not for publication or presentation · 2014-01-14 · not for publication or presentation c....

Not for publication or presentation

A G E N D A CIBMTR WORKING COMMITTEE FOR NON-MALIGNANT MARROW DISORDERS Honolulu, Hawaii Saturday, February 19, 2011, 12:15 pm - 2:15 pm Co-Chair: Mouhab Ayas, MD, King Faisal Specialist Hospital Research Center , Saudi Arabia Telephone: 966-1-442-3934; Fax: 966-1-442-4662; E-mail: [email protected] Co-Chair: H. Joachim Deeg, MD, Fred Hutchinson Cancer Research Center, Seattle, WA

Telephone: 206-667-5985; Fax: 206-667-6124; E-mail: [email protected] Co-Chair: Shalini Shenoy, MD, St. Louis Children’s Hospital; St. Louis, MO

Telephone: 314-454-6018; Fax: 314-454-2780; E-mail: [email protected] Statisticians: Jeanette Carreras, MPH, CIBMTR Statistical Center, Milwaukee, WI

Telephone: 414-805-0681; Fax: 414-805-0714; E-mail: [email protected] Jennifer Le-Rademacher, PhD, CIBMTR Statistical Center, Milwaukee, WI

Telephone: 414-456-4849; Fax: 414-805-0714; E-mail: [email protected] Scientific Director: Mary Eapen MD, MS, CIBMTR Statistical Center, Milwaukee, WI

Telephone: 414-805-0700; Fax: 414-805-0714; E-mail: [email protected] 1. Introduction

a. Minutes of February, 2010 meeting (Attachment 1)

2. Accrual summary (Attachment 2)

3. Published/submitted papers and presentations a. AA03-02 Sabloff M, Chandy M, Wang Z, Logan BR, Ghavamzadeh A, Li C-K, Irfan SM,

Bredeson CN, Cowan MJ, Gale RP, Hale GA, Horan J, Hongeng S, Eapen M and Walters MC. HLA-matched sibling bone marrow transplantation for β-thalassemia major. Blood, 2010 (doi: 10.1182/blood-2010-09-306829).

b. AA07-01 Gupta V, Eapen M, Carreras J, Bajorunaite R, Aljurf M Gale RP, Hale GA, Hows JM, Ilhan O, Passweg J, Ringden O, Sabloff M, Schrezenmeier H, Pasquini R, Socié G, March J. Impact of age on the outcomes of transplantation in acquired aplastic anemia using matched sibling donors. Haematologica, 2010, 95(12):2119-2125.

c. AA08-02 Ruggeri A, Eapen M, Scaravadou A, Cairo MS, Bhatia M, Kurtzberg J, Wingard J, Fasth A, Nigro LL, Ayas M, Purtill D, Chaves W, Walters M, Wagner J, Gluckman E, Rocha V. Unrelated donor umbilical cord blood transplantation for sickle cell disease and thalassemia. Submitted.

d. AA07-03 Eapen M, LeRademacher J, Carreras J, Deeg HJ, Antin JH, Champlin RE, Fay J, Passweg J, Tolar J, Marsh JCW, Horowitz MM. Effect of Stem Cell Source from Unrelated Donors on Transplant Outcomes in Severe Aplastic Anemia: a Comparison of Unrelated Bone Marrow and Peripheral Blood Progenitor Cells. Oral Presentation at the American Society of Hematology in Orlando, FL December 2010.

4. Studies in progress (Attachment 3)

a. AA02-03 Allogeneic transplants with fludarabine-based conditioning regimens for PNH (J Marsh)

Data Collection

b. AA05-01 Late graft failure after HLA identical sibling SAA BMT (R Pasquini)

Manuscript Preparation

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Not for publication or presentation

c. AA07-03 Effect of stem cell source from unrelated donors on transplant outcomes in severe aplastic anemia (M Eapen)


d. AA08-01 The role of the HLA DRB1 antigen DR15 in patients with severe aplastic anemia (SAA) undergoing HLA-matched BMT (M Battiwalla)


e. AA09-01 Outcome of allogeneic stem cell transplantation in patients with Fanconi anemia who present with myelodysplasia, clonal abnormalities and/or leukemia (M Ayas) (Attachment 4)

Data File Preparation

f. AA09-02 Outcomes of hematopoietic stem cell transplantation in patients with Dyskeratosis Congenita (S Gadalla)

Data Collection

g. AA10-01 Outcome of second allogeneic stem cell transplantation in patients with Fanconi Anemia (M Ayas)

Protocol Development

h. AA10-02 Outcomes after allogeneic stem cell transplantation for patients who developed AML/MDS after immunosuppressive therapy for severe aplastic anemia (H Joachim Deeg)

Data Collection

5. Future/ Proposed studies

a. PROP 1010-02 Outcomes after primary treatment with matched sibling donor transplantation and immunosuppressive therapy for patients >40 years with severe aplastic anemia: A joint study from European Bone Marrow Transplant aplastic anemia working party and Center for International Blood and Marrow Transplant Research (V Gupta) (Attachment 5)

b. PROP 1210-16 Durable engraftment and correction of hematological defects in children and congenital amegakaryocytic thrombocytopenia following myeloablative umbilical cord blood transplantation (KM Mahadeo) (Attachment 6)

6. Other business

a. Study priority allocation

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Not for publication or presentation Attachment 1

MINUTES CIBMTR WORKING COMMITTEE FOR NON-MALIGNANT MARROW DISORDERS Orlando, Florida Friday, February 26, 2010, 12:15 pm - 2:15 pm Co-Chair: Mark Walters, MD, Children's Hospital of Oakland Telephone: 510-428-3374; Fax: 510-601-3916; E-mail: [email protected] Co-Chair: Mouhab Ayas, MD, King Faisal Specialist Hospital Research Center Telephone: 966-1-442-3934; Fax: 966-1-442-4662; E-mail: [email protected] Co-Chair: H. Joachim Deeg, MD; Fred Hutchinson Cancer Research Center;

Telephone: 206-667-5985; Fax: 206-667-6124; E-mail: [email protected] Statisticians: Jeanette Carreras, MPH, CIBMTR Statistical Center

Telephone: 414-805-0681; Fax: 414-805-0714; E-mail: [email protected] Jennifer Le-Rademacher, PhD, CIBMTR Statistical Center Telephone: 414-456-4849; Fax: 414-805-0714; E-mail: [email protected]

Scientific Director: Mary Eapen MD, MS, CIBMTR Statistical Center Telephone: 414-805-0700; Fax: 414-805-0714; E-mail: [email protected]

1. Introduction

The CIBMTR Working Committee for Non-Malignant Marrow Disorders met on Friday, February 26, 2010 at 12:20 pm. Dr Mark Walters welcomed everyone and introduced Dr Shalini Shenoy the new Chair for the committee. Dr Shenoy replaces Dr Walters. The minutes of the February 2009 meeting were approved.

2. Presentations, published or submitted papers Working Committee activity for 2009 shown below.

a. AA03-01 Horan J, Carreras J, Tarima S, Camitta BM, Gale RP, Hale GA, Hinterberger W, Marsh J, Passweg JR, Walters MC, Mary Eapen M. Risk factors affecting outcome of second HLA-matched sibling donor transplantation for graft failure in severe acquired aplastic anemia. Biol Blood Marrow Transplant 15:626-631, 2009.

b. AA07-01 Gupta V, Eapen M, Carreras J, Bajorunaite R, Aljurf M Gale RP, Hale GA, Hows JM, Ilhan O, Passweg J, Ringden O, Sabloff M, Schrezenmeier H, Pasquini R, Socié G, March J. Impact of age on the outcomes of transplantation in acquired aplastic anemia using matched sibling donors. Submitted.

c. AA03-02 Sabloff M, Chandy M, Wang Z, Logan B, Li CK, Ifran SM, Eapen M, Walters M. Bone marrow transplantation from HLA-identical sibling for thalassemia. Presentation at the American Society of Hematology in New Orleans, LA, December 2009.

d. AA08-01 Minoo Battiwalla, Tao Wang, Jeanette Carreras, H. Joachim Deeg, Mouhab Ayas, Rajinder P.S. Bajwa, Biju George, Vikas Gupta, Ricardo Pasquini, Hubert Schrezenmeier, Kirk R. Schultz and Mary Eapen. The presence of HLA DR15 antigen in patients with severe aplastic anemia does not impact engraftment and survival after HLA-identical sibling transplantation. Presentation at the American Society of Hematology in New Orleans, LA, December 2009.

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3. Studies in progress a. AA02-03 Allogeneic transplants with fludarabine-based conditioning regimens for PNH (J

Marsh) Current status: data collection. The CIBMTR database has sixteen patients with PN who received reduced intensity conditioning. The EBMT has 37 patients who received reduced intensity conditioning. The Fred Hutchinson Cancer Center will also contribute their cases. Plan: complete data collection and prepare study file/analysis.

b. AA03-02 Bone marrow transplantation from HLA-identical sibling for thalassemia (M Sabloff) Current status: manuscript preparation. One hundred seventy nine patients aged ≤20 years received BM grafts from a HLA-matched sibling and myeloablative transplant conditioning regimen between 1995 and 2001 at 19 centers worldwide. The distribution of Lucarelli risk class I, II and III categories was 2%, 42%; and 36%, respectively. 52% of patients had hepatomegaly patients and 94%, inadequate iron chelation therapy. In multivariate analysis older age at BMT (≥10 years), RR 2.16, p=0.025) and hepatomegaly (>2 cm below right costal margin), RR 5.57, p<0.001) were associated with higher risks of overall mortality. The Lucarelli score did not predict transplant-outcome in this series. Suggested by some that manuscript should focus on the simple predictors (age and hepatomegaly) and the multi-center nature of this report.

c. AA05-01 Late graft failure after HLA identical sibling SAA BMT (R Pasquini). Current status: manuscript preparation.

d. AA07-03 Chronic GVHD and overall survival after unrelated donor hematopoietic stem cell transplants for SAA: comparison of outcomes after peripheral blood and bone marrow grafts (M Eapen). Current status: protocol development. The primary objective of this study is to compare overall survival after transplantation of BM and PBPC. 186 BM recipients 63 PBPC recipients are eligible; transplants between 2000 and 2007. In general older recipients received PBPC. Therefore, PBPC recipients were matched to BM recipients for age. Suggestions include: considering CD34 dose. We will need to check to make sure CD34 doses are available for both BM and PBPC grafts. to the details of conditioning regimens will be described and if possible, test in multivariate analysis. Infections including EBV reactivation should be considered (descriptive only). Check with NMDP whether time from search to graft procurement varies by graft source.

e. AA08-01 The role of the HLA DRB1 antigen DR15 in patients with severe aplastic anemia (SAA) undergoing HLA-matched BMT (M Battiwalla). Current status: manuscript preparation. 1422 patients with SAA (30% of 1422 were DR15+) who received HLA-identical sibling BM (85%) or PBPC (15%). Transplants between 1990 and 2006. The study was confined to matched sibling donor transplants to eliminate any differences that may occur from HLA-disparity. The presence or absence of DR15+ did not affect transplant-outcomes.

f. AA08-02 Unrelated donor umbilical cord blood transplantation for sickle cell disease and thalassemia (V Rocha). Current status: manuscript preparation. This study describes children with sickle cell disease and thalassemia who received single CB units between 1996 and 2009. The median age at transplant was 4 years for thalassemia and 6 years for sickle cell disease. 40 patients received myeloablative conditioning regimen and 10, reduced-intensity. Only 20 patients achieved full donor chimerism, 4 mixed chimerism and 24

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had autologous recovery. Infection was the primary cause of death. Multivariate analysis was not performed given the small sample size.

g. AA09-01 Outcome of allogeneic stem cell transplantation in patients with Fanconi anemia who present with myelodysplasia, clonal abnormalities and/or leukemia (M Ayas). Current study status: protocol development.

h. AA09-02 Outcomes of hematopoietic stem cell transplantation in patients with Dyskeratosis Congenita (S Gadalla). Current study status: data collection.

This is a descriptive report: early (≤100 days) and long term mortality will be described. In addition, long-term complications pulmonary, hepatic and other gastrointestinal complications will be described. There are 9 cases reported to the CIBMTR. We have had discussions with the EBMT and yet to receive a commitment to proceed with a joint study. There is an on-going study in the Netherlands and one in Switzerland. The CIBMTR does not have all US cases. Dr. Gadalla knows of 12 cases managed at the NIH. She had been requested to contact physicians (referring or transplant centers) for these patients to seek their interest in joining the CIBMTR study. The CIBMTR will contact Dr. Woolfry at the Fred Hutchinson Cancer Center for their cases.

5. Future/ Proposed studies

a. PROP 0609-06 Outcome of second allogeneic stem cell transplantation in patients with Fanconi Anemia (M Ayas). The primary aim of this study is to describe the outcome of second allogeneic SCT for Fanconi anemia. 30 patients were identified in the database and received a second for graft failure. Only US cases were included as the EBMT has a similar project.

b. PROP 1209-51 Outcomes after allogeneic stem cell transplantation for patients who developed AML/MDS after immunosuppressive therapy for severe aplastic anemia (H Joachim Deeg). There are 24 patients with AML and 82 with MDS. A supplemental data collection form has to be developed to obtain information on number of cycles of IST, response, date of diagnosis for SAA and response to IST and cytogenetics at diagnosis of SAA. Dr Judith Marsh will discuss with the EBMT as this has never been looked at before.

6. Other business None.

Both proposals were approved Meeting adjourned at 2:15 PM.

Allocation of statistical hours for the new proposals:

Proposal # PI Anticipated status

by 06-30-2011 0609-06 M Ayas Study file 1209-51 H Joachim Deeg Data collection

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Accrual Summary for Non-Malignant Marrow Disorders Working Committee

Characteristics of recipients of allogeneic BMT for aplastic anemia and thalassemia reported to the CIBMTR

between 1990 and 2010. Severe Aplastic Anemia Thalassemia Characteristics: Registration only Research Registration only ResearchNumber of patients 3771 4228 1076 1549Number of centers 381 350 128 108Age at transplant, years 20 (<1-77) 19 (<1-82) 7 (<1-59) 8 (<1-38)Sex

Male 2214 (59) 2452 (58) 585 (54) 840 (54)Female 1552 (41) 1776 (42) 490 (46) 708 (46)Missing 5 (<1) 0 1 (<1) 1 (<1)

Donor type HLA-identical siblings 2899 (77) 2719 (64) 908 (84) 1398 (90)Twins 46 ( 1) 52 ( 1) 0 0Other relative 212 ( 6) 203 ( 5) 92 ( 9) 82 ( 5)Unrelated 614 (16) 1254 (30) 71 ( 7) 67 ( 4)

Not specified 0 0 5 (<1) 2 (<1)Graft type

Bone marrow 2545 (67) 3352 (79) 725 (67) 1242 (80)Peripheral blood 1046 (28) 738 (17) 266 (25) 229 (15)Cord blood 80 ( 2) 134 ( 3) 73 ( 7) 78 ( 5)Missing 100 ( 3) 4 (<1) 12 ( 1) 0

Year of transplant 1990-1991 132 ( 4) 370 ( 9) 16 ( 1) 201 (13)1992-1993 239 ( 6) 417 (10) 37 ( 3) 240 (15)1994-1995 253 ( 7) 461 (11) 53 ( 5) 225 (15)1996-1997 329 ( 9) 476 (11) 73 ( 7) 147 ( 9)1998-1999 372 (10) 409 (10) 64 ( 6) 152 (10)2000-2001 388 (10) 395 ( 9) 91 ( 8) 176 (11)2002-2003 499 (13) 363 ( 9) 171 (16) 120 ( 8)2004-2005 432 (11) 479 (11) 148 (14) 77 ( 5)2006-2007 485 (13) 369 ( 9) 181 (17) 62 ( 4)2008-2009 326 ( 9) 475 (11) 122 (11) 143 ( 9)2010* 316 ( 8) 14 (<1) 120 (11) 6 (<1)

* Cases continue to be reported in this interval

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Characteristics of recipients of allogeneic BMT for fanconi anemia and PNH tumor cancer reported to the CIBMTR between 1990 and 2010.

Fanconi Anemia PNH Characteristics: Registration only Research Registration only ResearchNumber of patients 560 910 108 298Number of centers 146 126 71 130Age at transplant, years 9 (<1-53) 10 (1-49) 29 (9-57) 29 (3-72)Sex

Male 293 (52) 476 (52) 56 (52) 163 (55)Female 237 (42) 434 (48) 52 (48) 135 (45)Missing 30 ( 5) 0 0 0

Donor type HLA-identical siblings 256 (46) 418 (46) 73 (68) 176 (59)Twins 0 0 0 0Other relative 75 (13) 88 (10) 5 ( 5) 12 ( 4)Unrelated 229 (41) 404 (44) 29 (27) 104 (35)

Not specified 0 0 1 ( 1) 6 ( 2)Graft type

Bone marrow 352 (63) 651 (72) 55 (51) 183 (61)Peripheral blood 102 (18) 124 (14) 48 (44) 99 (33)Cord blood 97 (17) 132 (15) 3 ( 3) 14 ( 5)Missing 9 ( 2) 3 (<1) 2 ( 2) 2 ( 1)

Year of transplant 1990-1991 19 ( 3) 67 ( 7) 1 ( 1) 13 ( 4)1992-1993 19 ( 3) 84 ( 9) 5 ( 5) 12 ( 4)1994-1995 33 ( 6) 76 ( 8) 7 ( 6) 25 ( 8)1996-1997 48 ( 9) 100 (11) 7 ( 6) 23 ( 8)1998-1999 53 ( 9) 80 ( 9) 10 ( 9) 25 ( 8)2000-2001 59 (11) 101 (11) 11 (10) 39 (13)2002-2003 79 (14) 110 (12) 11 (10) 45 (15)2004-2005 57 (10) 112 (12) 11 (10) 53 (18)2006-2007 76 (14) 75 ( 8) 3 ( 3) 35 (12)2008-2009 65 (12) 99 (11) 23 (21) 28 ( 9)2010* 52 ( 9) 6 ( 1) 19 (18) 0


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Characteristics of recipients of allogeneic BMT for diamond-blackfan anemia and sickle cell anemia reported to the CIBMTR between 1990 and 2010.

Diamond-Blackfan Anemia

Sickle Cell Anemia

Characteristics: Registration only Research Registration only ResearchNumber of patients 99 132 301 279Number of centers 68 72 86 80Age at transplant, years 7 (1-37) 7 (<1-44) 10 (<1-54) 10 (<1-31)Sex

Male 51 (52) 63 (48) 166 (55) 154 (55)Female 48 (48) 69 (52) 134 (45) 125 (45)Missing 0 0 1 (<1) 0

Donor type HLA-identical siblings 78 (79) 71 (54) 245 (81) 213 (76)Twins 0 0 0 0Other relative 3 ( 3) 11 ( 8) 34 (11) 13 ( 5)Unrelated 18 (18) 50 (38) 22 ( 7) 53 (19)

Not specified 0 0 0 0Graft type

Bone marrow 71 (72) 91 (69) 227 (75) 204 (73)Peripheral blood 21 (21) 17 (13) 42 (14) 26 ( 9)Cord blood 6 ( 6) 24 (18) 32 (11) 48 (17)Missing 1 ( 1) 0 0 1 (<1)

Year of transplant 1990-1991 1 ( 1) 9 ( 7) 1 (<1) 8 ( 3)1992-1993 3 ( 3) 5 ( 4) 1 (<1) 10 ( 4)1994-1995 7 ( 7) 14 (11) 9 ( 3) 14 ( 5)1996-1997 5 ( 5) 12 ( 9) 15 ( 5) 23 ( 8)1998-1999 7 ( 7) 17 (13) 14 ( 5) 27 (10)2000-2001 10 (10) 10 ( 8) 34 (11) 37 (13)2002-2003 9 ( 9) 17 (13) 46 (15) 20 ( 7)2004-2005 13 (13) 19 (14) 36 (12) 27 (10)2006-2007 18 (18) 11 ( 8) 36 (12) 32 (11)2008-2009 12 (12) 16 (12) 56 (19) 74 (27)2010* 14 (14) 2 ( 2) 53 (18) 7 ( 3)


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TO: Non-malignant Marrow Disorders Working Committee Members FROM: Mary Eapen, MD, MS, Scientific Director for Non-Malignant Marrow Disorders

Working Committee RE: Studies in Progress Summary AA02-03 Allogeneic transplants with fludarabine-based conditioning regimens for PNH (J Marsh). The CIBMTR database has sixteen patients with PNH who received reduced intensity conditioning. The EBMT has 37 patients who received reduced intensity conditioning. The Fred Hutchinson Cancer Center will also contribute their cases. Plan: complete data collection and prepare study file/analysis by July 2011. AA05-01 Late graft failure after HLA identical sibling SAA BMT (R Pasquini). Late graft failure after HLA-matched sibling transplantation is a significant problem in South America. To overcome this, the transplant team at Curitiba developed a regimen with busulfan and cyclophosphamide in patients who received >15 red blood cell transfusions prior to BMT. The study compared two conditioning regimens (Cy and Bu + Cy) and red blood transfusions (≤15 vs. >15). All patients in the Bu + Cy group received >15 red blood cell transfusion whereas only 48 in the Cy group received >15 transfusions. Patients who received >15 red blood cell transfusions and Bu+Cy regimen experienced the lower rates of graft failure compared to those to received Cy and >15 transfusions. In all treatment groups, failure rates were lower in patients who received cyclosporine for longer than a year after transplantation. A manuscript is underway and it is expected to be submitted before July 2011. AA07-03 Chronic GVHD and overall survival after unrelated donor hematopoietic stem cell transplants for SAA: comparison of outcomes after peripheral blood and bone marrow grafts (M Eapen). The primary objective of this study is to to evaluate the effect of stem cell source on transplant outcomes for SAA. In recent years, PBPC instead of bone marrow are increasingly used and PBPC grafts now account for 25% of unrelated donor HCT for SAA. 249 patients transplanted from 2000-2007 received either BM (n=186) or PBPC (n=63) from unrelated adult donors matched at HLA-A, -B, -C, -DRB1. Median follow up was 3 years. In multivariate analysis, the risk of mortality was higher after PBPC than after BM (HR 1.79, p=0.02). The 3-year probability of overall survival adjusted for performance score and transplant conditioning regimen was 76% for BM and 60% for PBPC recipients (p=0.02). These data suggest that: (1) outcomes after URD HCT for SAA are now similar to outcomes observed in MRD HCT, (2) BM is the preferred graft source when considering unrelated donor HCT in patients with SAA and (3) the data also support low-dose total body irradiation in the preparative regimen for transplant conditioning. This study was an oral pesentation at the American Society of Hematology in Orlando, FL December 2010 and manuscript is underway. AA08-01 The role of the HLA DRB1 antigen DR15 in patients with severe aplastic anemia (SAA) undergoing HLA-matched BMT (M Battiwalla). 1422 patients with SAA (30% of 1422 were DR15+) who received HLA-identical sibling BM (85%) or PBPC (15%). Transplants between 1990 and 2006. The study was confined to matched sibling donor transplants to eliminate any differences that may occur from HLA-disparity. The presence or absence of DR15+ did not affect transplant-outcomes. A manuscript is underway and it is expected to be submitted before July 2011.

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AA09-01 Outcome of allogeneic stem cell transplantation in patients with Fanconi anemia who present with myelodysplasia, clonal abnormalities and/or leukemia (M Ayas). The primary aim of this study is to determine the impact of the presence of myelodysplasia, any clonal abnormality and/or acute myeloid leukemia in Fanconi anemia patients and their response to allogeneic stem cell transplantation (SCT). The secondary aim is to evaluate the effect of different conditioning regimens on the overall outcome of these patients (namely, regimens with or without radiation). Twenty-seven had MDS, 4 leukemia and 136 patients abnormal clone. A protocol was circulated to the Working Committee members for comments.

AA09-02 Outcomes of hematopoietic stem cell transplantation in patients with Dyskeratosis Congenita (S Gadalla). This is a descriptive report: early (≤100 days) and long term mortality will be described. In addition, long-term complications pulmonary, hepatic and other gastrointestinal complications will be described. There are 9 cases reported to the CIBMTR. We have had discussions with the EBMT and yet to receive a commitment to proceed with a joint study. Dr. Gadalla knows of 12 cases managed at the NIH. She had been requested to contact physicians (referring or transplant centers) for these patients to seek their interest in joining the CIBMTR study. Data is being collected and forms reviewed for disease verification. A draft protocol will be available by July 2011.

AA10-01 Outcome of second allogeneic stem cell transplantation in patients with Fanconi Anemia (M Ayas). The primary aim of this study is to describe the outcome of second allogeneic SCT for Fanconi anemia. 30 patients were identified in the database and received a second for graft failure. Only US cases were included as the EBMT has a similar project. A draft protocol will be available by July 2011.

AA10-02 Outcomes after allogeneic stem cell transplantation for patients who developed AML/MDS after immunosuppressive therapy for severe aplastic anemia (H Joachim Deeg). There are 24 patients with AML and 82 with MDS. A supplemental data collection form has to be developed to obtain information on number of cycles of IST, response, date of diagnosis for SAA and response to IST and cytogenetics at diagnosis of SAA. Dr Judith Marsh will discuss with the EBMT as this has never been looked at before.

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CIBMTR AA09-01

OUTCOMES OF FANCONI ANEMIA PATIENTS WITH CLONAL TRANSFORMATION PRIOR TO UNDERGOING ALLOGENEIC STEM CELL TRANSPLANTATION

Study Chair: Mouhab Ayas, MD King Faisal Specialist Hospital Research Center MBC #53 Riyadh, 11211 Saudi Arabia Telephone: 966-1-442-3934 Fax: 966-1-442-4662 Email: [email protected] Study Statisticians: Wael Saber, MD, MS Assistant Scientific Director CIBMTR Medical College of Wisconsin 9200 W. Wisconsin Ave, Suite C5500 Milwaukee, WI 53226 USA Telephone: 414-805-0700 Email: [email protected] Jennifer Le-Rademacher, PhD CIBMTR Medical College of Wisconsin 8701 Watertown Plank Road Milwaukee, WI 53226 USA Telephone: 414-955-4849 Fax: 414-955-6513 Email: [email protected] Scientific Director: Mary Eapen, MBBS MS CIBMTR 9200 West Wisconsin Ave, Suite C5500 Milwaukee, WI 53226 USA Telephone: 414-805-0700 Fax: 414-805-0714 Email: [email protected]

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Working Committee Chairs: Shalini Shenoy, MD St. Louis Children's Hospital One Children's Place St. Louis, MO 63110 USA Telephone: 314-454-6018 Fax: 314-454-2780 Email: [email protected] Mouhab Ayas, MD King Faisal Specialist Hospital Research Center MBC #53 Riyadh, 11211 Saudi Arabia Telephone: 966-1-442-3934 Fax: 966-1-442-4662 Email: [email protected] Joachim Deeg, MD Fred Hutchinson Cancer Research Center 1100 Fairview Ave. N. P.O. Box 19024 Seattle, WA 98109-1024 USA Telephone: 206-667-5985 Fax: 206-667-6124 Email: [email protected]

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1.0 OBJECTIVES: 1.1 To determine the impact of the presence of myelodysplasia, clonal abnormalities and/or

leukemia in patients with Fanconi anemia prior to allogeneic stem cell transplantation on overall survival post allogeneic SCT.

1.2 To evaluate the incidence of acute and chronic GHVD in these patients.

2.0 SCIENTIFIC JUSTIFICATION:

Allogeneic SCT is curative for patients with FA, and excellent disease free survival rates have been documented in several studies 1-5. However, FA patients with myelodysplasia or clonal abnormality on presentation are a distinct group that probably requires more intensive conditioning prior to SCT as the presence of either may herald the development of AML and is hence a marker for adverse outcome 6,7. This has been recognized in the early publications addressing transplant in FA patients; in a cohort of 17 patients reported by Flowers et al. in 1992, five had evidence of leukemic transformation before SCT; four of them were conditioned with CY 120 mg/kg plus 12 GY fractionated TBI, and one received busulfan 14 mg/kg and CY 100 mg/kg; four died of transplant related mortality and one was reported alive with no evidence of disease, 8 years post SCT8. When the underlying genetic defect in FA patients was clarified, lower doses of chemotherapy and radiation for conditioning were employed in order to avoid severe toxicity9,10. Patients with evidence of myelodysplasia or leukemia however continued to receive more intensive conditioning in preparation for SCT; in the latest update of their experience, Socié et al. reported 5 patients with FA and myelodysplasia on presentation who were prepared with thoraco-abdominal irradiation (TAI) plus CY 40 mg/kg instead of the 20 mg/kg routinely used for FA patients with no myelodysplasia; the authors reported an 8 year survival of 75% 2. Increasing the dose of CY to 60 or 80 mg/kg has permitted the transplanters to eliminate radiation from the preparatory regimens for FA patients, but attempts to apply the non-radiation regimens in patients with myelodysplasia or clonal abnormalities have not been successful; Zanis-Neto et al used only CY 60-80 mg/kg to condition their FA patients; but the two patients with cytogenetic abnormalities on presentation experienced delayed graft failure after the SCT with this regimen; one of them was salvaged with a second SCT 5. Recently, Fludarabine has been increasingly incorporated in the conditioning of patients with FA 11-14. Tan et al reported their experience using fludarabine with cytoxan and ATG; of the eleven transplanted patients, the one who presented with myelodysplasia and cytogenetic abnormalities relapsed 5 months after the transplant, and died from his disease about 48 months later despite a second SCT13. Bitan et al, on the other hand, reported more encouraging results with the use of fludarabine plus cytoxan and/or busulfan in addition to ATG in the preparation, one of their patients had myelodysplasia and two had frank leukemia pre-SCT; two of the 3 patients engrafted, and one had graft rejection but was rescued with a second SCT using fludarabine, busulfan and alemtuzumab; all three were reported alive and disease-free at the time of the report 14. Even more uncertainties surround the management of patients presenting with frank acute myeloid leukemia, since patients with AML generally have a much better prognosis if they were in remission before SCT and FA patients are usually believed to have low tolerance to induction chemotherapy although recently Mehta et al demonstrated that FA patients can tolerate chemotherapy with clearance of disease15; allogeneic SCT remains nevertheless the only decisive therapy for these patients.

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In Saudi Arabia, we (Ayas et al) recently reported our resulted in 11 patients using a CY/TBI regimen, this regimen appeared to be associated with tolerable toxicity. And at the time of the publication, ten out of eleven transplanted patients were alive, well and free of disease with a median follow up of almost 4 years16. As noted above, most of the reported results on this subject are on small numbers of patients, and the largest number is probably the one reported from our institution, this proposal therefore intends to determine -on a larger scale- if the overall survival for FA patients presenting with myelodysplasia, clonality and/or leukemia are different than those reported for FA patients who were transplanted just for marrow aplasia.

3.0 STUDY POPULATION:

The study population will include all patients entered in the CIBMTR database as having a diagnosis of Fanconi anemia with evidence of myelodysplasia, abnormal clones and/or leukemia on bone marrow examination prior to allogeneic SCT. Bone marrow, peripheral blood and cord blood grafts will be included. Related and unrelated donors will be included. Inclusions: 1. All patients with FA with myelodysplasia, abnormal clones and/or leukemia entered in the

CIBMTR database between 1985-2007 2. First allogeneic transplants:

a. Matched and mismatched related stem cell transplant b. Matched and mismatched unrelated stem cell transplant c. Matched and mismatched unrelated cord blood transplant

Exclusions: 1. FA patients who underwent allo SCT without evidence of myelodysplasia, abnormal clones

and/or leukemia prior to SCT. 2. Any SCT beyond the first SCT

4.0 OUTCOMES:

4.1 Overall survival: Time to death. Patients who are alive are censored at last follow-up.

4.2 Incidence of acute and chronic GVHD: Occurrence of grade II-IV and III-IV skin, gastrointestinal or liver abnormalities fulfilling the Consensus criteria of acute GVHD and limited and extensive chronic GVHD.

4.3 Secondary graft failure at 2 years: Sustained loss of neutrophil counts <0.5x109/L after

initial neutrophil recovery.

4.4 Hematopoietic recovery: Time to neutrophil recovery (ANC ≥500/μl for 3 days). Time to platelet recovery (≥20,000/ μl without transfusion for 7 days).

5.0 VARIABLES TO BE DESCRIBED:

Patient related - Age at transplant - Gender - Karnofsky performance status (≥ 90 vs. < 90)

14


Disease related - Status of clonal disease/leukemia immediately pre-transplant - Androgen therapy prior to transplant - Corticosteroids therapy prior to transplant - Growth factors therapy prior to transplant

Transplant related

- Use of ATG - Donor stem cell source - Degree of match - Type of GVHD prophylaxis - Chimerism at different intervals post transplant - Year of transplant - Time from diagnosis to transplantation - Donor-Recipient CMV status

6.0 STUDY DESIGN:

This proposed study is a retrospective analysis to determine the outcomes of allogeneic stem cell transplant in a special group of patients with Fanconi anemia who present with myelodysplasia, clonal abnormalities and/or leukemia.. Descriptive tables of patient-, disease-, and transplant-related factors will be prepared. These tables will list median and range for continuous variables and percent of total for categorical variables. The product-limit estimator proposed by Kaplan-Meier will be used to estimate the median and range of the follow-up time. The probability of overall survival will be calculated using the Kaplan-Meier estimator, with the variance estimated by Greenwood’s formula. Engraftment incidence, as well as the incidence of acute and chronic GVHD will be estimated using cumulative incidence estimates to accommodate for competing risks. Due to the small sample size, assessment of potential prognostic factors for the outcomes of interest will not be evaluated in multivariate analysis.

7.0 REFERENCES:

1. Farzin A, Davies SM, Smith FO, et al. Matched sibling donor haematopoietic stem cell transplantation in Fanconi anaemia: an update of the Cincinnati Children’s experience Br J Haematol. 2007; 136, 633–640.

2. Socié G, Devergie A, Girinski T, Piel G, Ribaud P, Esperou H et al. Transplantation for Fanconi's anaemia: long-term follow-up of fifty patients transplanted from a sibling donor after low-dose cyclophosphamide and thoraco-abdominal irradiation for conditioning. Br J Haematol 1998; 103: 249–255.

3. Ayas M, Solh H, Mustafa M.M, Al-Mahr M, Al-Fawaz I, Al-Jefri A et al. Bone marrow transplantation from matched siblings in patients with fanconi anemia utilizing low-dose cyclophosphamide, thoracoabdominal radiation and antithymocyte globulin. Bone Marrow Transplant 2001; 27: 139–143.

4. Ayas M, Al-Jefri A, Al-Mahr M, Rifai S, Al-Seraihi A, Tbakhi A et al. Stem cell transplantation for patients with Fanconi anemia with low-dose cyclophosphamide and antithymocyte globulins without the use of radiation therapy. Bone Marrow Transplant 2005; 35: 463–466.

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5. Zanis-Neto J, Flowers M.E, Medeiros C.R, Bitencourt M.A, Bonfim C.M, Setúbal D.C et al. Low-dose cyclophosphamide conditioning for haematopoietic cell transplantation from HLA-matched related donors in patients with Fanconi anaemia. Br J Haematol 2005; 130:99-106.

6. Alter B.P, Caruso J.P, Drachtman R.A, Uchida T, Velagaleti G.V, Elghetany M.T. Fanconi anemia. Myelodysplasia as a predictor of outcome. Cancer Genet Cytogenet 2000; 117: 125– 131.

7. Tischkowitz M, Dokal I. Fanconi anaemia and leukaemia - clinical and molecular aspects. Br J Haematol 2004; 126: 176-191.

8. Flowers M, Doney K.C, Storb R, Deeg H.J, Sanders J.E, Sullivan K.M et al. Marrow transplantation for Fanconi anemia with or without leukemic transformation: an update of the Seattle experience. Bone Marrow Transplant 1992; 9: 167–173.

9. Berger R, Bernheim A, Gluckman E, Gisselbrecht C. In vitro effect of cyclophosphamide metabolites on chromosomes of Fanconi anaemia patients. Br J Haematol 1980; 45: 565-568.

10. Gluckman E, Devergie A, Dutreix J. Radiosensitivity in Fanconi anaemia: application to the conditioning regimen for bone marrow transplantation. Br J Haematol 1983; 54: 431-440

11. De La Fuente J, Reiss S, McCloy M, Vulliamy T, Roberts I.A.G, Rahemtulla A. et al. Non-TBI stem cell transplantation protocol for Fanconi anaemia using HLA-compatible sibling and unrelated donors. Bone Marrow Transplant 2003; 32: 653-656.

12. George B, Mathews V, Shaji R.V, Srivastava V, Srivastava A, Chandy M. Fludarabine-based conditioning for allogeneic stem cell transplantation for multiply transfused patients with Fanconi's anemia. Bone Marrow Transplant 2005; 35: 341-343.

13. Tan P.L, Wagner J.E, Auerbach A.D, DeFor T.E, Slungaard A, MacMillan M.L Successful engraftment without radiation after fludarabine-based regimen in Fanconi anemia patients undergoing genotypically identical donor hematopoietic cell transplantation. Pediatric Blood and Cancer 2006; 46: 630-636.

14. Bitan M, Or R, Shapira M.Y, Aker M, Resnick I.B, Ackerstein A. et al. Fludarabine-based reduced intensity conditioning for stem cell transplantation of Fanconi anemia patients from fully matched related and unrelated donors. Biol Blood Marrow Transplant 2006; 12: 712-718.

15. Mehta P.A, Ileri T, Harris R.E, Williams D.A, Mo J, Smolarek T et al. Chemotherapy for myeloid malignancy in children with Fanconi anemia. Pediatr Blood Cancer 2007; 48: 668-672.

16. M. Ayas, A. Al-Jefri, A. Al-Seraihi, M. Al-Mahr, S. Rifai, A. Al-Ahmari, et al. Allogeneic stem cell transplantation in Fanconi anemia patients presenting with myelodysplasia and/or clonal abnormality: update on the Saudi experience. Bone Marrow Transplant 2008; 41 261-265.

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Table 1. Characteristics of 189 patients who underwent allogeneic transplantation for Fanconi Anemia with clonal transformation prior to allogeneic SCT, from 1985-2007.

Variable Related Unrelated Umbilical

cords Patient-related: Number of patients 137 22 30Number of centers 54 10 13Age at transplant, median (range), years 13 (1-57) 12 (5-31) 8 (3-19)Age at transplant, years

<=10 55 (40) 9 (41) 21 (70)11-20 59 (43) 7 (32) 9 (30)21-30 13 ( 9) 6 (27) 031-40 8 ( 6) 0 041-50 1 ( 1) 0 0>51 1 ( 1) 0 0

Sex Male 73 (53) 10 (45) 11 (37)Female 64 (47) 12 (55) 19 (63)

Karnofsky score prior to transplant <90 39 (28) 6 (27) 13 (43)>=90 97 (71) 15 (68) 16 (53)missing 1 ( 1) 1 ( 5) 1 ( 3)

Disease-related: Type of clonal disease prior to transplant

MDS 34 (25) 6 (27) 5 (17)AML± 8 ( 6) 3 (14) 1 ( 3)ALL║ 2 ( 1) 0 0Abnormal cytogenetics 93 (68) 13 (59) 24 (80)

Androgens therapy between diagnosis and transplant no 73 (53) 8 (36) 13 (43)yes 42 (31) 7 (32) 13 (43)missing 22 (16) 7 (32) 4 (13)

Corticosteroids therapy between diagnosis and transplant no 78 (57) 11 (50) 17 (5)7yes 35 (26) 4 (18) 8 (27)missing 24 (18) 7 (32) 5 (17)

Growth factors use between diagnosis and transplant no 72 (53) 13 (59) 17 (57)yes 8 ( 6) 2 ( 9) 8 (27)missing 57 (42) 7 (32) 5 (17)

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Table 1. Continued.


cords Transplant-related: Time from diagnosis to transplant, median (range), months 21 (<1-215) 26 (1-271) 31 (2-160)

missing† 0 4 0Donor age, median (range), years 16 (<1-76) 33 (21-53) 3 (<1-7)Donor age, years

< 11 42 (31) 0 24 (80)11-20 38 (28) 0 021-30 25 (18) 6 (27) 031-40 19 (14) 9 (41) 041-50 2 ( 1) 5 (23) 051-60 5 ( 4) 1 ( 5) 0missing 6 ( 4) 1 (5) 6 (20)

Year of transplant (grouped) 1985-1987 10 ( 7) 0 01988-1990 12 ( 9) 0 2 ( 7)1991-1993 17 (12) 2 ( 9) 01994-1996 26 (19) 2 ( 9) 2 ( 7)1997-1999 13 ( 9) 4 (18) 3 (10)2000-2002 30 (22) 7 (32) 7 (23)2003-2005 18 (13) 6 (27) 9 (30)2006-2007 11 ( 8) 1 ( 5) 7 (23)

Year of transplant 1985 1 ( 1) 0 01986 2 ( 1) 0 01987 7 ( 5) 0 01988 3 ( 2) 0 01989 3 ( 2) 0 01990 6 ( 4) 0 2 ( 7)1991 6 ( 4) 0 01992 7 ( 5) 0 01993 4 ( 3) 2 ( 9) 01994 5 ( 4) 1 ( 5) 1 ( 3)1995 11 ( 8) 0 01996 10 ( 7) 1 ( 5) 1 ( 3)1997 3 ( 2) 1 ( 5) 2 ( 7)1998 7 ( 5) 1 ( 5) 1 ( 3)1999 3 ( 2) 2 ( 9) 02000 7 ( 5) 0 1 ( 3)2001 17 (12) 5 (23) 3 (10)2002 6 ( 4) 2 ( 9) 3 (10)2003 9 ( 7) 2 ( 9) 2 ( 7)

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Table 1. Continued.


cords Year of transplant (continued)

2004 7 ( 5) 3 (14) 1 ( 3)2005 2 ( 1) 1 ( 5) 6 (20)2006 7 ( 5) 0 5 (17)2007 4 ( 3) 1 ( 5) 2 ( 7)

Donor recipient gender match M-M 43 (31) 5 (23) 6 (20)M-F 31 (23) 8 (36) 8 (27)F-M 30 (22) 5 (23) 4 (13)F-F 33 (24) 3 (14) 10 (33)Missing 0 1 ( 5) 2 ( 7)

Donor-recipient CMV status Pos-pos 68 (50) 3 (14) 1 ( 3)Pos-neg 18 (13) 7 (32) 2 ( 7)Neg-pos 14 (10) 6 (27) 8 (27)Neg-neg 30 (22) 6 (27) 5 (17)Not tested/inconclusive 7 ( 5) 0 14 (47)

Conditioning regimen TBI based* 34 (25) 18 (82) 7 (23)TLI and TAI based 31 ( 23) 1 ( 5) 7 (23)chemo-ATG** 20 (15) 3 (14) 11 (37)chemo-no ATG*** 52 (38) 0 5 (17)

Conditioning regimen Radiation-based conditioning 65 (47) 19 (86) 14 (47)Chemo-based conditioning 72 (53) 3 (14) 16 (53)

Donor-recipient HLA match HLA-id sib 108 (79) 0 0Other related 25 (18) 0 0Related unk/TBD 4 ( 3) 0 0URD well-matched 0 6 (27) 0URD partially matched 0 8 (36) 0URD mismatched 0 4 (18) 0URD matching unk/TBD 0 4 (18) 0cord-sib 6/6 0 0 4 (13)cord-rel 5/6 0 0 1 ( 3)cord-rel <=4/6 0 0 1 ( 3)cord-unrel 6/6 0 0 2 ( 7)cord-unrel 5/6 0 0 9 (30)cord-unrel 4/6 0 0 12 (40)cord HLA missing 0 0 1 ( 3)

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Table 1. Continued.


cords GVHD prophylaxis

T-cell depletion 10 ( 7) 12 (55) 0FK506+MTX+-oth 2 ( 1) 0 1 ( 3)FK506+-oth 1 ( 1) 1 ( 5) 0CsA+MTX+-oth 66 (48) 6 (27) 10 (33)CsA+-oth 53 (39) 3 (14) 19 (63)Other**** 2 ( 1) 0 0Not specified‡ 3 ( 2) 0 0

ATG at conditioning or as GVHD prophylaxis No 85 (62) 5 (23) 9 (30)Yes 52 (38) 17 (77) 21 (70)

Median (range) follow-up of survivors, m 75 (3-253) 77 (35-150) 62 (3-137) ±AML status prior to conditioning: Primary induction failure (4); CR1 (3); CR2 (1); unknown (4). ║ALL status prior to conditioning: Primary induction failure (1); CR1 (1). The completeness index FU as of 12-31-08 is 67%. The completeness index FU at 1, 3, and 5 years is 96%, 91% and 83%, respectively. †All 4 cases without date of diagnosis are from NMDP. *Related: 6 were myeloablative (MA) doses; unrelated: 2 were MA; cords: none were MA. ** 65% received ATG/Cy/fludara; 23% ATG/Cy; 9% ATG/Bu/fludara +/- cy; 3% ATG/Bu/Cy. ***72% Cy only; 14% Bu/Cy; 9% Cy/fludara; 2% BCNU/Mel/fludara; 2% Bu/Cy/ara-c; 2% Bu/Cy/thio ‡No regimen was listed; centers will be contacted. ****One patient is reported to have received MTX only; one patient is reported to have received MTX and steroids.

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Table 2. Disease status prior to transplant of 41 MDS patients based on worst status between FAB at diagnosis, FAB at tx and bone marrow blasts percentage at tx. mds2status dnrtype Frequency | Col Pct |Related |Unrelate|Umbilica| Total | |d |l cords | -----------------+--------+--------+--------+ Early MDS | 10 | 3 | 4 | 17 RA, RARS | 29.41 | 50.00 | 80.00 | -----------------+--------+--------+--------+ advanced MDS- RA | 11 | 2 | 1 | 14 EB, RAEBT | 32.35 | 33.33 | 20.00 | -----------------+--------+--------+--------+ Missing | 13 | 1 | 0 | 14 | 38.24 | 16.67 | 0.00 | -----------------+--------+--------+--------+ Total 34 6 5 45 Table 3. FAB classification at diagnosis of 41 MDS patients. fabdx(fab type at diagnosis) dnrtype Frequency | Col Pct |Related |Unrelate|Umbilica| Total | |d |l cords | --------------+--------+--------+--------+ RA* | 2 | 1 | 1 | 4 | 6.45 | 20.00 | 20.00 | --------------+--------+--------+--------+ RAEB** | 6 | 1 | 1 | 8 | 19.35 | 20.00 | 20.00 | --------------+--------+--------+--------+ RAEB-T║ | 1 | 0 | 0 | 1 | 3.23 | 0.00 | 0.00 | --------------+--------+--------+--------+ RARS± | 2 | 0 | 0 | 2 | 6.45 | 0.00 | 0.00 | --------------+--------+--------+--------+ Other specify† 1 | 0 | 0 | 1 (hypoplastic MDS) 3.23 | 0.00 | 0.00 | --------------+--------+--------+--------+ unknown | 22 | 4 | 3 | 25 | 64.71 | 66.67 | 60.00 | --------------+--------+--------+--------+ Total 31 5 5 45 *3 cases remained as RA and one case progressed to RAEB-T prior to transplant. **5 cases remained as RAEB prior to transplant; 2 progressed to RAEB-T; and one has an unknown transformation status. ║One case remained as RAEB-T prior to transplant. ±One case progressed to RAEB and one case remained as RARS. †One case of hypoplastic MDS remained as such prior to transplant.

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Table 4. Fanconi Anemia disease status at transplant based on clonal disease. fastatpr(Disease status prior to cond.) disordergp Frequency | Col Pct |MDS |AML |ALL |abnl cg | Total | | | |at prese| | | | |ntation | -----------------+--------+--------+--------+--------+ stable cytopenia | 5 | 0 | 0 | 47 | 52 | 11.11 | 0.00 | 0.00 | 36.15 | -----------------+--------+--------+--------+--------+ improvement | 1 | 0 | 0 | 4 | 5 | 2.22 | 0.00 | 0.00 | 3.08 | -----------------+--------+--------+--------+--------+ progressive cyto | 5 | 0 | 0 | 49 | 54 penia | 11.11 | 0.00 | 0.00 | 37.69 | -----------------+--------+--------+--------+--------+ Myelodysplasia w | 10 | 0 | 0 | 0 | 10 ith excess blast | 22.22 | 0.00 | 0.00 | 0.00 | s | | | | | -----------------+--------+--------+--------+--------+ Leukemia, treate | 1 | 1 | 0 | 0 | 2 d | 2.22 | 8.33 | 0.00 | 0.00 | -----------------+--------+--------+--------+--------+ missing | 23 | 11 | 2 | 30 | 66 | 51.11 | 91.67 | 100.00 | 23.08 | -----------------+--------+--------+--------+--------+ Total 45 12 2 130 189 *abnl cg: abnormal cytogenetics

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Study Proposal 1010-02 Study Title: Outcomes after primary treatment with matched sibling donor transplantation and immunosuppressive therapy for patients >40 years with severe aplastic anemia: A joint study from European Bone Marrow Transplant (EBMT) aplastic anemia working party and Center for International Blood and Marrow Transplant Research (CIBMTR) Vikas Gupta, MD, FRCP, FRCPath, Princess Margaret Hospital, Toronto, Canada, Judith Marsh, King’s College Hospital, London, UK Andrea Bacigalupo, MD, Ospedele S Martino, Genovo, Italy Jacob Passweg, Hopitaux Universitaires de Geneve, Geneva, Switzerland Study Hypothesis: BMT from matched sibling donor when given as first line treatment may result in better long term survival in comparison to immunosuppressive therapy in patients >40 years with severe aplastic anemia (SAA) Study Objectives: To evaluate and compare the outcomes of matched sibling donor (MSD) transplants and Immunosuppressive therapy (IST) given as first line treatment in patients >40 years with SAA

Outcomes of Interest: Primary Outcome:

– Overall survival Secondary Outcomes:

– Failure-free survival – Neutrophil and platelet recovery (depending on data availability on IST patients) – Cumulative incidence of relapse – Cumulative incidence of clonal disorders – Acute and chronic graft-versus-host disease (GVHD) (BMT patients only)

Scientific Rationale: Marrow transplantation from matched sibling donor (MSD) is the treatment of choice for young patients with SAA.1-4 In the absence of such a donor, immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG) and cyclosporine (CsA) may be equally successful. The upper age limits for HLA-identical donor transplantation as first line therapy for SAA varies with different centers. While some support HLA-identical sibling donor transplantation as first line therapy for patients up to the age 50-55 years,5,6 others limit transplantation as first line treatment to those younger than 30-40 years.1,7 Age has a significant impact on outcomes of transplantation. In a recent study from CIBMTR, the impact of age was analyzed on 1307 patients [<20 years (n=717; 20-40 years (n=506); and >40 years (n=84)] undergoing MSD transplantation8.In this study, mortality risk were significantly higher in patients >40 years compared to those aged <20 years (RR 2.7, p<0.0001) and those 20-40 years (RR1.69, p<0.0001). Additionally, mortality was higher in those with poor performance scores, and interval from diagnosis to transplant ≥3 months irrespective of age at transplantation. The probability of overall survival after adjusting for performance scores, and interval between diagnosis to BMT, were 82%, 72% and 53% in patients age <20 years, 20-40 years and >40 years, respectively. A recent study from Seattle reported an encouraging long term survival of 65% in 23 patients age ≥40 years with AA undergoing MSD transplantation9.

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The long-term survival after BMT in patients >40 years in this study does not appear much different from the published literature on outcomes of IST in older patients. Age has a significant impact on response rate to IST as well as long-term survival after IST.10,11 The response rate to IST in patients under the age 18 years was significantly better in comparison to older patients (74% vs. 58%).10 An EBMT study reported significantly inferior survival of IST in patients age 50-59 years when compared to those age 20-49 years (57% vs. 72%). A study from Seattle showed similar outcomes of BMT and IST when given as primary treatment in patients >40 years. However there were only 11 patients in the BMT group in comparison to 67 patients in IST4. Recently, the outcome of marrow transplantation appears to be getting better even in older patients. Using a fludarabine based regimen, EBMT group recently reported outcomes of matched sibling donor transplants.12 In this study, there were 21 patients >40 years and long term survival of these patients >70% in this small cohort. As the survival of BMT improves, there is need for a focused study comparing the outcomes of primary treatment with BMT or IST in older patients. Ideally, a randomized study will be the best way to answer whether if one treatment approach is superior to the other. The practical chances of such a randomized study are negligible due to several reasons:

– Rarity of AA – Patients >40 year is a small subset of patients with an extremely rare disease – Physician biases in favor of one treatment over the other

In the absence of such a randomized study, it would be reasonable to compare the outcomes of older patients undergoing primary treatment with BMT or IST. A large collaboration will be required for such an endeavor. Therefore, we propose such as study through EBMT-AA working committee and Non-malignant working party of CIBMTR. Study Population: In patients with a diagnosis of severe aplastic Anemia and age >41-65 years, who received BMT or IST as first line treatment and meet the following eligibility criteria: BMT Arm:

Inclusion Criteria: – BMT as first line treatment – Diagnosis to BMT <120 days – Transplant from a matched sibling donor

Exclusion Criteria: – Immunosuppressive therapy prior to transplant – Alternative donor transplant – Syngeneic donor

Immunosuppressive Therapy Arm: Inclusion Criteria:

– IST with ATG+CsA* as first line treatment – Received full dose ATG with either ATGAM (horse ATG), thymoglobuline (rabbit ATG) or

lymphoglobuline (Horse ATG) – Diagnosis to start of ATG <120 days

Exclusion Criteria: – Received either ATG or cyclosporine alone

* If patient received GCSF, mycophenolate or sirolimus in addition to ATG and CsA, they will be eligible for the study. Patient who received ATG or CsA alone will not be eligible for the study. ** Full dose of ATG will be defined as

– Horse ATG (160 mg/kg or higher) – Thymoglobuline (12.5 mg/kg or higher)

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– Lymphoglobuline (Judith to confirm dose used commonly in Europe) References:

1. Marsh JC, Ball SE, Cavenagh J, Darbyshire P, Dokal I, Gordon-Smith EC, Keidan J, Laurie A, Martin A, Mercieca J, Killick SB, Stewart R, Yin JA. Guidelines for the diagnosis and management of aplastic anaemia. Br J Haematol. 2009;147:43-70

2. Young N, Bacigalupo A, Marsh J. Aplastic Anemia: Pathophysiology and Treatment. Biol Blood Marrow Transplant. 2009

3. Gupta V, Marsh J. Acquired Aplastic Anemia and Fanconi Anemia. In:Barrett J and Trealeaven J eds. Practical Stem Cell Transplantation. 2009:165-177

4. Doney K, Leisenring W, Storb R, Appelbaum FR. Primary treatment of acquired aplastic anemia: outcomes with bone marrow transplantation and immunosuppressive therapy. Seattle Bone Marrow Transplant Team. Ann Intern Med. 1997;126:107-115

5. Armand P, Antin JH. Allogeneic stem cell transplantation for aplastic anemia. Biol Blood Marrow Transplant. 2007;13:505-516

6. Bacigalupo A. Treatment strategies for patients with severe aplastic anemia. Bone Marrow Transplant. 2008;42 Suppl 1:S42-S44

7. Bagby GC, Lipton JM, Sloand EM, Schiffer CA. Marrow failure. Hematology Am Soc Hematol Educ Program. 2004:318-336

8. Gupta V, Eapen M, Brazauskas R, Carreras J, Aljurf M, Gale RP, Hale GA, Ilhan O, Passweg JR, Ringden O, Sabloff M, Schrezenmeier H, Socie G, Marsh JC. Impact of age on outcomes after transplantation for acquired aplastic anemia using HLA-identical sibling donors. Haematologica. 2010 (In Press)

9. Sangiolo D, Storb R, Deeg HJ, Flowers ME, Martin PJ, Sandmaier BM, Kiem HP, Nash RA, Doney K, Leisenring WM, Georges GE. Outcome of allogeneic hematopoietic cell transplantation from HLA-identical siblings for severe aplastic anemia in patients over 40 years of age. Biol Blood Marrow Transplant. 2010;16:1411-1418

10. Scheinberg P, Wu CO, Nunez O, Young NS. Predicting response to immunosuppressive therapy and survival in severe aplastic anaemia. Br J Haematol. 2009;144:206-216

11. Tichelli A, Socie G, Henry-Amar M, Marsh J, Passweg J, Schrezenmeier H, McCann S, Hows J, Ljungman P, Marin P, Raghavachar A, Locasciulli A, Gratwohl A, Bacigalupo A. Effectiveness of immunosuppressive therapy in older patients with aplastic anemia. European Group for Blood and Marrow Transplantation Severe Aplastic Anaemia Working Party. Ann Intern Med. 1999;130:193-201

12. Maury S, Bacigalupo A, Anderlini P, Aljurf M, Marsh J, Socie G, Oneto R, Passweg JR. Improved outcome of patients older than 30 years receiving HLA-identical sibling hematopoietic stem cell transplantation for severe acquired aplastic anemia using fludarabine-based conditioning: a comparison with conventional conditioning regimen. Haematologica. 2009;94:1312-1315

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Characteristics of patients that underwent a matched sibling donor for patients >40 years with severe aplastic anemia reported to the CIBMTR (study AA07-01)

Variable >40 years Number of patients

84

Male

49 (58)

Performance score <90 45 (54) ≥90 37 (44) Not reported

2 ( 2)

Blood transfusions prior to transplantation <20 30 (36) 20-50 18 (21) >50 17 (20) Not reported

19 (23)

Conditioning regimen Cyclophosphamide + ATG 40 (48) Cyclophosphamide alone 22 (26)

Cyclophosphamide + limited field irradiation 11 (13) Busulfan +cyclophosphamide 9 (11) Fludarabine + other agents*

2 ( 2)

Time from diagnosis to transplant, months ≤3 42 (50) >3

42 (50)

Immunosuppresive therapy prior to transplant 50 (60)Donor - recipient sex match Male donor – male recipient 28 (33) Male donor – female recipient 23 (27) Female donor – male recipient 21 (25) Female donor – female recipient 12 (14) Not reported Donor - recipient cytomegalovirus serostatus Donor positive – recipient positive 42 (50) Donor positive – recipient negative 9 (11) Donor negative – recipient positive 13 (15) Donor negative – recipient negative 11 (13) Not reported

9 (11)

26


Continued.

Variable >40 years GVHD prophylaxis Cyclosporine +methotrexate ± other 69 (82) Cyclosporine ± other 15 (18)

Year of transplant 1991-1994 61 (73) 1995-1998 19 (23) 1999-2002 4 ( 5) 2003-2004 61 (73)Median follow-up of survivors, months 83 (1 - 171)

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Study Proposal 1210-16 Study Title: Durable Engraftment and Correction of Hematological Defects in Children with Congenital Amegakaryocytic Thrombocytopenia following Myeloablative Umbilical Cord Blood Transplantation Kris M Mahadeo, MD, MPH, Duke University Medical Center, Durham, NC Joanne Kurtzberg, MD, Duke University Medical Center, Durham, NC Vinod K Prasad, MD, MRCP, Duke University Medical Center, Durham, NC

Specific Aims:

- To assess outcomes of patients with congenital amegakaryocytic thrombocytopenia (CAMT) following allogeneic hematopoietic stem cell transplantation (HSCT)

- To assess the impact of graft source, cytoreduction regimen, transfusions, and prior therapy on clinical outcomes including engraftment time and durability, GvHD and overall survival

Scientific Justification: CAMT is a rare but potentially fatal pediatric disease that can be cured by HSCT. Successful utilization of unrelated cord blood donors has extended access to HSCT to most children with CAMT. This current study will examine the outcomes of patients with CAMT who have undergone HSCT with various graft sources. A retrospective review of all HSCTs (n=1457) performed at Duke between 1994 and 2010 revealed five children (3 females, 5 Caucasian) transplanted for CAMT. All had absent or markedly decreased megakaryocytes in bone marrow (BM), elevated thrombopoietin level and normal cytogenetics with no evidence of other genetic BM failure syndromes, including Fanconi anemia. Homozygous C-MPL mutation was detected in one patient. BM in 3 showed dysplasia. Prior treatments included IVIG (n=4), steroids (n=3), or Danazol (n=1). Graft source in all patients were cord blood units (CBU) derived either from unrelated (n= 4) or sibling (n=1) donors. CBU were 4/6 (n=3), 5/6 (n=1) or 6/6 (n=1) matched by low resolution for HLA-A and B and high resolution DRB1. All received myeloablative conditioning with Bu/Cy/ATG. In one patient, cyclophosphamide was partially substituted with Melphalan due to pre-existing cardiomyopathy. Children were diagnosed at median age of 18 months (range, 2-30 months) and transplanted at median age of 31 months (range, 13-60 months). Median (range)/Kg of cryopreserved total nucleated cell (TNC), reinfused TNC, CD34, and CFU doses were 8(6-12.5)x10e7, 7.3(6.1-9.3)x10e7, 1.8(.2-13.6)x10e5, and 6.8(3.3-22.4)x10e4, respectively. All patients engrafted with median (range) time to neutrophil and platelet engraftment of 19 days (14-19) and 36 days (22-41), respectively. Grades II-IV acute GvHD developed in 3 (II, n=1; III, n=2) and chronic GvHD in none. Two patients developed auto-immune hemolytic anemia requiring temporary transfusion support but both resolved with steroid therapy. At a median follow-up of 10 years (range 0.16 to 16), all patients are alive with normal platelet counts (median 262k/uL, range 176-438k/uL), >98% donor chimerism. Our pilot data suggests that cord blood transplantation from unrelated or related donors following myeloablative chemotherapy based conditioning corrects thrombocytopenia and results in sustainable high-level donor chimerism and excellent survival outcomes among patients with CAMT and that this approach should be considered shortly after diagnosis for these patients to maximize curative results with HSCT. The proposed study will assess these outcomes among the larger cohort of patients registered with the Center for International Blood & Marrow Transplant Research. The larger sample, with varied conditioning regimens and graft sources, will allow for more detailed outcome analysis. Such data is important, as it will assist us in deducing optimal times for transplant, conditioning regimens and graft selection for patients afflicted with CAMT.

Patient Eligibility Population:

- Diagnosis of Congenital Amegakaryocytic Thrombocytopenia - Recipient of allogeneic hematopoietic stem cell transplantation

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Data Requirements:

- The following CIBMTR forms will be used for data collection in this study: - 2000 (Recipient Baseline Data) - 2004 (Infectious Disease Markers) - 2005 (Confirmation of HLA Typing) - 2006 (Hematopoietic Stem Cell Transplant Infusion) - 2035 (Congenital Amegakaryocytic Thrombocytopenia Pre-HSCT Data) - 2135 (Congenital Amegakaryocytic Thrombocytopenia Post-HSCT Data) - 2200 (Six Months to Two Years Post-HSCT Data) - 2300 (Yearly Follow-Up for Greater than Two Years Post-HSCT Data) - 2400 (Pre-Transplant Essential Data)

Sample Requirements (if study will use biologic samples from the NMDP Research Sample Repository)

- Not applicable

Study Design (Scientific Plan): - In this cross-sectional study the outcomes of HSCT for patients with CAMT will be analyzed.

Clinical and demographic variables of patients with the diagnosis of CAMT will be obtained from the CIBMTR. Variables to be analyzed include, age at diagnosis, age at transplant, treatments received prior to transplant, sex, ethnicity, graft source and cell doses, conditioning regimen, pre-transplant functional status and co-morbidities. These variables will be analyzed as a function of outcome status related to time to engraftment, donor chimerism, functional status, GvHD, post-transplant morbidities and survival.

- Correlations between post-transplant outcomes and pre-transplant clinical and demographic variables, graft source and conditioning regimen will be analyzed. Descriptive statistics will include calculation of the mean, standard deviation and use of Fischer exact T-test for continuous variables and chi-square test for categorical variables. Unconditional logistic regression analysis will be used to estimate the odds ratio (OR) and the 95% confidence intervals (CI). A p-value of less than 0.05 will be considered statistically significant.

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Characteristics of patients that underwent an umbilical cord blood allogeneic stem cell transplantation in children <10 years of age with congenital amegakaryocytic thrombocytopenia

reported to the CIBMTR*

Characteristics of patients N (%)Number of patients 14Number of centers 10Age, median (range), years 2 (<1-6)Sex

Male 9 (64)Female 5 (36)

Karnofsky score <90% 2 (14)>=90% 11 (79)Missing 1 ( 7)

Conditioning regimen cy+tbi>500cGY-single-tbi>800cGY-fract 1 ( 7)bu+cy 11 (79)lpam<=150 mg/m^2 1 ( 7)flud+cy 1 ( 7)

Donor Other relative 1 ( 7)URD well-matched 1 ( 7)URD mismatched 3 (21)URD matching to be classified 9 (64)

D-R sex match M-M 2 (14)M-F 3 (21)F-M 6 (43)F-F 2 (14)Missing 1 ( 7)

D-R CMV status +/- 1 ( 7)-/+ 2 (14)-/- 1 ( 7)Missing 10 (71)

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Continued.

Characteristics of patients N (%)Year of HCT

1994-1996 2 (15)1999-2000 1 ( 7)2001-2002 2 (15)2003-2004 3 (21)2005-2006 3 (21)2007-2008 3 (21)

GVHD prophylaxis FK506+MTX+-other 2 (14)CsA+MTX+-other 2 (14)CsA+-other 9 (64)Other 1 ( 7)

Median FU of survivors (range), months 63 (25-191)*There are 29 additional BM cases (n=11 HLA identical siblings, 5 other relative and 13 unrelated). There are 7 additional PB cases (n=1 HLA identical siblings, 1 other relative and 5 unrelated).

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not for publication or presentation · 2014-01-14 · not for publication or presentation c....

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