Not for publication or presentation
AGENDA
CIBMTR WORKING COMMITTEE FOR LYMPHOMA
San Diego, CA
Friday, February 13, 2015, 12:15 – 2:15 pm
Co-Chair:
Co-Chair:
Co-Chair:
Statisticians:
Scientific Director:
1.
David Maloney, MD, PhD, Fred Hutchinson Cancer Center, Seattle, WA;
Telephone: 206-667-5616; Fax: 206-667-6124; E-mail: dmaloney@fredhutch.org
Sonali Smith, MD, The University of Chicago, Chicago, IL; Telephone: 773-702-4400;
Fax: 773-702-0963; E-mail: smsmith@medicine.bsd.uchicago.edu
Anna Sureda, MD, PhD, Hospital Duran i Reynals, Barcelona, Spain;
Telephone: +34 9326 07750; Fax: +34 9326 07353; E-mail: asureda@iconcologia.net
Kwang Woo Ahn, PhD, CIBMTR Statistical Center, Milwaukee, WI;
Telephone: 414-456-7387; Fax: 414-955-6513; E-mail: kwooahn@mcw.edu
Jeanette Carreras, MPH, CIBMTR Statistical Center, Milwaukee, WI;
Telephone: 414-805-0681; Fax: 414-805-0714; E-mail: jcarrera@mcw.edu
Alyssa DiGilio, MS, CIBMTR Statistical Center, Milwaukee, WI;
Telephone: 414-805-0660; Fax: 414-805-0714; E-mail: adigilio@mcw.edu
Mehdi Hamadani, MD, CIBMTR Statistical Center, Milwaukee, WI;
Telephone: 414-805-0700; Fax: 414-805-0714; E-mail: mhamadani@mcw.edu
Introduction
a. Minutes and Overview Plan from February 2014 meeting (Attachment 1)
b. Introduction of incoming Co-Chair: Timothy Fenske, MD; Medical College of Wisconsin; Email:
tfenske@mcw.edu
2.
Accrual Summary (Attachment 2)
3.
Presentations, published or submitted papers
LY09-01 Wirk B, Fenske TS, Hamadani M, Zhang M-J, Hu Z-H, Akpek G, Aljurf MD, Armand P, Ayala E,
Bachanova V, Bolwell B, Cairo MS, Cashen A, Chen Y-B, Costa LJ, Farhan S, Freytes CO, Gajewski JL,
Gibson J, Hale GA, Holmberg LA, Hsu JW, Inwards DJ, Kamble RT, Maharaj D, Maziarz RT, Munker R,
Nath R, Reddy NM, Reeder CB, Rizzieri DA, Sauter CS, Savani BN, Schouten HC, Sureda A, Vose JM,
Waller EK, Wiernik PH, Gale RP, Burns LJ, Saber W. Outcomes of hematopoietic cell transplantation for
diffuse large B cell lymphoma transformed from follicular lymphoma. Biology of Blood and Marrow
Transplantation: Journal of the American Society for Blood and Marrow Transplantation. 2014 Jul 1;
20(7):951-959.
b. LY07-02 Lechowicz MJ, Lazarus HM, Carreras J, Laport GG, Cutler CS, Wiernik PH, Hale GA, Maharaj D,
Gale RP, Rowlings PA, Freytes CO, Miller AM, Vose JM, Maziarz RT, Montoto S, Maloney DG, Hari PN.
Allogeneic hematopoietic cell transplantation for mycosis fungoides and sezary syndrome. Bone
Marrow Transplantation. 2014 Nov 1; 49(11):1360-1365.
a.
1
Not for publication or presentation
LY13-01 Hamadani M, Hari PN, Zhang Y, Carreras J, Akpek G, Aljurf MD, Ayala E, Bachanova V, Chen AI,
Chen Y-B, Costa LJ, Fenske TS, Freytes CO, Ganguly S, Hertzberg MS, Holmberg LA, Inwards DJ, Kamble
RT, Kanfer EJ, Lazarus HM, Marks DI, Nishihori T, Olsson R, Reddy NM, Rizzieri DA, Savani BN, Solh M,
Vose JM, Wirk B, Maloney DG, Smith SM, Montoto S, Saber W. Early failure of frontline rituximabcontaining chemoimmunotherapy in diffuse large B-cell lymphoma does not predict futility of
autologous hematopoietic cell transplantation. Biology of Blood and Marrow Transplantation: Journal
of the American Society for Blood and Marrow Transplantation. 2014 Nov 1; 20(11):1729-1736.
d. LY10-02 Bachanova V, Burns LJ, Wang T, Carreras J, Gale RP, Wiernik PH, Ballen KK, Wirk B, Munker R,
Rizzieri DA, Chen Y-B, Gibson J, Akpek, Costa LJ, Kamble RT, Aljurf MD, Hsu JW, Cairo MS, Schouten HC,
Bacher U, Savani BN, Wingard JR, Lazarus HM, Laport GG, Montoto S, Maloney DG, Smith SM,
Brunstein C, Saber W. Alternative donors extend transplantation for patients with lymphoma who lack
an HLA matched donor. Bone Marrow Transplantation. doi:10.1038/bmt.2014.259. Epub 2014 Nov
17.
e. LY12-02/GV11-01 Alvaro Urbano Ispizua, Steve Pavletic, Mary Flowers, Mei-Jie Zhang, Jeanette
Carreras, Sonali Smith, David Maloney, Silvia Montoto, Corey Cutler, Steve Spellman, Mukta Arora, and
Wael Saber. Association of graft vs. host disease with a lower relapse/progression rate after allogeneic
hemopoietic stem cell transplantation with reduced intensity conditioning in patients with follicular
and mantle cell lymphoma. Submitted
f. LY12-01 Veronika Bachanova, Linda Burns, Kwang Woo Ahn, Jeanette Carreras, David Maloney, Anna
Sureda, Sonali Smith, Mehdi Hamadani. Positive pre-allogeneic hematopoietic cell transplantation PET
scan in patients with non-Hodgkin lymphoma predicts higher risk of relapse but has no impact on
survival. Oral presentation at the BMT Tandem Meetings in San Diego, CA, February 2015.
g. LY13-02 Prakash Satwani, Kwang Woo Ahn, Jeanette Carreras, David Maloney, Anna Sureda, Sonali
Smith, Mehdi Hamadani. Risk Factors Predicting Outcomes of Autologous Hematopoietic Cell
Transplantation in Children, Adolescents and Young Adults (CAYA) with Relapsed/Refractory (Rel/Ref)
Classical Hodgkin Lymphoma: A CIBMTR Analysis. Oral presentation at the BMT Tandem Meetings in
San Diego, CA, February 2015.
c.
4.
Studies in progress (Attachment 3)
a.
b.
c.
d.
e.
5.
LY12-01 Positron Emission Tomography Imaging Prior to AlloHCT for
lymphoma (V Bachanova)
LY13-02 Outcome after AutoHCT for CAYA with relapsed/refractory
Hodgkin lymphoma (P Satwani)
LY13-03 Auto vs NMA/RIC for relapsed/refractory follicular
lymphoma (E Klyuchnikov)
LY06-03 Sib vs MUD for follicular NHL/EBMT with CIBMTR (A Sureda)
LY14-02 AlloHCT for DLBCL after a failed AutoHCT (T Fenske)
Manuscript Preparation
Manuscript Preparation
Analysis
Data File Preparation
Protocol Development
Future/proposed studies
a.
b.
c.
PROP 1410-09 Comparison of allogeneic stem cell transplantation to autologous stem cell
transplantation for patients with early relapsed and primary refractory diffuse large B cell lymphoma
(N Ghosh) (Attachment 4)
PROP 1410-10 Does Autologous Stem Cell Transplant Overcome the Increased Risk of Death in
Patients with Follicular Lymphoma Relapsing Early after First Line Chemoimmunotherapy? (C Casulo/J
Friedberg) (Attachment 5)
PROP 1411-17/1411-93 Hematopoietic Cell Transplantation for NK/T-cell Non-Hodgkin Lymphoma
(S Barta/H Fung/G Akpek) (Attachment 6)
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d.
e.
f.
g.
h.
PROP 1411-35 Allogeneic Hematopoietic Stem Cell Transplantation in HTLV-1 associated Adult T-cell
Lymphoma/Leukemia (P Dahi/C Sauter/MA Perales) (Attachment 7)
PROP 1411-15 Hematopoietic cell transplantation (HCT) outcomes for relapsed or refractory marginal
zone lymphomas (B William/B Hill/H Lazarus) (Attachment 8)
PROP 1411-83 A retrospective review of outcomes with allogeneic and autologous transplant
outcomes for t cell large granular lymphocytic lymphoma and gamma-delta T cell lymphoma (J
Gajewski/R Maziarz) (Attachment 9)
PROP 1408-02/1411-27 Alternative Donor Allogeneic Hematopoietic Transplantation Strategies for
Lymphoid Malignancies in Adult Patients: Comparing Matched Unrelated versus Haploidentical
Related Donor Transplantation (A Kanate/A Mussetti/K Dabaja) (Attachment 10)
PROP 1411-06/1411-36/1412-13 Comparing Outcomes between Haploidentical and HLA Matched
Related Donor Transplants for Patients with Lymphoid Malignancies (R Karmali/N Gosh/V Rocha)
(Attachment 11)
Dropped proposed studies
a.
b.
c.
d.
e.
f.
g.
h.
i.
j.
k.
LY14-01: Updated prognostic information for lymphoma survivors beyond 1 year from allogeneic
hematopoietic cell transplantation. A landmark CIBMTR analysis (A Lazaryan). Dropped due to
feasibility.
PROP 1408-01 Comparison of twin and autologous transplants for Non-Hodgkin Lymphoma (M Mir)
Dropped due to limited by heterogeneity and feasibility-low number of twin patients.
PROP 1408-03 Role of FDG‐PET prior to allogeneic transplantation in predicting outcomes for patients
with relapsed or refractory Hodgkin lymphoma: A CIBMTR Analysis (A Lazaryan) Dropped due to
feasibility-supplemental data and low number of patients (n=70).
PROP 1409-01 Allogeneic transplantation for older patients with non-Hodgkin Lymphoma (V
Bachanova) Dropped due to overlap with LK07-03c.
PROP 1409-06 Outcome following autologous hematopoietic cell transplantation (AHCT) in
plasmablastic lymphoma (PBL): A combined analysis of CIBMTR and EBMT data (M Al Malk) Dropped
due to feasibility-low number of patients (n=3).
PROP 1409-08 Outcomes of upfront autologous stem cell transplantation in adult mantle cell
lymphoma - is there an ideal induction regimen? (L Veltri) Dropped due to feasibility.
PROP 1401-01 Case control study of busulfan, melphalan, and thiotepa (BuMelTt) versus alternative
myeloablative conditioning regimens in autologous hematopoietic stem cell transplant for
relapsed/refractory Hodgkin’s Lymphoma (HL) (J Brammer) Dropped due to feasibility-low number of
patients (n=3).
PROP 1410-06 Comparison of outcomes for patients with relapsed/refractory mantle cell lymphoma
after RIT-based versus standard autologous stem cell transplantation (E Klyuchnikov) Dropped due to
feasibility-low number of patients (n=7).
PROP 1410-14 Comparison of consolidation with allogeneic versus autologous hematopoietic cell
transplantation for patients with relapsed/refractory diffuse large B cell lymphoma achieving a partial
metabolic response to salvage chemotherapy (D Landsburg) Dropped due to feasibility-supplemental
data.
PROP 1411-04 Identifying Prognostic Factors and Treatment Strategies that Impact Clinical Outcomes
in Patients with Primary Central Nervous System Lymphoma (PCNSL) undergoing Autologous Stem
Cell Transplantation in the Rituximab Era (R Karmali) Dropped due to feasibility-low number of
patients (n=24).
PROP 1411-05 Impact of Obesity and Diabetes on Outcomes after Autologous Hematopoietic Stem
Cell Transplantation in Aggressive Lymphomas (R Karmali) Dropped due to feasibility-supplemental
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data.
l.
m.
n.
o.
p.
q.
r.
s.
t.
u.
v.
6.
PROP 1411-08 Multi-center retrospective study of outcomes of autologous hematopoietic cell
transplantation for patients with EBER-ISH/LMP positive relapsed/refractory Hodgkin lymphoma (P
Satwani) Dropped due to feasibility.
PROP 1411-25 Prognostic model for patients with DLBCL relapsing after auto-HCT (L Costa) Dropped
due to feasibility-supplemental data.
PROP 1411-34 Prognostic model for relapsed Diffuse Large B Cell Lymphoma undergoing
consolidation with hematopoietic cell transplant (HCT) (A Hallack Neto) Dropped due to feasibilitysupplemental data.
PROP 1411-48 Is Reduced Intensity BEAM as equally effective as BEAM for relapsed Diffuse Large Bcell Lymphoma in 2nd Remission? (M Sharma) Dropped due to feasibility.
PROP 1411-51 Retrospective comparative study of blood or bone marrow transplantation for
relapsed/refractory Hodgkin lymphoma by donor type (J Kanakry) Dropped due to overlap with LY1002 and low number of patients (n=27 in haploidentical cohort).
PROP 1411-52 Impact of mobilization strategies with plerixafor versus chemomobilization with
cyclophosphamide for non-Hodgkin lymphoma (NHL) on outcomes after autologous stem cell
transplant (C Vigil) Dropped due to feasibility-supplemental data.
PROP 1411-62 Impact of brentuximab vedotin on outcomes of allogeneic hematopoietic cell
transplantation for relapsed or refractory Hodgkin lymphoma (B Wirk) Dropped due to feasibility-low
number of patients (n=5).
PROP 1412-07 Brentuximab Vedotin used to bridge patients into successful reduced intensity
allogeneic or second autologous stem cell transplantation in relapsed or refractory Hodgkin’s
lymphoma post autologous stem cell transplantation (S Altouri) Dropped due to feasibility-low number
of patients (n=5).
PROP 1411-91 Outcomes Following Allogeneic Stem Cell Transplant for Relapsed Primary or
Secondary Central Nervous System Lymphoma (S Jaglowski) Dropped due to low number of cases.
PROP 1411-70 Autologous stem cell transplant in elderly patients with Hodgkin Lymphoma (MA
Perales) Dropped due to feasibility-low number of patients (n=39).
PROP 1412-06 Efficacy of BCNU vs. non- BCNU containing conditioning regimens on the outcomes of
autologous stem cell transplantation for relapsed Diffuse large B-cell lymphoma and Hodgkin’s
Lymphoma (S Altouri) Dropped due to overlap with SC10-06.
Other Business
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Attachment 1
MINUTES AND OVERVIEW PLAN
CIBMTR WORKING COMMITTEE FOR HODGKIN AND NON-HODGKIN LYMPHOMA
Grapevine, TX
Thursday, February 27, 2014, 12:15 pm – 2:15 pm
Co-Chair:
Silvia Montoto, MD, St. Bartholomew’s Hospital, London, United Kingdom
Telephone: 44 207-601-7456; Fax: 44-207-796-3979; E-mail: s.montoto@qmul.ac.uk
Co-Chair:
David Maloney, MD, PhD, Fred Hutchinson Cancer Research Center, Seattle, WA
Telephone: 206-667-5000; Fax: 206-667-6124; E-mail: dmaloney@fhcrc.org
Co-Chair:
Sonali Smith, MD, University of Chicago Hospitals, Chicago, IL
Telephone: 773-834-2895; Fax: 773-702-0963;
E-mail: smsmith@medicine.bsd.uchicago.edu
Statisticians:
Jeanette Carreras, MPH, CIBMTR Statistical Center, Milwaukee, WI
Telephone: 414-805-0681; Fax: 414-805-0714; E-mail: jcarrera@mcw.edu
Mei-Jie Zhang, PhD, CIBMTR Statistical Center, Milwaukee, WI
Telephone: 414-456-8375; Fax: 414-805-0714; E-mail: meijie@mcw.edu
Scientific Director: Mehdi Hamadani MD, Medical College of Wisconsin, Milwaukee, WI
Telephone: 414-805-0700; Fax: 414-805-0714; E-mail: mhamadani@mcw.edu
1.
Introduction
The CIBMTR Hodgkin and Non-Hodgkin Lymphoma Working Committee was called to order at
12:16 pm on Thursday, February 27, 2014, by Dr. Silvia Montoto. Working Committee Leadership
was introduced and audience was asked to fill out the Working Committee evaluations and voting
sheets for proposals. Dr. Mehdi Hamadani introduced Dr. Anna Sureda as the newly appointed
Chair for the Hodgkin & Non-Hodgkin Lymphoma Working Committee starting March 1, 2014. Dr.
Montoto was acknowledged for all of her efforts during these past years as Co-Chair. Dr. Rodney
Sparapani was introduced as the incoming PhD statistician and Dr. Hamadani as the incoming
Scientific Director. Dr. Wael Saber was acknowledged for all of his efforts and statistical expertise
these past years as Scientific Director. Working Committee goals, expectations and limitations were
discussed as well as the CIBMTR guidelines for voting by Dr. David Maloney. The guidelines are
based on a scale from 1 to 9; 1= high scientific impact, 9= low scientific impact. These are
consistent across all Working Committees. Each proposal was limited to 5 minutes (maximum 3-4
overheads) to allow for adequate time for discussion. Rules of authorship were discussed. Authors
must meet the following 3 conditions to assure authorship: 1) substantial and timely contributions
to conception and design, or acquisition of data, or analysis and interpretation of data; 2) drafting
the article or revising it critically for important intellectual content; 3) final approval of the version
to be published. The minutes of the February 2013 meeting were approved. A significant increase
in productivity of the Working Committee was reported including 8 published/submitted papers, 3
manuscripts in preparation, 2 presentations at the American Society of Hematology in New
Orleans, LA and 1 presentation at the BMT Tandem Meetings in Grapevine, TX.
2.
Accrual summary
Due to the full agenda, the accrual summary of registration and research cases between 2000 and
2013 were not presented to the committee but were available as part of the Working Committee
5
Not for publication or presentation
Attachment 1
attachments:
Non-Hodgkin Lymphoma
Registration only
Research
Hodgkin Lymphoma
Registration only
Research
3.
HLA-identical
Alternative Donor
Autologous
3973
1313
1418
3121
5262
673
368
82
174
198
11521
1424
Presentations, published or submitted papers
Due to the full agenda, the 2013 presentations and published papers were mentioned but not
presented.
LY04-03 Maziarz RT, Wang Z, Zhang MJ, Bolwell BJ, Chen AI, Fenske TS, Freytes CO, Gale RP,
Gibson J, Hayes-Lattin BM, Holmberg L, Inwards DJ, Isola LM, Khoury HJ, Lewis VA, Maharaj D,
Munker R, Phillips GL, Rizzieri DA, Rowlings PA, Saber W, Satwani P, Waller EK, Maloney DG,
Montoto S, Laport GG, Vose JM, Lazarus HM, Hari PN. Autologous hematopoietic cell
transplantation for non-Hodgkin lymphoma with CNS involvment. British Journal of
Haematology. 2013 Sep 1; 162(5):648-656.
LY06-05 Smith SS, Burns LJ, van Besien K, LeRademacher J, He W, Fenske T, Suzuki R, Hsu JW,
Schouten HC, Hale GA, Holmberg LA, Sureda A, Freytes CO, Maziarz RT, Inwards DJ, Gale RP,
Gross TG, Cairo MS, Costa LJ, Lazarus HM, Wiernik PH, Maharaj D, Laport GG, Montoto S, Hari
PN. Autologous or allogeneic hematopoietic stem cell transplantation for systemic mature Tcell non-Hodgkin lymphoma. Journal of Clinical Oncology. 2013 Sep 1; 31(25):3100-3109.
LY10-01a Hamadani M, Saber W, Ahn KW, Carreras J, Cairo MS, Fenske TS, Gale RP, Gibson J,
Hale GA, Hari PN, Hsu JW, Inwards DJ, Kamble RT, Klein A, Maharaj D, Marks DI, Rizzieri DA,
Savani BN, Schouten HC, Waller EK, Wirk B, Laport GG, Montoto S, Maloney DG, Lazarus HM.
Impact of pretransplant conditioning regimens on outcomes of allogeneic transplantation for
chemotherapy-unresponsive diffuse large B-cell lymphoma and grade-III follicular lymphoma.
Biology of Blood & Marrow Transplantation. 2013 May 1; 19(5):746-753.
LY10-01b Hamadani M, Saber W, Ahn KW, Carreras J, Cairo MS, Fenske TS, Gale RP, Gibson J,
Hale GA, Hari PN, Hsu JW, Inwards DJ, Kamble RT, Klein A, Maharaj D, Marks DI, Rizzieri DA,
Savani BN, Schouten HC, Waller EK, Wirk B, Lazarus HM. Allogeneic hematopoietic cell
transplantation for chemotherapy-unresponsive mantle cell lymphoma: a cohort analysis from
the CIBMTR. Biology of Blood & Marrow Transplantation. 2013 Apr 1; 19(4):625-631.
LY06-06 Hahn T, McCarthy PL, Carreras J, Zhang MJ, Lazarus HM, Laport GG, Montoto S, Hari
PN. Simplified validated prognostic model for progression-free survival autologous
transplantation for relapsed or refractory Hodgkin lymphoma. In Press, Biology of Blood &
Marrow Transplantation.
LY08-02 Fenske TS, Zhang MJ, Carreras J, Ayala E, Burns LJ, Cashen A, Costa LC, Freyte CO,
Gale RP, Hamadani M, Holmberg LA, Inwards DJ, Lazarus HM, Maziarz RT, Munker R, Perales
6
Not for publication or presentation
Attachment 1
MA, Rizzieri DA, Schouten HC, Smith SM, Waller EK, Wirk BM, Laport GG, Maloney DG,
Montoto S, and Hari PN. Autologous or reduced-intensity allogeneic hematopoietic cell
transplantation for chemotherapy-sensitive mantle cell lymphoma: analysis of transplant
timing and modality. In Press, Journal of Clinical Oncology.
LY07-02 Lechowicz MJ, Lazarus HM, Carreras J, Laport GG, Cutler CS, Wiernik PH, Hale GA,
Maharaj D, Gale RP, Rowlings PA, Freytes CO, Miller AM, Vose JM, Maziarz RT, Montoto S,
Maloney DG, Hari PN. Allogeneic hematopoietic cell transplantation for cutaneous T cell
lymphoma. Submitted.
LY09-01 B Wirk, Fenske TS, Hamadani M, Hu ZH, Akpek G, Aljurf MD, Armand P, Ayala, E,
Bachanova V, Bolwell B, Cairo MS, Cashen A, Chn YB, Costa LJ, Farhan S, Freytes CO, Gajewski
JL, Gibson J, Hale GA, Holmerg LA, Hsu JW, Inwards DJ, Kamble RT, Maharaj D, Maziarz RT,
Munker R, Nath R, Reddy NM, Reeder CB, Rizzieri DA, Sauter CS, Savani BN, Shouten HC,
Sureda A, Vose JM, Waller EK, Wiernik PH, Gale RP, Burns LJ, Saber W. Outcomes of
hematopoietic cell transplantation for diffuse large B cell lymphoma transformed from
follicular lymphoma. Submitted.
LY10-02 Veronika Bachanova, Claudio Brunstein, Linda Burns, Tao Wang, Jeanette Carreras,
Ginna Laport, Sonali M. Smith, Silvia Montoto, David Maloney and Wael Saber. Alternative
Donor Transplantation for Adults with Lymphoma: Comparison of Umbilical Cord Blood versus
8/8 HLA-matched Donor (URD) versus 7/8 URD. Oral presentation at the American Society of
Hematology in New Orleans, LA, December 2013; Manuscript Preparation.
LY12-02/GV11-01 Alvaro Urbano Ispizua, Steve Pavletic, Mary Flowers, Mei-Jie Zhang,
Jeanette Carreras, Sonali Smith, David Maloney, Silvia Montoto, Corey Cutler, Steve Spellman,
Mukta Arora, and Wael Saber. Association of graft vs. host disease with a lower
relapse/progression rate after allogeneic hemopoietic stem cell transplantation with reduced
intensity conditioning in patients with follicular and mantle cell lymphoma. Presentation at
the American Society of Hematology in New Orleans, LA, December 2013; Manuscript
Preparation.
4.
Studies in progress
The studies in progress were not presented in order to provide reasonable time to the new
proposals for presentation and discussion. Attendees were asked to review the materials to assess
the progress of ongoing studies. These were:
LY10-02: Alternative donor transplantation for adults with lymphoma: comparison of umbilical cord
blood versus 8/8 HLA-matched URD versus 7/8 URD (V Bachanova). We compared outcomes of
1593 non-Hodgkin and Hodgkin lymphoma patients who underwent alternative donor HCT from
2000-2010. UCB (n=142), 8/8 HLA URD (n=1176) and 7/8 matched URD (n=275) HCT recipients
were followed for 25, 57 and 65 months, respectively. In multivariate analysis 7/8 URD had 1.3-fold
higher risk of TRM than the 8/8 URD. Acute graft-versus-host disease risk were higher with URD
donors compared to UCB group (8/8 URD HR 1.47 [95% CI 1.0-2.17]; p=0.049 and 7/8 URD HCT HR
2.12 [95%CI 1.52-2.95]; p<0.001). Manuscript will be submitted soon after the BMT Tandem
meetings.
LY12-02/GV11-01: Association of graft-versus-host disease with a lower relapse/progression rate
after allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning in
7
Not for publication or presentation
Attachment 1
patients with follicular and mantle cell lymphoma. A CIBMTR analysis (A Urbano-Ispizua/S
Pavletic/M Flowers). RIC transplantation is an established platform of immunotherapy for
lymphoma due to the graft-vs.-lymphoma (GVLy) effect. The objective of this study was to
determine if GVLy was associated with aGVHD or cGVHD in B cell and T cell lymphomas, and to
analyze whether this effect differs in myeloablative and RIC transplants. Inclusion criteria were
patients older than 18 years undergoing HLA-identical sibling or unrelated donor HSCT between
1997 and 2009, with diagnosis of HL, DLBCL, follicular lymphoma (FL), peripheral T-NHL, and MCL.
Twin transplants, cord blood, and ex vivo T-cell depletion cases were excluded. Landmark analysis
will be performed and manuscript is underway and will be submitted before July 1st, 2014.
LY06-03: Allogeneic hematopoietic cell transplantation for relapsed follicular lymphoma: impact of
donor type and prognostic risk score for surviva. (A Sureda). This study compared the outcomes of
702 recipients of allogeneic HCT for FL (198 unrelated and 504 sibling donors) from 171 centers
world-wide reporting to the CIBMTR or EBMT between 1997 and 2005. This study shows that
unrelated HCTs are performed later in the treatment course for FL; in higher risk patients; most
commonly with reduced intensity conditioning; and in multivariate analysis adjusting for baseline
differences between the 2 groups, unrelated HCTs were significantly associated with worse PFS and
OS compared to sib HCT. This study was submitted to JCO and based on reviewer’s comments and
internal discussion inclusion criteria will be modified with different transplant years to pick up a
more “modern” cohort. Data file preparation is underway and a conference call for further
collaboration will be scheduled after the BMT Tandem meetings.
LY13-01: Autologous transplantation for diffuse large B cell lymphomas patients refractory to, or
relapsing early after rituximab-containing first line chemo immunotherapies (M Hamadani). Among
patients with chemosensitive DLBCL at transplant (CR2, PR1/PR2) that received rituximab-containing
induction chemoimmunotherapy and either never responded to that first line or subsequently
relapsed, we will compare post transplantation outcomes in Early Rituximab Failure (ERF) patients
(refractory or relapsed within 1 year since diagnosis) vs. Late Rituximab Failure (LRF) patients
(relapsed greater than a year since diagnosis). Abstract is submitted to 2014 Annual Meetings of
ASCO and manuscript is underway and will be submitted before July 1st, 2014.
LY12-01: Positron Emission Tomography Imaging Prior to AlloHCT for Lymphoma. (V Bachanova).
The purpose of this study is to determine the role of positron emission tomography imaging
performed prior to start of preparative regimen for allogeneic transplants in predicting the
recurrence, lymphoma-free survival and overall survival in patients with non-Hodgkin lymphoma
(NHL, B and T cell) and Hodgkin lymphoma. Patients with PET scan negative/positive who underwent
allogeneic transplants from 2008 and 2010 and reported to the CIBMTR will be analyzed. Protocol is
in development.
LY13-02: Outcome of autologous hematopoietic cell transplantation for children, adolescents, and
young adults with relapsed/refractory hodgkin lymphoma (P Satwani). Autologous stem cell
transplantation (AutoSCT) has become a standard of care in children, adolescents and young adults
(CAYA) with relapsed/refractory Hodgkin Lymphoma (HL). However, due to a small number of
patients reported in few retrospective and prospective studies, the risk factors associated with poor
outcomes have not been well established. We hypothesize that after receiving AutoSCT, CAYA
relapsing with HL within 1 year of original diagnosis, and CAYA with refractory HL, will have
significantly poor 2 year overall survival (OS) and disease-free survival (DFS) compared to those who
relapse after 1 year of original diagnosis. Protocol is in development.
8
Not for publication or presentation
Attachment 1
LY13-03: Comparison of autologous versus allogeneic hematopoietic cell transplantation after
reduced/non-myeloablative conditioning for relapsed/refractory patients with follicular lymphoma
(E Klyuchnikov). This study intends to compare overall (OS) and progress-free survival (PFS) in
patients aged ≥18 years with relapsed/refractory follicular lymphoma (FL) who underwent reducedintensity/non-myeloablative allogeneic stem cell transplantation (RIC/NMAC-HSCT) versus
autologous stem cell transplantation (auto-HSCT) as second-line approach. Protocol is in
development.
5.
Future/ Proposed studies
PROP 1304-03 Comparison between Total Body Irradiation and non-TBI based conditioning
regimens for allogeneic hematopoietic cell transplant in patients with diffuse large B-cell nonHodgkin’s Lymphoma (J Hsu).
Dr. Hsu presented the study. This study will determine the effect of TBI in the conditioning regimen
in allogeneic HCT for diffuse large B-cell non-Hodgkin’s Lymphoma on efficacy and toxicity
outcomes. The amount of TBI may also have a significant effect on outcomes. A CIBMTR analysis of
502 patients with ALL who received a matched sibling allograft in first or second remission using
either Cy/TBI or VP16/TBI conditioning found no significant differences in TRM, leukemia free
survival, cumulative incidence of relapse, and overall when comparing dose of TBI for patients who
were transplanted in CR1. There are also differences in late effects between TBI and non-TBI
containing conditioning regimens. A recent report by the CIBMTR on late effects in 1718 patients
with aplastic anemia who underwent a matched sibling or matched unrelated donor transplant
found a greater proportion of late effects in patients exposed to TBI. Because radiation is
considered an effective treatment modality for DLBCL, registry analysis will include TBI vs. non-TBI
containing regimens as a covariate in the analysis. This study will investigate the role of TBI in
allogeneic conditioning regimens of patients with DLBCL. There are 465 TBI and 555 non TBI
patients with AlloHCT for DLBCL registered to the CIBMTR between 2000-2012. The Working
Committee suggested dividing myeloablative and RIC/NST since it might have a different outcome
effect.
PROP 1304-04 Impact of conditioning regimen on outcomes of autologous hematopoietic cell
transplantation for relapsed follicular and diffuse large B-cell lymphomas (B William)
Dr. William presented the study. This study will determine the impact of the conditioning regimen
used for autologous HCT for follicular and diffuse large B-cell non-Hodgkin’s Lymphoma on efficacy
and toxicity outcomes. There are 43 TBI and 347 non TBI patients with autoHCT for
relapsed/refractory follicular lymphoma reported to the CIBMTR between 2000-2012. If accepted,
the Committee suggested including Rituximab in the analysis.
PROP 1310-17 Transplant Outcomes in Nodular Lymphocyte Predominant Hodgkin Lymphoma
(G Akpek)
Dr. Akpek presented the study. The study proposed will analyze CIBMTR data to address the
working hypothesis that patients with relapsed or primary refractory NLPHL have greater than 50%
probability of surviving without progression at 5 years following HCT. The study aims to generate
data on standard transplant outcomes after autologous and allogeneic HCT in patients with NLPHL
and to identify variables associated with favorable survival outcomes. There are 306 patients with
AutoHCT for Hodgkin lymphoma registered to the CIBMTR between 2004-2013. The Committee
suggested restricting the study to 2007-2013. Transformed lymphoma cannot be analyzed since it is
not collected on the registration forms. Only 26 of 306 patients have research detailed information.
9
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Attachment 1
Dr. Montoto mentioned the high percentage (44%) of CR2 prior to transplant status reported.
PROP 1311-01 Outcomes of diffuse large B-cell lymphoma with skeletal involvement after
autologous hematopoietic cell transplantation (B Wirk)
Dr. Wirk presented the study. This study aims to analyze the outcomes of autologous
hematopoietic cell transplantation for diffuse large B-cell lymphoma with or without skeletal
involvement. There are 131 bone involvement and 1158 non bone involvement patients with
AutoHCT for relapse/refractory DLBCL reported to the CIBMTR between 2000-2012. Dr. Wirk
suggested including Rituximab in the analysis. Dr. Philip Rollings suggested looking at the PET scan
to confirm skeletal involvement. Matched-pair analysis was suggested and sites of skeletal
involvement would need to be reported.
PROP 1311-08 High-Dose Therapy and Autologous Transplantation for Intravascular Large B-cell
Lymphoma (M Hamadani)
Dr. Abraham Kanate presented the study. The study aims to describe the outcomes with high-dose
therapy (HDT) and autologous hematopoietic cell transplantation of intravascular large B-cell
lymphoma (IVLBCL) and to identify patient-, disease-, and HCT-related characteristics that are
associated with post-HCT outcomes among patients with IVLBCL. There are 213 registration only
and 35 research patients with autoHCT for IVLBCL reported to the CIBMTR from 2006-2012. Study
pitfalls: unknown denominator (selection bias), question of best timing cannot be answered,
uncertain if analysis will be clinically useful or will it inform practice. Dr. Montoto asked going back
to the centers to identify how many patients they have. It was concluded not worth the effort since
this special supplemental request will take at least a year.
PROP 1311-68 Outcome of Hematopoietic Cell Transplantation in non-Hodgkin’s Lymphoma
patients aged 70 years or older (K Wudhikarn)
Dr. Wudhikarn presented the study. There are 3 hypothesis for this study: 1) Hematopoietic cell
transplantation (HCT) for Non-Hodgkin’s Lymphoma (NHL) patients age 70 years or older is an
effective treatment strategy; 2) transplant related complications of HCT in NHL patients aged 70
years or older are higher than NHL patients who undergo HCT at a younger age; 3) survival
outcomes of HCT in NHL patients aged 70 years or older are inferior to patients in the younger age
group of 65-69 years old. This study aims to describe the characteristics of NHL patients aged 70
years or older who undergo autologous or allogeneic HCT. There are 347 patients between 65-69
years of age and 73 ≥70 years of age with alloHCT in NHL registered to the CIBMTR from 2000-2012.
There are 3390 patients between 65-69 years of age and 1642 ≥70 years of age with autoHCT in
NHL registered to the CIBMTR from 2000-2012. Committee members mentioned the higher number
of autoHCT patients as compared to alloHCT. It was suggested to look at comorbidities & Sorror
score and look only at ≥70 years of age vs. rest.
PROP 1311-75 Trends in allograft use and survival after reduced intensity/non-myeloablative
conditioning allogeneic hematopoietic cell transplantation for Hodgkin lymphoma: 1999-2013
(V Bachanova)
Dr. Bachanova presented the study. This study aims to describe and compare outcomes in Hodgkin
lymphoma (HL) patients undergoing a reduced intensity /non-myeloablative (RIC/NST) allogeneic
cell transplant (alloHCT) in 3 time periods: (1999-2004 vs. 2005-2009 vs. 2010-2013) and to describe
changes in utilization of alloHCT and in 1) patient 2) disease and 3) transplant characteristics,
including the treatment with brentuximab, prior to allograft during these 3 time periods. There are
157 patients transplanted between 1999-2004, 140 in 2005-2009 and 91 in 2010-2013 with alloHCT
10
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Attachment 1
in NHL registered to the CIBMTR. Myeloablative conditioning regimen was excluded. Year of
transplant cut-offs were questioned by the Committee and especially the later years. Committee
suggested waiting 1-2 years to increase number of patients to increase scientific interest. It was
also suggested to include myeloablative regimens. Suggested to include prior therapy and
rituximab prior to transplant. Dr. Timothy Fenske suggested looking and those patients who had an
alloHCT following an autoHCT. Audience agreed that additional follow-up is needed and suggested
to distinguish between HLA-identical siblings, haplo-identical donors and cord blood grafts.
PROP 1311-76 Hematopoietic cell transplantation outcomes for relapsed or refractory marginal
zone lymphomas (B William)
Dr. William presented the study. This study aims to descriptive study to analyze trends in utilization
and outcomes of autologous and/or allogeneic HCT in relapsed or refractory marginal zone
lymphomas (MZL). We have 151 alloHCT and 250 autoHCT patients with MZL registered to the
CIBMTR from 2000-2012. Committee members suggested describing FLIPI score in the study.
Potential collaboration with EBMT on a combined analysis for allogeneic transplant outcomes was
discussed. A total of 413 non-transplanted MZL were presented from various institutions for
collaboration: University Hospitals Case Medical Center (n=99), Cleveland Clinical Foundation
(n=218) and University of Nebraska Medical Center (n=96).
PROP 1311-77 Hematopoietic Stem Cell Transplantation for Hepatosplenic T-cell Lymphoma
(M Alghamdi)
Dr. Alghamdi presented the study. This study aims to analyze outcomes of hematopoietic cell
transplantation (HCT) for hepatosplenic T-cell lymphoma. Given the low incidence of HSTCL and the
absence of prospective studies with HCT for HSTCL, analysis of cumulative registry data remains the
best way to study the safety and efficacy of HCT in this disease. There are 72 alloHCT and 35
autoHCT patients for Hepatosplenic T-cell Lymphoma registered to the CIBMTR from 1999-2012.
Working Committee members mentioned a similar ASH abstract with potential patient overlap from
the University of Nebraska that was presented in 2013.
PROP 1311-79 Updated prognostic information for lymphoma survivors beyond 1 year from
allogeneic hematopoietic cell transplantation. A landmark CIBMTR analysis (A Lazaryan)
Dr. Lazaryan presented the study. This study aims to generate updated individualized prognostic
models for outcomes of allograft recipients with lymphoma who survive beyond the 1st year after
allo-HCT. There are 621 follicular lymphoma, 196 DLBCL and 114 Hodgkin disease patients who
survived more than 1 year post alloHCT for relapsed/refractory lymphoma reported to the CIBMTR
from 1990-2010. Committee members suggested to restrict to 1997, eliminate Hodgkin disease and
include transformed cases to eliminate older cases. It was suggested to do a landmark analysis of
each subsequent year to prognosticate survival. Dr. Patrick Stiff reiterated the importance of this
study. Members suggested that performing the calculator is not the primary objective. Primary
outcome will be survival and secondary outcomes include non-relapse mortality,
relapse/progression, disease-free survival and acute and chronic GVHD.
PROP 1311-85 Evaluation of potential anti-lymphoma clinical benefit with sirolimus-based graftversus-host disease prevention after allogeneic hematopoietic cell transplantation (J Mathews)
Dr. Mathews presented the study. The study aims to determine the existence of anti-lymphoma
effect with sirolimus-based GVHD prophylaxis and to discern subtypes of lymphoma in which
sirolimus-based GVHD prophylaxis might be particularly effective. There are 149 sirolimus-based
and 1488 no sirolimus- based alloHCT lymphoma patients reported to the CIBMTR from 2002-2012.
In a retrospective study, Armand et al. compared the outcomes of patients who received sirolimus
11
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Attachment 1
for GVHD prophylaxis with those patients who received allogeneic HCT with a combination of a
calcineurin inhibitor and methotrexate. Overall survival was significantly superior in the sirolimus
group and the benefit was restricted to patients undergoing reduced-intensity conditioning.
Sirolimus was associated with decreased incidence of disease progression. In addition, the effect of
sirolimus persisted after adjusting for the occurrence of GVHD. Therefore, the study hypothesizes
that the use of sirolimus-based GVHD prophylaxis may reduce the incidence of lymphoma
progression compared to combination regimens of a calcineurin inhibitor and methotrexate. The
Committee suggested a possible matched-pair analysis. 149 patients were previously reported by
different institutions and uncertain how much can be added to these reports. Dr. Robert Peter Gale
reiterated the importance of not using an observational database in these types of studies since we
will get the same results as the clinical trial.
PROP 1311-89 Outcome of patients with relapsed diffuse large B-cell lymphoma treated with
allogeneic hematopoietic cell transplantation following a failed autologous HCT (T Fenske)
Dr. Tara Graff presented the study. This study aims to 1) determine overall survival (OS),
progression-free survival (PFS), relapse/progression and treatment-related mortality (NRM) at 1
year, 3 years and 5 years in DLBCL patients who underwent an allo-HCT following a failed auto-HCT;
2) to determine the impact of age on OS, PFS, relapse/progression and NRM at 1 year, 3 years and 5
years, using different age cutoffs (50, 60, or 70 years); 3) to determine the impact of time elapsed
from auto-HCT to allo-HCT on OS, PFS, relapse/progression and NRM at 1 year, 3 years and 5 years,
using different time cutoffs (0-6 months, 6-12 months, or >12 months); 4) to determine the impact
of performance status (PS), HCT comorbidity index (HCT-CI), disease status, and donor type (related
vs unrelated) on OS, PFS, relapse/progression and NRM at 1 year, 3 years and 5 years; and 5) to
define a specific group of patients (using some combination of age, PS, HCT-CI, time from auto-HCT
and disease status and donor type), for whom allo-HCT is a reasonable option. There are 133
alloHCT after an autoHCT transplanted for relapsed DLCBL from 2005-2011 reported to the CIBMTR.
Committee member suggested to perform a matched control of those patients who relapsed after
an autoHCT but did not undergo an alloHCT and compare outcomes. CIBMTR does not collect
treatment for relapse. It was informed that University of Nebraska published this idea with fewer
numbers of cases.
Nine additional proposals were submitted to the committee but not presented due to the reasons
stated below:
PROP 1309-05 Comparison of syngeneic with autologous transplant for patients with Hodgkin’s
lymphoma (K Van Besien). Dropped due to low number {n=23 cases received syngeneic transplant
(research and registration) from 2000-2013}.
PROP 1310-18 Impact of brentuximab vedotin on outcomes of allogeneic hematopoietic cell
transplantation for relapsed or refractory Hodgkin lymphoma (B Wirk). No patients in the
allogeneic database received brentuximab from 2005-2012.
PROP 1310-20 A Comparison of Busulfan/Cyclophosphamide/Etoposide with
BCNU/Etoposide/Cytarabine/Melphalan for Patients Undergoing Autologous Stem Cell Transplant
for Relapsed Hodgkin’s Lymphoma (J Cohen). Overlap with SC10-06.
PROP 1311-13 Clinical Outcomes in Patients with HIV related lymphoma undergoing autologous
HSCT (H Haddad). Dropped due to low number of patients (n=48 HIV+).
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Attachment 1
PROP 1311-16 Impact of Radioimmunotherapy (RIT) Exposure on Survival after Autologous Stem
Cell Transplantation for Diffuse Large B-Cell Lymphoma (R Karmali). Dropped due to low number
of patients (n=64 RIT exposure).
PROP 1311-22 The Impact of Conditioning Regimen Intensity on the Outcomes of Allogeneic
Hematopoietic Cell Transplantation for Patients with Lymphoma who have Chemo-sensitive
Disease (N Ghosh). Overlap with LY12-02.
PROP 1311-47 The Prognostic Impact of Cytogenetic and Molecular Abnormalities on Autologous
Hematopoietic Cell Transplant Outcomes for Patients with Diffuse Large B Cell Lymphoma (B
Trottier). Dropped due to no cytogenetic information available for lymphoma.
PROP 1311-52 Impact of Post-Hematopoietic Cell Transplantation (HCT) Rituximab (R) on
Progression-Free and Overall Survival in B-cell non-Hodgkin Lymphoma (B-NHL) Patients
Undergoing Reduced-Intensity Conditioning Allogeneic HCT (C Sauter). Dropped due to low
number (31 post transplant Rituximab).
PROP 1312-07 Outcomes of hematopoietic cell transplantation in Adult T cell leukemialymphoma (AE Hallack Neto). Dropped due to low number of cases (Registration=103 AlloHCT &
34AutoHCT; Research=61 AlloHCT & 4 AutoHCT).
6.
Other business
After the new proposals were presented, each participant in the meeting had the opportunity to
rate each proposal using paper ballots. Without additional comments, the meeting was adjourned
at 2:15 pm.
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Attachment 1
Working Committee Overview Plan for 2014-2015
a. LY10-02 Umbilical cord blood versus unrelated donor allogeneic hematopoietic cell
transplantation for patients with lymphoma. We anticipate submitting the manuscript for peerreview before July 1, 2014.
b. LY12-02/GV11-01 Graft-vs-lymphoma post allogeneic hematopoietic cell transplantation. We
anticipate finalizing the landmark analysis and submitting the manuscript for peer-review before
July 1, 2014.
c. LY06-03 Allogeneic hematopoietic cell transplantation for relapsed follicular lymphoma: impact
of donor type and prognostic risk score for survival. Final dataset from EBMT is expected, no
later than June 30, 2014. The combined analysis with EBMT is expected to start by July 1, 2014
(pending EBMT collaboration). We anticipate a finalized analysis by July 1, 2015.
d. LY13-01 Autologous transplantation for diffuse large B-cell lymphomas patients refractory or
relapsing early after Rituximab-containing first line chemoimmunotherapies. We anticipate
submitting the manuscript for peer-review before July 1, 2014.
e. LY12-01 Positron Emission Tomography Imaging Prior to AlloHCT for Lymphoma. We anticipate
finalizing the data file before July 1, 2014 and submitting the manuscript for peer-review before
July 1, 2015.
f.
LY13-02 Outcomes of autologous stem cell transplantation for children, adolescents and young
adults with relapsed/refractory Hodgkin lymphoma. We anticipate finalizing the data file before
July 1, 2014 and submitting the manuscript for peer-review before July 1, 2015.
g. LY13-03 Comparison of autologous versus RIC allogeneic stem cell transplantation for
relapsed/refractory patients with follicular lymphoma. We anticipate finalizing the data file
before July 1, 2014 and submitting the manuscript for peer-review before July 1, 2015.
h. LY14-01 (PROP 1311-79) Updated prognostic information for lymphoma survivors beyond 1 year
from allogeneic hematopoietic cell transplantation. A landmark CIBMTR analysis. We anticipate
finalizing the protocol before July 1, 2015.
i.
LY14-02 (PROP 1311-89) Outcome of patients with relapsed diffuse large B-cell lymphoma
treated with allogeneic hematopoietic cell transplantation following a failed autologous HCT.
We anticipate finalizing the analysis before July 1, 2015.
14
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Attachment 1
Work Assignments for Working Committee Leadership (March 2014)
David Maloney
LY12-01: Positron Emission Tomography Imaging Prior to AlloHCT for
Lymphoma.
LY14-01 (PROP 1311-79) Updated prognostic information for lymphoma
survivors beyond 1 year from allogeneic hematopoietic cell transplantation.
A landmark CIBMTR analysis
Sonali Smith
LY14-02 (PROP 1311-89) Outcome of patients with relapsed diffuse large Bcell lymphoma treated with allogeneic hematopoietic cell transplantation
following a failed autologous HCT
Anna Sureda
LY06-03: Allogeneic hematopoietic cell transplantation for relapsed follicular
lymphoma: impact of donor type and prognostic risk score for survival
Wael Saber
LY10-02: Umbilical cord blood versus unrelated donor allogeneic
hematopoietic cell transplantation for patients with lymphoma.
LY12-02/GV11-01: Graft-vs-lymphoma post allogeneic hematopoietic cell
transplantation.
Mehdi Hamadani
LY13-01: Autologous transplantation for diffuse large B-cell lymphomas
patients refractory or relapsing early after Rituximab-containing first line
chemoimmunotherapies.
LY13-02: Outcomes of autologous stem cell transplantation for children,
adolescents and young adults with relapsed/refractory Hodgkin lymphoma.
LY13-03: Comparison of autologous versus RIC allogeneic stem cell
transplantation for relapsed/refractory patients with follicular lymphoma.
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Attachment 2
Accrual Summary for Hodgkin and Non-Hodgkin Lymphoma Working Committee: 2000-2014
Anaplastic large cell
PIF
CR 1
Relapse 1
CR 2
Other / Unknown
Burkitt/small noncleaved
PIF
CR 1
Relapse 1
CR 2
Other / Unknown
Diffuse large cell
/Immunoblastic
PIF
CR 1
Relapse 1
CR 2
Other / Unknown
Follicular
PIF
CR 1
Relapse 1
CR 2
Other / Unknown
Lymphoblastic
PIF
CR 1
Relapse 1
CR 2
Other / Unknown
Mantle
PIF
CR 1
Relapse 1
CR 2
Other / Unknown
HLA-identical Sibling
TED only
Research
N (%)
N (%)
132
29
14 (11)
5 (17)
24 (18)
3 (10)
17 (13)
5 (17)
33 (25)
9 (31)
44 (33)
7 (24)
132
41
17 (13)
5 (12)
32 (24)
10 (24)
18 (14)
5 (12)
34 (26)
16 (39)
31 (23)
5 (12)
813
182 (22)
82 (10)
161 (20)
100 (12)
288 (35)
953
113 (12)
74 ( 8)
151 (16)
108 (11)
507 (53)
155
16 (10)
48 (31)
25 (16)
28 (18)
38 (25)
514
79 (15)
137 (27)
75 (15)
61 (12)
162 (32)
218
57 (26)
35 (16)
29 (13)
18 ( 8)
79 (36)
444
69 (16)
33 ( 7)
100 (23)
64 (14)
178 (40)
50
8 (16)
13 (26)
7 (14)
13 (26)
9 (18)
186
38 (20)
42 (23)
25 (13)
23 (12)
58 (31)
Alternative Donor
TED only
Research
N (%)
N (%)
42
90
3 ( 7)
8 ( 9)
9 (21)
14 (16)
2 ( 5)
4 ( 4)
6 (14)
29 (32)
22 (52)
35 (39)
43
85
4 ( 9)
12 (14)
9 (21)
13 (15)
4 ( 9)
13 (15)
12 (28)
37 (44)
14 (33)
10 (12)
262
45 (17)
34 (13)
29 (11)
35 (13)
119 (45)
289
29 (10)
20 ( 7)
36 (12)
33 (11)
171 (59)
87
7 ( 8)
16 (18)
8 ( 9)
25 (29)
31 (36)
175
20 (11)
43 (25)
20 (11)
23 (13)
69 (39)
658
181 (28)
69 (10)
91 (14)
102 (16)
215 (33)
770
111 (14)
58 ( 8)
121 (16)
100 (13)
380 (49)
126
19 (15)
25 (20)
19 (15)
42 (33)
21 (17)
480
66 (14)
102 (21)
85 (18)
98 (20)
129 (27)
Autologous
TED only
Research
N (%)
N (%)
968
122
84 ( 9)
9 ( 7)
271 (28)
38 (31)
115 (12)
22 (18)
240 (25)
30 (25)
258 (27)
23 (19)
476
74
47 (10)
12 (16)
157 (33)
28 (38)
47 (10)
5 ( 7)
111 (23)
19 (26)
114 (24)
10 (14)
14389
1437 (10)
2133 (15)
2623 (18)
3743 (26)
4453 (31)
3719
329 ( 9)
397 (11)
660 (18)
794 (21)
1539 (41)
287
15 ( 5)
125 (44)
25 ( 9)
37 (13)
85 (30)
4654
255 ( 5)
2806 (60)
201 ( 4)
274 ( 6)
1118 (24)
2052
228 (11)
379 (18)
390 (19)
533 (26)
522 (25)
844
54 ( 6)
100 (12)
171 (20)
175 (21)
344 (41)
41
2 ( 5)
23 (56)
3 ( 7)
6 (15)
7 (17)
736
53 ( 7)
461 (63)
27 ( 4)
49 ( 7)
146 (20)
16
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Attachment 2
Accrual Summary for Hodgkin & Non-Hodgkin Lymphoma Working Committee: 2000-2014
Continued.
HLA-identical Sibling
Alternative Donor
Autologous
TED only
Research
TED only
Research
TED only
Research
N (%)
N (%)
N (%)
N (%)
N (%)
N (%)
61
26
21
51
253
30
Marginal
8 (13)
8 (31)
6 (29)
12 (24)
20 ( 8)
6 (20)
PIF
5 ( 8)
3 (12)
0
7 (14)
41 (16)
3 (10)
CR 1
9 (15)
1 ( 4)
4 (19)
6 (12)
32 (13)
3 (10)
Relapse 1
7 (11)
2 ( 8)
1 ( 5)
6 (12)
42 (17)
7 (23)
CR 2
32
(52)
12
(46)
10
(48)
20
(39)
118
(47)
11
(37)
Other / Unknown
176
44
64
175
522
70
NK T cell
25 (14)
5 (11)
10 (16)
29 (17)
45 ( 9)
6 ( 9)
PIF
46 (26)
10 (23)
20 (31)
60 (34)
192 (37)
33 (47)
CR 1
15 ( 9)
6 (14)
3 ( 5)
9 ( 5)
52 (10)
5 ( 7)
Relapse 1
28
(16)
5
(11)
10
(16)
43
(25)
92
(18)
12
(17)
CR 2
62 (35)
18 (41)
21 (33)
34 (19)
141 (27)
14 (20)
Other / Unknown
345
122
139
352
1226
185
T cell
86 (25)
33 (27)
34 (24)
85 (24)
106 ( 9)
17 ( 9)
PIF
94 (27)
27 (22)
36 (26)
90 (26)
497 (41)
83 (45)
CR 1
38
(11)
12
(10)
8
(
6)
35
(10)
136
(11)
19 (10)
Relapse 1
36 (10)
19 (16)
21 (15)
45 (13)
166 (14)
23 (12)
CR 2
91 (26)
31 (25)
40 (29)
97 (28)
321 (26)
43 (23)
Other / Unknown
111
3
55
4
686
17
NHL Not specified
8 ( 7)
1 (33)
5 ( 9)
1 (25)
52 ( 8)
4 (24)
PIF
7 ( 6)
0
4 ( 7)
0
76 (11)
2 (12)
CR 1
12
(11)
1
(33)
3
(
5)
1
(25)
36
(
5)
1 ( 6)
Relapse 1
3 ( 3)
0
10 (18)
0
77 (11)
3 (18)
CR 2
81 (73)
1 (33)
33 (60)
2 (50)
445 (65)
7 (41)
Other / Unknown
536
203
202
582
3124
495
Other
108 (20)
59 (29)
39 (19)
146 (25)
363 (12)
66 (13)
PIF
81
(15)
24
(12)
26
(13)
108
(19)
821
(26)
155
(31)
CR 1
52 (10)
21 (10)
30 (15)
61 (10)
414 (13)
50 (10)
Relapse 1
64 (12)
12 ( 6)
28 (14)
62 (11)
559 (18)
76 (15)
CR 2
231 (43)
87 (43)
79 (39)
205 (35)
967 (31)
148 (30)
Other / Unknown
364
88
174
218
12124
1589
Hodgkin
97
(27)
20
(23)
31
(18)
52
(24)
1499
(12)
213
(13)
PIF
21 ( 6)
5 ( 6)
6 ( 3)
21 (10)
1026 ( 8)
156 (10)
CR 1
48 (13)
27 (31)
17 (10)
35 (16)
2557 (21)
315 (20)
Relapse 1
32 ( 9)
9 (10)
18 (10)
30 (14)
3129 (26)
397 (25)
CR 2
166 (46)
27 (31)
102 (59)
80 (37)
3913 (32)
508 (32)
Other / Unknown
17
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Attachment 2
Accrual Summary for Hodgkin & Non-Hodgkin Lymphoma Working Committee: 2000-2014
Continued.
HLA-identical Sibling
Alternative Donor
Autologous
TED only
Research
TED only
Research
TED only
Research
N (%)
N (%)
N (%)
N (%)
N (%)
N (%)
4292
1454
1553
3591
42428
6255
Graft type
598 (14)
139 (10)
416 (27)
719 (20)
629 ( 1)
68 ( 1)
BM
3649 (85) 1312 (90)
1051 (68) 2497 (70)
40834 (96) 6094 (97)
PBSC
45
(
1)
3
(<1)
86
(
6)
375
(10)
965 ( 2)
93 ( 1)
Other / Unknown
18
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Attachment 3
TO:
Lymphoma Working Committee Members
FROM:
Mehdi Hamadani, MD; Scientific Director for the Lymphoma Working Committee
RE:
Studies in Progress Summary
LY12-01: Positron Emission Tomography Imaging Prior to AlloHCT for Lymphoma (V Bachanova) Adult
patients with follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma and T- or NKcell NHL undergoing alloHCT between 2007-12 were eligible. Chemorefractory pts (by CT criteria), and
cases where interval between PET scan and alloHCT was >3 months were excluded. Three hundred and
thirty six patients eligible for this analysis were divided into PET+ve and PET-ve groups, based on pre
alloHCT PET status, as determined by individual transplant centers. On multivariate analysis, PET+ve
status was associated with a higher risk of relapse/progression, but was not predictive of inferior OS, PFS
or NRM. PET status had no impact on incidence of grade II-IV acute GVHD and chronic GVHD. The study
is in the manuscript preparation phase.
LY13-02: Outcome of autologous hematopoietic cell transplantation for children, adolescents, and
young adults with relapsed/refractory hodgkin lymphoma (P Satwani) CAYA (age <30yrs) with Rel/Ref
classical HL undergoing autoHCT during 1995-2010 were eligible. On multivariate analysis nonABVD/ABVD-like 1st line therapy (RR 1.8; p=0.03) was associated with a higher NRM. Factors predicting
higher risk of R/P included Lansky score or KPS<90, extranodal disease, resistant disease and CBV
conditioning. Long first complete remission was associated with a reduced R/P risk. MVA for PFS
identified END, resistant disease and KPS<90 as risk factors for therapy failure; while LgCR1 was
predictive of reduced therapy failure risk. Finally for OS, non-ABVD/ABVD-like 1st line therapy, END and
resistant disease were associated with higher mortality; while LgCR1 and peripheral blood graft were
associated with reduced mortality risk. The study is in the manuscript preparation phase.
LY13-03: Comparison of autologous versus allogeneic hematopoietic cell transplantation after
reduced/non-myeloablative conditioning for relapsed/refractory patients with follicular lymphoma (E
Klyuchnikov) This study intends to compare overall and progress-free survival in patients aged ≥18 years
with relapsed/refractory follicular lymphoma who underwent reduced-intensity/non-myeloablative
allogeneic stem cell transplantation versus autologous stem cell transplantation as second-line
approach. Analysis is underway.
LY06-03: Allogeneic hematopoietic cell transplantation for relapsed follicular lymphoma: impact of
donor type and prognostic risk score for survival (A Sureda) This study compared the outcomes of 702
recipients of allogeneic HCT for FL (198 unrelated and 504 sibling donors) from 171 centers world-wide
reporting to the CIBMTR or EBMT between 1997 and 2005. This study shows that unrelated HCTs are
performed later in the treatment course for FL; in higher risk patients; most commonly with reduced
intensity conditioning; and in multivariate analysis adjusting for baseline differences between the 2
groups, unrelated HCTs were significantly associated with worse PFS and OS compared to sib HCT. This
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Attachment 3
study was submitted to JCO and based on reviewer’s comments and internal discussion inclusion criteria
will be modified with different transplant years to pick up a more “modern” cohort. Data file
preparation is underway in collaboration with the EBMT.
Studies previously proposed, but not initiated
LY04-02: Outcome of patients with relapsed diffuse large B-cell lymphoma treated with allogeneic
hematopoietic cell transplantation following a failed autologous HCT (T Fenske) This study will describe
the transplantation outcomes of DLBCL patients undergoing an allo-HCT, after relapsing after a prior
auto-HCT. Also will compare “Post Auto-HCT Relapse Survival” of DLBCL patients undergoing an alloHCT after relapsing following a prior auto-HCT against a cohort of patients NOT undergoing an allo-HCT
following a post auto-HCT relapse/progression. The study protocol is under development.
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Attachment 4
Study Proposal 1410-09
Study Title:
Comparison of allogeneic stem cell transplantation to autologous stem cell transplantation for patients
with early relapsed and primary refractory diffuse large B cell lymphoma
Nilanjan Ghosh, MD, PhD, Director of Lymphoma program, Department of Hematologic Oncology and
Blood Disorders, Levine Cancer Institute/Carolinas Health Care System,
Nilanjan.Ghosh@carolinashealthcare.org
Specific Aims:
1. To compare the efficacy i.e. progression free survival and overall survival of allogeneic stem cell
transplant to autologous stem cell transplant (LY13-01) for diffuse large B cell lymphoma which has
relapsed less than 1 year after diagnosis or has been refractory to primary therapy (early treatment
failure).
2. To compare the toxicity i.e. non relapse mortality and relapse rate of allogeneic stem cell transplant
to autologous stem cell transplant (LY13-01) for relapsed diffuse large B cell lymphoma which has
relapsed less than 1 year after diagnosis or has been refractory to primary therapy (early treatment
failure).
3. To identify factors that are associated with relapse, PFS and OS after allogeneic stem cell
transplantation. The following factors will be studied for their association with outcomes: disease
characteristics at diagnosis, early relapse vs. late relapse, chemosensitive vs. chemorefractory, type
of salvage chemotherapy regimen, type of conditioning regimen, graft type, type of donor, and
disease status prior to transplant.
Scientific Justification:
Curative treatment options for relapsed or refractory lymphoma are limited. Both autologous and
allogeneic hematopoietic stem cell transplantation (allo HCT) have been used in this setting [1-3]. Allo
HCT offers advantages over autologous SCT: a) graft-versus-lymphoma effect, b) lymphoma free grafts,
and c) use of cell products which have not been exposed to prior chemotherapy induced DNA damage.
For patients with relapsed/refractory diffuse large B cell lymphoma (DLBCL), salvage chemotherapy
followed by autologous stem cell transplantation (ASCT) is widely considered as the standard treatment
for patients with chemo-sensitive disease. The CORAL study reported the 3 year PFS of 53% with salvage
chemotherapy combined with rituximab in the patients who underwent ASCT in the setting of chemosensitive disease [4]. However, patients who relapsed <12 months from diagnosis had a 3 year PFS of
only 23%. In a recent report from the CIBMTR, patients with primary refractory disease or early relapse
after an initial rituximab chemotherapy regimen had a 3 year PFS and OS of 44% and 50% respectively
[5]. Although the results reported in this study are better than were reported in the CORAL study, a
significant number of patients relapse following an autologous transplant.
Allo HCT has been explored in lymphoma with the expectation of a graft vs. lymphoma effect and a graft
without tumor contamination. Historically, several studies have shown a low rate of relapse with allo
SCT. Traditionally, the benefit of reduced relapse from this procedure did not translate into an overall
survival benefit due to high non relapse mortality [6-9].
A CIBMTR analysis comparing outcomes in DLBCL patients undergoing autologous or myeloablative allo
SCT performed between 1995 and 2003 showed that MA allo SCT was associated with higher TRM,
treatment failure and mortality when compared to auto SCT. However, allo HCT recipients were more
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Attachment 4
likely to had high risk features including older age, more pretreatment and chemoresistant disease [10].
Similarly, a retrospective study from the Washington University School of Medicine, showed that auto
SCT provided superior outcomes compared to allo SCT in patients with early relapse or primary
refractory diffuse large B cell lymphoma. However, in comparison with auto SCT, majority of the allo SCT
were performed before 2003 and included a higher proportion of patients who were heavily pretreated
and had primary refractory and chemoresistant disease at the time of transplant [11]. Since the
potential advantages from allo SCT might be minimized by NRM, allo SCT with RIC or NMA conditioning
has been tested as a means to reduce NRM. However, these two modalities are difficult to compare
because the patient and disease characteristics in individuals undergoing RIC/NMA are different from
those receiving MA regimens. Patients receiving RIC/NMA allo SCT tend to be older, more heavily pretreated and have more comorbidities. 2-4 year PFS ranging from 35-48% has been reported with allo SCT
using RIC/NMA conditioning in this setting [12-14]. The NRM in these studies has been 23-32%.
More recently, the German High Grade Lymphoma study group conducted a prospective trial of allo-SCT
with MA conditioning for patients with primary refractory disease, early relapse (<12 months) or relapse
after ASCT. At 3 years the PFS and NRM were 40% and 35% respectively [15]. Castagna et. al. reported a
2 year PFS and NRM of 63% and 16.3% using Haploidentical donors and NMA conditioning in advanced
lymphomas [16]. In this study which included transplants from 2009-12, 55% patients had a prior auto
SCT and 14% patients had a prior allo SCT. These evolving trends of improved progression free survival
and lower NRM suggest that allo SCT can be a useful in the treatment of high risk lymphomas.
Currently, the decision to use allo SCT for diffuse large B cell lymphoma is based on physician preference
and varies widely across instructions. Analysis of results with allo SCT in DLBCL from the CIBMTR is likely
to provide a basis for an evidence based approach for the use of this treatment modality. It may allow
identification of subsets of patients who benefit most from this approach. In the absence of prospective
randomized data, a matched pair comparison of a high risk allo SCT group (relapsed less than 1 year
after diagnosis) with a subset of closely matched auto SCT patients may allow physicians to make
unbiased decisions regarding transplantation for these high risk patients.
Patient Eligibility Population:
 Diagnosis of diffuse large B cell lymphoma
 Treatment with allogeneic stem cell transplantation
Data Requirements:
 Data collection forms: 2000 R3.0, 2005 R4.0, 2006 R3.0, 2018 R2.0, 2100 R3.0, 2118 R2.0, 2200 R3.0,
2300 R3.0, 2400 R3.0, 2450 R3.0, 2451 R2.0.
 Autologous stem cell transplant population as a comparator: LY1301
 No supplemental data collection
 Do not need to combine CIBMTR data with other groups
Variables:
1. Patient: Age, Karnofsky score at diagnosis and pre-transplant
2. Disease: a) Stage, b) Extranodal involvement, c) CNS involvement, d) Bone marrow involvement, e)
LDH, f) B symptoms.
3. Pre-transplant treatment: a) Number of therapies b) Rituximab for B cell lymphoma, c) Prior auto
HCT c) Pre-transplant disease remission: CR, CRu,PR, PET negative CR, first remission or subsequent
remission.
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Attachment 4
4. Transplant: a) Conditioning regimens, b) Graft type, c) Type of donor, d) graft source, e) year of
transplant, f) duration between diagnosis and allo HCT, g) duration between auto-HCT and allo HCT,
h) GVHD prophylaxis
5. Outcomes: a) Time to ANC and platelet recovery, b) Day 100 Acute GVHD (II-IV), c) Chronic GVHD at
years 1 and 3, d) NRM day 100, 1 year, 3 year, e) Relapse rate at 1 year, 3 years, f) PFS at 1 and 3
years, g) OS at 1 and 3 years.
Sample requirements: None
Study Design:
The CIBMTR database has transplant data from more than 500 transplant transplantation centers. This
resource has been invaluable in answering seminal questions in SCT. The overall analysis is exploratory
and will test multiple variables (patient factors, disease factors, pre-transplant treatment, transplant
factors) on outcomes such as relapse rate, PFS, NRM, OS. The CIBMTR database has all the variables
needed to test this hypothesis.
Statistical methodology: Probabilities of PFS and OS will be calculated using the Kaplan-Meier product
limit estimate. Probabilities of relapse, NRM, acute and chronic GVHD and engrafment will be calculated
using cumulative incidence curves to accommodate for competing risks. The intensity of conditioning
regimens will be categorized as MAC or RIC or NMA using established consensus criteria [17].
Associations among patient, disease, pre-transplant remission status and transplantation related
variables and outcomes will be evaluated using a multivariate Cox proportional hazards regression. A
stepwise selection multivariate model will be built to identify covariates that influence outcomes.
Covariates with a p<0.05 will be considered significant. For the group of patients who relapsed less than
1 year from diagnosis, a matched pair comparison of the allo SCT group with a subset of closely matched
auto SCT patients selected by propensity score matching will be performed as reported previously [10].
The propensity score is the probability of receiving an allo SCT and is calculated based on a logistic
regression model. The logistic regression model will include patient and disease oriented risk factors.
Multivariate analysis will be performed by fitting a Cox model stratified on matched-pairs.
References
1.
Philip, T., et al., Autologous bone marrow transplantation as compared with salvage
chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med,
1995. 333(23): p. 1540-5.
2.
van Kampen, R.J., et al., Allogeneic stem-cell transplantation as salvage therapy for patients with
diffuse large B-cell non-Hodgkin's lymphoma relapsing after an autologous stem-cell
transplantation: an analysis of the European Group for Blood and Marrow Transplantation
Registry. J Clin Oncol, 2011. 29(10): p. 1342-8.
3.
Bishop, M.R., et al., Clinical evidence of a graft-versus-lymphoma effect against relapsed diffuse
large B-cell lymphoma after allogeneic hematopoietic stem-cell transplantation. Ann Oncol,
2008. 19(11): p. 1935-40.
4.
Gisselbrecht, C., et al., Salvage regimens with autologous transplantation for relapsed large Bcell lymphoma in the rituximab era. J Clin Oncol, 2010. 28(27): p. 4184-90.
5.
Hamadani, M., et al., Early Failure of Frontline Rituximab-Containing Chemo-immunotherapy in
Diffuse Large B Cell Lymphoma Does Not Predict Futility of Autologous Hematopoietic Cell
Transplantation. Biol Blood Marrow Transplant, 2014.
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6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
Attachment 4
Chopra, R., et al., Autologous versus allogeneic bone marrow transplantation for non-Hodgkin's
lymphoma: a case-controlled analysis of the European Bone Marrow Transplant Group Registry
data. J Clin Oncol, 1992. 10(11): p. 1690-5.
Jones, R.J., et al., Evidence of a graft-versus-lymphoma effect associated with allogeneic bone
marrow transplantation. Blood, 1991. 77(3): p. 649-53.
Ratanatharathorn, V., et al., Prospective comparative trial of autologous versus allogeneic bone
marrow transplantation in patients with non-Hodgkin's lymphoma. Blood, 1994. 84(4): p. 10505.
Schimmer, A.D., et al., Allogeneic or autologous bone marrow transplantation (BMT) for nonHodgkin's lymphoma (NHL): results of a provincial strategy. Ontario BMT Network, Canada.
Bone Marrow Transplant, 2000. 26(8): p. 859-64.
Lazarus, H.M., et al., A comparison of HLA-identical sibling allogeneic versus autologous
transplantation for diffuse large B cell lymphoma: a report from the CIBMTR. Biol Blood Marrow
Transplant, 2010. 16(1): p. 35-45.
Ghobadi, A., Nolley E, Liu J, McBride, A, Stockerl-Goldstein K and Cashen A, Retrospective
comparison of allogeneic vs autologous transplantation for diffuse large B-cell lymphoma with
early relapse or primary induction failure. Bone Marrow Transplant, 2014. e pub ahead of print.
Rezvani, A.R., et al., Non-myeloablative allogeneic haematopoietic cell transplantation for
relapsed diffuse large B-cell lymphoma: a multicentre experience. Br J Haematol, 2008. 143(3): p.
395-403.
Sirvent, A., et al., Low nonrelapse mortality and prolonged long-term survival after reducedintensity allogeneic stem cell transplantation for relapsed or refractory diffuse large B cell
lymphoma: report of the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire. Biol
Blood Marrow Transplant, 2010. 16(1): p. 78-85.
Thomson, K.J., et al., Favorable long-term survival after reduced-intensity allogeneic
transplantation for multiple-relapse aggressive non-Hodgkin's lymphoma. J Clin Oncol, 2009.
27(3): p. 426-32.
Glass, B., et al., Rituximab after lymphoma-directed conditioning and allogeneic stem-cell
transplantation for relapsed and refractory aggressive non-Hodgkin lymphoma (DSHNHL R3): an
open-label, randomised, phase 2 trial. Lancet Oncol, 2014. 15(7): p. 757-66.
Castagna, L., et al., Nonmyeloablative conditioning, unmanipulated haploidentical SCT and postinfusion CY for advanced lymphomas. Bone Marrow Transplant, 2014.
Bacigalupo, A., et al., Defining the intensity of conditioning regimens: working definitions. Biol
Blood Marrow Transplant, 2009. 15(12): p. 1628-33.
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Attachment 4
Characteristics of patients with HCT for early relapsed and primary refractory diffuse large B cell
lymphoma
AutoHCT
Variable
AlloHCT
(Study LY13-01)
Number of patients
77
300
49 (21-70)
58 (19-77)
18-29
6 ( 8)
16 ( 5)
30-39
17 (22)
18 ( 6)
40-49
17 (22)
48 (16)
50-59
19 (25)
84 (28)
≥60
18 (23)
134 (45)
Male
47 (61)
189 (63)
Female
30 (39)
111 (37)
<90%
34 (44)
95 (32)
90-100%
39 (51)
185 (62)
4 ( 5)
20 ( 7)
Age at transplant, years
Median
Sex
Karnofsky score
Missing
Prior autologous transplant
N/A
No
58 (75)
Yes
19 (25)
Disease stage at diagnosis
I-II
22 (29)
60 (20)
III-IV
51 (66)
219 (73)
4 ( 5)
21 ( 7)
CR
13 (17)
43 (14)
I-II
9 (12)
35 (12)
III-IV
25 (32)
42 (14)
Not restaged/unknown
30 (39)
180 (60)
PR
60 (78)
199 (66)
CR
17 (22)
101 (34)
Unknown
Disease stage at transplant
Disease status preHCT
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Attachment 4
AlloHCT
AutoHCT
(Study LY13-01)
77
300
1999-2000
2 ( 3)
3 ( 1)
2001-2002
4 ( 5)
15 ( 5)
2003-2004
16 (21)
34 (11)
2005-2006
21 (27)
82 (27)
2007-2008
22 (29)
115 (38)
2009-2010
8 (10)
40 (13)
2011
4 ( 5)
11 ( 4)
72 (3-147)
48 (3-147)
Variable
Number of patients
Year of transplant
Median follow-up of survivors, median (range)
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Attachment 5
Study Proposal 1410-10
Study Title:
Does Autologous Stem Cell Transplant Overcome the Increased Risk of Death in Patients with Follicular
Lymphoma Relapsing Early after First Line Chemoimmunotherapy?
Carla Casulo, MD, Wilmot Cancer Institute, University of Rochester, carla_casulo@urmc.rochester.edu
Jonathan W. Friedberg , MD, M.M.Sc, Wilmot Cancer Institute, University of Rochester,
jonathan_friedberg@urmc.rochester.edu
Hypothesis:
20% of patients with follicular lymphoma (FL) experience progression of disease (POD) within 2 years of
initial chemoimmunotherapy. Recent data from the National LymphoCare Study (NLCS) identified that
early POD in FL has poor outcomes. To that end, we hypothesize that patients with FL with relapsed
disease may be able to overcome the negative impact of early progression through consolidation with
autologous stem cell transplant (ASCT).
Specific Aims:
1. To determine the progression free (PFS) and overall survival (OS) of patients with FL undergoing
ASCT for relapsed disease within 2 years of chemoimmunotherapy
2. To determine whether ASCT abrogates the negative prognostic impact of early relapse following
primary chemoimmunotherapy
Scientific Justification:
The implementation of ASCT for FL is a commonly used strategy in the relapsed setting, and randomized
data demonstrates an OS benefit when compared to conventional chemotherapy, solidifying the role of
salvage chemotherapy followed by ASCT in this setting1,2-4. Both prospective and retrospective studies
have demonstrated high response rates, and a suggestion of long-term survival5,4. Moreover, outcomes
are improved when ASCT is performed after first or second remission, compared to following
subsequent remissions, with plateaus in both PFS and OS5-7.
Whether remission duration impacts outcome after ASCT for relapsed FL is not known. However this
may be an important consideration, since our recent data from the National LymphoCare Study (NLCS)
has established that progression of FL within two years of primary treatment with
chemoimmunotherapy is significantly associated with poor outcomes8. Until recently stratification of
risk in the setting of disease progression of FL, and its influence on subsequent patient survival, has not
been previously validated. Depth and duration of response to previous treatments have been proposed
as prognostic indicators without widespread acceptance, however the timing of progression in FL may
be an underappreciated adverse risk factor. We analyzed data from the NLCS to identify patients with FL
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Attachment 5
who are at high risk for death following R-CHOP treatment to determine whether early progression
predicts for inferior OS in this disease, and we validated our findings in an independent cohort. This data
was presented as an oral abstract at the 2013 American Society of Hematology Meeting. We sought to
understand whether time to progression after diagnosis in patients who received first-line
chemoimmunotherapy may be a factor impacting survival outcomes in FL. We found that early disease
progression defines a group of patients at substantially greater risk of death beyond two years,
compared to a reference group of patients treated with R-CHOP for the same indications without
progression. Progression of disease within 2 years of initial therapy with R-CHOP was significantly
associated with poor outcomes. Overall survival at 5 years was 50% in the early progressor group and
95% in a reference group of patients not progressing within 2 years of treatment (Figure 1). Independent
of clinical prognostic indices, early progression was significantly associated with worse overall survival,
with a hazard ratio of 12.3.
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Attachment 5
Figure 1: Overall Survival Following Diagnosis in Patients who Received R-CHOP in the NLCS. This figure
shows OS from progression in patients who received R-CHOP chemotherapy. Patient with early
progression have poor survival compared to a reference group without early progression after R-CHOP.
Two-year OS (95% CI) was 68% (58.2–76.3). Five-year OS (95% CI) was 50% (39.4–59.2). At 2 years, OS in
the reference group was 97% (94.6–98.1) and at 5 years was 90% (86.2–92.4).
Based on the survival benefit observed with ASCT in relapsed FL, it would be relevant to characterize the
optimal time to introduce this treatment modality. Should high risk patients relapsing early after
primary chemoimmunotherapy be offered ASCT, or should ASCT be delayed until the next remission is
attained, regardless of when relapse occurred? Introduction of ASCT after early failure of first line
chemoimmunotherapy may be more important than timing it after attainment of remission, given that
other variables affect achievement of remission, such as lines of therapy required. In the largest series of
BEAM based ASCT in FL, 57% of patients undergoing ASCT at first relapse had a length of remission
under two years6. Outcomes specific to this sub-population are not available.
To better understand the impact of early relapse on ASCT outcome, we seek to determine PFS and OS of
patients with FL undergoing ASCT who relapsed within 2 years of first line chemoimmunotherapy. We
hypothesize that ASCT in this context may be able to overcome the negative impact of early disease
progression. Should we establish that ASCT for patients with FL relapsing early confers better outcomes,
it could support a strategy of aggressive second-line treatments, including ASCT, in this setting.
Patient Eligibility Population:
Eligible patients include those with FL of any stage, treated with chemoimmunotherapy in the first line
setting, and relapsed within the first two years of treatment. Patients should have received ASCT for
relapsed disease at first relapse. Patients must not have transformed histology, should not have
received ASCT in the first line setting (for example as consolidation, or without relapse).
Data Requirements:
1. Form 2018 R3.0: Hodgkin and Non Hodgkin Lymphoma (LYM) Pre-HSCT Data (diagnostic data, etc)
2. Form 2118 R3.0: Hodgkin and Non Hodgkin Lymphoma (LYM) Post-HSCT Data (response, etc)
3. Form 2200 R3.0: Six Months to Two Years Post –HSCT Data (heme recovery, survival, etc)
4. Form 2300 R3.0: Yearly Follow-up for Greater Than Two Years Post-HSCT Data (secondary
malignancy, toxicity etc)
5. Form 2400 R4.0: Pre-Transplant Essential Data (comorbidities, details on stem cell product, cell
dose, t cell deplete, etc)
6. Form 2900 R2.0: Recipient Death Data
Study Design:
This study involves the evaluation of existing data and documents in the form of data available through
the CIBMTR, and historical data from another cohort (NLCS dataset referenced above). A list of patients
that meet the above criteria through the CIBMTR should be accessible through the forms noted above.
Patients will be classified as recipients of ASCT for relapsed FL. They will then be subcategorized by date
from first relapse, and grouped into early relapse (within 2 years or less from first line treatment) or
later relapse (after 2 years from first line treatment).
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Attachment 5
A descriptive analysis of key demographic and baseline characteristics, including FLIPI, LDH, race, ECOG
performance status, B symptoms, nodal sites, hemoglobin, bone marrow involvement, histologic grade,
age, gender, and stage will be assessed. A log-rank test will be performed to compare OS, from time of
first progression, between patients who relapse early and receive ASCT and patients who relapse early
and do not receive ASCT. Historical data is available for the cohort of patients who relapse early and do
not receive ASCT. Cox proportional hazards model will be used to estimate the hazard ratio associated
with ASCT, as well as to identify additional risk factors from baseline and demographic characteristics
collected.
References:
1. Schouten HC, Qian W, Kvaloy S, et al. High-dose therapy improves progression-free survival and
survival in relapsed follicular non-Hodgkin's lymphoma: results from the randomized European CUP
trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology
2003;21:3918-27.
2. Sabloff M, Atkins HL, Bence-Bruckler I, et al. A 15-year analysis of early and late autologous
hematopoietic stem cell transplant in relapsed, aggressive, transformed, and nontransformed
follicular lymphoma. Biology of blood and marrow transplantation : journal of the American Society
for Blood and Marrow Transplantation 2007;13:956-64.
3. Pettengell R, Schmitz N, Gisselbrecht C, et al. Rituximab purging and/or maintenance in patients
undergoing autologous transplantation for relapsed follicular lymphoma: a prospective randomized
trial from the lymphoma working party of the European group for blood and marrow
transplantation. Journal of clinical oncology : official journal of the American Society of Clinical
Oncology 2013;31:1624-30.
4. Robinson SP, Canals C, Luang JJ, et al. The outcome of reduced intensity allogeneic stem cell
transplantation and autologous stem cell transplantation when performed as a first transplant
strategy in relapsed follicular lymphoma: an analysis from the Lymphoma Working Party of the
EBMT. Bone marrow transplantation 2013;48:1409-14.
5. Evens AM, Vanderplas A, LaCasce AS, et al. Stem cell transplantation for follicular lymphoma
relapsed/refractory after prior rituximab: a comprehensive analysis from the NCCN lymphoma
outcomes project. Cancer 2013;119:3662-71.
6. Kothari J, Peggs KS, Bird A, et al. Autologous stem cell transplantation for follicular lymphoma is of
most benefit early in the disease course and can result in durable remissions, irrespective of prior
rituximab exposure. British journal of haematology 2014.
7. Vose JM, Bierman PJ, Loberiza FR, et al. Long-term outcomes of autologous stem cell transplantation
for follicular non-Hodgkin lymphoma: effect of histological grade and Follicular International
Prognostic Index. Biology of blood and marrow transplantation : journal of the American Society for
Blood and Marrow Transplantation 2008;14:36-42.
8. Casulo C BM, Dawson K, et al. Early Relapse of Follicular Lymphoma After R-CHOP Defines Patients
at High Risk for Death: An Analysis From the National LymphoCare Study. Blood Supplement,
abstract 2013.
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Attachment 5
Characteristics of patients who received an autologous transplantation for follicular lymphoma
relapsing early after first Line chemoimmunotherapy reported to the CIBMTR from 2000-2012*
Variable
Number of cases
N (%)
169
Age at transplant, years
Median
56 (23-79)
18-29
3 ( 2)
30-39
11 ( 7)
40-49
40 (24)
50-59
54 (32)
≥60
61 (36)
Male
99 (59)
Female
70 (41)
Sex
Karnofsky score
<90%
90-100%
Missing
42 (25)
111 (66)
16 ( 9)
Sub disease
Follicular I
43 (25)
Follicular II
62 (37)
Follicular III
64 (38)
Conditioning regimen-auto
TBI-based
BEAM and similar
CBV or similar
20 (12)
111 (66)
30 (18)
BuMEL/BuCy
5 ( 3)
Others
3 ( 2)
Graft type
Bone marrow
Peripheral blood
1 ( 1)
168 (99)
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Attachment 5
Table. Continued.
Variable
Number of cases
N (%)
169
Year of transplant
2001
3 ( 2)
2002
3 ( 2)
2003
4 ( 2)
2004
9 ( 5)
2005
20 (12)
2006
37 (22)
2007
19 (11)
2008
28 (17)
2009
41 (24)
2010
1 ( 1)
2011
3 ( 2)
2012
1 ( 1)
Median follow up of survivors, months (range)
61 (3-120)
*Selection criteria: First autoHCT for FL between 2000-2012 (n=705), R+ plus other drugs in the first chemo line
st
(n=266), progression/stable disease or CR/PR (within 2 years from first line therapy to 1 line relapse) (n=188), at
least 100 day form received (n=173) and consent cases (N=169)
32
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Attachment 6
Study Proposal 1411-17/1411-93
Study Title:
Hematopoietic Cell Transplantation for NK/T-cell Non-Hodgkin Lymphoma
Stefan Klaus Barta, MD, MS, MRCP(UK), Temple University Health System/Fox Chase Cancer Center,
Stefan.Barta@fccc.edu
Henry Chi Hang Fung, MD, FRCPE, Temple University Health System/Fox Chase Cancer Center,
Henry.Fung@tuhs.temple.edu
Görgün Akpek, MD, MHS, Banner MD Anderson Cancer Center, GAkpek@mdanderson.org
Hypothesis:
We wish to better characterize clinical outcomes post hematopoietic cell transplantation in patients
with Natural Killer/T-cell Lymphoma
Specific Aims:
1. To describe clinical outcomes [progression-free survival (PFS), overall survival (OS), and nonrelapse mortality (NRM)] following autologous or allogeneic hematopoietic cell transplantation
in patients with extranodal NK/T-cell lymphoma
2. To identify the impact of patient-, disease-, and transplant-related factors on the outcomes PFS,
OS and NRM.
Scientific Justification:
Natural Killer (NK)/T-cell lymphoma is an aggressive lymphoma, that is strongly associated with EpsteinBarr virus (EBV).1 While rare in the US, it occurs more commonly in Asia, Central and South America.2
NK/T-cell lymphomas have traditionally been associated with a poor prognosis when treated with
anthracycline-containing chemotherapy with a median OS and failure-free survival (FFS) of only 7.8 and
5.8 months respectively.3,4 This is at least in part related to increased expression of the multidrugresistance mediating P-glycoprotein.5 However, since the use of concurrent chemoradiotherapy (CCRT)
for localized disease,6,7 and introduction of asparaginase-based chemotherapy, such as the SMILE 8 or
AspaMetDex9 regimens, outcomes have improved (5-year OS 50%; 4-year disease-free-survival (DFS)
64%).8 Established poor prognostic factors are advanced stage, higher International Prognostic Index
(IPI) scores, non-nasal phenotype, bone and skin involvement, and high circulating EBV-DNA levels.4,8,10
The role of hematopoietic cell transplantation (HCT) for this rare disease remains unclear, especially in
the current era of CCRT and asparaginase-based therapy. Before more effective therapies for NK/T-cell
lymphomas had become the standard of care, autologous HCT (autoHCT) was commonly used as
consolidative therapy in first remission (CR1). While autoHCT was associated with 50-70% long-term
survival, a case-control study suggested benefit only for high-risk patients.11-13 Allogeneic hematopoietic
cell transplantation (alloHCT) is mainly reserved for poor-risk NK/T-cell lymphoma patients with a
reported OS and PFS in the pre-SMILE era of only 30-40%.14 A more recent retrospective analysis of
outcomes for alloHSCT in NK/T-cell lymphoma by the Asia Lymphoma Study Group (ALSG) reported a 5year OS of 57%, and a 5-year EFS of 51%.15 Although better than earlier results, these outcomes are
comparable with what has been reported with the SMILE regimen alone in the relapsed refractory
setting.8 Interpretation of HCT data in NK/T-cell lymphomas is limited by the small sample size and
heterogeneity of the studies.16 Therefore, the current role for both autologous and allogeneic HCT
remains largely undefined.
33
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Attachment 6
The objective of our proposed study is the better define outcomes and factors impacting outcomes for
autoHCT and alloHCT in patients with NK/T-cell lymphoma. Because of the rarity of this specific subtype
of mature T-cell NHL, we propose to combine CIBMTR data with data from the Asia Lymphoma Study
Group (ALSG).
Patient Eligibility Population:
Patients with NK/T-cell NHL aged 18-65 who received a first autologous HCT or allogeneic HCT between
2000 and 2013. Patients with other mature T-cell NHL will be excluded as well as patients receiving their
second HCT, and identical twin donor transplantations will be excluded. The same eligibility criteria will
apply for patients treated by the ASLG.
Data Requirements:
Data from the CIBMTR and the Asia Lymphoma Study Group will be combined and a pooled analysis of
the data will be performed.
Primary outcomes will be overall survival (OS), progression-free survival (PFS) and non-relapse mortality
(NRM).
Secondary outcomes will be the incidence of acute graft-versus-host disease (AGVHD), chronic graftversus-host-disease (CGHVD) as well as cause of death (COD), and hematopoietic recovery (defined as
time to ANC > 0.5 x 109/L sustained for 3 consecutive days, and time to achieve platelet count >20 x
109/L without support of transfusions for 7 continuous days).
We will also analyze the association of the following patient- treatment-, and disease-related factors on
primary and secondary outcomes:
Patient-related factors:
- age at transplantation,
- Karnofsky performance score (< 90 vs. ≥90),
- gender: male vs. female
- race: Caucasian vs. African American vs. Hispanic vs. others
Disease-related factors:
- “B” symptoms
- number of lines of therapy before transplantation
- disease stage at diagnosis,
- extranodal involvement at diagnosis,
- nasal type (primary involved sites including nasopharynx, paranasal sinuses, tonsils or
- Waldeyer’s ring, ororpharynx) vs. non-nasal type17
- International Prognostic Index score (age, ECOG performance status, LDH, number of
- involved extranodal sites, Ann Arbor Stage),18
- NK/T-cell lymphoma prognostic index (LDH, B-symptoms, Ann Arbor Stage, regional
- lymph node status),19
- time from diagnosis to HCT (continuous or <12 vs. 12-18 vs. 18-24 vs. >24 mos)
- disease status before HCT (i.e. CR1; CR2; primary induction failure; relapsed)
- chemotherapy sensitivity (sensitive vs. resistant), and
- EBV viral load (if available);
Treatment-related variables:
- conditioning regimen,
34
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-
Attachment 6
graft type (bone marrow or peripheral blood stem cells),
year of transplantation,
alloHCT vs. autoHCT, and
location of transplantation (i.e. CIBMTR site vs. ALSG site)
For AlloHCT recipients:
- myeloablative or reduced intensity,
- donor-recipient sex match,
- donor-recipient cytomegalovirus status,
- donor type (HLA-identical sibling vs. matched unrelated vs. mismatched unrelated), and
- GVHD prophylaxis (T-cell depletion vs. other).
This data can be abstracted from the following collection forms: “Form 2018: Hodgkin and Non-Hodgkin
Lymphoma (LYM) Pre-HCT Data” and “Form 2118: Hodgkin and Non-Hodgkin Lymphoma (LYM) Post-HCT
Data”.
Sample Requirements: No samples are required
Study Design:
Data from both CIBMTR and the Asia Lymphoma Study Group will be pooled and analyzed as one
dataset. We will calculate probabilities for PFS (time from transplant to death or lymphoma
relapse/progression) and OS (time from transplant to death of any cause) using the Kaplan-Meier
method. Probabilities of NRM (defined as death of any cause in the first 100 days or death without
evidence of lymphoma relapse/progression), lymphoma relapse/progression, AGVHD and CGVHD will be
calculated by using cumulative incidence curves to accommodate competing risks.
The association of other variables with the primary and secondary outcomes will be determined using a
multivariate Cox proportional hazard regression model.
After discussions with Dr. Sonali Smith and obtaining preliminary estimates from the CIBMTR database,
it appears that data for at least 99 patients undergoing alloHCT and 51 patients undergoing autoHCT for
NK/T-cell NHL is available. Additionally, Dr. Yok Lam Kwong, Chair of the Division of Hematology,
Oncology and Bone Marrow Transplantation at the University of Hong Kong, and Chair of the Asia
Lymphoma Study Group, has shown strong interest in collaboration and confirmed his interest during an
in-person meeting at ASH 2014 in San Francisco.
References:
1. Swerdlow SH, Jaffe ES, Brousset P, et al: Cytotoxic T-cell and NK-cell lymphomas: current questions
and controversies. Am J Surg Pathol 38:e60-71, 2014
2. Swerdlow SH ea, eds. : WHO Classification of Tumours of Haematopoietic and LymphoidTissues. 4th
ed. International Agency for Research on Cancer: Lyon, 2008., 2008
3. Au W-y, Weisenburger DD, Intragumtornchai T, et al: Clinical differences between nasal and
extranasal natural killer/T-cell lymphoma: a study of 136 cases from the International Peripheral TCell Lymphoma Project, 2009
4. Chim CS, Ma SY, Au WY, et al: Primary nasal natural killer cell lymphoma: long-term treatment
outcome and relationship with the International Prognostic Index. Blood 103:216-21, 2004
5. Yamaguchi M, Kita K, Miwa H, et al: Frequent expression of P-glycoprotein/MDR1 by nasal T-cell
lymphoma cells. Cancer 76:2351-6, 1995
35
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Attachment 6
6. Tsai HJ, Lin SF, Chen CC, et al: Long-term results of a phase II trial with frontline concurrent
chemoradiotherapy followed by consolidation chemotherapy for localized nasal natural killer/T-cell
lymphoma. Eur J Haematol, 2014
7. Yamaguchi M, Tobinai K, Oguchi M, et al: Phase I/II study of concurrent chemoradiotherapy for
localized nasal natural killer/T-cell lymphoma: Japan Clinical Oncology Group Study JCOG0211. J Clin
Oncol 27:5594-600, 2009
8. Kwong Y-L, Kim WS, Lim ST, et al: SMILE for natural killer/T-cell lymphoma: analysis of safety and
efficacy from the Asia Lymphoma Study Group, 2012
9. Jaccard A, Petit B, Girault S, et al: L-asparaginase-based treatment of 15 western patients with
extranodal NK/T-cell lymphoma and leukemia and a review of the literature. Ann Oncol 20:110-6,
2009
10. Suzuki R: Pathogenesis and treatment of extranodal natural killer/T-cell lymphoma. Semin Hematol
51:42-51, 2014
11. Lee J, Au W-Y, Park MJ, et al: Autologous Hematopoietic Stem Cell Transplantation in Extranodal
Natural Killer/T Cell Lymphoma: A Multinational, Multicenter, Matched Controlled Study. Biology of
Blood and Marrow Transplantation 14:1356-1364, 2008
12. Chen AI, McMillan A, Negrin RS, et al: Long-Term Results Of Autologous Hematopoietic Cell
Transplantation For Peripheral T Cell Lymphoma: The Stanford Experience. Biology of Blood and
Marrow Transplantation 14:741-747, 2008
13. Kim HJ, Bang SM, Lee J, et al: High-dose chemotherapy with autologous stem cell transplantation in
extranodal NK//T-cell lymphoma: a retrospective comparison with non-transplantation cases. Bone
Marrow Transplant 37:819-824, 2006
14. Ennishi D, Maeda Y, Fujii N, et al: Allogeneic hematopoietic stem cell transplantation for advanced
extranodal natural killer/T-cell lymphoma, nasal type. Leuk Lymphoma 52:1255-61, 2011
15. Tse E, Chan TS, Koh LP, et al: Allogeneic haematopoietic SCT for natural killer/T-cell lymphoma: a
multicentre analysis from the Asia Lymphoma Study Group. Bone Marrow Transplant 49:902-6, 2014
16. Tse E, Kwong Y-L: How I treat NK/T-cell lymphomas, 2013
17. Kwong YL: Natural killer-cell malignancies: diagnosis and treatment. Leukemia 19:2186-94, 2005
18. A Predictive Model for Aggressive Non-Hodgkin's Lymphoma. New England Journal of Medicine
329:987-994, 1993
19. Lee J, Suh C, Park YH, et al: Extranodal natural killer T-cell lymphoma, nasal-type: a prognostic model
from a retrospective multicenter study. J Clin Oncol 24:612-8, 2006
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Attachment 6
Characteristics patients who received a first allogeneic transplant for NK/T-cell lymphoma between
2010 and 2012 registered with the CIBMTR
Characteristic
Number of patients
Research only cases
Year of transplant, N (%)
2000-2002
2003-2005
2006-2008
2009-2011
2012
Age, in years, median (range)
Age,in years, N (%)
0 -9
10 - 19
20 - 29
30 - 39
40 - 49
50 - 59
60 - 69
70+
Gender, N (%)
Male
Female
Disease, N (%)
Extranodal NK/ T-cell lymphoma, nasal type
Other T/NK-cell lymphoma
Graft Source, N (%)
Bone Marrow
Peripheral Blood
Cord Blood
Donor, N (%)
HLA-identical sibling
Other Related donor
Unrelated donor
ALLO - Allogeneic AUTO - Autologous
378
484
99
51
47 (12)
40 (11)
84 (22)
150 (40)
57 (15)
36 (1-75)
112 (23)
89 (18)
87 (18)
153 (32)
43 (9)
47 (2-78)
24 (6)
61 (16)
59 (16)
78 (21)
66 (17)
52 (14)
33 (9)
5 (1)
6 (1)
13 (3)
63 (13)
81 (17)
103 (21)
116 (24)
87 (18)
15 (3)
235 (62)
143 (38)
341 (70)
143 (30)
72 (19)
306 (81)
141 (29)
343 (71)
77 (20)
270 (71)
31 (8)
8 (2)
476 (98)
0
180 (48)
34 (9)
164 (43)
----
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Attachment 7
Study Proposal 1411-35
Study Title:
Allogeneic Hematopoietic Stem Cell Transplantation in HTLV-1 associated Adult T-cell
Lymphoma/Leukemia
Parastoo Bahrami Dahi, MD, Memorial Sloan Kettering Cancer Center, dahip@mskcc.org
Craig S. Sauter, MD, Memorial Sloan Kettering Cancer Center, sauterc@mskcc.org
Miguel-Angel Perales, MD, Memorial Sloan Kettering Cancer Center, peralesm@mskcc.org
Hypothesis:
Allogeneic transplant can improve survival in patients with HTLV-1 associated lymphoma.
Specific Aims:
1. To assess outcomes of allogeneic transplantation after myeloablative or reduced intensity/ nonmyeloablative conditioning in patients with HTLV-1 associated lymphoma:
1.1 Transplant-related mortality;
1.2 Disease relapse or progression;
1.3 Progression-free survival;
1.4 Overall survival;
1.5 Cause of death;
1.6 Acute graft-versus-host disease (GVHD);
1.7 Chronic GVHD.
Scientific Justification:
Adult T-cell lymphoma/leukemia (ATLL) is an aggressive T-cell malignancy associated with viral infection
of lymphocytes by human T-lymphotropic virus-1 (HTLV-1). ATLL carries a dismal prognosis (1-4).
Allogeneic hematopoietic stem cell transplantation (HSCT) has been explored as a promising treatment
option for long-term survival in Japanese series (5-7). Data on HSCT in patients of non-Japanese
descent is extremely limited (8). The impact of HSCT on survival of non-Japanese patients with HTLV-1
associated ATLL is yet to be elucidated and in the absence of randomized clinical trials, a registry analysis
is indicated to further evaluate the benefit of HSCT in these patients.
Patient Eligibility Population:
This study will include adult patients 18 years or older with HTLV-1 associated ATLL that have received
HSCT between 01/2000 and 12/2013 from 7-8/8 HLA-matched related or unrelated donor, or from a 46/6 donor-recipient HLA-match cord blood unit (either single-unit or double-unit), after a reduced
intensity/ non-myeloablative or myeloablative conditioning reported to the CIBMTR. Recipients of prior
allografts will be excluded.
Data Requirements:
The proposal will utilize data collected by the CIBMTR pre- and post-HSCT, which includes infectious
disease markers form #2004, Hodgkin and non-Hodgkin lymphoma pre-transplant data form #2018,
Hodgkin and non-Hodgkin lymphoma post-transplant data form #2118, 100 day post-HSCT data form
#2100, pre-transplant essential data form #2400, post-transplant essential data form #2450, chimerism
studies form #2451, selective post-transplant selective data form #2455, and recipient death data form
#2900. The parameters to be assessed are outlined below.
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Attachment 7
Potential predictors will be tested for their association with survival and for an interaction with any
significant donor factors
Patient characteristics:
 Disease and disease stage
 Remission status
 Patient age at transplant
 Patient gender
 Patient HTLV-1 serostatus (HTLV-1+ vs. -)
 HCT-CI (0 vs. 1-2 vs. 3+)
 Patient race/ethnicity (White, African-American, Hispanic, Asian, other)
 Time from diagnosis to transplantation
 Patient HLA type – HLA-A, B, C, DRB1, DQ
 Patient weight
 Prior autologous transplant
Transplant characteristics:
 Myeloablative vs. reduced-intensity/non-myeloablative
 TBI or no TBI
 GVHD prophylaxis: calcineurin inhibitor based (CSA or Tacrolimus)], no calcineurin inhibitor
(sirolimus, corticosteroid, methotrexate, ATG or Campath). (Note: Ex vivo T cell depletion is
excluded).
 Peripheral blood or bone marrow or cord blood
 Year of transplant
Donor characteristics:
 Donor age (<32, 33-50, > 50)
 Donor weight
 Donor sex (to calculate M/M, F/M, M/F, F/F)
 Donor HTLV-1 status (to calculate D-/R-, D+/R-, D-/R+; D+/R+)
 Donor HLA type – HLA-A, B, C, DRB1, DQ (to calculate 8/8 vs. 7/8 vs. 6.8 plus locus of mismatch
plus DQ (DQ matched vs. mismatched)
 Cord blood HLA match to the recipient (4/6; 5/6; 6/6 HLA-match)
Outcome measures:
 Engraftment:
Time to absolute neutrophil count >500 cells/mm3 for 3 consecutive laboratory readings
Time to unsupported platelets >20 x 109 cells/L and >50 x 109 cells/L
 GVHD:
Acute GVHD (aGVHD)
Incidence of grade II-IV acute GVHD (aGVHD) (subset evaluating grade III-IV aGVHD)
Time to aGVHD
GVHD after day 100
Incidence of chronic GVHD (cGVHD)
Severity of GVHD after day 100
 Mortality:
Time to mortality
Day 100, 6 months and 1 year mortality
Treatment related mortality at 6 months and 1 year
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
Attachment 7
Cause of mortality
Disease relapse:
Incidence of disease relapse or progression
Time to disease relapse or progression
Study Design:
A retrospective study will be conducted utilizing CIBMTR data. Patients will be eligible for inclusion if
they received allogeneic transplant for the treatment of HTLV-1 associated ATLL between the years of
2000 and 2013. Recipients of prior allograft will be excluded.
The objectives of this analysis are to determine transplant-related mortality, disease recurrence or
progression, PFS, overall survival, and cause of death in the described study population according to
donor type, donor HTLV-1 status and conditioning regimen.
Incidences of neutrophil and platelet engraftment, donor chimerism, acute and chronic GVHD and
relapse will be estimated using the cumulative incidence function. PFS and OS will be estimated using
Kaplan-Meier methodology.
References:
1. Shimoyama M. Diagnostic criteria and classification of clinical subtypes of adult T-cell
leukaemialymphoma. A report from the Lymphoma Study Group (1984-87). Br J Haematol.
1991;79(3):428- 437.
2. Vose J, Armitage J, Weisenburger D, et al. International T-Cell Lymphoma Project. International
peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical
outcomes. J Clin Oncol. 2008;26(25):4124-4130.
3. Uchiyama T, Yodoi J, Sagawa K, Takatsuki K, Uchino H. Adult T-cell leukemia: clinical and
hematologic features of 16 cases. Blood. 1977; 50(3):481-492.
4. Tsukasaki K, Hermine O, Bazarbachi A, et al. Definition, prognostic factors, treatment, and
response criteria of adult T-cell leukemia-lymphoma: A proposal from an international
consensus.
5. Utsunomiya A, Miyazaki Y, Takatsuka Y, et al. Improved outcome of adult T cell
leukemia/lymphoma with allogeneic hematopoietic stem cell transplantation. Bone Marrow
Transplant. 2001; 27(1):15-20.
6. Okamura J, Utsunomiya A, Tanosaki R, et al. Allogeneic stem-cell transplantation with reduced
conditioning intensity as a novel immunotherapy and antiviral therapy for adult T-cell
leukemia/lymphoma. Blood. 2005;105(10):4143-4145.
7. Fukushima T, Miyazaki Y, Honda S, et al. Allogeneic hematopoietic stem cell transplantation
provides sustained long-term survival for patients with adult T-cell leukemia/lymphoma.
Leukemia. 2005;19(5):829-834.
8. Bazarbachi A, Cwynarski K, Boumendil A, et al. Outcome of patients with HTLV-1-associated
adult T-cell leukemia/lymphoma after SCT: a retrospective study by the EBMT LWP. Bone
Marrow Transplant. 2014; 49, 1266-1268.
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Attachment 7
Characteristics of ≥18 years of age patients with an allogeneic Hematopoietic Stem Cell
Transplantation in HTLV-1 associated Adult T-cell Lymphoma/Leukemia from 2000-2013
Variable
Registration only
Research
101
70
48 (19-73)
53 (19-70)
10-19
1 ( 1)
1 ( 1)
20-29
15 (15)
5 ( 7)
30-39
14 (14)
6 ( 9)
40-49
26 (26)
14 (20)
50-59
30 (30)
32 (46)
≥60
15 (15)
12 (17)
Male
52 (51)
36 (51)
Female
49 (49)
34 (49)
<90%
37 (37)
41 (59)
90-100%
51 (50)
14 (20)
Missing
13 (13)
15 (21)
HLA-identical siblings
50 (50)
27 (39)
Other relative
13 (13)
6 ( 9)
Unrelated
38 (38)
37 (53)
Bone marrow
19 (19)
20 (29)
Peripheral blood
77 (76)
42 (60)
5 ( 5)
8 (11)
2001
8 ( 8)
4 ( 6)
2002
3 ( 3)
4 ( 6)
2003
5 ( 5)
6 ( 9)
2004
3 ( 3)
10 (14)
2005
6 ( 6)
8 (11)
2006
4 ( 4)
12 (17)
Number of patients
Age at transplant, years
Median
Sex
Karnofsky score
Donor type
Graft type
Cord blood
Year of transplant
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Variable
Attachment 7
Registration only
Research
2007
9 ( 9)
6 ( 9)
2008
4 ( 4)
5 ( 7)
2009
14 (14)
4 ( 6)
2010
7 ( 7)
1 ( 1)
2011
17 (17)
2 ( 3)
2012
14 (14)
2 ( 3)
2013
7 ( 7)
6 ( 9)
0
2 ( 3)
CD34 select ± other
3 ( 3)
1 ( 1)
Cyclophosphamide ± others
4 ( 4)
1 ( 1)
Tacrolimus + MMF
5 ( 5)
4 ( 6)
25 (25)
16 (23)
8 ( 8)
8 (11)
CSA + MMF
12 (12)
3 ( 4)
CSA + MTX
21 (21)
17 (24)
CSA alone
16 (16)
18 (26)
7 ( 7)
0
25 (3-140)
25 (3-136)
Year of transplant (continued)
GVHD prophylaxis
T-cell depletion ± other
Tacrolimus + MTX
Tacrolimus alone
Other GVHD Prophylaxis
Median follow-up of survivors, months
42
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Attachment 8
Study Proposal 1411-15
Study Title:
Hematopoietic cell transplantation (HCT) outcomes for relapsed or refractory marginal zone lymphomas
Basem M. William, MD, Case Western Reserve University, Bmw93@case.edu
Brian T. Hill, MD, PhD, Cleveland Clinic Foundation, Hillb2@ccf.org
Hillard M. Lazarus, MD, Case Western Reserve University, Hillard.Lazarus@case.edu
Specific Aims:
We propose a descriptive study to analyze trends in utilization and outcomes of autologous and/or
allogeneic HCT in relapsed or refractory marginal zone lymphomas (MZL). Primary outcomes measures
include:
- Time to relapse, progression free, event free and overall survivals
- Transplant related mortality at 100 days and 1, 3, and 5 years
Secondary outcomes will include:
- Time to neutrophil or platelet engraftment
- Incidence of organ toxicity (pneumonitis/VOD)
- Incidence and severity of graft versus host disease (GVHD)
- Incidence of secondary malignancies
- Cause of death
Scientific Justification:
Marginal zone lymphomas (MZL) are a group of mature B-cell neoplasms including splenic B-cell
marginal zone lymphoma (SMZL), nodal marginal zone lymphoma (NMZL), and extranodal marginal zone
lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) (1). Marginal zone lymphomas are
so named because the tumor cells share a characteristic immunotype with B-lymphocytes occupying the
marginal zone of normal lymph node follicles. The first entity recognized in this group was MALT
lymphoma (2) which comprises approximately 9% of all B-cell lymphoma in adults (3) and up to 50% of
primary gastric lymphomas (4). MALT lymphomas represent small B-cell lymphomas that can originate
at any epithelial site but are most frequent in the stomach where they are frequently associated with
infection by Helicobacter pylori. MALT lymphomas are usually, but not always, localized, and durable
remissions in stage I MALT lymphomas can be achieved with surgery, radiotherapy or Helicobacter pylori
irradication in some gastric MALT lymphomas (5). NMZL, formerly known as monocytoid B-cell
lymphoma, usually presents with widespread lymphadenopathy (6). SMZL is a rare subtype that typically
presents with splenomegaly, bone marrow involvement, and circulating tumor cells, but no
lymphadenopathy (7). All subtypes are highly responsive to rituximab (8-12) but cure of patients with
widespread disease is uncertain (13). A recent subgroup analysis of Eastern Cooperative Oncology Group
protocol E4402 (RESORT) showed that maintenance rituximab improves time to treatment failure and
time to first cytotoxic therapy but it is likely that more time is needed to demonstrate survival benefit
(14). Prognosis and prognostic factors remain poorly defined and most data is from small institutional
retrospective series and from extrapolation from large NHL trial where a minority of patients with MZL
were enrolled. For NMZL, five-year overall survival in various series has ranged from 55 to 79%(15-19).
Prognostic factors are not well defined either. In one study, a higher FLIPI (Follicular lymphoma
international prognostic index) score predicted a worse overall survival (15, 20).
The optimal therapy for patients who have relapsed/refractory marginal zone lymphoma has not been
defined. Like follicular lymphomas, patients who progressed after induction therapy and have aggressive
43
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Attachment 8
behaving disease are considered for HCT (21). The benefit of high-dose therapy followed autologous
stem cell transplant (autoSCT) for patients who have relapsed/refractory follicular lymphoma has been
shown in the randomized CUP trial (22). The results of studies such as this are often extrapolated to
other types of indolent lymphomas without clear data from specific disease entities. The role of autoSCT
for patients who have marginal zone lymphoma is unclear based primarily on paucity of data. Only 2
small single-institution case series reports were published: Brown and colleagues at Dana Farber Cancer
Institute (23) retrospectively analyzed the outcomes of 11 patients with chemosensitive but
disseminated marginal zone lymphomas who underwent uniform conditioning with cyclophosphamide
and total body irradiation followed by transplantation with anti-B cell monoclonal antibody-purged
autologous bone marrow (auto BMT) from 1994-1999. All patients had stage IV disease and received
multiple chemotherapy regimens prior to autologous BMT. Only 36% were in complete remission at the
time of bone marrow harvest, and 36% had overt bone marrow infiltration at that time. Two treatmentrelated deaths occurred between 100 days and 6 months. Three patients relapsed and died of disease.
One patient developed and died of myelodysplasia. Five patients remain in continuous complete
remission at a median follow-up of 52 months (45%). The median PFS for these patients was 56 months,
with median OS of 58 months. The only significant predictor of disease-free and OS was age at the time
of transplant (23).
Subsequently, Li and colleagues at the University of Nebraska Medical Center analyzed the clinical
outcomes of 14 patients who had relapsed or refractory MZL and underwent autoSCT from 1992-2008
(24). The median age was 48 years (29-62 years). Five patients had NMZL, two had SMZL, and seven had
MALT lymphoma. Four patients had early-stage disease at diagnosis and the remainder had advancedstage disease. All had relapsed or progressed before beginning the transplantation process. The median
number of previous chemotherapy regimens was 2 (1-4). Thirteen patients received mobilized
peripheral blood as their source of hematopoietic cells and one patient received marrow. Seven patients
were sensitive to initial standard chemotherapy but subsequently relapsed, whereas the other seven
patients did not achieve a complete response to initial therapy. However, all patients were sensitive to
salvage chemotherapy immediately before transplantation. The preparative regimens included CY/TBI (n
= 4), BEAC (n = 6), or BEAM (n = 4). With a median duration of follow-up for surviving patients of 138
months, median PFS and OS were 108 and 120 months respectively. Three treatment-related deaths
were seen in the first 100 days posttransplantation. Only two patients have relapsed. Secondary
malignancies were seen in three patients (myelodysplastic syndrome, n = 2; gastric carcinoma. n = 1).
Beyond few case reports, there is virtually no data on outcomes of alloSCT for MZL (25-27).
This study will investigate the outcomes of patients who received autologous and/or allogeneic HCT for
relapsed or refractory marginal zone lymphomas. We attempt to define disease, treatment, and
transplant-related factors that result in poor outcomes.
Patient Eligibility:
The study will include patients with the following:
 Diagnosis of marginal zone lymphoma (MALT, NMZL, or SMZL)
 Age of 18 years or older
 Autologous or allogeneic HCT for MZL
 Patients who have had CNS lymphomatous involvement are eligible
Excluded are:
 Patients with the diagnosis of other B-cell or T-cell lymphomas, or more than 1 lymphoma
diagnosis
44
Not for publication or presentation
Attachment 8
 Patients who transformed to diffuse large B-cell or other aggressive lymphomas
Outcome definitions:
 Time to engraftment: Defined as time between day of transplantation and recovery of neutrophils
and/or platelets.
 Time to progression: Defined as time between day of transplantation and documentation of disease
recurrence/progression. Patients alive and disease free will be censored at last follow up.
 Event free survival: an event is defined as progression/recurrence or death.
 Transplant Related Mortality: Defined as death within 28 days of transplantation or time to death
without recurrence of disease.
 Overall survival: time to death. Patients are censored at last follow-up.
 Causes of death: as defined by Copeland et al (32)
Variables to be analyzed :
Patient Related:
- Age at transplantation (≤60 vs. >60)
- Karnofsky performance status (<70 vs. ≥70)
- Gender (male vs. female)
- CMV status in donor and recipient
- Hepatitis C virus seropositivity
Disease related at diagnosis:
- Histology (MALT, NMZL, SMZL)
- Stage at diagnosis (I/II vs. III/IV)
- Age adjusted IPI
- B-symptoms (yes/no)
- Bone marrow involvement (yes/no)
- Extranodal/splenic involvement (yes/no)
Disease related at transplant:
- Type of lymphoma (relapsed or refractory)
- B-symptoms (yes/no)
- Extranodal/splenic involvement (yes/no)
- Bone marrow involvement (yes/no)
- Time from diagnosis to transplant
- Number of lines of therapy
- Prior autologous transplant (yes/no)
- Disease status
o 2nd vs. 3rd or greater CR/PR
o Duration of 1st CR
- Disease sensitivity (sensitive vs. resistant vs. untreated)
Peri-transplant therapy:
- Pre-transplant
o Rituximab exposure (yes/no)
o Prior involved field radiotherapy (yes/no)
 Lung shielding (yes/no)
o Other prior radiotherapy
- Post- transplant
o Involved field radiotherapy (yes/no)
45
Not for publication or presentation
Attachment 8
o Rituximab (yes/no)
o Chemotherapy (yes/no)
o Other
Post-transplant outcomes:
- Peri-transplant performance status
o Pre-transplant organ dysfunction
o Post-transplant organ dysfunction (pneumonitis, VOD)
- Post-transplant outcomes
o PFS
o OS
o Cumulative incidence of relapse
o Sites of relapse
- Graft versus host disease (GVHD)
o Acute (site, grade)
o Chronic (site, grade)
- CMV reactivation
o CMV viremia
o Invasive CMV disease
- Long term outcomes
o Secondary malignancies
o Organ dysfunction
Transplant related:
- Conditioning regimen
o AutoSCT conditioning regimen
o Myeloablative vs reduced-intensity conditioning
o Type of conditioning regimen
o Dose of TBI (<4 Gy, 4-13 Gy, ≥13Gy) and number of fractions
o T-cell depletion (antithymocyte globulin or alemtuzumab)
o Graft source (MRD, MUD, umbilical cord blood)
o Number of HLA mismtaches
- Year of transplant
- Stem cell source (bone marrow vs peripheral blood stem cells)
- Time to neutrophil/platelet engraftment
Data Requirements:
Patients, disease and transplant related characteristics will be obtained from the CIBMTR database. No
additional supplemental data collection is anticipated.
Study Design (Scientific Plan):
This study will determine trends in utilization and outcomes of autoSCT and/on alloSCT for MZL
including PFS, OS, relapse, and long term complications after transplant. All patients with the diagnosis
of MZL who underwent autoSCT and/or alloSCT who meet the eligibility criteria will be enrolled. We also
aim to define disease, treatment, and transplant related characteristics that result in poor outcomes.
As most of these patients had an alloSCT after failure of autoSCT; will analyze those groups separately
and correct for the confounding effect of disease-related characteristics for the difference in outcomes
between both groups.
46
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Attachment 8
Patient-, disease-, and transplantation-related variables and outcomes will be described in three
cohorts: recipients of (1) autoSCT or (2) alloSCT from MRD (3) MUD/mismatched related donors.
Univariate probabilities of developing acute or chronic GVHD, TRM, and lymphoma progression will
calculated using cumulative incidence curves to accommodate competing risks. Probabilities of OS and
PFS will be calculated using Kaplan-Meier estimator. Confidence intervals (CIs) will calculated with a log
transformation. Multivariate analyses were not performed because of the imbalance in baseline
characteristics of the cohorts and the changes in MZL management over the period studied. The
propensity score will be calculated using a logistic-regression model using the following factors: age,
gender, Karnofsky performance status pre-transplant, disease stage, B-symptoms, extranodal
involvement, bone marrow involvement at diagnosis, number of regimens prior to transplant, disease
sensitivity prior to transplant, time from diagnosis to transplant, graft source, year of transplant, and
transplant center.
The Center of International Bone Marrow Transplant Research (CIBMTR) has registered 451 transplants
for patients with MZL (please see table below for details).
AutoSCT
AlloSCT
Total
Extranodal marginal zone B-cell
144
40
184
Nodal marginal zone B-cell
106
84
190
Splenic marginal zone B-cell
43
34
77
Total
293
158
451
We are also planning to compare outcomes of MZL who were transplanted to a comparator cohort of
MZL who had not been transplanted from University Hospitals Case Medical Center (UHCMC), Cleveland
Clinic Foundation, and University of Nebraska Medical Center (please see table below for details). We
have currently reviewed 141 cases with histologically confirmed diagnosis of MZL at UHCMC and are
currently reviewing 218 cases of MZL at CCF.
University
Cleveland
University of Total
Hospitals Case
Clinic
Nebraska
Medical Ctr
Foundation
Medical Ctr
Extranodal marginal zone B- 54
cell
160
66
280
Nodal marginal zone B-cell
28
33
23
84
Splenic marginal zone B-cell
17
25
7
49
Total
99
218
96
413
References:
1.
Swerdlow S. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon,
France: International Agency for Research on Cancer; 2008.
2.
Isaacson PG. Mucosa-associated lymphoid tissue lymphoma. Seminars in hematology. 1999
Apr;36(2):139-47. PubMed PMID: 10319382.
3.
A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's
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15.
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Attachment 8
Doglioni C, Wotherspoon AC, Moschini A, de Boni M, Isaacson PG. High incidence of primary
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1347858.
Tsang RW, Gospodarowicz MK, Pintilie M, Wells W, Hodgson DC, Sun A, et al. Localized mucosaassociated lymphoid tissue lymphoma treated with radiation therapy has excellent clinical
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Berger F, Felman P, Thieblemont C, Pradier T, Baseggio L, Bryon PA, et al. Non-MALT marginal
zone B-cell lymphomas: a description of clinical presentation and outcome in 124 patients.
Blood. 2000 Mar 15;95(6):1950-6. PubMed PMID: 10706860.
Catovsky D, Matutes E. Splenic lymphoma with circulating villous lymphocytes/splenic marginalzone lymphoma. Seminars in hematology. 1999 Apr;36(2):148-54. PubMed PMID: 10319383.
Conconi A, Martinelli G, Thieblemont C, Ferreri AJ, Devizzi L, Peccatori F, et al. Clinical activity of
rituximab in extranodal marginal zone B-cell lymphoma of MALT type. Blood. 2003 Oct
15;102(8):2741-5. PubMed PMID: 12842999.
Jager G, Neumeister P, Brezinschek R, Hinterleitner T, Fiebiger W, Penz M, et al. Treatment of
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type with
cladribine: a phase II study. Journal of clinical oncology : official journal of the American Society
of Clinical Oncology. 2002 Sep 15;20(18):3872-7. PubMed PMID: 12228207.
Kalpadakis C, Pangalis GA, Dimopoulou MN, Vassilakopoulos TP, Kyrtsonis MC, Korkolopoulou P,
et al. Rituximab monotherapy is highly effective in splenic marginal zone lymphoma.
Hematological oncology. 2007 Sep;25(3):127-31. PubMed PMID: 17514771.
Leahy MF, Seymour JF, Hicks RJ, Turner JH. Multicenter phase II clinical study of iodine-131rituximab radioimmunotherapy in relapsed or refractory indolent non-Hodgkin's lymphoma.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2006
Sep 20;24(27):4418-25. PubMed PMID: 16940276.
Witzig TE, Geyer SM, Kurtin PJ, Colgan JP, Inwards DJ, Micallef IN, et al. Salvage chemotherapy
with rituximab DHAP for relapsed non-Hodgkin lymphoma: a phase II trial in the North Central
Cancer Treatment Group. Leukemia & lymphoma. 2008 Jun;49(6):1074-80. PubMed PMID:
18569634.
Raderer M, Streubel B, Woehrer S, Puespoek A, Jaeger U, Formanek M, et al. High relapse rate in
patients with MALT lymphoma warrants lifelong follow-up. Clinical cancer research : an official
journal of the American Association for Cancer Research. 2005 May 1;11(9):3349-52. PubMed
PMID: 15867234.
Williams ME, Hong F, Kahl BS, Gascoyne RD, Wagner LI, Krauss JC, et al. A subgroup analysis of
small lymphocytic and marginal zone lymphomas in the Eastern Cooperative Oncology Group
protocol E4402 (RESORT): A randomized phase III study comparing two different rituximab
dosing strategies for low tumor burden indolent non-Hodgkin lymphoma. ASCO Meeting
Abstracts. 2012 May 30, 2012;30(15_suppl):8007.
Arcaini L, Paulli M, Burcheri S, Rossi A, Spina M, Passamonti F, et al. Primary nodal marginal zone
B-cell lymphoma: clinical features and prognostic assessment of a rare disease. British journal of
haematology. 2007 Jan;136(2):301-4. PubMed PMID: 17233821.
Camacho FI, Algara P, Mollejo M, Garcia JF, Montalban C, Martinez N, et al. Nodal marginal zone
lymphoma: a heterogeneous tumor: a comprehensive analysis of a series of 27 cases. The
American journal of surgical pathology. 2003 Jun;27(6):762-71. PubMed PMID: 12766579. Epub
2003/05/27. eng.
Nathwani BN, Anderson JR, Armitage JO, Cavalli F, Diebold J, Drachenberg MR, et al. Marginal
zone B-cell lymphoma: A clinical comparison of nodal and mucosa-associated lymphoid tissue
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18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
Attachment 8
types. Non-Hodgkin's Lymphoma Classification Project. Journal of clinical oncology : official
journal of the American Society of Clinical Oncology. 1999 Aug;17(8):2486-92. PubMed PMID:
10561313.
Nathwani BN, Drachenberg MR, Hernandez AM, Levine AM, Sheibani K. Nodal monocytoid B-cell
lymphoma (nodal marginal-zone B-cell lymphoma). Seminars in hematology. 1999
Apr;36(2):128-38. PubMed PMID: 10319381. Epub 1999/05/13. eng.
Traverse-Glehen A, Felman P, Callet-Bauchu E, Gazzo S, Baseggio L, Bryon PA, et al. A
clinicopathological study of nodal marginal zone B-cell lymphoma. A report on 21 cases.
Histopathology. 2006 Jan;48(2):162-73. PubMed PMID: 16405665. Epub 2006/01/13. eng.
Heilgeist A, McClanahan F, Ho AD, Witzens-Harig M. Prognostic value of the Follicular
Lymphoma International Prognostic Index score in marginal zone lymphoma: an analysis of
clinical presentation and outcome in 144 patients. Cancer. 2013 Jan 1;119(1):99-106. PubMed
PMID: 22736411. Epub 2012/06/28. eng.
Zinzani PL. The many faces of marginal zone lymphoma. Hematology / the Education Program of
the American Society of Hematology American Society of Hematology Education Program.
2012;2012:426-32. PubMed PMID: 23233614.
Schouten HC, Qian W, Kvaloy S, Porcellini A, Hagberg H, Johnsen HE, et al. High-dose therapy
improves progression-free survival and survival in relapsed follicular non-Hodgkin's lymphoma:
results from the randomized European CUP trial. Journal of clinical oncology : official journal of
the American Society of Clinical Oncology. 2003 Nov 1;21(21):3918-27. PubMed PMID:
14517188.
Brown JR, Gaudet G, Friedberg JW, Neuberg D, Mauch P, Kutok JL, et al. Autologous bone
marrow transplantation for marginal zone non-Hodgkin's lymphoma. Leukemia & lymphoma.
2004 Feb;45(2):315-20. PubMed PMID: 15101717. Epub 2004/04/23. eng.
Li L, Bierman P, Vose J, Loberiza F, Armitage JO, Bociek RG. High-dose therapy/autologous
hematopoietic stem cell transplantation in relapsed or refractory marginal zone non-Hodgkin
lymphoma. Clinical lymphoma, myeloma & leukemia. 2011 Jun;11(3):253-6. PubMed PMID:
21658651. Epub 2011/06/11. eng.
Busemann C, Gudzuhn A, Hirt C, Kirsch M, Vogelgesang S, Schmidt CA, et al. Treatment of
splenic marginal zone lymphoma of the CNS with high-dose therapy and allogeneic stem cell
transplantation. Experimental hematology & oncology. 2012;1(1):32. PubMed PMID: 23210733.
Pubmed Central PMCID: PMC3515347. Epub 2012/12/06. eng.
Lee L, Lipton JH, Bailey D, Kukreti V. Tale of two lymphomas: peripheral T-cell lymphoma after
allogeneic stem-cell transplantation for marginal zone lymphoma. Journal of clinical oncology :
official journal of the American Society of Clinical Oncology. 2012 Nov 1;30(31):e309-11.
PubMed PMID: 22965958. Epub 2012/09/12. eng.
Ferraccioli G, Damato R, De Vita S, Fanin R, Damiani D, Baccarani M. Haematopoietic stem cell
transplantation (HSCT) in a patient with Sjogren's syndrome and lung malt lymphoma cured
lymphoma not the autoimmune disease. Annals of the rheumatic diseases. 2001 Feb;60(2):1746. PubMed PMID: 11203719. Pubmed Central PMCID: PMC1753470. Epub 2001/02/24. eng.
Gutierrez-Delgado F, Holmberg L, Hooper H, Petersdorf S, Press O, Maziarz R, et al. Autologous
stem cell transplantation for Hodgkin's disease: busulfan, melphalan and thiotepa compared to
a radiation-based regimen. Bone Marrow Transplant. 2003 08//;32(3):279-85.
Salar A, Sierra J, Gandarillas M, Caballero MD, Marín J, Lahuerta JJ, et al. Autologous stem cell
transplantation for clinically aggressive non-Hodgkin's lymphoma: the role of preparative
regimens. Bone Marrow Transplant. 2001 02//;27(4):405-12.
Liu HW, Seftel MD, Rubinger M, Szwajcer D, Demers A, Nugent Z, et al. Total body irradiation
compared with BEAM: Long-term outcomes of peripheral blood autologous stem cell
49
Not for publication or presentation
31.
32.
Attachment 8
transplantation for non-Hodgkin's lymphoma. International journal of radiation oncology,
biology, physics. 2010 Oct 1;78(2):513-20. PubMed PMID: 20137862. Epub 2010/02/09. eng.
Cao TM, Horning S, Negrin RS, Hu WW, Johnston LJ, Taylor TL, et al. High-dose therapy and
autologous hematopoietic-cell transplantation for follicular lymphoma beyond first remission:
the Stanford University experience. Biol Blood Marrow Transplant. 2001 //;7(5):294-301.
Copelan E, Casper JT, Carter SL, van Burik JA, Hurd D, Mendizabal AM, et al. A scheme for
defining cause of death and its application in the T cell depletion trial. Biol Blood Marrow
Transplant. 2007 Dec;13(12):1469-76. PubMed PMID: 18022577. Epub 2007/11/21. eng.
50
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Attachment 8
Characteristics of ≥18 year old patients who underwent HCT for marginal zone lymphoma registered
to the CIBMTR from 2000-2013
Variable
Number of patients
Number of centers
AlloHCT
AutoHCT
Registration Registration
only
only
AlloHCT
Research
AutoHCT
Research
50
39
29
23
109
71
259
128
56 (23-68)
57 (23-75)
20-29
3 ( 3)
2 ( 1)
0
1 ( 3)
30-39
7 ( 6)
25 (10)
3 ( 6)
1 ( 3)
40-49
22 (20)
44 (17)
15 (30)
7 (24)
50-59
49 (45)
92 (36)
23 (46)
6 (21)
≥60
28 (26)
96 (37)
9 (18)
14 (48)
Extranodal marginal zone B-cell of MALT
30 (28)
124 (48)
11 (22)
10 (34)
Nodal marginal zone B-cell
56 (51)
94 (36)
28 (56)
12 (41)
Splenic marginal zone B-cell
23 (21)
41 (16)
11 (22)
7 (24)
Male
65 (60)
154 (59)
28 (56)
14 (48)
Female
44 (40)
105 (41)
22 (44)
15 (52)
<90%
48 (44)
125 (48)
19 (38)
15 (52)
90-100%
42 (39)
88 (34)
19 (38)
7 (24)
Missing
19 (17)
46 (18)
12 (24)
7 (24)
Age at transplant, years
Median
53 (31-67) 57 (23-72)
Subdisease
Sex
Karnofsky score
Conditioning regimen
N/A
N/A
RIC/NST
71 (65)
28 (56)
Myeloablative
36 (33)
18 (36)
2 ( 2)
4 ( 8)
Missing
Donor type
HLA-identical siblings
Other relative
Unrelated donor
Autologous
64 (59)
0
24 (48)
0
8 ( 7)
0
2 ( 4)
0
37 (34)
0
24 (48)
0
0
259
0
29
51
Not for publication or presentation
Variable
Number of patients
Attachment 8
AlloHCT
AutoHCT
Registration Registration
only
only
AlloHCT
Research
AutoHCT
Research
109
259
50
29
Bone marrow
12 (11)
0
6 (12)
1 ( 3)
Peripheral blood
95 (87)
259
41 (82)
28 (97)
2 ( 2)
0
3 ( 6)
0
2000-2005
32 (30)
106 (41)
27 (54)
15 (52)
2006-2013
77 (70)
153 (59)
23 (46)
14 (48)
26 (4-144)
30 (2-148)
Graft type
Cord blood
Year of HCT
Follow up of survivors, median (range)
64 (3-144) 84 (3-139)
52
Not for publication or presentation
Attachment 9
Study Proposal 1411-83
Study Title:
A retrospective review of outcomes with allogeneic transplant for gamma-delta T cell lymphoma
James Leonard Gajewski, MD, Oregon Health Science University, gajewski@ohsu.edu
Richard Thomas Maziarz, MD, Oregon Health Science University, Maziarz@ohsu.edu
Hypothesis:
Allogeneic transplantation can provide durable disease control in gamma-delta T-cell lymphomas.
Specific Aims:
Descriptive review of transplant outcomes with 3 year post transplant overall survival, progression free
survival, treatment related mortality and relapse rate.
Scientific Justification:
Non-transplant therapies published have had very short followup only 3-6 months. These diseases have
much longer survival. Non transplant therapies at some point fail. There has been no published study on
transplant outcomes.
A preliminary review of CIBMTR data base for these diseases show:
3 year Kaplan Meier overall survival of:
 Allogeneic HCT for gamma delta t-cell lymphoma-40%
Patient Eligibility Population:
Patients reported to CIBMTR between 1999 and 2013 with gamma-delta t cell lymphoma undergoing
first allogeneic transplantation. All graft and donor sources are eligible.
Data Requirements: None
Sample Requirements: None
Study Design:
Retrospective review of patients treated with autologous transplants for gamma-delta t cell lymphoma
Descriptive analysis of date of transplant, age at transplant, gender, graft source, donor and Kaplan
Meier survival, progression free survival, treatment related mortality and relapse
References:
1. Hosing C, Champlin RE Stem Cell Transplantation in T cell Non Hodgkin’s Lymphoma Ann Oncol
2011:22, 1471
2. Lamy T, Loughran TP, Jr. clinical features of large granular lymphocytic lymphoma. Semin
Hematology 2003:40, 185
53
Not for publication or presentation
Attachment 9
Characteristics of patients who received an allogeneic transplantation for Hepatosplenic gamma-delta
T-cell registered to the CIBMTR from 1999-2013*
Variable
Registration only
Research
65
26
29 (9-64)
33 (3-70)
1 ( 2)
1 ( 4)
10-19
14 (22)
3 (12)
20-29
20 (31)
6 (23)
30-39
12 (18)
6 (23)
40-49
11 (17)
6 (23)
50-59
6 ( 9)
2 ( 8)
≥60
1 ( 2)
2 ( 8)
Male
42 (65)
24 (92)
Female
23 (35)
2 ( 8)
<90%
27 (42)
11 (42)
90-100%
26 (40)
13 (50)
Missing
12 (18)
2 ( 8)
38 (59)
12 (44)
8 (12)
4 (15)
19 (29)
10 (38)
RIC/NST
13 (20)
7 (27)
Myeloablative
50 (77)
16 (62)
2 ( 3)
3 (12)
Bone marrow
16 (25)
3 (12)
Peripheral blood
42 (65)
19 (73)
7 (11)
4 (15)
Number of patients
Age at transplant, years
Median
<10
Sex
Karnofsky score
Donor type
HLA-identical siblings
Other relative
Unrelated donor
Conditioning regimen
Missing
Graft type
Cord blood
54
Not for publication or presentation
Variable
Number of patients
Attachment 9
Registration only
Research
65
26
Year of transplant
1999
1 ( 2)
2000
1 ( 2)
0
2001
3 ( 5)
0
2002
2 ( 3)
0
2003
1 ( 2)
1 ( 4)
2004
3 ( 5)
1 ( 4)
2005
5 ( 8)
3 (12)
2006
7 (11)
0
2007
5 ( 8)
1 ( 4)
2008
6 ( 9)
4 (15)
2009
4 ( 6)
2 ( 8)
2010
7 (11)
0
2011
5 ( 8)
4 (15)
2012
8 (12)
3 (12)
2013
7 (11)
7 (27)
26 (3-166)
23 (3-100)
Median follow up of survivors (range)
*No cases registered prior 1999.
55
Not for publication or presentation
Attachment 10
Study Proposal 1408-02/1411-27
Study Title:
Alternative Donor Allogeneic Hematopoietic Transplantation Strategies for Lymphoid Malignancies in
Adult Patients: Comparing Matched Unrelated versus Haploidentical Related Donor Transplantation
Abraham S. Kanate, MD, Osborn Hematopoietic Malignancy and Transplantation Program, West Virginia
University, askanate@hsc.wvu.edu
Alberto Mussetti, MD, Department of Hematology and Bone Marrrow Transplantation, Istituto
Nazionale dei Tumori di Milano, Università degli Studi di Milano,
alberto.mussetti@istitutotumori.mi.it
Mohamed A. Kharfan-Dabaja, MD, Department of Blood and Marrow Transplantation, Department of
Oncologic Sciences, H. Lee Moffitt Cancer Center/University of South Florida College of
Medicine, Tampa, FL, USA, Mohamed.Kharfan-Dabaja@moffitt.org
Objectives:
The primary objective is to compare the one-year overall survival (OS) for 8/8 HLA-matched unrelated
donor (URD) hematopoietic cell transplantation (HCT) versus T-cell replete haploidentical related donor
HCT using post-transplant cyclophosphamide (PT-Cy) in patients with lymphomas (Hodgkin and nonHodgkin lymphoma).
The secondary objective is to compare graft failure, incidence of acute and chronic graft-versus-host
disease (GVHD) relapse rate, progression-free survival (PFS) and non-relapse mortality (NRM) for 8/8
HLA matched URD transplantation versus T-cell replete haploidentical related donor HCT using PT-Cy in
patients with various subtypes of lymphomas. Diseases will be stratified by disease type – Hodgkin
Lymphoma (HL) vs. non-Hodgkin Lymphoma (NHL).
Scientific Justification:
Allogeneic HCT (allo-HCT) remains a potentially curative strategy in patients with various subtypes of
lymphomas. Myeloablative conditioning (MAC) while considered in selected patients is often
contraindicated due to advanced age, existing co-morbidities, or in some cases prior high-dose therapy
and autologous HCT leading to high NRM (1-5). With the increasing utilization of reduced intensity/nonmyeloablative conditioning (RIC/NMA) allo-HCT regimens more patients are now eligible for allo-HCT (69); however, lowering the intensity of the preparative regimen might be associated with increased risk
of disease relapse (2, 3, 10).
Advances in HLA-typing coupled with better supportive care have improved procedure related
complications after URD allo-HCT. Unrelated donor searches can be time consuming and often fail to
identify a suitable HLA-matched donor especially for minority populations. Haploidentical related donors
are a more readily available donor source for most patients and are currently being utilized when
suitable HLA-matched sibling or unrelated donors are unavailable (11, 12). Initial studies evaluating
haploidentical allo-HCT were associated with prohibitive GVHD and NRM. To circumvent this, T-cell
depleted grafts were utilized (with high CD34+ cell doses in some studies) but this approach was
associated with graft failure, delayed immune reconstitution and infectious complications. Recently Tcell replete haploidentical allo-HCT followed by post transplant cyclophosphamide (PT-Cy) to mitigate
donor T-cells alloreactivity has yielded promising results in several studies (13-15). Retrospective studies
have reported comparable survival rates to URD allo-HCT and low chronic GVHD, ranging between 5 15% at 2 years post-HCT (17-18).
56
Not for publication or presentation
Attachment 10
We hypothesize that haploidentical allo-HCT with PT-Cy would decrease relapse risk due to a higher
degree of HLA disparity between donor and recipient and graft-versus-lymphoma effect without
significantly increasing GVHD compared to URD allo-HCT, thereby ultimately improving survival.
A large majority of the lymphoma patients being considered for an allo-HCT are likely to have received
salvage therapy for relapsed/progressive disease and durability of achieved responses is always a
concern. Accordingly, timely intervention is of paramount importance. Prospective studies comparing
post-transplant outcomes with URD or haploidentical related donor (with PT-Cy) allo-HCT in lymphoma
patients are lacking. Considering the low likelihood of a prospective randomized controlled study,
performing a non-randomized comparison using registry data from the Center for International Bone
Marrow Transplantation Research (CIBMTR) would be the most desirable approach to answer such
question at present. Duly noting the limitations of a retrospective (registry) analysis, this study may
support the use of haploidentical related donor allo-HCT as an alternative to URD allografts. This in turn
can potentially justify the use of readily available donor. Since NHL and HL have differing disease
presentations and clinical courses and taking into account recent reports suggesting improved outcomes
with haploidentical donor allo-HCT in HL (16), evaluating outcomes stratified by disease status is
necessary. If the sample size is adequate, a multivariate analysis, stratifying NHL subtypes (indolent vs.
aggressive) and conditioning regimens (MAC vs. RIC/NMA) will be considered.
Study Population:
Patients aged ≥18 years who received their first allo-HCT an 8/8 HLA matched URD or haploidentical
related donor (defined as > 2 antigen level mismatches) for a diagnosis of lymphoma (HL or NHL) from
2007 to 2013. The URD group must be 8/8 HLA matched at HLA -A, -B, -C and -DRB1 using bone marrow
or peripheral blood grafts. The haploidentical related donor group is to be limited to only those
receiving post-transplantation cyclophosphamide using bone marrow or peripheral blood grafts.
Outcomes:
 Hematopoietic recovery: time to neutrophil (ANC) recovery >0.5×109/L; time to platelet recovery
≥20×109/L.
 Acute graft-versus-host disease: maximum overall grade of grade II-IV and grade III-IV acute GVHD,
we do not collect date of onset of acute GVHD.
 Chronic graft-versus-host disease: maximum extent of chronic GVHD, and time to chronic GVHD.
 Relapse/progression: Time of relapse or progression of the original malignancy post-HCT.
 Non-relapse mortality: time to death without disease relapse.
 Disease-free survival: survival without relapse. Patients are censored at time of last contact.
 Overall survival: Events are death from any cause. Surviving patients are censored at time of last
contact.
 Primary cause of death: according to the Copelan algorithm, descriptive only.
Variables to be analyzed:
Patient-related:
 Age: continuous to find the appropriate cut point for the survival model
 Gender: male vs. female
 Karnofsky performance score: <90% vs. ≥90%
 Co-morbidity index: 0 vs. 1-2 vs. 3
 CMV status: recipient positive vs. recipient negative vs. unknown
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Disease-related:
 Disease subtype: NHL vs. HL
 NHL subtype: indolent vs. aggressive
 Disease status at time of transplant: sensitive vs. resistant
 Disease stage at diagnosis: I/II vs. III/IV
Transplant-related:
 Prior autologous HCT: Yes vs. No
 Prior radiation therapy: Yes vs. No
 Interval from diagnosis to transplant: <12m vs. ≥ 12m
 Main effect: Haploidentical HCT vs. HLA 8/8 URD
 Conditioning: MAC vs. RIC/NMA
 ATG use: Yes vs. No
Study Design:
A retrospective multicenter study will be conducted utilizing CIBMTR data. Patients will be eligible if they
satisfied the criteria detailed in the “Patient eligibility population” section. Patients will then be
stratified according to URD or haploidentical PT-Cy. The objective of this analysis is to compare these
two approaches and their effects on allo-HCT outcomes.
Chi-square or the Wilcoxon statistic will be used to compare patient, disease and transplantation
characteristics between the 2 groups for categorical or continuous variables respectively. The
probabilities of neutrophils and platelets recovery, acute GVHD, chronic GVHD, NRM, relapse rate will be
calculated using the cumulative incidence estimator. PFS and OS will be calculated using the KaplanMeier estimator. For neutrophil and platelet recovery, acute GVHD and chronic GVHD, death without the
event will be the competing event. For NRM, relapse/progression will be the competing event. For
relapse rate, NRM will be the competing event. Data on patients without an event will be censored at
last follow up.
For univariate analysis, Gray test and log-rank test will be used to identify factors influencing cumulative
incidence and survival respectively. The association between treatment groups and outcomes will be
studied with multivariate Cox regression models. P values are 2 sided and values < 0.05 will be
considered significant.
The treatment group will be included in all steps of model building regardless of level of significance. The
other variables tested will be retained in the final multivariate model if the variable will attain the level
of significance set for these analyses. Results will be expressed as hazard ratio (HR) with 95% confidence
intervals (CI). Possible interactions within the treatment groups and other variables will be tested. All
models will be tested regarding proportional hazard of assumptions (PHA). If the assumption will be
violated, time dependent covariates will be constructed.
Potential Pitfalls:
Even with the increasing utilization of haploidentical allo-HCT with PT-Cy, the sample size may
be small to perform meaningful statistical analysis. If so additional data could be requested from
European Bone Marrow transplantation (EBMT) registry or from the Gruppo Italinao Midollo
Osseo (GITMO) registry.
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Attachment 10
References:
1. Lazarus HM, Zhang M-J, Carreras J, et al. A Comparison of HLA-Identical Sibling Allogeneic versus
Autologous Transplantation for Diffuse Large B Cell Lymphoma: A Report from the CIBMTR. Biology
of Blood and Marrow Transplantation. 2010;16(1):35–45.
2. Bacher U, Klyuchnikov E, Le-Rademacher J, et al. Conditioning regimens for allotransplants for
diffuse large B-cell lymphoma: myeloablative or reduced intensity? Blood. 2012.
3. van Kampen RJW, Canals C, Schouten HC, et al. Allogeneic Stem-Cell Transplantation As Salvage
Therapy for Patients With Diffuse Large B-Cell Non-Hodgkin’s Lymphoma Relapsing After an
Autologous Stem-Cell Transplantation: An Analysis of the European Group for Blood and Marrow
Transplantation Registry. Journal of Clinical Oncology. 2011;29(10):1342–1348.
4. van Besien K, Loberiza FR, Bajorunaite R, et al. Comparison of autologous and allogeneic
hematopoietic stem cell transplantation for follicular lymphoma. Blood. 2003;102(10):3521 –3529.
5. Gajewski JL, Phillips GL, Sobocinski KA, et al. Bone marrow transplants from HLA-identical siblings in
advanced Hodgkin’s disease. Journal of Clinical Oncology. 1996;14(2):572–578.
6. McSweeney PA, Niederwieser D, Shizuru JA, et al. Hematopoietic cell transplantation in older
patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versustumor effects. Blood. 2001;97(11):3390 –3400.
7. Morris E, Thomson K, Craddock C, et al. Outcomes after alemtuzumab-containing reduced-intensity
allogeneic transplantation regimen for relapsed and refractory non-Hodgkin lymphoma. Blood.
2004;104(13):3865–3871.
8. Khouri IF, Saliba RM, Giralt SA, et al. Nonablative allogeneic hematopoietic transplantation as
adoptive immunotherapy for indolent lymphoma: low incidence of toxicity, acute graft-versus-host
disease, and treatment-related mortality. Blood. 2001;98(13):3595 –3599.
9. Sorror ML, Storer BE, Maloney DG, et al. Outcomes after allogeneic hematopoietic cell
transplantation with nonmyeloablative or myeloablative conditioning regimens for treatment of
lymphoma and chronic lymphocytic leukemia. Blood. 2008;111(1):446–452
10. Rodriguez R, Nademanee A, Ruel N, et al. Comparison of Reduced-Intensity and Conventional
Myeloablative Regimens for Allogeneic Transplantation in Non-Hodgkin’s Lymphoma. Biology of
blood and marrow transplantation : journal of the American Society for Blood and Marrow
Transplantation. 2006;12(12):1326–1334.
11. Aversa F, Terenzi A, Tabilio A, Falzetti F, Carotti A, Ballanti S et al. Full haplotype-mismatched
hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk
of relapse. J Clin Oncol 2005; 23(15): 3447-54.
12. Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A et al. Effectiveness of donor
natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002; 295(5562):
2097-100.
13. Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M et al. HLA-haploidentical bone
marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and
high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 2008; 14(6): 64150.
14. Tuve S, Gayoso J, Scheid C, Radke J, Kiani A, Serrano D et al. Haploidentical bone marrow
transplantation with post-grafting cyclophosphamide: multicenter experience with an alternative
salvage strategy. Leukemia 2011; 25(5): 880-3.
15. Bacigalupo A, Dominietto A, Di Grazia C, Tamparelli T, Gualandi F, Ibatici A et al. Unmanipulated
haploidentical transplants compared with other alternative donors and matched sibling grafts: a
single center experience in 488 patients (abstract). Bone Marrow Transplant 2013; 48(suppl 2): S63.
16. Raiola A, Dominietto A, Varaldo R, et al. Unmanipulated haploidentical BMT following nonmyeloablative conditioning and post-transplantation CY for advanced Hodgkin's lymphoma.
59
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Attachment 10
17. Bone Marrow Transplant. 2014 Feb;49(2):190-4.
18. Castagna L, Bramanti S, Furst S, et al. Nonmyeloablative conditioning, unmanipulated haploidentical
SCT and post-infusion CY for advanced lymphomas. Bone Marrow Transplant. 2014 Sep 15.
19. Bashey A, Zhang X, Sizemore CA, et al. T-Cell-Replete HLA-Haploidentical Hematopoietic
Transplantation for Hematologic Malignancies Using Post-Transplantation Cyclophosphamide
Results in Outcomes Equivalent to Those of Contemporaneous HLA-Matched Related and Unrelated
Donor Transplantation. J. Clin. Oncol. 31, 1310–1316 (2013).
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Attachment 10
Characteristics of patients who underwent a RIC/NST allogeneic HCT for NHL or HD registered to the
CIBMTR from 2007-2013*
Variable
Haplo-identical
Matched unrelated
Number of patients
136
553
Number of centers
14
103
39 (29)
143 (26)
58 (15-75)
57 (7-75)
0
1 (<1)
10-19
3 ( 2)
5 ( 1)
20-29
6 ( 4)
25 ( 5)
30-39
9 ( 7)
34 ( 6)
40-49
18 (13)
81 (15)
50-59
41 (30)
191 (35)
≥60
59 (43)
216 (39)
Male
86 (63)
342 (62)
Female
50 (37)
211 (38)
19 (14)
189 (34)
105 (77)
310 (56)
12 ( 9)
54 (10)
119 (88)
524 (95)
17 (13)
29 ( 5)
132 (97)
44 ( 8)
4 ( 3)
509 (92)
Research cases
Age at transplant, years
Median (range)
<10
Sex
Karnofsky score
<90%
90-100%
Missing
Disease
Non-Hodgkin
Hodgkin
Graft type
Bone marrow
Peripheral blood
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Attachment 10
Continued.
Variable
Haplo-identical
Matched unrelated
2007
1 ( 1)
71 (13)
2008
18 (13)
57 (10)
2009
17 (13)
100 (18)
2010
26 (19)
83 (15)
2011
26 (19)
72 (13)
2012
29 (21)
86 (16)
2013
19 (14)
84 (15)
T-cell depletion ± other
0
1 (<1)
CD34 select ± other
0
3 ( 1)
Cyclophosphamide alone
0
1 (<1)
136
2 (<1)
Tacrolimus + MMF
0
90 (16)
Tacrolimus + MTX
0
248 (45)
Tacrolimus alone
0
73 (13)
CSA + MMF
0
82 (15)
CSA + MTX
0
13 ( 2)
CSA alone
0
23 ( 4)
Other /Missing
0
17 ( 2)
26 (1-73)
33 (2-77)
Year of transplant
GVHD prophylaxis
Cyclophosphamide ± others
Median follow-up of survivors, median (range)
*4 cord blood grafts were excluded. Myeloablative was excluded (52 haplos and 509 MUD). Post HCT
Cy was selected for haplo-identical group.
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Attachment 11
Study Proposal 1411-06/1411-36/1412-13
Study Title:
Comparing Outcomes between Haploidentical and HLA Matched Related Donor Transplants for Patients
with Lymphoid Malignancies
Vanderson Rocha, MD, PhD, Oxford University Hospitals NHS Trust, Churchill Hospital,
vanderson.rocha@ouh.nhs.uk
Nilanjan Ghosh, MD, PhD, Levine Cancer Institute/Carolinas Health Care System,
Nilanjan.Ghosh@carolinashealthcare.org
Reem Karmali, MD, MS, Rush University Medical Center, reem_karmali@rush.edu
Objectives:
The primary objective is to compare the one-year overall survival (OS) for HLA-matched sibling donor
versus haploidentical hematopoietic stem cell transplantation (haploSCT) with post-transplant
cyclophosphamide in patients with lymphomas (Hodgkin and non-Hodgkin).
The secondary objective is to compare graft failure, incidence of acute and chronic graft-versus-host
disease (GVHD) relapse incidence, disease-free survival (DFS) and non-relapse mortality (NRM) for
matched sibling donor versus haploSCT with post-transplant cyclophosphamide in patients with
lymphoid malignancies. We will also identify patient, disease and transplant related factors that are
predictive of OS, NRM, PFS after haploSCT. Diseases will be stratified by disease type – Hodgkin
Lymphoma (HL) vs. non-Hodgkin Lymphoma (NHL).
Scientific Justification:
Allo SCT has been used effectively in advanced hematologic malignancies (Copelan 2006).
Conventionally, the best donor for allo SCT is a HLA matched sibling. Unfortunately, a number of
limitations exist to this approach including high transplant related mortality associated with
myeloablative preparative regimens, suboptimal disease control with reduced intensity conditioning
(RIC; Robinson 2002; Corradini 2007), and the limited availability of HLA matched donors. HaploSCT
followed by post-transplant cyclophosphamide is emerging as an approach that may have the potential
to circumvent these aforementioned limitations in lymphoid malignancies (Luznik 2008).
Though limited, data looking at the feasibility and toxicity of this approach have been encouraging:
Castagna et al reported that haploidentical SCT with RIC and post-infusion cytoxan (n=49) could achieve
reasonable projected 2-year overall and progression free survival (71 and 63% respectively) with a low
cumulative non-relapse mortality (16.3%; 95% CI: 5.9-26.8%) comparable to related and unrelated
donor transplants. Additionally, rates of acute and chronic graft versus host disease were acceptable
(25.6%; 95% CI: 12.9-38.3% and 5.2%; 95% CI: 0-12.4%, respectively) as was time to engraftment. The
same group reported improved outcomes with 3 year PFS and OS of 63% and 77% respectively, using
halpoSCT in advanced Hodgkins lymphoma (Raiola 2014). These evolving trends of improved progression
free survival and lower NRM suggest that haploSCT can be useful in the treatment of high risk
lymphomas. Nonetheless, whether outcomes after haploSCT with post-infusion cytoxan for patients
with lymphoid malignancies are comparable to other strategies are still not known.
A retrospective comparison using registry data from the Center for International Bone Marrow
Transplantation Research (CIBMTR) might be the most desirable approach to answer such a question.
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Attachment 11
This study may identify haploSCT as a feasible alternative to matched sibling allografts that provides the
advantage of superior control given greater HLA disparity. In our deeper analysis of data, we expect to
identify patient, disease and treatment related factors that predict for the greatest benefit with a
haploSCT approach to potentially justify the use of these readily available donors in subset patient
populations.
Study Population:
Patients aged ≥18 years who received their first allo-SCT after either myeloablative (MA) conditioning or
RIC from an HLA matched sibling or a haploidentical related donor (defined as > 2 antigen level
mismatches) for a diagnosis of lymphoma (HL or NHL) from 2007 to 2013, will be included. Graft source
will include marrow or PBSC donors in either group. The haploidentical related donor group will be
limited to only those who received post-transplantation cyclophosphamide. Patients who underwent T
cell depletion will be excluded from the study.
Outcomes:
 Hematopoietic recovery: time to neutrophil (ANC) recovery >0.5×109/L; time to platelet recovery
≥20×109/L.
 Acute and chronic graft-versus-host disease (GVHD): Acute GVHD is graded according to the
modified Glucksberg criteria from the Consensus Conference Classification and chronic GVHD is
assessed according to the Seattle criteria. We will collect information on incidence of Day 100 acute
GVHD (grade II-IV), and incidence of chronic GVHD at years 1 and 2
 Graft failure: Incidence of primary and secondary graft failure.
 Relapse incidence: defined as hematologic disease recurrence by the transplant center.
 Non-relapse mortality: time to death without disease relapse.
 Disease-free survival: survival without relapse. Patients are censored at time of last contact.
 Overall survival: Events are death from any cause. Surviving patients are censored at time of last
contact.
Variables to be analyzed:
Patient-related:
 Age: continuous or in groups
 Gender: male vs. female
 Karnofsky performance score: <90% vs. ≥90%
 Co-morbidity index: 0 vs. 1-2 vs. 3
 CMV status: recipient positive vs. recipient negative vs. unknown
 Ethnicity and race: Caucasian, African-American, other
Donor-related:
 Donor age: continuous or in groups
 Donor-recipient sex match: M/M, M/F, F/M, F/F, missing
 Donor-recipient CMV status match: +/+, +/-, -/+, -/-, missing
Disease-related:
 Disease subtype: NHL vs. HL (and specific histology)
 Disease status at time of transplant: CR1 or > CR2, CRu, PR, SD, PD
 Disease stage at diagnosis: I/II vs. III/IV
 Extranodal involvement (including CNS and bone marrow involvement)
Transplant-related:
 Graft source: marrow vs PBSC
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





Attachment 11
Preparative regimen: MA vs RIC
Prior autologous SCT: Yes vs. No; duration between auto SCT and allo-SCT
Number of prior therapies: 1, 2 vs ≥3
Prior radiation therapy: Yes vs. No
Interval from diagnosis to transplant: <3, 3-6, 6-12, 12-24, vs. ≥ 24 months, missing
Main effects: HaploSCT vs. matched sibling donor (including MA and RIC groups combined); RIC
haploSCT vs. RIC matched sibling donor; if numbers permit, analysis of MA haploSCT vs. MA
matched sibling donor
Study Design:
Retrospective Comparison of Outcomes for HaploSCT vs Matched Sibling Donor
Median values and ranges will be used for continuous variables and percentages for categorical
variables. For each continuous variable, the study population will be initially split into quartiles and in
two groups by the median. Patient, disease, and transplant related variables of the groups will be
compared using Chi-square or Fischer exact test for categorical variables, and Mann-Whitney test for
continuous variables. The probabilities of OS and DFS will be calculated using the Kaplan-Meier method
and log-rank test for univariate comparisons. Probabilities of relapse, NRM, acute and chronic GVHD and
engraftment will calculated using cumulative incidence curves to accommodate for competing risk
(Prentice 1978). The cumulative incidence of grade II‐IV acute GVDH and chronic GVHD (limited and
extensive) will also be determined using the competing risks method. The competing risks include
disease progression and death. Patients who do not experience GVHD or progression of disease and
alive at the last follow‐up will be censored. Associations among patient, disease, and transplant related
variables and outcomes will be evaluated using a multivariate Cox proportional hazards regression. A
stepwise selection multivariate model will be built to identify covariates that influence outcomes.
Covariates with a p<0.05 will be considered significant. Taking into account recent reports suggesting
improved outcomes with haploidentical donor allo-SCT in HL (Raiola 2014), evaluating outcomes
stratified by disease status (i.e. NHL vs HL) will be necessary.
References:
1. Copelan, E.A., Hematopoietic stem-cell transplantation. N Engl J Med, 2006. 354(17): p. 1813-26.
2. Corradini P, Dodero A, Farina L, Fanin R, Patriarca F, Miceli R et al Allogeneic SCT following
reduced-intensity conditioning can induce durable clinical and molecular remissions in relapsed
lymphomas: pre-transplant disease status and histotype heavily influence outcome. Leukemia
2007; 21: 2316–2323.
3. Castagna L, Bramanti S, Furst S, Giordano L, Crocchiolo R, Sarina B, Mauro E, Morabito L,
Bouabdallah R, Coso D, Balzarotti M, Broussais F, Cheick JE, Stella CC, Brusamolino E, Blaise D,
Santoro A. Nonmyeloablative conditioning, unmanipulated haploidentical SCT and post-infusion
CY for advanced lymphomas. Bone Marrow Transplant. 2014 Sep 15. [Epub ahead of print]
4. Luznik, L., et al., HLA-haploidentical bone marrow transplantation for hematologic malignancies
using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide.
Biol Blood Marrow Transplant, 2008. 14(6): p. 641-50.
5. Prentice, R.L., et al., The analysis of failure times in the presence of competing risks. Biometrics,
1978. 34(4): p. 541-54.
6. Raiola A, Dominietto A, Varaldo R, et al. Unmanipulated haploidentical BMT following nonmyeloablative conditioning and post-transplantation CY for advanced Hodgkin's lymphoma.
Bone Marrow Transplant. 2014 Feb;49(2):190-4.
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Attachment 11
7. Robinson SP., Goldstone AH, Mackinnon S, Carella A, Russell N, Ruiz de Elvira C et al
Chemoresistant or aggressive lymphoma predicts for a poor outcome following reducedintensity allogeneic progenitor cell transplantation: an analysis from the lymphoma working
party of the european group for blood and bone marrow transplantation. Blood 2002; 100:
4310–4316.
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Attachment 11
Characteristics of patients who underwent a RIC/NST allogeneic HCT for NHL or HD registered to the
CIBMTR from 2007-2013*
Variable
Haplo-identical
HLA-identical siblings
136
1141
39 (29)
201 (18)
58 (15-75)
55 (5-77)
0
1 (<1)
10-19
3 ( 2)
23 ( 2)
20-29
6 ( 4)
42 ( 4)
30-39
9 ( 7)
86 ( 8)
40-49
18 (13)
208 (18)
50-59
41 (30)
474 (42)
≥60
59 (43)
307 (27)
Male
86 (63)
709 (62)
Female
50 (37)
432 (38)
19 (14)
318 (28)
105 (77)
694 (61)
12 ( 9)
129 (11)
119 (88)
1068 (94)
17 (13)
73 ( 6)
132 (97)
62 ( 5)
4 ( 3)
1079 (95)
Number of patients
Research cases
Age at transplant, years
Median (range)
<10
Sex
Karnofsky score
<90%
90-100%
Missing
Disease
Non-Hodgkin
Hodgkin
Graft type
Bone marrow
Peripheral blood
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Attachment 11
Continued.
Variable
Haplo-identical
HLA-identical siblings
2007
1 ( 1)
155 (14)
2008
18 (13)
175 (15)
2009
17 (13)
184 (16)
2010
26 (19)
160 (14)
2011
26 (19)
160 (14)
2012
29 (21)
157 (14)
2013
19 (14)
150 (13)
T-cell depletion ± other
0
6 (<1)
CD34 select ± other
0
26 ( 2)
Cyclophosphamide alone
0
3 (<1)
136
21 ( 2)
Tacrolimus + MMF
0
140 (12)
Tacrolimus + MTX
0
348 (30)
Tacrolimus alone
0
104 ( 9)
CSA + MMF
0
179 (16)
CSA + MTX
0
132 (12)
CSA alone
0
120 (11)
Other /Missing
0
53 ( 5)
26 (1-73)
27 (3-77)
Year of transplant
GVHD prophylaxis
Cyclophosphamide ± others
Median follow-up of survivors, median (range)
*Myeloablative was excluded (22 haplos and 1203 HLA identical siblings). Post HCT Cy was selected for
haplo-identical group.
68