, Equitani F, Pagano L. The incidence of secondary leukemias.
Haematologica 1999; 84: 937-945.
2. Witherspoon RP, Deeg HJ. Allogeneic bone marrow transplantation for secondary leukemia or
myelodysplasia. Haematologica 1999; 84: 1085-1087.
3. Pagana L, Pulsoni A, Tosti ME, Avvisati G, Mele L, Mele M, et al. Clinical and biological features of
acute myeloid leukaemia occurring as second malignancy: GIMEMA archive of adult acute
leukaemia. Br J Haematol 2001; 112: 109-117.
4. Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, et al. The 2008 revision of the
World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale
and important changes. Blood 2009; 114: 937-951.
5. Abdelhameed A, Pond GR, Mitsakakis N, Brandwein J, Chun K, Gupta V, et al. Outcome of patients
who develop acute leukemia or myelodysplasia as a second malignancy after solid tumors treated
surgically or with strategies that include chemotherapy and/or radiation. Cancer 2008; 112: 15131521.
6. Anderson JE, Gooley TA, Schoch G, Anasetti C, Bensinger WI, Clift RA, et al. Stem cell transplantation
for secondary acute myeloid leukemia: evaluation of transplantation as initial therapy or following
induction chemotherapy. Blood 1997; 89: 2578-2585.
7. Ostgård LS, Kjeldsen E, Holm MS, Brown Pde N, Pedersen BB, Bendix K, et al. Reasons for treating
secondary AML as de novo AML. Eur J Haematol 2010; 85: 217-226.
8. Preiss BS, Bergmann OJ, Friis LS, Sørensen AG, Frederiksen M, Gadeberg OV, et al. Cytogenetic
findings in adult secondary acute myeloid leukemia (AML): frequency of favorable and adverse
chromosomal aberrations do not differ from adult de novo AML. Cancer Genet Cytogenet 2010; 202:
108-122.
9. Dann EJ, Rowe JM. Biology and therapy of secondary leukaemias. Best Pract Res Clin Haematol 2001;
14: 119-137.
10. Josting A, Wiedenmann S, Franklin J, May M, Sieber M, Wolf J, et al. Secondary myeloid leukemia
and myelodysplastic syndromes in patients treated for Hodgkin's disease: a report from the German
Hodgkin's Lymphoma Study Group. J Clin Oncol 2003; 21: 3440-3446.
11. Kayser S, Döhner K, Krauter J, Köhne CH, Horst HA, Held G, et al. The impact of therapy-related acute
myeloid leukemia (AML) on outcome in 2853 adult patients with newly diagnosed AML. Blood 2011;
117: 2137-2145.
12. Della Porta MG. Prognosis of secondary acute myeloid leukemia. Leuk Res 2013; 37: 857-858.
13. Park SH, Chi HS, Cho YU, Jang S, Park CJ. Evaluation of prognostic factors in patients with therapyrelated acute myeloid leukemia. Blood Res 2013; 48: 185-192.
14. Ornstein MC, Mukherjee S, Mohan S, Elson P, Tiu RV, Saunthararajah Y, et al. Predictive Factors for
Latency Period and a Prognostic Model for Survival in Patients with Therapy-related AML. Am J
Hematol 2014; 89: 168-173.
15. Michelis FV, Atenafu EG, Gupta V, Kim DD, Kuruvilla John, Lipton JH, Loach D, Seftel MD, Uhm J, Alam
N, Lambie A, McGillis L, Messner HA. Comparable outcomes post allogeneic hematopoietic cell
transplant for patients with de novo and secondary acute myeloid leukemia in first remission.
Revision re-submitted to Bone Marrow Transplant, October 29, 2014.
66
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16. Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG et al. Hematopoietic cell
transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic
HCT. Blood 2005; 106: 2912–2919.
17. Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A, Paietta E, Willman CL,
Head DR, Rowe JM, Forman SJ, Appelbaum FR. Karyotypic analysis predicts outcome of preremission
and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern
Cooperative Oncology Group Study. Blood. 2000;96:4075-4083
18. Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V, Apperley J, Slavin S, Pasquini M, Sandmaier
BM, Barrett J, Blaise D, Lowski R, Horowitz M. Defining the intensity of conditioning regimens:
working definitions. Biol Blood Marrow Transplant. 2009;15:1628-1633
19. D'Agostino RB Jr. Propensity score methods for bias reduction in the comparison of a treatment to a
non-randomized control group. Stat Med 1998; 17: 2265-2281.
20. Liem YS, Wong JB, Hunink MM, de Charro FT, Winkelmayer WC. Propensity scores in the presence of
effect modification: A case study using the comparison of mortality on hemodialysis versus
peritoneal dialysis. Emerg Themes Epidemiol 2010; 7: 1.
Appendix 1:
Appendix 1. Univariate comparison of OS for patients with de novo (n=180) and sAML (n=84) after
allogeneic HCT (p=0.18).
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Appendix 2:
Appendix 2. Univariate comparison between de novo and sAML following propensity score matched
analysis (62 pairs) A) for OS, p=0.54, B) for LFS, p=0.40.
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Attachment 10
Characteristics of Study Population
Variable
De-novo AML
sAML
Number of patients
2880
1050
Number of centers
211
159
47 (18-75)
55 (18-76)
18-29
493 (17)
83 (8)
30-39
473 (16)
66 (6)
40-49
737 (26)
228 (22)
50-59
799 (28)
382 (36)
60-69
346 (12)
265 (25)
>=70
32 (1)
26 (2)
Male
1519 (53)
534 (51)
Female
1361 (47)
516 (49)
<90%
718 (25)
337 (32)
>=90%
2050 (71)
648 (62)
112 (4)
65 (6)
Median (range)
9 (<1-999)
4 (<1-700)
<= 10
1310 (45)
663 (63)
996 (35)
255 (24)
264 (9)
26 (2)
310 (11)
106 (10)
2880
0
Transformed from MDS/MPS
0
775 (74)
Therapy linked
0
275 (26)
No
2865 (99)
1029 (98)
Yes
15 (<1)
21 (2)
0
573 (20)
173 (16)
1
138 (5)
38 (4)
2
110 (4)
43 (4)
Age in decades
Median (range)
Gender
Karnofsky score
Missing
White blood count at diagnosis
10 - 100
> 100
Missing
Type of AML
De-novo
Prior auto HCT
HCT-CI
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Variable
Attachment 10
De-novo AML
sAML
230 (8)
132 (13)
1822 (63)
662 (63)
7 (<1)
2 (<1)
922 (32)
243 (23)
101 (4)
27 (3)
Intermediate
694 (24)
240 (23)
Poor
654 (23)
311 (30)
TBD (needs review)
8 (<1)
12 (1)
Not tested
87 (3)
35 (3)
414 (14)
182 (17)
5 (<1-82)
5 (1-118)
0-3 months
272 (9)
166 (16)
3-6 months
1730 (60)
587 (56)
6-12 months
783 (27)
262 (25)
95 (3)
35 (3)
1
1111 (39)
356 (34)
2
524 (18)
116 (11)
3
71 (2)
23 (2)
4
24 (<1)
11 (1)
5
33 (1)
16 (2)
1117 (39)
528 (50)
2106 (73)
607 (58)
536 (19)
311 (30)
NMA
139 (5)
91 (9)
TBD
48 (2)
31 (3)
Missing
51 (2)
10 (<1)
No
1775 (62)
734 (70)
Yes
1105 (38)
316 (30)
HLA-identical sibling
1438 (50)
363 (35)
Well-matched unrelated
1115 (39)
488 (46)
3+
N/A, earlier than 2007
Missing
Cytogenetics scoring
Normal
Favorable
Missing
Time from diagnosis to HCT
Median (range)
>12 months
Total cycles of induction for CR1 cases
Missing
Conditioning regimen intensity
Myeloablative
RIC
TBI
Type of donor
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Variable
Attachment 10
De-novo AML
sAML
327 (11)
199 (19)
M/M
963 (33)
370 (35)
M/F
818 (28)
308 (29)
F/M
554 (19)
163 (16)
F/F
540 (19)
207 (20)
5 (<1)
2 (<1)
-/-
722 (25)
275 (26)
-/+
782 (27)
327 (31)
+/-
302 (10)
112 (11)
+/+
988 (34)
305 (29)
TBD
86 (3)
31 (3)
1444 (50)
481 (46)
Minor mismatch
546 (19)
208 (20)
Major mismatch
510 (18)
214 (20)
Bidirectional mismatch
147 (5)
67 (6)
Missing
233 (8)
80 (8)
611 (21)
181 (17)
2269 (79)
869 (83)
No GVHD prophylaxis
30 (1)
10 (<1)
Ex-vivo T-cell depletion
66 (2)
37 (4)
CD34 selection
78 (3)
24 (2)
14 (<1)
6 (<1)
FK506 + MMF +- others
310 (11)
148 (14)
FK506 + MTX +- others
1062 (37)
413 (39)
107 (4)
36 (3)
70 (2)
23 (2)
CSA + MMF +- others
188 (7)
121 (12)
CSA + MTX +- others
787 (27)
173 (16)
CSA + others
48 (2)
18 (2)
CSA alone
89 (3)
30 (3)
23 (<1)
8 (<1)
Partially matched unrelated
Donor/Recipient sex match
TBD
Donor/Recipient CMV match
Donor/recipient ABO match
Matched
Graft type
Bone marrow
Peripheral blood
GVHD prophylaxis
Post-tx cy
FK506 + others
FK506 alone
Other GVHD prophylaxis
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Variable
Attachment 10
De-novo AML
sAML
8 (<1)
3 (<1)
2000
142 (5)
38 (4)
2001
155 (5)
46 (4)
2002
172 (6)
59 (6)
2003
165 (6)
74 (7)
2004
262 (9)
101 (10)
2005
332 (12)
108 (10)
2006
303 (11)
117 (11)
2007
291 (10)
119 (11)
2008
319 (11)
125 (12)
2009
298 (10)
113 (11)
2010
241 (8)
83 (8)
2011
95 (3)
42 (4)
2012
105 (4)
25 (2)
66 (2-172)
71 (3-171)
Missing
Year of HCT
Median follow-up of survivors (range), months
Selection:
st
1 allo HCT for adult AML in CR1 between 2000 and 2012 after CAP modeling
HLA-identical sibling or well/partially matched unrelated donor
Excluding FAB M3 (APL)
Complete research form
Patient consent
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Attachment 11
Study Proposal 1411-77/1312-09
Study Title:
Comparison of total body irradiation (TBI)-based with intravenous (i.v.) busulfan (Bu) containing
chemotherapy-only myeloablative transplant conditioning regimens in adult patients with acute
lymphoblastic leukemia (ALL)
Partow Kebriaei, MD, MD Anderson Cancer Center, pkebriae@mdanderson.org
Ibrahim Aldoss, MD, City of Hope Medical Center, ialdoss@coh.org
Vinod Pullarkat, MD, City of Hope Medical Center, vpullarkat@coh.org
Claudio Anasetti, MD, Moffitt Cancer Center, Claudio.Anasetti@moffitt.org
David Marks, MD, University Hospitals Bristol Foundation Trust, David.Marks@UHBristol.nhs.uk
Collaborators:
Joseph Alvarnas, MD, City of Hope Medical Center, jalvarnas@coh.org
Stephen Forman, MD, City of Hope Medical Center, sforman@coh.org
Hypothesis:
We hypothesise that i.v. Bu containing regimens will achieve similar survival to TBI based regimens in
patients with ALL
Specific Aims:
Aim 1: To compare post-hematopoietic cell transplantation (HCT) outcomes [overall survival (OS),
leukemia-free survival (LFS), relapse rate (RR) and non-relapse mortality (NRM)] between TBI- and nonTBI-, i.v. Bu-based myeloablative conditioning regimens in adults with ALL undergoing allogeneic HCT.
Aim 2: To evaluate the influence of the conditioning regimen (TBI versus i.v. Bu) on post HCT outcomes
among ALL risk subgroups (standard versus high) classified based on age, initial WBC and cytogenetics at
diagnosis in adults with ALL undergoing allogeneic HCT. This aim will also address the effect of remission
status (CR1 versus CR2) on the outcomes after TBI based versus Bu-based conditioning.
Aim 3: To evaluate the impact on extramedullary relapse patterns, specifically central nervous system
relapse, with the two different conditioning approaches.
Aim 4: To evaluate the regimen related toxicity profile, and to compare graft versus host disease, of the
two different conditioning approaches.
Scientific Justification:
Patient Eligibility Population:
Inclusion criteria:
 Age 18-65
 Patients with diagnosis of B or T-cell acute lymphoblastic leukemia (ALL) in CR1 or CR2
 Patients who have undergone full-intensity conditioning regimen Definition of full-intensity
regimen include:
 TBI: non-fractionated dose ≥ 5.5 Gy, fractionated ≥ 9 Gy
 Busulfan dose of ≥ 9 mg/kg
 First allogeneic HCT from an HLA-identical sibling or matched unrelated donor
 HCT beginning in 2000 and beyond
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Exclusion criteria:
 Recipients of reduced-intensity conditioning (R) or nonmyeloablative conditioning (NMA)
regimens
 Patients with active leukemia at the time HCT
 Umbilical Cord Blood or haploidentical HCT
 HCT from ≤ 7/8 unrelated donor
 Syngeneic donor HCT
 Ex vivo T-cell deplete
Scientific Justification:
TBI-based transplant conditioning regimens are considered the standard of care for patients
undergoing HCT for ALL, with expected survival of 50% to 60% in first complete remission
(CR1)(1, 2). However, TBI is associated with acute and long-term toxicity (including secondary
malignancy), with non-relapse mortality (NRM) rates of 20%-45% following SCT (2-4). In
efforts to minimize toxicity, the combination of oral Bu and cyclophosphamide (Cy) was
developed. But a retrospective (5) and prospective analysis (6) in children comparing Cy-TBI with Bu-Cy
demonstrated that although relapse rates were equivalent in the two groups, TRM was actually
increased in the Bu-Cy group with greater rates of veno-occlusive disease and interstitial pneumonitis,
and thus survival was better with Cy-TBI.
Since these studies, the intravenous formulation of Bu has been developed and increasingly used, and
study results across disease types show a better safety profile (7, 8) (ref). Furthermore, PK- directed
dosing of intravenous Bu affords even greater safety (9, 10) (Ansari EBMT 2012) and efficacy (Andersson
ASH 2011). Interestingly, a recent CIBMTR multicenter cohort analysis in patients with acute myeloid
leukemia (AML) receiving HCT following Cy-TBI or
myeloablative, intravenous Bu-based conditioning regimens found superior survival for the Bu-based
group (56% vs. 48%, p=.02) (11).
Several phase II studies have reported excellent transplant outcomes with intravenous Bu combined
with fludarabine (12, 13) and clofarabine(14) in patients receiving SCT for ALL. An updated analysis of
MD Anderson data with Bu and clofarabine SCT conditioning for ALL patients in CR1 (n=44) and CR2
(n=21) revealed that 70% and 52%, respectively, of patients are alive and in remission with a median
follow-up of 18 months. Thus, we would like to do a comparison of myeloablative TBI-based
conditioning regimens versus intravenous Bu-based regimens in patients receiving allogeneic HCT for
ALL. If we have sufficient numbers, we propose to evaluate the patients receiving i.v. Bu combined with
a nucleoside analogue (Flu or Clo) separately from those receiving Bu combined with another alkylator,
commonly cyclophosphamide, since the two approaches may not show similar results. We, and others,
showed excellent disease control but increased toxicity in the form of interstitial pneumonia and
hemorrhagic cystitis with the combination of Bu and the alkylator melphalan (15, 16).
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Attachment 11
Data Requirements: Data collection from standard CIBMTR forms.
For i.v. Bu-based cases, data from MD Anderson and Moffitt Cancer Center, data readily
available; both centers have published on these regimen results.
MD Anderson (BuClo CR1 n=65, CR2 n=37; BuFlu CR1 n=6; BuMel CR1 n=28, CR2 n=15)
Moffitt (BuFlu CR1 n=86, CR2 n=17)
Sample Requirements: None
Study Design:
We propose a retrospective, case-controlled comparison of patients receiving radiation-based,
myeloablative conditioning (TBI>5.5Gy in a single fraction or >9 Gy fractionated plus Cy >60
mg/kg or etoposide >30 mg/kg) compared with intravenous Bu >9 mg/kg plus
cyclophosphamide, fludarabine or clofarabine for HCT in CR1 or CR2. Due to the relatively few
cases of i.v. Bu-based regimens in the CIBMTR database, we will include data from the
additional centers specified above. We plan to look at the i.v.-Bu or Clo cases separately from
i.v. Bu combined with Cy if sufficient numbers exist.
Primary outcomes:
Overall survival, DFS, GVHD (acute and chronic), NRM at 2 years and relapse
Study Variables:
Patient-related:
- Age (by decades, or as a continuous variable)
- Gender (M vs F)
- Karnofsky PS (<90% vs 90% or more)
Disease-related:
- Cytogenetic abnormalities: t(4;11), t(9;22), hypodiploidy or near triploidy, complex
cytogenetics (>5 abnormalities) vs. diploid vs. other abnormalities vs. not known
- Lineage (T vs. B vs. not known)
- WBC at diagnosis <25, 25-100, 100-200, >200
- Time to achieve CR1: <4 weeks, >8 weeks, 4-8 weeks
- Time from diagnosis to transplant for CR1 patients
- Relapse on chemotherapy (yes/no)
- Extramedullary disease at diagnosis: CNS (yes/no), testis (yes/no), other (yes/no)
Transplant-related:
- Time from remission to transplant (CR1 and CR2)
- Duration of CR1 for CR2 transplants
- Alemtuzamab vs ATG (dose to be collected)
- GVHD prophylaxis for UD transplants: ex vivo T cell depletion vs. CsA+MTX vs.
tacrolimus+MTX vs. post SCT cytoxan
- Donor age for unrelated donors (continuous variable)
- Gender match (F-M vs M-F vs M-M vs F-F)
- CMV status: -/- vs +/- vs _/+ vs +/+
- Year of transplant
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-
Attachment 11
Matching of unrelated donors: well matched vs. partly matched vs. mismatched (CIBMTR
criteria)
Post-transplant therapy: DLI (yes/no); chemotherapy (yes/no); intrathecal chemotherapy
(yes/no)
PBSC vs. BM
Busulfan PK monitoring, yes/no
Daily Busulfan dose <130 mg/2 vs. > 130 or AUC <5000 vs. > 5000
Busulfan + nucleoside analogue (Fludarabine or Clofarabine) vs. others
Dose of TBI <13 Gy vs. >13 Gy
Cytoxan vs.VP16 vs. others + TBI
cell dose data
References:
1.
Marks DI, Forman SJ, Blume KG, Perez WS, Weisdorf DJ, Keating A, et al. A comparison of cyclophosphamide
and total body irradiation with etoposide and total body irradiation as conditioning regimens for patients
undergoing sibling allografting for acute lymphoblastic leukemia in first or second complete remission.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow
Transplantation. 2006;12(4):438-53. Epub 2006/03/21.
2.
Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, et al. In adults with standard-risk
acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic
transplantation in first complete remission, and an autologous transplantation is less effective than
conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL
Trial (MRC UKALL XII/ECOG E2993). Blood. 2008;111(4):1827-33. Epub 2007/12/01.
3.
Sutton L, Kuentz M, Cordonnier C, Blaise D, Devergie A, Guyotat D, et al. Allogeneic bone marrow
transplantation for adult acute lymphoblastic leukemia in first complete remission: factors predictive of
transplant-related mortality and influence of total body irradiation modalities. Bone marrow
transplantation. 1993;12(6):583-9. Epub 1993/12/01.
4.
Oliansky DM, Camitta B, Gaynon P, Nieder ML, Parsons SK, Pulsipher MA, et al. The role of cytotoxic therapy
with hematopoietic stem cell transplantation in the treatment of pediatric acute lymphoblastic leukemia:
update of the 2005 evidence-based review. ASBMT Position Statement. Biology of blood and marrow
transplantation : journal of the American Society for Blood and Marrow Transplantation. 2012;18(7):979-81.
Epub 2012/04/12.
5.
Davies SM, Ramsay NK, Klein JP, Weisdorf DJ, Bolwell B, Cahn JY, et al. Comparison of preparative regimens
in transplants for children with acute lymphoblastic leukemia. Journal of clinical oncology : official journal of
the American Society of Clinical Oncology. 2000;18(2):340-7. Epub 2000/01/19.
6.
Bunin N, Aplenc R, Kamani N, Shaw K, Cnaan A, Simms S. Randomized trial of busulfan vs total
body
irradiation containing conditioning regimens for children with acute lymphoblastic leukemia: a Pediatric
Blood and Marrow Transplant Consortium study. Bone marrow transplantation. 2003;32(6):543-8. Epub
2003/09/04.
7.
Kashyap A, Wingard J, Cagnoni P, Roy J, Tarantolo S, Hu W, et al. Intravenous versus oral busulfan as part of
a busulfan/cyclophosphamide preparative regimen for allogeneic hematopoietic stem cell transplantation:
decreased incidence of hepatic venoocclusive disease (HVOD), HVOD-related mortality, and overall 100-day
76
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Attachment 11
mortality. Biology of blood and marrow transplantation : journal of the American Society for Blood and
Marrow Transplantation. 2002;8(9):493-500. Epub 2002/10/11.
8.
Russell JA, Tran HT, Quinlan D, Chaudhry A, Duggan P, Brown C, et al. Once-daily intravenous
busulfan
given with fludarabine as conditioning for allogeneic stem cell transplantation: study of
pharmacokinetics
and early clinical outcomes. Biology of blood and marrow transplantation :
journal of the American
Society for Blood and Marrow Transplantation. 2002;8(9):468-76. Epub 2002/10/11.
9.
Andersson BS, Thall PF, Madden T, Couriel D, Wang X, Tran HT, et al. Busulfan systemic exposure relative
to regimen-related toxicity and acute graft-versus-host disease: defining a therapeutic window for i.v.
BuCy2 in chronic myelogenous leukemia. Biology of blood and marrow transplantation : journal of the
American Society for Blood and Marrow Transplantation. 2002;8(9):477-85. Epub 2002/10/11.
10.
Geddes M, Kangarloo SB, Naveed F, Quinlan D, Chaudhry MA, Stewart D, et al. High busulfan exposure is
associated with worse outcomes in a daily i.v. busulfan and fludarabine allogeneic transplant regimen.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow
Transplantation. 2008;14(2):220-8. Epub 2008/01/25.
11.
Bredeson C, LeRademacher J, Kato K, Dipersio JF, Agura E, Devine SM, Appelbaum FR, Tomblyn MR, Laport
GG, Zhu X, McCarthy PL, Ho VT, Cooke KR, Armstrong E, Smith A, Rizzo JD, Burkart JM, Pasquini MC.
Prospective cohort study comparing intravenous busulfan to total body irradiation in hematopoietic cell
transplantation. Blood. 2013 Dec 5;122(24):3871-8. doi: 10.1182/blood-2013-08-519009. Epub 2013 Sep
30.
12.
Russell JA, Savoie ML, Balogh A, Turner AR, Larratt L, Chaudhry MA, et al. Allogeneic transplantation for
adult acute leukemia in first and second remission with a novel regimen incorporating daily intravenous
busulfan, fludarabine, 400 CGY total-body irradiation, and thymoglobulin. Biology of blood and marrow
transplantation : journal of the American Society for Blood and Marrow Transplantation. 2007;13(7):81421. Epub 2007/06/21.
13.
Santarone S, Pidala J, Di Nicola M, Field T, Alsina M, Ayala E, et al. Fludarabine and pharmacokinetictargeted busulfan before allografting for adults with acute lymphoid leukemia. Biology of blood and
marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.
2011;17(10):1505-11. Epub 2011/03/10.
14.
Kebriaei P, Basset R, Ledesma C, Ciurea S, Parmar S, Shpall EJ, et al. Clofarabine combined with busulfan
provides excellent disease control in adult patients with acute lymphoblastic leukemia undergoing
allogeneic hematopoietic stem cell transplantation. Biology of blood and marrow transplantation : journal
of the American Society for Blood and Marrow Transplantation. 2012;18(12):1819-26. Epub 2012/07/04.
Kebriaei P, Madden T, Wang X, Thall PF, Ledesma C, de Lima M, et al. Intravenous BU plus Mel: an
effective, chemotherapy-only transplant conditioning regimen in patients with ALL. Bone marrow
transplantation. 2013;48(1):26-31. Epub 2012/06/27.
15.
16.
Small TN, Young JW, Castro-Malaspina H, Prockop S, Wilton A, Heller G, et al. Intravenous busulfan and
melphalan, tacrolimus, and short-course methotrexate followed by unmodified HLA-matched related or
unrelated hematopoietic stem cell transplantation for the treatment of advanced hematologic
malignancies. Biology of blood and marrow transplantation : journal of the American Society for Blood
and Marrow Transplantation. 2007;13(2):235-44.
77
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Attachment 11
Characteristics of Study Population from CIBMTR Database
Variable
CIBMTR
MDACC
MOFFITT
Number of patients
1183
151
103
Number of centers
174
0
0
Median (range)
35 (18-65)
37 (19-64)
44 (20-65)
18-29
445 (38)
54 (36)
21 (21)
30-39
272 (23)
29 (19)
24 (23)
40-49
262 (22)
26 (17)
23 (22)
50-59
187 (16)
30 (20)
25 (24)
60-69
17 (1)
12 (8)
10 (10)
Male
735 (62)
N/A
56 (54)
Female
448 (38)
Age in decades
Gender
47 (46)
Karnofsky score
<90%
298 (25)
35 (23)
19 (18)
>=90%
828 (70)
116 (77)
83 (81)
Missing
57 (5)
0
1 (1)
Median (range)
12 (<1-8930)
14 (<1-3000)
<= 30
654 (55)
83 (55)
30 - 100
175 (15)
25 (17)
> 100
157 (13)
25 (17)
Missing
197 (17)
18 (12)
T-cell
199 (17)
24 (16)
7 (7)
B-cell
698 (59)
119 (79)
89 (86)
Unspecified
286 (24)
8 (5)
7 (7)
CR1
838 (71)
99 (66)
86 (83)
CR2
345 (29)
52 (34)
17 (17)
Median (range)
6 (2-229)
8 (2-129)
6 (2-196)
<6 months
602 (51)
51 (34)
39 (38)
6 months - 1 year
268 (23)
41 (27)
48 (47)
White blood count at diagnosis
FAB classification
Disease status prior to HCT
Time from diagnosis to HCT
78
Not for publication or presentation
Variable
Attachment 11
CIBMTR
MDACC
MOFFITT
313 (26)
59 (39)
16 (15)
Median (range)
17 (<1-164)
N/A
N/A
<6 months
57 (5)
6 months - 1 year
49 (4)
>1 year
171 (14)
88
838 (71)
Missing
68 (6)
N/A
N/A
>1 year
Duration of CR1 for CR2 patients
Time to achieve CR1
Median (range)
6 (<1-612)
<4 weeks
158 (13)
4-8 weeks
479 (40)
>=8 weeks
469 (40)
Missing
77 (7)
Extramedullary disease at diagnosis
No
992 (84)
121 (80)
Yes
184 (16)
24 (16)
Missing
7 (<1)
6 (4)
No
1115 (94)
136 (90)
Yes
61 (5)
9 (6)
Missing
7 (<1)
6 (4)
No
1047 (89)
129 (85)
Yes
129 (11)
16 (11)
Missing
7 (<1)
6 (4)
ATG alone
121 (10)
65 (43)
0 or 1 (double blind)
CAMPATH alone
13 (1)
0
0
No ATG or CAMPATH
1049 (89)
86 (57)
102 or 103 (100)
EMD at CNS at diagnosis
EMD at other site at diagnosis
ATG or campath
Conditioning regimen for CIBMTR cases
TBI + VP16 + Cy
60 (5)
TBI + VP16
226 (19)
TBI + Cy
792 (67)
IV Bu + Fludara
58 (5)
79
Not for publication or presentation
Variable
Attachment 11
CIBMTR
IV Bu + Cy
47 (4)
Missing
0
MDACC
MOFFITT
Conditioning regimen for MDACC cases
Bu+Clo
54 (36)
Bu+Clo+ATG
48 (32)
Flu+Bu
4 (3)
Bu+Mel
28 (19)
Bu+Mel+ATG
15 (10)
Flu+Bu+Clo+ATG
2 (1)
Missing
0
Conditioning regimen for Moffitt cases
Flu+Bu (AUC 3500)
Flu+Bu (AUC 5300)
Flu+Bu (AUC 5300)+R
Flu+Bu (AUC 5300) ATG-F/Placebo
Flu+Bu (AUC 6000)
Flu+Bu (AUC 7500)
1 (1)
87 (84)
1 (1)
1 (1)
5 (5)
8 (8)
Total body irradiation
No
89 (8)
151
103
Yes
1094 (92)
0
0
Median (range)
12 (4-55)
N/A
N/A
<13 Gy
691 (58)
>=13 Gy
403 (34)
Not applicable
89 (8)
N/A
23 (22)
TBI dose
Donor/Recipient CMV match
-/-
322 (27)
-/+
280 (24)
28 (27)
+/-
146 (12)
14 (14)
+/+
395 (33)
38 (37)
Missing
40 (3)
0
Donor/Recipient sex match
M/M
477 (40)
N/A
30 (29)
80
Not for publication or presentation
Variable
Attachment 11
CIBMTR
MDACC
MOFFITT
M/F
249 (21)
30 (29)
F/M
258 (22)
26 (25)
F/F
198 (17)
17 (17)
Missing
1 (<1)
0
Type of donor
HLA-identical sibling
655 (55)
85 (56)
52 (50)
Well-matched unrelated
528 (45)
66 (44)
51 (50)
Bone marrow
320 (27)
36 (24)
1 (1)
Peripheral blood
863 (73)
115 (76)
102 (99)
2000
42 (4)
0
0
2001
53 (4)
0
0
2002
91 (8)
0
0
2003
97 (8)
0
0
2004
122 (10)
0
0
2005
154 (13)
2 (1)
5 (5)
2006
135 (11)
4 (3)
5 (5)
2007
109 (9)
9 (6)
7 (7)
2008
119 (10)
16 (11)
11 (11)
2009
82 (7)
15 (10)
15 (14)
2010
48 (4)
18 (12)
12 (12)
2011
74 (6)
25 (17)
16 (15)
2012
21 (2)
21 (14)
8 (8)
2013
36 (3)
28 (19)
15 (14)
2014
0
13 (9)
9 (9)
30 (1-93)
36 (1-97)
Graft type
Year of HCT
Median follow-up of survivors (range), months 71 (3-173)
81
Not for publication or presentation
Attachment 11
Crosstab of disease status by conditioning regimen group
Conditioning
1 Bu+Clo
2 Bu+Clo+ATG
3 Flu+Bu
5 Bu+Mel
6 Bu+Mel+ATG
7 Flu+Bu+Clo+ATG
Total
Disease status
2 CR1
3 CR2
Total
36
18
54
29
19
48
4
0
4
18
10
28
10
5
15
2
0
2
99
52
151
82
Not for publication or presentation
Attachment 12
Study Proposal 1411-85
Study Title:
Allogeneic (allo) stem cell transplant (SCT) for AML: A comparison of three different reduced intensity
conditioning (RIC) regimens in the CIBMTR data base.
Rajneesh Nath, MD, UMass Memorial Medical Center, MA, neeshr@aol.com;
Rajneesh.nath@umassmemorial.org
Zheng (Frank) Zhou, MD, PhD, UMass Memorial Medical Center, MA, zheng.zhou@umassmemorial.org
Jan Cerny, MD, PhD, UMass Memorial Medical Center, MA, jan.cerny@umassmemorial.org
Hypothesis:
Allo- SCT is a curative option in patients with AML. RIC conditioning is frequently employed for older
patients and those with co morbidities. The three most commonly used RIC regimens are Buslfan (B)
based (B oral dose < 9mg/kg or IV equivalent), Melphalan (M) based (M dose <150 mg/m2) or TBI based
(TBI dose>200 cGy and <500cGYsingle dose or TBI dose < 800cGY fractionated). The relative organ
toxicity and anti leukemia effect for these regimens is currently not known. The incidence of non-relapse
mortality, relapse rate and overall survival of these three regimens in a large registry dataset of AML
patients will help determine the relative efficacy of these regimens.
Specific Aims:
The aim of this study will be to evaluate from the CIBMTR database
1. The relative frequencies of three different RIC regimens for AML patients.
2. To compare the treatment related toxicity of the three RIC regimens in terms of non relapse
mortality and incidence and severity of acute and chronic GVHD.
3. To compare the incidence of relapse and overall survival in the three groups
Scientific Justification:
RIC regimens are being increasingly used for allo SCT in AML. While several studies have compared the
outcomes of conventional ablative with RIC regimens in AML, there is limited data about the relative
toxicity and efficacy of the different RIC regimens. A single center analysis of 151 patients comparing M
and B based RIC revealed that M based regimen was more myelosuppressive , had higher grade III-IV
organ toxicity (53% versus 31%; P=0.005) and higher grade II-IV acute GVHD (53% versus 33%; P=0.01).
M based RIC was also associated with higher non-relapse mortality (40% versus 16%; P=0.003).
However, there was better disease control with M based RIC conditioning. CIBMTR database will provide
a larger dataset to compare the relative toxicities and efficacy of these three RIC regimens in AML.
Results will guide the development of future prospective RIC protocols in AML.
Patient Eligibility Population:
All patients over the age of 18 years who have undergone an allogeneic SCT for AML using related or
unrelated
donor and had data reported to the CIBMTR and had a minimum follow-up of 4 years.
Data Requirements:
 Age
 Gender
 Donor-Recipient Sex Match
83
Not for publication or presentation



























Attachment 12
AML FAB subtype
Therapy related/secondary AML
Cytogenetics risk category
Karnofsky
HSCT-comorbidity index
Disease Status at SCT
Time from diagnosis to SCT
Durations of prior CRs
Bone marrow blast percentage
Stem cell source (BM, PBSC, Cord blood)
Donor age
Donor recipient CMV status
Prior auto SCT
Conditioning regimen used
Documented organ toxicity
GVHD prophylaxis regimen
T cell antibody use
Date of SCT
Time to Neutrophil engraftment time
Time to Platelet engraftment time
Immune recovery (objective measures, including CD4 counts recovery)
Mixed chimerism at 30 days, 6 months and 1 year
Post-transplant infection (bacteria, fungal and/or viral)
Acute GVHD, organ involved and grade
Chronic GVHD, organ involved and grade
Relapse-free survival at different time points (day 100, 1 year, 3 and 5 years)
Overall survival at different time points (day 100, 1 year, 3 and 5 years)
Sample Requirements:
This is a retrospective study from the CIBMTR database. No actual biological sample needed.
Study Design:
A retrospective cohort study of consecutive adult AML patients in the CIBMTR database, who underwent
RIC based allogeneic stem cell transplantation using related or unrelated stem cell donor.
Study endpoints:
Primary endpoints:

Overall mortality (OS) at Day +100, 1 year and 3 years
Secondary endpoints:

Treatment-related mortality (TRM) at Day +100, 1 year and 3 years

Relapse free survival (RFS) at Day+100, 1 year and 3 years

Engraftment rate and Time to engraftment (neutrophil, platelet and immunorecovery)

Cumulative incidence and severity of GVHD (acute and chronic)

Mixed Chimerism (%) at day 30, 6 months and 1 year

TRM is defined as death during continuous disease remission after transplant;

Relapse is defined as clinical or hematological recurrence;
84
Not for publication or presentation


Attachment 12
RFS is defined as clinical or hematological relapses or deaths from any cause;
OS is defined as death from any cause
Surviving patients will be censored at the time of last clinic follow-up or the date of last contact,
whichever is later.
Methods of analysis:
Comparison will be made for 3 different RIC condition regimens with respect to the study endpoints
listed above.
Descriptive Statistics
Descriptive statistics for patient demographic, baseline clinical information and disease characteristics
will be summarized among the RIC regimens. For continuous variables, mean, median, standard
deviation (SD) and range of values will be provided; and for categorical variables, number in each
category and proportion, % will be provided.
Survival Analysis
Multivariate Cox proportional hazard regression will be performed with adjustment for patient baseline
clinical and disease characteristics to determine significance of difference in outcomes related to the RIC
condition regimens. Hazard ratio with 95% confidence interval (CI) will be provided.
Cumulative Incidence and Competing Risk
Rates of relapse, TRM, success in engraftment (neutrophil, platelet and CD4) and GVHD (acute and
chronic) will be estimated using cumulative incidence approach.
In the analysis of the cumulative incidence of engraftments, early mortality will be considered as
competing risk;
In the analysis of GVHD, relapse and mortality will be considered a competing risk.
Kaplan-Meier Curves
OS, TRM and RFS will be compared with stratification by the 3 condition regimens using Kaplan-Meier
curves. Log-rank P-value will be reported.
References:
1. Luger SM, Ringden O, Zhang M-J et al . Similar outcomes using myeloablative vs reducedintensity allogeneic transplant preparative regimens for AML or MDS. Bone Marrow Transplantation
(2012) 47, 203–211.
2. Russell NH, Kjeldsen L, Craddock C et al. A comparative assessment of the curative potential of
reduced intensity allografts in acute myeloid leukaemia. Leukemia (2014) doi:10.1038/leu.2014.319.
3. Shimoni A, Hardan I, Shem-Tov V et al. Comparison between two fludarabine-based reducedintensity conditioning regimens before allogeneic hematopoietic stem-cell transplantation:
fludarabine/Melphalan is associated with higher incidence of acute graft-versus-host disease and
non-relapse mortality and lower incidence of relapse than fludarabine/busulfan. Leukemia (2007)
21, 2109–2116
85
Not for publication or presentation
Attachment 12
Characteristics of Study Population
Variable
Number of patients
Number of centers
Age in decades
TBI based
534
75
Bu based
729
94
Mel based
658
84
57 (19-76)
24 (4)
36 (7)
81 (15)
186 (35)
185 (35)
22 (4)
59 (18-79)
39 (5)
37 (5)
78 (11)
249 (34)
299 (41)
27 (4)
58 (18-77)
36 (5)
45 (7)
83 (13)
216 (33)
258 (39)
20 (3)
Male
Female
Karnofsky score
286 (54)
248 (46)
419 (57)
310 (43)
364 (55)
294 (45)
<90%
>=90%
Missing
White blood count at diagnosis
169 (32)
350 (66)
15 (3)
242 (33)
431 (59)
56 (8)
255 (39)
380 (58)
23 (3)
6 (<1-801)
257 (48)
146 (27)
36 (7)
95 (18)
6 (<1-1300)
409 (56)
202 (28)
50 (7)
68 (9)
7 (<1-1105)
305 (46)
194 (29)
45 (7)
114 (17)
375 (70)
128 (24)
31 (6)
495 (68)
187 (26)
47 (6)
417 (63)
193 (29)
48 (7)
107 (20)
27 (5)
32 (6)
71 (13)
288 (54)
9 (2)
98 (13)
54 (7)
30 (4)
90 (12)
452 (62)
5 (<1)
75 (11)
19 (3)
16 (2)
45 (7)
501 (76)
2 (<1)
66 (12)
257 (48)
111 (21)
79 (11)
420 (58)
156 (21)
161 (24)
262 (40)
96 (15)
Median (range)
18-29
30-39
40-49
50-59
60-69
>=70
Gender
Median (range)
<= 10
10 - 100
> 100
Missing
Type of AML
De-novo
Transformed from MDS/MPS
Therapy linked
HCT-CI
0
1
2
3+
N/A, earlier than 2007
Missing
Disease status prior to HCT
Primary induction failure
CR1
CR2
86
Not for publication or presentation
Variable
>=CR3
Relapse
Cytogenetics scoring
Attachment 12
TBI based
18 (3)
82 (15)
Bu based
10 (1)
64 (9)
Mel based
4 (<1)
135 (21)
148 (28)
27 (5)
94 (18)
144 (27)
28 (5)
10 (2)
83 (16)
211 (29)
43 (6)
156 (21)
152 (21)
11 (2)
28 (4)
128 (18)
133 (20)
34 (5)
132 (20)
160 (24)
12 (2)
25 (4)
162 (25)
7 (<1-313)
234 (44)
149 (28)
151 (28)
7 (1-146)
325 (45)
218 (30)
186 (26)
6 (<1-185)
323 (49)
177 (27)
158 (24)
TBI + Bu
TBI + Cy + Flu +- other
TBI + Cy +- other
TBI + Flu +- other
Other TBI based
Bu + Flu
Mel + Flu
Mel + Flu + Nitro + BCNU
Mel + Flu + other
Graft type
112 (21)
308 (58)
11 (2)
56 (10)
47 (9)
0
0
0
0
0
0
0
0
0
729
0
0
0
0
0
0
0
0
0
535 (81)
94 (14)
29 (4)
Bone marrow
Peripheral blood
Umbilical cord blood
Type of donor
HLA-identical sibling
Other related
Well-matched unrelated
Partially matched unrelated
Mismatched unrelated
Unrelated TBD
Cord blood
Donor/Recipient sex match
75 (14)
256 (48)
203 (38)
82 (11)
636 (87)
11 (2)
104 (16)
507 (77)
47 (7)
76 (14)
53 (10)
81 (15)
63 (12)
16 (3)
42 (8)
203 (38)
243 (33)
24 (3)
297 (41)
85 (12)
15 (2)
54 (7)
11 (2)
131 (20)
16 (2)
287 (44)
107 (16)
28 (4)
42 (6)
47 (7)
181 (34)
130 (24)
283 (39)
175 (24)
241 (37)
183 (28)
Normal
Favorable
Intermediate
Poor
TBD (needs review)
Not tested
Missing
Time from diagnosis to HCT
Median (range)
<6 months
6 - 12 months
>12 months
Conditioning regimen
M/M
M/F
87
Not for publication or presentation
Variable
F/M
F/F
TBD
Donor/Recipient CMV match
Attachment 12
TBI based
104 (19)
116 (22)
3 (<1)
Bu based
134 (18)
134 (18)
3 (<1)
Mel based
122 (19)
110 (17)
2 (<1)
-/-/+
+/+/+
TBD
GVHD prophylaxis
101 (19)
145 (27)
50 (9)
148 (28)
90 (17)
143 (20)
220 (30)
68 (9)
266 (36)
32 (4)
118 (18)
215 (33)
64 (10)
216 (33)
45 (7)
No GVHD prophylaxis
Ex-vivo T-cell depletion
CD34 selection
Post-tx cy
FK506 + MMF +- others
FK506 + MTX +- others
FK506 + others
FK506 alone
CSA + MMF +- others
CSA + MTX +- others
CSA + others
CSA alone
Other GVHD prophylaxis
Missing
In-vivo TCD
5 (<1)
19 (4)
10 (2)
20 (4)
114 (21)
36 (7)
10 (2)
19 (4)
235 (44)
32 (6)
10 (2)
7 (1)
14 (3)
3 (<1)
8 (1)
7 (<1)
4 (<1)
0
98 (13)
311 (43)
20 (3)
31 (4)
50 (7)
102 (14)
8 (1)
76 (10)
13 (2)
1 (<1)
13 (2)
4 (<1)
18 (3)
0
112 (17)
145 (22)
37 (6)
45 (7)
111 (17)
92 (14)
49 (7)
26 (4)
4 (<1)
2 (<1)
No
Yes
Missing
Year of HCT
371 (69)
154 (29)
9 (2)
279 (38)
440 (60)
10 (1)
283 (43)
331 (50)
44 (7)
13 (2)
21 (4)
42 (8)
55 (10)
44 (8)
55 (10)
58 (11)
83 (16)
102 (19)
61 (11)
68 (3-145)
38 (5)
41 (6)
43 (6)
53 (7)
79 (11)
93 (13)
105 (14)
121 (17)
101 (14)
55 (8)
68 (2-151)
26 (4)
44 (7)
72 (11)
84 (13)
104 (16)
86 (13)
85 (13)
83 (13)
52 (8)
22 (3)
73 (3-145)
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
Median follow-up of survivors (range), months
88
Not for publication or presentation
Attachment 12
Selection:
st
1 allo HCT for AML between 2001 to 2010 after CAP modeling
Reduced intensity conditioning containing TBI/Bu/Mel
Excluding syngeneic twin donor
Complete research form
Patient consent
89