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A G E N D A CIBMTR WORKING COMMITTEE FOR PRIMARY IMMUNE DEFICIENCIES, INBORN ERRORS OF METABOLISM AND OTHER NON-MALIGNANT MARROW DISORDERS Honolulu, Hawaii Thursday, February 18, 2016, 12:15 – 2:15 pm

Co-Chair: Paolo Anderlini, MD, MD Anderson Cancer Center, Houston, TX; Telephone: 713-745-4367; E-mail: [email protected] Co-Chair: Neena Kapoor, MD, Children’s Hospital of Los Angeles, Los Angeles, CA; Telephone: 323-361-2546; E-mail: [email protected] Co-Chair: Jaap Jan Boelens, MD, PhD, University Medical Center Utrecht, Utrecht, Netherlands; Telephone: +31 8875 54003; E-mail: [email protected] Co-Chair: Vikram Mathews, MD, DM, MBBS, Christian Medical College Hospital, Vellore, India; Telephone: +011 91 416 228 2891; E-mail: [email protected] Scientific Director: Mary Eapen, MBBS, MS, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-805-0700; E-mail: [email protected] Statistical Ruta Brazauskas, PhD, CIBMTR Statistical Center, Milwaukee, WI; Directors: Telephone: 414-456-8687; E-mail: [email protected] Soyoung Kim, PhD, CIBMTR Statistical Center, Milwaukee Telephone: 414-955-8271; E-mail: [email protected]

1. Introduction

a. Minutes and Overview Plan from February 2015 meeting (Attachment 1)

2. Accrual summary (Attachment 2)

3. Presentations, published or submitted papers

a. AA12-01 Ayas M, Eapen M, Le-Rademacher J, Carreras J, Abdel-Azim H, Alter BP, Anderlini P, Battiwalla M, Bierings M, Buchbinder DK, Bonfim C, Camitta BM, Fasth AL, Gale RP, Lee MA, Lund TC, Myers KC, Olsson RF, Page KM, Prestidge TD, Radhi M, Shah AJ, Schultz KR, Wirk B, Wagner JE, Deeg HJ. Second Allogeneic Hematopoietic Cell Transplantation for Patients with Fanconi Anemia and Bone Marrow Failure. Biol Blood Marrow Transplant 2015 Oct;21(10):1790-5.

b. ID98-05 Orchard PJ, Fasth AL, Le Rademacher J, He W, Boelens JJ, Horwitz EM, Al-Seraihy A, Ayas M,Bonfim CM, Boulad F, Lund T, Buchbinder DK, Kapoor N, O'Brien TA, Perez MA, Veys PA,Eapen M. Hematopoietic stem cell transplantation for infantile osteopetrosis. Blood. 2015 Jul 9;126(2):270-6.

c. ID09-02 Veys PA, Nanduri V, Baker KS, He W, Bandini G, Biondi A, Dalissier A, Davis JH, Eames GM,Egeler RM, Filipovich AH, Fischer A, Jürgens H, Krance R, Lanino E, Leung WH, Matthes S, Michel G, Orchard PJ, Pieczonka A, Ringdén O, Schlegel PG, Sirvent A, Vettenranta K, Eapen M. Haematopoietic stem cell transplantation for refractory Langerhans cell histiocytosis: outcome by intensity of conditioning. Br J Haematol. 2015 Jun;169(5):711-8.

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d. ID10-02 Gennery A et. al. International study on outcomes of hematopoietic stem cell transplant for DNA DSB repair defects. Submitted

4. Studies in progress (Attachment 3) a. ID11-01 Outcomes in allogeneic hematopoietic cell transplantation for adrenoleukodystrophy (P Orchard) Manuscript Preparation b. AA13-01 Correlation of levels of donor cell chimerism with hemoglobinopathy symptoms following allogeneic hematopoietic cell transplantation (A Abraham) Analysis c. AA13-02 Malignancies in patients with fanconi anemia (J Wagner) Data File Preparation d. ID12-01 Allogeneic hematopoietic cell transplantation for combined immunodeficiency and common variable immunodeficiency (G Cuvelier/G Guilcher/N Wright) Data Collection e. ID13-01 Second and subsequent hematopoietic cell transplants for congenital neutropenia/kostmann agranulocytosis (S Keogh/P Shaw/J Levine/J Connelly) Analysis f. NM14-01 An investigation of the long term neurological outcomes of Hematopoietic Stem Cell Transplant (HCT) in boys with X-linked Adrenoleukodystrophy (X-ALD) (R Wynn/J Boelens/P Orchard) Protocol Development g. NM14-02 Outcomes of allogeneic hematopoietic cell transplant in patients with Shwachman diamond syndrome (K Myers) Protocol Development h. NM15-01 Outcome of Allogeneic Hematopoietic Cell Transplant in Erythropoietic Porphyria (A Saad/H Abdel-Azim/J Bloomer) Protocol Development

5. Future/proposed studies a. PROP 1505-03/1511-25 Outcomes Of Allogeneic Stem Cell Transplantation In Patients (Above 18 Years Of Age Or Older) With Paroxysmal Nocturnal Hemoglobinuria (Pnh): A Cibmtr Analysis (S Ganguly/P Mehta) (Attachment 4) b. PROP 1510-18 Outcomes for adults with hemophagocytic lymphohistiocytosis requiring HSCT (BKN Tomlinson) (Attachment 5) c. PROP 1511-09 Clinical course and outcome of allogeneic hematopoietic stem cell transplantation in Glanzmann thrombasthenia (S Savasan) (Attachment 6) d. PROP 1511-13 Allogeneic Hematopoietic Cell Transplantation for Primary Immune Deficiencies: Current Patterns of Practice and Change over the last 10 years (R Marsh) (Attachment 7) f. PROP 1511-44 Pulmonary complications of hematopoietic cell transplantation in sickle cell disease (J Dill) (Attachment 8) g. PROP 1511-71 The effect of Conditioning Regimen on Clinical Outcomes of Allogeneic Hematopoietic Cell Transplantation in Severe Aplastic Anemia (N Bejanyan) (Attachment 9) h. PROP 1511-82 Second Allogeneic Hematopoietic Cell Transplantation (HCT) for Hemoglobin Disorders (NR Lalefar) (Attachment 10) i. PROP 1511-101 Evaluation of the impact of changing clinical profile, transplant conditioning regimens and stem cell source on clinical outcome in patients with Thalassemia major (V Mathews) (Attachment 11) j. PROP 1511-110 Unrelated donor marrow transplantation for children, adolescents and young adults with relapsed or refractory severe aplastic anemia (S Arnold) (Attachment 12) k. PROP 1511-131 Results of transplants from genetically-identical twin donors in persons with aplastic anaemia (RP Gale) (Attachment 13) l. PROP 1512-01 Non-interventional prospective study request proposal for severe aplastic anemia: a joint EBMT/CIBMTR proposals (J Marsh) (Attachment 14)

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Dropped proposed studies a. PROP 1509-01 Review of Allogenic Stem Cell Transplantation for severe congenital Neutropenia: CIBMTR experience. Dropped due to overlap with ID13-01

7. Other Business

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MINUTES AND OVERVIEW PLAN CIBMTR WORKING COMMITTEE FOR PRIMARY IMMUNE DEFICIENCIES, INBORN ERRORS OF METABOLISM AND OTHER NON-MALIGNANT MARROW DISORDERS San Diego, CA Friday, February 13, 2015, 12:15 – 2:15 pm

Co-Chair: Harry Malech, MD, National Institute of Allergy and Infectious Diseases, Bethesda, MD; Telephone: 301-480-6916; Fax: 301-402-0789; E-mail: [email protected] Co-Chair: Shalini Shenoy, MD, Washington University/St. Louis Children’s Hospital, St. Louis, MO; Telephone: 314-454-6018; Fax: 314-454-2780; E-mail: [email protected] Co-Chair: Paolo Anderlini, MD, MD Anderson Cancer Center, Houston, TX; Telephone: 713-745-4367; Fax: 713-794-4902; E-mail: [email protected] Co-Chair: Neena Kapoor, MD, Children’s Hospital of Los Angeles, Los Angeles, CA; Telephone: 323-361-2546; Fax: 323-361-8068; E-mail: [email protected] Co-Chair: Jaap Jan Boelens, MD, PhD, University Medical Center Utrecht, Utrecht, Netherlands; Telephone: +31 8875 54003; Fax: +31 6140 26510; E-mail: [email protected] Co-Chair: Vikram Mathews, MD, DM, MBBS, Christian Medical College Hospital, Vellore, India; Telephone: +011 91 416 228 2891; Fax: +011 91 416 222 6449; E-mail: [email protected] Statisticians: Jennifer Le-Rademacher, PhD, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-955-4849; Fax: 414-955-6513; E-mail: [email protected] Wensheng He, MS, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-805-0670; Fax: 414-805-0714; E-mail: [email protected] Scientific Director: Mary Eapen, MBBS, MS, CIBMTR Statistical Center, Milwaukee, WI; Telephone: 414-805-0700; Fax: 414-805-0714; E-mail: [email protected]

1. Introduction

The CIBMTR Working Committee for Primary Immune Deficiencies, Inborn Errors of Metabolism and other Non-Malignant Disorders met on Friday, February 13, 2015 at 12:15 pm. Minutes from the 2014 Tandem meeting in Grapevine, TX were approved. Dr. Kapoor welcomed the audience and introduced the working committee leadership. Drs. Malech and Shenoy were acknowledged for their efforts for the past 5 years.

Dr. Malech reviewed the CIBMTR guidelines for assigning priority/scientific merit for study proposals, and rules of authorship.

2. Accrual Summary

The accrual tables were referenced for review but not formally presented.

3. Presentations, published or submitted papers

Publications for year 2014 were briefly reviewed. The committee had 3 publications and 1 manuscript is under review. These are listed below:

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a . AA10-02 Kim SY, Le Rademacher J, Antin JH, Anderlini P, Ayas M, Battiwalla M, Carreras J, Kurtzberg J, Nakamura R, Eapen M, Deeg HJ. Myelodysplastic syndrome evolving from aplastic anemia treated with immunosuppressive therapy: efficacy of hematopoietic stem cell transplantation. Haematologica 2014 Dec;99(12):1868-75.

b . ID11-02 Lund TC, Cathey SS, Miller WP, Eapen M, Andreansky M, Dvorak CC, Davis JH, Dalal JD, Devine SM, Eames GM, Ferguson WS, Giller RH, He W, Kurtzberg J, Krance R, Katsanis E, Lewis VA, Sahdev I, Orchard PJ. Outcomes after hematopoietic stem cell transplant for children with I-cell disease. Biol Blood Marrow Transplant 2014 Nov;20(11):1847-51.

c . ID99-02 Veys PA, Nanduri V, Baker KS, He W, Bandini G, Biondi A, Dalissier A, Davis JH, Eames GM, Egeler RM, Filipovich AH, Fischer A, Jürgens H, Krance R, Lanino E, Leung WH, Matthes S, Michel G , Orchard PJ, Pieczonka A, Ringdén O, Schlegel PG, Sirvent A, Vettenranta K, Eapen M. Hematopoietic Stem Cell Transplantation for Refractory Langerhans Cell Histiocytosis: Outcome by Intensity of Conditioning. B J Haematol (In press; 2015).

Presented at the 30th Annual Meeting of the Histiocyte Society, Toronto, Canada. October 2014. Awarded the President's prize (The Nesbit award) for the best clinical presentation.

d. ID98-05 Orchard PJ, Fasth A, Le Rademacher J, He W, Horwitz E, Boelens JJ, Ayas MF, Al-Seraihy A, Buchbinder D, Bonfim C, Boulad F, O’Brien T, Kapoor N, Diaz Perez MD, Veys P, Eapen M. Hematopoietic stem cell transplantation for osteopetrosis. Submitted.

4. S tudies in progress a . ID10-02 Outcome of HCT for DNA repair disorders (A Gennery). This is a collaborative study with EBMT. It is in manuscript preparation and anticipated submission by June 2015. b. ID11-01 Allo HCT for adrenoleukodystrophy (P Orchard). Submission June 2015. c . AA12-01 Outcome of second allogeneic stem cell transplantation in patients with Fanconi anemia (M Ayas). Submission March 2015.

Data files are being prepared for the studies listed below: d . AA13-01 Correlation of levels of donor cell chimerism after alloHCT for hemoglobinopathy (A Abraham/M Hsieh/C Fitzhugh/J Tisdale/S Shenoy)

e . AA13-02 Malignancies in patients with FA (J Wagner/B Alters) f. ID13-01 HCT for Congenital Neutropenia (S Keogh/P Shaw/J Levine/J Connelly)

The following two studies are in the stage of data collection. g . ID12-01 Allo HCT for CID/CVID (G Cuvelier/G Guilcher/N Wright). Dr. Malech will discuss with the investigators regarding supplemental data collection that was intended to confirm the diagnosis. However, diagnosis of CID/CVID are moving targets in that with better diagnostic tests these patients are now being assigned a proper diagnosis instead of common variable immune deficiency. Therefore It might be best to determine selection criteria based on some of the variables that have been collected by the CIBMTR for those patients for whom the indication for transplant was reported as CID or CVID.

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h. NM14-01 Outcomes of HCT in boys with X-ALD (R Wynn/J Boelens/P Orchard). Dr. Wynn presented a brief update of the study. The study aims to investigate the quality of life of long term survivors of HCT for X-ALD. There are 46 eligible patients from CIBMTR and 93 eligible patients from EBMT. Supplemental data collection form has been developed to study functional status of these patients as adults. Will follow up with Drs Wyn and Boelens regarding the logistics of data collection. Fortunately these transplants were performed at a few centers and most of these centers are motivated to better understand whether transplantation cures these patients to the extend they can function as independent adults.

There is no update for NM14-02 Allo HCT for Shwachman Diamond Syndrome (K Myers). 5. F uture/proposed studies

a . PROP 1405-02 A decision analysis to determine the optimal timing of unrelated donor marrow transplantation for children, adolescents and young adults with severe aplastic anemia (S Arnold/M Bhatia/J Horan/P Scheinberg/D Townsley/N S Young)

Dr. Staci Arnold presented the proposal. This study will compare treatment strategies for children, adolescents and young adults with severe aplastic anemia and without a HLA-matched family donor, on the basis of discounted quality of life adjusted life expectancy. There will be 3 cohorts: transplantation at diagnosis, transplantation after having failed 1 course of IST and transplantation after having failed two courses of IST. The primary purpose of these analyses is to define the role of transplantation across the groups.

The CIBMTR (based on inclusion criteria per investigators) identified 91 patients; 5 patients proceeded to transplantation without prior IST, the remaining patients had had 1 or more courses of IST. The CIBMTR data collection form only asks whether patients received IST bit not the number of courses or dates of administration. Additional information on IST (number of courses) would require supplemental data collection and not always feasible.

Potential collaboration with NHLBI and the EBMT.

The NHLBI database has 240 patients who received IST for newly diagnosed SAA and 108 patients treated for recurrent or refractory SAA. Among the 108 patients treated with IST for recurrent or refractory SAA there were concerns re: ability to identify these patients in the CIBMTR database in the event some of these patients received transplant outside of the NHLBI. The CIBMTR is unable to share identifiers with others. There was no information available re: data sharing rules regarding the NHLBI database. Further, there was no information available with respect to description of population, timing of IST, duration of follow-up etc.

The investigators had contacted the EBMT and we were told about 20 patients in the EBMT database had received an unrelated donor transplant without prior IST. There was no additional information offered on potentially eligible patients from the EBMT.

Taken together, this proposal poses several challenges:

1. Given the very few numbers of patients who proceeded to unrelated donor transplant without IST, this group will have to be excluded from the analysis. 2. To perform a decision analysis on role of unrelated donor transplantation versus IST we would need a better description of the IST cohort, ability to identify duplicate cases in the

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CIBMTR and NHLBI to allow us determine feasibility. 3. No information available on EBMT cases.

Therefore, this study was not approved to proceed to protocol development. b. PROP 1408-04 Outcome of allogeneic Hematopoietic Cell Transplant (HCT) in Erythropoietic Porphyria (A Saad)

Dr. Ayman Saad presented the proposal. The proposed study aims to describe the outcome of allogeneic HCT for erythropoietic porphyria (EP). There are 15 eligible patients in CIBMTR database. We will not be able to perform an analysis of prognostic factors as suggested by the investigator – this will be a descriptive study only and will require supplemental data collection: date of diagnosis, ferritin level (or other marker of iron overload), skin photosensitivity, hepatic involvement including pre-transplant liver function test, involvement of other organs, was the patient transfusin dependent, chelation prior to transplant and reason for HCT. Outcomes of interest include: VOD, transfusion dependence, immune suppression at last follow up and chimerism at last follow up. By describing 10-15 patients all we are trying to determine is whether the disease can be cured by transplantation. Of note, 15 patients were reported by 15 centers; 8 center representatives were in attendance at the meeting and eager to facilitate the study. Paul Veys has transplanted 2 cases and should have been reported to CIBMTR via EBMT. As there are delays in data transfer between the EBMT central office and CIBMTR, Dr. Veys will provide his cases separately to CIBMTR.

As this would be the first report on role of transplantation for EP, the proposal was approved to proceed to protocol development. c. PROP 1411-09 Risk factors for graft failure in patients with non-malignant conditions receiving alemtuzumab based conditioning regimens

Dr. Prakash Satwani presented the proposal. The study proposed to investigate the incidence of graft failure in pediatric patients who had HCT for non-malignant disorders receiving alemtuzumab based conditioning regimens.

There are 240 potentially eligible patients with a variety of non-malignant / immune / metabolic disorders. The committee members questioned the feasibility of the study based on the following:

1. There isn’t a single disease with sufficient numbers; it would be challenging to interpret the results in a group of patients with heterogeneous diseases 2. Although the 240 transplants represent all donor sources, almost 80% are unrelated donors and could have limited the dataset to unrelated donor transplants if there had been at least 1 disease category with a large enough population to study. 3. The timing and alemtuzumab dose was not collected consistently across the time period of interest.

Therefore, this study proposal was not approved to proceed to protocol development. d. PROP 1411-16 Effect of recipient age on outcomes after allogeneic HCT in Patients with acquired or inherited bone marrow failure (S Gadalla/B P Alter)

Dr. Shahinaz Gadalla presented the proposal. The proposed study aims to examine the role of

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recipient age in outcomes after allogeneic HCT in aplastic anemia with the hypothesis that outcomes after transplantation are age dependent and differ by disease subtypes. Of note, this may be of particular concern for patients with inherited bone marrow failure syndrome as patients with clinical features consistent with aplasia may be treated conservatively rather than referral for transplantation.

The CIBMTR has published a paper (Vikas Gupta et al, Haematologica 2010) on the effect of patient age on outcomes after HLA-matched sibling transplantation for aplastic anemia. A similar study was not undertaken in the setting of unrelated donor transplantation because the CIBMTR does not collect detailed information on number of IST treatments, dates and response to IST. For inherited marrow failure diseases such as Fanconi anemia, CIBMTR forms collect the date of diagnosis but not the date of onset of cytopenia / date of progression to pancytopenia. The CIBMTR forms collect clonal abnormality prior to transplant but not the date of onset of clonal abnormality – all of which makes it challenging to conduct this study without an exhaustive supplemental disease-specific data collection form.

Therefore, this study proposal was not approved to proceed to protocol development. e. PROP 1411-29 Outcome after unrelated donor hematopoietic cell transplantation for sickle cell disease (M Bhatia/M Walters/N Kamani)

Dr. Bhatia presented the proposal. The aim of the proposed study is to describe the outcome of unrelated donor HCT in patients with sickle cell disease. There are 31 unrelated bone marrow and 32 unrelated cord blood patients with comprehensive report forms eligible for the study. Reviewing the conditioning regimen for the 31 unrelated donor bone marrow transplants, the regimen is similar to that used for BMTCTN 0601, a 30-35 patient phase II, multi-center trial in the US conducted by the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). We anticipate significant overlap with BMT CTN 0601. The results of BMT CTN 0601 will be available in the later half of 2015. Although there are 32 unrelated cord blood patients with comprehensive report forms, published reports suggest graft failure rates are high. The data presented at the working committee meeting suggest patients received two predominant conditioning regimens: busulafan + cyclophosphamide and melphalan + fludarabine. However, the relatively small sample size suggest this will be a descriptive report and unlikely to report anything beyond what is already known. Alternative donor transplantation for sickle cell disease is of great interest but will require several more transplants before one can conduct a study that can begin to address transplantation strategies for this disease.

Therefore, this study proposal was not approved to proceed to protocol development. f. PROP 1411-96 Outcome of allogeneic HCT using Busulfan, Fludarabine with or without in vivo T cell Depletion in pediatrics nonmalignant disease apart from immunodeficiency disorders (N Shah/J Dalal/A Pawlowska)

Dr. Niketa Shah presented the proposal. The study aims to evaluate the outcomes of allogeneic HCT in pediatrics using busulfan, fludarabine with or without thymoglobulin or alemtuzumab in nonmalignant diseases excluding immunodeficiency.

There are 115 eligible patients from 5 broad disease groups (N=15 aplastic anemia; N=3 Fanconi

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anemia; N=34 thalassemia; N=15 sickle cell disease; N=48 Inborn errors of metabolism). As with PROP 1411-09, the study population is heterogeneous with respect to diseases, donor source and regimen intensity (about 60% received myeloablative doses and 40%, reduced intensity doses of busulfan). These raised concerns regarding feasibility.

Therefore, this study proposal was not approved to proceed to protocol development.

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Working Committee Overview Plan for 2015 - 2016 a. ID10-02 Outcome of HCT for DNA repair disorders (A Gennery). Submit manuscript for peer review June 2015 b. ID11-01 Allo HCT for adrenoleukodystrophy (P Orchard). Submit manuscript for peer review June 2015 c. AA12-01 Outcome of second allogeneic stem cell transplantation in patients with Fanconi anemia (M Ayas). Submit manuscript for peer review March 2015 d. AA13-01 Correlation of levels of donor cell chimerism after alloHCT for hemoglobinopathy (A Abraham). Submit manuscript for peer review before June 2016. e. AA13-02 Malignancies in patients with FA (J Wagner). Submit manuscript for peer-review before June 2016. f. ID12-01 Allo HCT for CID/CVID (G Cuvelier/G Guilcher/N Wright). Manuscript preparation by Dec 2015. g. ID13-01 HCT for Congenital Neutropenia/Kostmann Agranulocytosis (S Keogh/P Shaw/J Levine/J Connelly). Completing date file preparation of transplant data and data integration with Congenital Neutropenia Registry by June 2015. h. NM14-01 Outcomes of HCT in boys with X-ALD (R Wynn/J Boelens/P Orchard) Supplemental data collection. i. NM14-02 Allo HCT for Shwachman Diamond Syndrome (K Myers). Completing protocol development and data file preparation by Dec 2015. j. NM15-01 Outcome of allogeneic Hematopoietic Cell Transplant (HCT) in Erythropoietic Porphyria (A Saad). Case ascertainment and supplemental data collection by June 2015, manuscript preparation by Dec 2015.

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Oversight Assignments for Working Committee Leadership (March 2015) Mary Eapen ID11-01 Allo HCT for adrenoleukodystrophy AA13-02 Malignancies in patients with FA

ID13-01 HCT for Congenital Neutropenia/Kostmann Agranulocytosis

NM15-01 Outcome of allogeneic HCT in Erythropoietic Porphyria

Shalini Shenoy AA13-01 Correlation of levels of donor cell chimerism after alloHCT for hemoglobinopathy

Jaap J Boelens NM14-01 Long-term neurological outcomes of allogeneic transplantation for X-linked adrenoleukodystrophy

ID10-02 Outcome of HCT for DNA repair disorders Harry Malech ID12-01: Hematopoietic cell transplantation for common variable immunodeficiency

Paolo Anderlini NM14-02 Allo HCT for Shwachman Diamond Syndrome

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Accrual Summary for the Primary Immune Deficiencies, Inborn Errors of Metabolism and Other Non- Malignant Marrow Disorders Working Committee

Allogeneic Transplants for Immune Deficiencies reported to the CIBMTR from 2000-2014

TED Research Variable N N Number of patients 4564 2104 Number of centers 262 171 Immune Deficiencies (ID), NOS 70 16 SCID ADA deficiency 133 77 SCID absence of T and B cells 226 130 SCID absence of T, normal B cell SCID 271 160 Omenn syndrome 130 77 Reticular dysgenesis 10 7 Bare lymphocyte syndrome 88 35 SCID, NOS 201 80 SCID other, specify 370 240 Wiskott Aldrich syndrome 464 223 DiGeorge anomaly 15 8 Chronic granulomatous disease 358 139 Chediak-Higashi syndrome 76 26 Common variable immunodef 79 33 X-linked lymphoproliferative syndrome 130 63 Leukocyte adhesion deficiencies 79 40 Kostmann agranulocytosis 133 42 Cartilage hair hypoplasia 38 14 TED Immune deficiency plus neutropenia 1 0 CD40 ligand deficiency 64 23 Griscelli syndrome type 2 6 4 Combined immunodef dis (CID), NOS 12 7 CID other, specify 17 17 Other immunodeficiencies, specify 422 135 Histiocytic disorder, NOS 26 5 FELH Familial erythrohemophagocytic lymphohis 760 333 Langerhans Cell Histiocytosis 74 31 Hemophagocytosis 187 81 Malignant histiocytosis 15 2 Other histiocytic disord 109 56 Abbreviations: ADA = adenosine deaminase; NOS = not specified; HIV = Human immunodeficiency virus. *Only first transplants are included in this accrual.

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Allogeneic Transplants for Inborn Errors of metabolism reported to the CIBMTR from 2000-2014

TED Research Variable N N Number of patients 1606 822 Number of centers 191 112 Inherited disorders of metabolism, NOS 22 1 Osteopetrosis 277 119 Lesch-Nyhan(HGPTR defic ) 2 2 Neuronal ceroid lipofuscinosis 4 3 Other inherited metabolism disorders, specify 72 31 Mucopolysaccharidosis, NOS 13 5 IH Hurler syndrome 431 254 II Hunter syndrome 28 20 III Sanfillippo 31 25 VI Maroteaux-Lamy 35 22 VII B-glucuronidase deficiency 2 1 V Mucopolysaccharidosis 2 1 Other mucopolysaccharidosis 4 3 Mucolipidoses, NOS 4 3 Gaucher disease 11 2 Metachromatic leukodystrophy(MLD) 140 76 Adrenoleukodystrophy(ALD) 349 157 Globoid leukodystrophy/Krabbe disease 89 55 Neiman-Pick disease 21 10 I-cell disease 25 15 Wolman disease 13 7 Glucose storage disease 1 0 Other mucolipidoses 1 1 Asparty1 glucosaminuria 3 0 Fucosidosis 3 3 Mannosidosis 23 6 *Only first transplants are included in this accrual.

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Allogeneic Transplants for non-malignant disorder reported to the CIBMTR from 2000-2014

TED Research Variable N N Number of patients 11862 4430 Number of centers 421 286 Disease Severe aplastic anemia 6861 2513 Fanconi anemia 1319 631 Diamond-Blackfan anemia 263 98 Shwachman-Diamond 49 20 Sickle cell disease 1247 463 Thalassemia 2123 705 *Only first transplants are included in this accrual.

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TO: Primary Immune Deficiencies, Inborn Errors of Metabolism and Other Non-Malignant Marrow Disorders Working Committee Members

FROM: Mary Eapen, MBBS, MS; Scientific Director for the Primary Immune Deficiencies, Inborn Errors of Metabolism and Other Non-Malignant Marrow Disorders Working Committee

RE: Studies in Progress Summary

ID11-01: Outcomes in allogeneic hematopoietic cell transplantation for adrenoleukodystrophy (P Orchard) This study will describe the population of patients with ALD and examine the outcomes post- transplant. The manuscript is being prepared.

AA13-01: Correlation of levels of donor cell chimerism after alloHCT for hemoglobinopathy (A Abraham) This study aims to correlate the kinetics and levels of donor cell engraftment with hemoglobin electrophoresis results. Data analysis is underway.

AA13-02: Malignancies in patients with Fanconi anemia (J Wagner) The aim of the study is to determine whether the risk of solid cancer is higher after allogeneic transplantation compared to non-transplanted patients with Fanconi anemia, and describe the types of solid cancer and the outcome. Data file preparation is underway.

ID12-01: Allogeneic hematopoietic cell transplantation for combined immunodeficiency and common variable immunodeficiency (G Cuvelier/G Guilcher/N Wright) The aim of the study is to analyze the immunologic and transplant outcomes in patients undergoing allogeneic HCT for CID/CVID. Protocol is under development.

ID13-01: Second and Subsequent HCT for congenital neutropenia/kostmann agranulocytosis (S Keogh/P Shaw/J Levine/J Connelly) The aim of the study is to describe the population of patients with severe congenital neutropenia who have undergone HCT, and examine the outcomes post-transplant. Data analysis is underway.

NM14-01: An investigation of the long term neurological outcomes of Hematopoietic Stem Cell Transplant (HCT) in boys with X-linked Adrenoleukodystrophy (X-ALD) (R Wynn/J Boelens/P Orchard) This study aims to evaluate a population of males who have undergone HCT and who are now older than 18 years. In addition, the study will evaluate a similar age-matched population of young men with the biochemical defect of ALD but who have not received HCT. Protocol is under development.

NM14-02: Outcomes of allogeneic hematopoietic cell transplant in patients with Shwachman diamond syndrome (K Myers) The aim of the study is to describe the population of children or adults with Shwachman diamond syndrome who have undergone HCT, and examine the outcomes post-transplant. Protocol is under development.

NM15-01 Outcome of allogeneic Hematopoietic Cell Transplant (HCT) in Erythropoietic Porphyria (A Saad/H Abdel-Azim/J Bloomer). Protocol is under development and supplemental data collection.

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Proposal 1505-03/1511-25

Title: Outcomes Of Allogeneic Stem Cell Transplantation In Patients (Above 18 Years Of Age Or Older) With Paroxysmal Nocturnal Hemoglobinuria (Pnh): A CIBMTR Analysis

Siddhartha Ganguly, MD, FACP, Professor of Medicine, Blood and Marrow Transplantation Program University of Kansas Medical Center, [email protected] Parinda A Mehta, M.D, Cincinnati Children’s Hospital Medical Center, [email protected] Stella M. Davies, MBBS, MRCP, PhD, Cincinnati Children’s Hospital Medical Center, [email protected]

Hypothesis: There is no large study in recent years looking into outcomes after allogeneic stem cell transplantation (HCT) in patients with Paroxysmal Nocturnal Hemoglobinuria (PNH). It will be important to determine which patients are likely to benefit from transplantation, determine proper timing and analyze outcomes after HCT.

Specific aims: • To describe outcomes of patients undergoing allo-HCT for PNH • To identify patient, disease, and transplant related characteristics associated with outcomes in this patient population

Scientific justification: Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal hematopoietic stem cell disease due to an acquired mutation in the X-linked PIG-A gene (1-4) that can present with bone marrow failure, hemolytic anemia, smooth muscle dystonias, and thrombosis (5,6). Once suspected, diagnosing PNH is straightforward because a deficiency of GPI-APs on peripheral blood cells can be readily demonstrated by flow cytometry (7). According to the recommendations of the International PNH Interest Group, patients can be placed into one of the following 3 categories: (1) classic PNH, (2) PNH in the setting of another BM failure syndrome, or (3) subclinical PNH. The PNH clone in patients with subclinical disease is insufficiently large to produce even biochemical evidence of hemolysis, and consequently, patients who fit into this category require no PNH-specific therapy. Patients with PNH in the setting of another BM failure syndrome (usually aplastic anemia or low-risk myelodysplastic syndrome) have at least biochemical evidence of hemolysis, but typically the PNH clone is small (<10%) so that hemolysis does not contribute significantly to the underlying anemia. In these cases, the focus of treatment is on the BM failure component of the disease (8). The PIG-A gene mutation results in deficiency of all glycosyl phosphatidylinositol-anchored proteins (GPI-APs) expressed by hematopoietic cells. Deficiency of CD55 and CD59, which are GPI-anchored complement regulatory proteins, activates the complement cascade on the cell surface and thus causes hemolysis by the terminal complement complex (the membrane-attack complex) (9) The recent introduction of eculizumab, a humanized monoclonal antibody directed against the terminal complement protein C5, has had a significant impact on the management of PNH (10-13.) In patients with classic PNH with symptomatic hemolysis and a large PNH clone (>50%), eculizumab improves hemolysis within days to weeks in majority of patients. Eculizumab is also indicated in patients with PNH and associated thrombosis. However, eculizumab does not correct the inherent clonal defect in PIG-A mutated stem cells and needs to be continued indefinitely. Logically, eculizumab does not treat

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PNH with associated marrow failure syndromes. Bone marrow failure is the second most common cause of death in patients with PNH, next to thrombosis (14). Bone marrow transplantation (BMT) is still the only curative therapy for PNH but is associated with significant morbidity and mortality. Patients meeting criteria for severe aplastic anemia with PNH clones continue to be good candidates for BMT if they are young and have a suitable donor (6).Non myeloablative syngeneic transplantation appears to have no curative role in patients with PNH, suggesting a probable graft versus PNH effect (15) Bemba et al. (16) reported the largest single institution series of 16 patients (female=6, male=10), with a median age of 28 (9-46) years, with PNH treated with allo-HCT from MRD over a period of 20 years. Six of 16 patients were in aplastic phase and the rest were transfusion dependent. Conditioning regimens included Cy plus thoracoabdominal irradiation (N=8) or Cy plus TBI (N=1), or Cy plus other (N=7). All patients engrafted. Nine patients were alive at a median follow-up of 53 (3-169) months. The 5-year survival rate was 58%. A registry study by the International Bone Marrow Transplant Registry (IBMTR) reported outcome of 57 patients, median age 28 (10-47) years, who received an allo-BMT for PNH at 31 transplant centers between 1978 and 1995 (17). Source of hematopoietic cells consisted of MRD (N=48), syngeneic (N=2), or alternative donors (MUD=6, haploidentical=1) (N=7). The majority of patients received a myeloablative preparative regimen. The 2-year probability of survival for the matched sibling group was 56%. Survival was significantly better for those patients with sustained engraftment after allo-BMT (70% versus 10%, P=.0003). Two recipients of syngeneic transplants were well and alive at 8 and 12 years post-transplantation. Only 1 (14%) of 7 alternative donor allograft recipients was alive at the 5-year follow-up. This suggests that TRM may be more pronounced in recipients of alternative donor allografts. Nonetheless, the study is limited by its retrospective nature and the relative small sample size. The most common causes of adverse outcomes were graft failure and infections. Reduced intensity transplantation is associated with less treatment related mortality and being used more frequently in recent years for patients with PNH requiring BMT (18, 19). Since the introduction of eculizumab, number of patients referred for stem cell transplantation might have gone down (6, 20), but the exact data is not available. Introduction of eculizumab has introduced several new challenges since the last report from IBMTR in 1999 (17), including possible delay in referral for transplantation, increased susceptibility to infection, significant cost burden to the society and selection bias (18,21). The application of BMT to treat PNH is also limited by the lack of suitable donors. However, use of post transplantation cyclophosphamide and haplo-identical transplantation might increase the availability of potential donors in future (22). Several questions remain unaddressed. 1. When is the right time to consider HSCT? 2. Is there a plateau in survival or a graft versus PNH effect in patients undergoing allo-HCT? 3. What is the most effective preparative regimen for PNH? 4. What is the preferred regimen for GVHD prophylaxis? 5. What risks factors should be considered when selecting patients for HCT? And, 6. The role of eculizumab before transplantation

Large-scale studies to investigate the role of allo-HCT in patients with PNH have not been performed. The large size of the CIBMTR registry provides an opportunity to study these prognostic factors in a well powered study. The data from this study will provide useful information as below:

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a. Identifying patients likely to benefit from HCT will give confidence to the referring physicians in the option of HCT, and improve the referral of these patients to transplant centers. b. Identifying patients unlikely to benefit from HCT will spare these patients side-effects associated with HCT. In addition, these patients could benefit from novel transplant or non-transplant related treatment options. c. Patient counseling d. Design of future clinical trials comparing allogeneic and non-allogeneic treatment options, as well as clinical trials designed to improve the dismal outcome post-HCT of advanced patients with BPDCN.

Study population: Using the CIBMTR database, patients with PNH who underwent HCT between 2000 and 2013 and meet the following criteria will be identified. Inclusion Criteria (should meet all the criteria): • Age 18 years and older • First allogenic transplantation • Diagnosis of classic PNH • Transplant from a matched related donor, well-matched unrelated donor or partially matched unrelated donor including haplo-identical donor and cord blood transplantation Exclusion Criteria: • In vitro T cell depletion • Previous allogeneic transplantation • Progression to leukemia • Marrow failure syndromes with insignificant PNH clone

Outcomes: Primary outcomes to be studied include: • Non-Relapse Mortality: time to death without evidence of disease relapse. Relapse is the competing risk, and patients surviving in continuous complete remission are censored at last follow up. • Cumulative Incidence of Relapse: time to onset of PNH recurrence. NRM is the competing risk, and patients surviving in continuous complete remission will be censored at last contact. • Disease-Free survival: Time to treatment failure (death or relapse). Patients surviving in continuous complete remission are censored at time of last follow-up. • Overall Survival: Time to death from any cause. Surviving patients are censored at time of last follow-up. • Acute graft-versus-host disease: Time to onset of grades II-IV or III-IV aGVHD by Glucksburg criteria, death is a competing risk. • Chronic graft-versus-host disease: Time to onset of cGvHD, death is a competing risk.

Variables to be analyzed: Patient Related: • Age at HCT • Gender • Karnofsky Performance scores: <90 vs ≥90 • Hematopoietic cell transplant-comorbidity index (HCT-CI) (23) (depending on availability of data)

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Disease Related: • Indication of Transplantation: Marrow failure without associated hemolysis or thrombosis versus marrow failure with associated hemolysis and/or thrombosis versus others • Prior use of eculizumab: yes or no • Time from diagnosis to transplant • Hb at the time of transplant: <7 versus 7-10 versus >10 • Thrombosis at the time of transplant: yes or no • Hemolysis present at the time of transplant: yes or no • Ferritin at the time of transplant: <1000 versus >1000 • Creatinine at the time of transplant: <2 versus >2 Transplant Related: • ABO Compatibility: yes versus no • Conditioning regimen: MAC vs. RIC vs. NMA as defined by CIBMTR (24). • Donor type: MSD vs. well matched URD vs. others • CMV status of donor and recipient: +/+ vs. +/- vs. -/+ vs. -/- • Source of hematopoietic cells: BM vs. PBSC • GVHD prophylaxis: Calcineurin inhibitor (CNI) + MTX vs. CNI + MMF versus others • Received Serotherapy with either campath or ATG: yes/no • TBI yes or no • Time period transplant was performed: 2000-2004; 2005-2008 vs. 2009-2013

Study design: This is a retrospective study of CIBMTR data between 2000 and 2013. The purpose of the proposed study is to examine the outcomes of patients age ≥18 undergoing allo-HCT for PNH. For all patients undergoing allo-HCT for PNH, the distribution of the previously described patient, disease and transplant related variables will be examined. Subgroup comparisons may be performed using chi-square test for categorical variables and Kruskal Wallis test for continuous variables. Univariate analysis will be performed using Kaplan-Meier Method and will be compared using log-rank test for OS and LFS, while non-relapse mortality (NRM) and cumulative incidence of relapse (CIR) will be calculated using the cumulative incidence method considering competing risks, with comparisons performed using Gray method (25) Multivariate analysis will also be performed using Cox proportional hazard model for OS, LFS, NRM and CIR. The variables to be considered in the multivariate models are listed in Sections 6.0. The assumption of proportional hazards for each factor in the Cox model will be tested using time-dependent covariates. When the test indicated differential effects over time (non-proportional hazards), models will be constructed breaking the post-transplant time course into two periods, using the maximized partial likelihood method to find the most appropriate breakpoint. The proportionality assumptions will be further tested. A backward stepwise model selection approach will be used to identify all significant risk factors. Each step of model building contained the main effect for remission status, which is the primary object of this proposed study. Factors which are significant at a 5% level will be kept in the final model. The potential interactions between main effect and all significant risk factors will be tested. The subsequent analysis plan will be developed depending on sample size after discussion with the statistics team at CIBMTR. In order to assess the variable HCT-CI score, a subgroup analysis may be performed which looks only at patients with an available HCT-CI score (documented since 2007). The distribution of patient, disease and transplant related variables will be compared between patients with vs. without HCT-CI score after 2007 using Chi-square test and Kruskal-Wallis test to ensure there is no potential selection bias.

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Patients may be divided into two groups: those with low risk (HCT-CI 0-2) and those with high-risk comorbidities (HCT-CI ≥3). If univariate analysis for outcomes demonstrates p-value <0.1, then repeat multivariable analysis may be performed for this subgroup in order to assess the impact of the co- morbidity score. In order to assess the role of pre transplant eculizumab, a subgroup analysis may be performed which looks only at patients with pre transplant eculizumab exposure versus those who were never been treated with eculizumab (documented since 2007). The distribution of patient, disease and transplant related variables will be compared between patients with vs. without eculizumab exposure after 2007 using Chi-square test and Kruskal-Wallis test to ensure there is no potential selection bias. Patients may be divided into two groups: those with pre transplant exposure to eculizumab and those without. If univariate analysis for outcomes demonstrates p-value <0.1, then repeat multivariable analysis may be performed for this subgroup in order to assess the impact of the co-morbidity score. The above analysis plan may be modified depending on sample size in the final data set, and further input from statistical team at the CIBMTR.

References: 1. Kinoshita T, Inoue N, Takeda J. Role of phosphatidylinositol linked proteins in paroxysmal nocturnal hemoglobinuria pathogenesis. Ann Rev Med 1996; 47: 1–10. 2. Rosse WF, Ware RE. The molecular basis of paroxysmal nocturnal hemoglobinuria. Blood 1995; 86: 3277–3286. 3. Takeda J, Miyata T, Kawagoe K, Iida Y, Endo Y, Fujita T, et al. Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria. Cell. 1993; 73(4):703–11. 4. Brodsky RA. Narrative review: paroxysmal nocturnal hemoglobinuria: the physiology of complement- related hemolytic anemia. Ann Intern Med. 2008; 148(8):587–95. 5. Parker CJ. Historical aspects of paroxysmal nocturnal haemoglobinuria: “defining the disease.” Br J Haematol. 2002; 117:3-22. 6. Brodsky R. How I Treat Paroxysmal Nocturnal hemoglobinuria. Blood 2009; 113: 6522-6527 7. Borowitz MJ, Craig FE, Digiuseppe JA, et al. Guidelines for the diagnosis and monitoring of paroxysmal nocturnal hemoglobinuria and related disorders by flow cytometry. Cytometry B Clin Cytom. 2010;78:211-230 10. Parker CJ. Management of Paroxysmal Nocturnal Hemoglobinuria in the Era of Complement Inhibitory Therapy. Hematology Am Soc Hematol Educ Program. 2011;2011:21-9 11. Brodsky RA. Paroxysmal Nocturnal hemoglobinuria. Blood 2014; 124: 2804-2811 12. Hillmen P, Young NS, Schubert J, Brodsky RA, Socie G, Muus P, et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med. 2006;355(12):1233–43 13. Hillmen P, Muus P, Duhrsen U, Risitano AM, Schubert J, Luzzatto L, et al. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood. 2007; 110(12):4123–8. 14. Brodsky RA, Young NS, Antonioli E, Risitano AM, Schrezenmeier H, Schubert J, et al. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood. 2008;111(4): 1840–7 15. Kanakura Y, Ohyashiki K, Shichishima T, Okamoto S, Ando K, Ninomiya H, et al. Safety and efficacy of the terminal complement inhibitor eculizumab in Japanese patients with paroxysmal nocturnal hemoglobinuria: the AEGIS clinical trial. Int J Hematol. 2011;93(1):36–46 Paroxysmal Nocturnal Hemoglobinuria and the Glycosylphosphatidylinositol-linked Proteins. In: Young NS and Moss J, eds. Academic Press, 2000 16. Dunn DE, Liu JM, and Young NS. Paroxysmal Nocturnal Hemoglobinuria and the Glycosylphosphatidylinositol-linked Proteins. In: Young NS and Moss J, eds. Academic Press, 2000; p116.

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17. Bemba M, Guardiola P, Garderet L, et al. Bone marrow transplantation for paroxysmal nocturnal haemoglobinuria. Br J Haematol. 1999;105:366-368 18. Saso R, Marsh J, Cevreska L, et al. Bone marrow transplants for paroxysmal nocturnal haemoglobinuria. Br J Haematol. 1999; 104:392-396 19. Nelson A. Matos-Fernandez, Yasser R. Abou Mourad, William Caceres, Mohamed A. Kharfan-Dabaja. Current Status of Allogeneic Hematopoietic Stem Cell Transplantation for Paroxysmal Nocturnal Hemoglobinuria. Biol Blood Marrow Transplant 2009; 15: 656-661 20. Pantin J, Tian X, Geller N, Ramos C, Cook L, Cho E, Scheinberg P, Vasu S, Khuu H, Stroncek D, Barrett J, Young NS, Donohue T, Childs RW. Long-term outcome of fludarabine-based reduced-intensity allogeneic hematopoietic cell transplantation for debilitating paroxysmal nocturnal hemoglobinuria. Biol Blood Marrow Transplant. 2014 Sep;20(9):1435-9 21. Parker CJ. Bone marrow failure syndromes: paroxysmal nocturnal hemoglobinuria. Hematol Oncol Clin North Am. 2009;23: 333-346 22. Kyoko Taniguchi, Masaya Okada, Satoshi Yoshihara, Akihiro Sawada, Tazuko Tokugawa, Shinichi Ishii, Katsuji Kaida, Kazuhiro Ikegame, Kentaro Minagawa, Toshimitsu Matsui, Hiroyasu Ogawa. Strategy for bone marrow transplantation in eculizumab-treated paroxysmal nocturnal hemoglobinuria. Int J Hematol (2011) 94:403–407 23. RA Brodsky, L Luznik, J Bolaños-Meade, MS Leffell, RJ Jones, and EJ Fuchs. Reduced intensity HLA- haploidentical BMT with post transplantation cyclophosphamide in nonmalignant hematologic diseases. Bone Marrow Transplant. 2008 October ; 42(8): 523–527 24. Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106:2912–2919 25. Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V, Apperley J, Slavin S, Pasquini M, Sandmaier BM, Barrett J, Blaise D, Lowski R, Horowitz M. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant. 2009;15:1628-1633 26. Fine J, Gray R. A proportional hazards model for the sub distribution of a competing risk. J Am Stat Assoc. 1999; 94: 496-509

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Characteristics of patients in U.S.A. who underwent an alloHCT for PNH reported to the CIBMTR from 2000-2013 - supplemental data required

HLA identical siblings Unrelated Variable N (%) N (%) Number of patients 22 49 Number of centers 18 37 Age at transplant, years Median 30 (11-55) 28 (9-71) ≤10 0 2 ( 4) 11-18 5 (23) 13 (27) 19-29 6 (27) 10 (20) 30-39 6 (27) 17 (35) 40-49 4 (18) 3 ( 6) 50-59 1 ( 5) 3 ( 6) ≥60 0 1 ( 2) Sex Male 12 (55) 20 (41) Female 10 (45) 29 (59) Graft type Bone marrow 11 (50) 17 (35) Peripheral blood 11 (50) 23 (47) Umbilical cord blood 0 9 (18) HLA donor match (unrelated) Well-matched N/A 26 (53) Partially matched 10 (20) Mismatched 9 (18) Unknown 4 ( 8) Year of HCT 2000 0 2 ( 4) 2001 4 (18) 4 ( 8) 2002 2 ( 9) 1 ( 2) 2003 4 (18) 2 ( 4) 2004 1 ( 5) 4 ( 8) 2005 4 (18) 4 ( 8) 2006 1 ( 5) 9 (18) 2007 2 ( 9) 2 ( 4) 2008 3 (14) 10 (20) 2009 0 6 (12) 2011 0 2 ( 4) 2013 1 ( 5) 3 ( 6)

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Proposal 1510-18

Title: Outcomes for adults with hemophagocytic lymphohistiocytosis requiring HSCT

Benjamin Kent Nagy Tomlinson, MD, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer center, [email protected] Marcos de Lima, MD, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer center [email protected]

Hypothesis: Allogeneic stem cell transplant can be an effective treatment strategy for select adults with familial, persistent, or relapsed hemophagocytic lymphohistiocytosis.

Specific aims: Primary Objective: • Evaluated overall survival of patients age 18 and older receiving allogeneic HSCT for hemophagocytic lymphohistiocytosis Secondary Objectives: • Evaluate disease free survival • Evaluate outcome of transplant, including rates of acute and chronic GVHD and treatment related mortality • Evaluate disease, patient, and treatment related factors for potentially prognostic benefit

Scientific justification: Hemophagocytic lymphohistiocytosis (HLH) is a rare disease defined by an uncontrolled immune response with very high levels of cytokines felt due to aberrant NK and cytotoxic T-cell function. HLH is usually classified as primary (familial) or secondary with numerous underlying etiologies including malignant, infectious, and autoimmune.(1, 2) It presents with a variable combination of fevers, cytopenias, hepatosplenomegaly, and involvement of the CNS often identified in the literature as the hematophagocytic syndrome.(3) Diagnosis is often difficult as not all clinical features and laboratory findings are always present, and no validated diagnostic criteria exist, although generally accepted criteria are 5 of 8 features defined in the HLH-2004 protocol.(4) These features are fevers, splenomegaly, cytopenia, hypertriglyceridemia, hyperferritinemia, elevated soluable IL-2 receptor, reduced NK-cell activity, and pathologically documented hemophagocytosis.(5) Most experience with the disease and its treatment is derived from the pediatric population and the HLH-94 and the ongoing HLH-2004 protocols.(6) For familial, relapsed or persistent HLH in children, the standard of care is HSCT, which can be curative in over 60% of patients who are able to receive a transplant. Moreover, pediatric data has also found that reduced intensity condition can be effective.(7, 8) In adults, however, optimal treatments and outcomes are poorly defined. The incidence in the adult population is unknown, but it’s notable that publication of reports has increased in recent years. The vast majority of cases in the literature are parts of retrospective series, but over 1000 have been reported.(9-19) Most authors posit that the vast majority of cases in adults are secondary, though some cases of primary HLH have been reported.(20, 21)

Reports of treatment and outcomes in adults with HLH vary widely. Most reports denote treatment with immunosuppressive therapy including steroids and etoposide. Reported mortality rates range from 20% to 75% but with wildly variable median follow up, sometimes less than 2 months.(12, 15, 22)

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Published treatment algorithms are derived from treatment of the pediatric population, but treatment is tailored to the individual patient as often underlying disease needs to be treated. Moreover, there are published observations of spontaneous remissions without treatment and good outcomes with therapy alone.(23) HSCT is recommended by authors for adults with persistent or familial disease.(1) Unfortunately, few reports of HSCT for adults with HLH exist, and so outcomes are poorly defined. Park et al described a cohort of 23 patients in a single institution in Korea with HLH not associated with lymphoma. 5 of these patients underwent allogeneic stem cell transplant which appeared to be associated with improved outcome.(24) Case reports in an adult patients have also found successful transplantation following treatment with alemtuzumab.(1, 25) Analysis of CIBMTR data may be able to evaluated treatment outcomes for adult patients who undergo allogeneic stem cell transplant for HLH. While this would not capture the entire adult population with this disease, it would likely capture a high risk cohort and test the hypothesis that allogeneic stem cell transplant is an effective therapy for adults with HLH, as well as help define the rates of mortality and treatment toxicity.

Patient eligibility population: Inclusion criteria: • Allogeneic HSCT recipients 2000 to 2014 age 18 and over with a primary diagnosis of HLH. Exclusion criteria • Any prior stem cell transplant • HLH not the primary diagnosis (e.g. patients with lymphoma as the primary reason for HSCT

Data requirements: • Patient Data • Age • Gender • Race HLH related data • Date of diagnosis • Family history • Genetic testing and pertinent positives • Clinical features at diagnosis: • Fevers, Hepatomegaly, splenomegaly • Anemia, neutropenia, thrombocytopenia • Labs: Ferritin level, Triglycerides, fibrinogen • CSF: neopterin, protein, WBC • Documented sites of hemophagocytosis • Disease assessment prior to preparative regimen • Neurologic abnormalities • CNS imaging abnormalities • History of infection – if yes, what infection • Therapy with details • Therapy response • Clinical details prior to HSCT • Fevers, Hepatomegaly, splenomegaly • Anemia, neutropenia, thrombocytopenia • Labs: Ferritin level, Triglycerides, fibrinogen

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• CSF: neopterin, protein, WBC • Documented sites of hemophagocytosis Allogeneic HSCT related data • Date of allogeneic HSCT • HSCT type • Preparative regimen and preparative regimen intensity • Donor type • Stem cell source • GVHD prophylaxis • GVHD occurrences and grade • Date of relapse (if applicable) • Date of death or last known contact • Cause of death (treatment vs disease vs unrelated)

Study design: This will be a retrospective review of all patients meeting inclusion criteria. Patient and disease characteristics will be collected from the CIBMTR registry. Overall survival and disease free survival will be evaluated with Kaplan-Meier methods. Treatment related mortality and HLH relapse will be calculated using cumulative incidence curves. Potential patient, disease, and treatment related prognostic factors will be evaluated with multivariate analysis with Cox proportional hazards regression.

References: 1. Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult patient. 2015;125:2908-14. 2. George MR. Hemophagocytic lymphohistiocytosis: review of etiologies and management. Journal of blood medicine. 2014;5:69-86. 3. Huang W, Wang Y, Wang J, Zhang J, Wu L, Li S, et al. [Clinical characteristics of 192 adult hemophagocytic lymphohistiocytosis]. Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi. 2014;35:796-801. 4. Hejblum G, Lambotte O, Galicier L, Coppo P, Marzac C, Aumont C, et al. A web-based delphi study for eliciting helpful criteria in the positive diagnosis of hemophagocytic syndrome in adult patients. PloS one. 2014;9:e94024. 5. Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatric blood & cancer. 2007;48:124- 31. 6. Trottestam H, Horne A, Arico M, Egeler RM, Filipovich AH, Gadner H, et al. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol. Blood. 2011;118:4577-84. 7. Cooper N, Rao K, Gilmour K, Hadad L, Adams S, Cale C, et al. Stem cell transplantation with reduced- intensity conditioning for hemophagocytic lymphohistiocytosis. Blood. 2006;107:1233-6. 8. Marsh RA, Vaughn G, Kim MO, Li D, Jodele S, Joshi S, et al. Reduced-intensity conditioning significantly improves survival of patients with hemophagocytic lymphohistiocytosis undergoing allogeneic hematopoietic cell transplantation. Blood. 2010;116:5824-31. 9. Shabbir M, Lucas J, Lazarchick J, Shirai K. Secondary hemophagocytic syndrome in adults: a case series of 18 patients in a single institution and a review of literature. Hematological oncology. 2011;29:100-6.

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10. Dhote R, Simon J, Papo T, Detournay B, Sailler L, Andre MH, et al. Reactive hemophagocytic syndrome in adult systemic disease: report of twenty-six cases and literature review. Arthritis and rheumatism. 2003;49:633-9. 11. Karlsson T. Secondary haemophagocytic lymphohistiocytosis: Experience from the Uppsala University Hospital. Upsala journal of medical sciences. 2015:1-6. 12. Otrock ZK, Eby CS. Clinical characteristics, prognostic factors, and outcomes of adult patients with hemophagocytic lymphohistiocytosis. Blood. 2015;90:220-4. 13. Li J, Wang Q, Zheng W, Ma J, Zhang W, Wang W, et al. Hemophagocytic lymphohistiocytosis: clinical analysis of 103 adult patients. Medicine. 2014;93:100-5. 14. Takahashi N, Chubachi A, Kume M, Hatano Y, Komatsuda A, Kawabata Y, et al. A clinical analysis of 52 adult patients with hemophagocytic syndrome: the prognostic significance of the underlying diseases. International journal of hematology. 2001;74:209-13. 15. Arca M, Fardet L, Galicier L, Riviere S, Marzac C, Aumont C, et al. Prognostic factors of early death in a cohort of 162 adult haemophagocytic syndrome: impact of triggering disease and early treatment with etoposide. Blood. 2015;168:63-8. 16. Riviere S, Galicier L, Coppo P, Marzac C, Aumont C, Lambotte O, et al. Reactive hemophagocytic syndrome in adults: a retrospective analysis of 162 patients. The American journal of medicine. 2014;127:1118-25. 17. Imashuku S, Kuriyama K, Sakai R, Nakao Y, Masuda S, Yasuda N, et al. Treatment of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) in young adults: a report from the HLH study center. Medical and pediatric oncology. 2003;41:103-9. 18. Parikh SA, Kapoor P, Letendre L, Kumar S, Wolanskyj AP. Prognostic factors and outcomes of adults with hemophagocytic lymphohistiocytosis. Mayo Clinic proceedings. 2014;89:484-92. 19. Fardet L, Lambotte O, Meynard JL, Kamouh W, Galicier L, Marzac C, et al. Reactive haemophagocytic syndrome in 58 HIV-1-infected patients: clinical features, underlying diseases and prognosis. AIDS (London, England). 2010;24:1299-306. 20. Zhang K, Jordan MB, Marsh RA, Johnson JA, Kissell D, Meller J, et al. Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood. 2011;118:5794-8. 21. Clementi R, Emmi L, Maccario R, Liotta F, Moretta L, Danesino C, et al. Adult onset and atypical presentation of hemophagocytic lymphohistiocytosis in siblings carrying PRF1 mutations. Blood. 2002;100:2266-7. 22. Oto M, Yoshitsugu K, Uneda S, Nagamine M, Yoshida M. Prognostic Factors and Outcomes of Adult- Onset Hemophagocytic Lymphohistiocytosis: A Retrospective Analysis of 34 Cases. Hematology reports. 2015;7:5841. 23. Belyea B, Hinson A, Moran C, Hwang E, Heath J, Barfield R. Spontaneous resolution of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Pediatric blood & cancer. 2010;55:754-6. 24. Park HS, Kim DY, Lee JH, Lee JH, Kim SD, Park YH, et al. Clinical features of adult patients with secondary hemophagocytic lymphohistiocytosis from causes other than lymphoma: an analysis of treatment outcome and prognostic factors. Annals of hematology. 2012;91:897-904. 25. Strout MP, Seropian S, Berliner N. Alemtuzumab as a bridge to allogeneic SCT in atypical hemophagocytic lymphohistiocytosis. Nature reviews Clinical oncology. 2010;7:415-20.

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Characteristics of ≥ 18 years patients who underwent an alloHCT for hemophagocytic lymphohistiocytosis registered to the CIBMTR from 2000-2014 - supplemental data required

Variable N (%) Number of patients 33

Number of centers 18

Age at HCT, years Median 23 (18-68) 18-29 24 (73) 30-39 5 (15) 40-49 1 ( 3) 50-59 1 ( 3) ≥60 2 ( 6)

Donor type HLA-identical sibling 6 (18) Unrelated donor 27 (82)

Graft type Bone marrow 18 (55) Peripheral blood 14 (42) Umbilical cord blood 1 ( 3)

Year of HCT 2004-2010 12 (36) 2011-2014 21 (64)

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Proposal 1511-09

Title: Clinical course and outcome of allogeneic hematopoietic stem cell transplantation in Glanzmann thrombasthenia

Sureyya Savasan, MD, Children’s Hospital of Michigan/Wayne State University, [email protected] Voravit Ratanatharathorn, MD, Barbara Ann Karmanos Cancer Center/Wayne State University, [email protected]

Specific aims: • To determine clinical course and outcome of allogeneic hematopoietic stem cell transplantation (HSCT) in Glanzmann thrombasthenia (GT) • To review frequency and effect of platelet alloimmunization on the course and outcome of allogeneic HSCT in GT

Scientific justification: Glanzmann thrombasthenia is a rare qualitative platelet defect, which is characterized by severely decreased expression of glycoprotein IIb-IIIa complex on the platelet surface in the most severe (type I) form associated with significant and at times life-threatening bleeding episodes. Several different interventions have been used with varying degree of success in controlling the local bleeding. Platelet transfusions are often left for life-threatening episodes, since they are associated with the development of platelet alloimmunization complicating the management further (1). Food and Drug Administration has recently approved use of recombinant activated Factor VII (rFVIIa) for the management of bleeding in GT. Only allogeneic HSCT is the curative form of therapy for severe GT. Since the first report of successful HSCT in 1985, the largest reported series has included a total of 19 transplants in 18 patients performed for GT (2-3). Since the publication of that report, there have been two more cases that appeared in the literature (4-5). Matched related and unrelated donors and umbilical cord blood cells and both myeloablative and reduced intensity conditioning have been utilized.

Patient eligibility population: Data will be collected from patients who meet the following inclusion criteria: • Allogeneic HSCT recipients for GT of all ages reported to CIBMTR • Related or unrelated bone marrow or peripheral stem cell donors as well as umbilical cord blood cells

Data requirements: In addition information from pre-transplant essential data form along with reporting forms for day 100, 6 months – 2yrs and annual forms thereafter will provide the needed data Platelet alloimmunization, platelet and packed red blood cell (PRBC) transfusion, and use of rFVIIa data prior to and following HSCT, if available

Sample requirements: Preliminary data obtained from CIBMTR in May 2015 revealed 29 allogeneic HSCT recipients for GT reported. Characteristics of these 29 patients will be summarized in the attached table.

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Study design: Data will be collected on all patients who underwent allogeneic HSCT for GT. The following date will be attempted to be collected when they are available: Patient demographics, clinical course and outcomes Number of platelet and PRBC transfusion history prior to transplant and following transplant Incidence of both pre-and post-HSCT platelet alloimmunization Effect of platelet alloimmunization on the course and outcome of transplant when data are available. Use of rFVIIa use before and after stem cell infusion

Data analysis: Primary Outcome: • Overall survival: time to death from any cause. Event will be summarized by a survival curve. Patients are censored at time of last follow-up visit. There are no competing risks. Secondary Outcomes: • Acute GVHD, grades II-IV: development of Grades II – IV acute GVHD using Glucksberg system which grades GVHD based on the pattern and severity of abnormalities in skin, gastrointestinal and liver. The event will be summarized by the cumulative incidence estimate with death and second transplant as competing risks. • Acute GVHD, grades III-IV: development of Grades III – IV acute GVHD using Glucksberg system which grades GVHD based on the pattern and severity of abnormalities in skin, gastrointestinal and liver. The event will be summarized by the cumulative incidence estimate with death and second transplant as competing risks. • Chronic GVHD: development of symptoms in any organ system fulfilling the criteria of limited or extensive chronic GVHD. The event will be summarized by the cumulative incidence estimate with death and second transplants as competing risks. • Relapse/Graft failure: Graft failure or disease recurrence. The event will be summarized by the cumulative incidence estimate with treatment-related mortality as competing risk. • Disease-free survival: Survival without graft failure or recurrence. Recurrence or graft failure and death are events. The event is summarized by a survival curve. Those who survive without recurrence or progression are censored at last contact. • Treatment-related mortality (TRM): Death in the first 28 days post-transplant or death without graft failure or in continuous remission. The event is summarized by the cumulative incidence estimate with graft failure or relapse as the competing risk.

Variables to include in the analyses: Patient Related: • Age: categorical based on the data: 21-40 vs. 41-50 vs. 51-70 • Gender: male vs. female • Lansky/Karnofsky performance score: < 90 vs. ≥ 90 Disease Related: • Platelet alloimmunization • Bleeding locality and severity • Platelet and PRBC transfusion history • History of rFVIIa history Transplant Related: • Source of stem cells: bone marrow vs. peripheral blood vs cord blood • Donor type: HLA-identical sibling vs. unrelated donor

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• Interval from diagnosis to transplant: will have to look at the distribution of the interval between diagnosis and transplantation and determine the cutoff point • Conditioning regimen: myeloblative vs. reduced intensity • GVHD prophylaxis: Cyclosporine (CSA) ± others vs. tacrolimus (FK506) ± others • Donor-recipient sex match: M-M vs. M-F vs. F-M vs. F-F • Donor parity: female donor, one or more pregnancies vs. others • HLA matching: well-matched vs. partially matched vs. mismatched (see attached table 1 for details) • Donor-recipient CMV serology: -/- vs. others • Year of transplant: based on the data

References: 1. Solh T, Botsford A, Solh M. Glanzmann's thrombasthenia: pathogenesis,diagnosis, and current and emerging treatment options. J Blood Med. 2015;8;6:219-27. 2. Bellucci S, Devergie A, Gluckman E, Tobelem G, Lethielleux P, Benbunan M,Schaison G, Boiron M. Complete correction of Glanzmann's thrombasthenia by allogeneic bone-marrow transplantation. Br J Haematol. 1985;59:635-41. 3. Wiegering V, Sauer K, Winkler B, Eyrich M, Schlegel PG. Indication for allogeneic stem cell transplantation in Glanzmann's thrombasthenia. Hamostaseologie. 2013;33:305-12. 4. Ramzi M, Dehghani M, Haghighat S, Nejad HH. Stem Cell Transplant in Severe Glanzmann Thrombasthenia in an Adult Patient. Exp Clin Transplant. 2015 Jul 2. 5. Walz A, Lenzen A, Curtis B, Canner J, Schneiderman J. Use of allogeneic stem cell transplantation for moderate-severe Glanzmann thrombasthenia. Platelets. 2015;26:702-4.

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Characteristics of patients who underwent an alloHCT for Glanzmann thrombasthenia registered to the CIBMTR from 2000-2013- supplemental data required

Variable N (%) Number of patients 30

Number of centers 21

Age at HCT, years Median 9 (1-42) <10 20 (67) 10-19 8 (27) 20-29 1 ( 3) 40-49 1 ( 3)

Donor type HLA-identical sibling 10 (33) Unrelated donor 20 (67)

Graft type Bone marrow 16 (53) Peripheral blood 4 (13) Umbilical cord blood 10 (33)

Year of HCT 2000-2006 13 (44) 2008-2013 17 (56)

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Proposal 1511-13

Title: Allogeneic Hematopoietic Cell Transplantation for Primary Immune Deficiencies: Current Patterns of Practice and Change over the last 10 years

Rebecca Marsh, MD, Cincinnati Children’s Hospital, [email protected]

Hypothesis : We hypothesize that allogeneic hematopoietic cell transplantation practice patterns have changed for patients with primary immune deficiencies and that outcomes have improved over the last 10 years.

Specific aims: • To compare the choice of conditioning regimen intensity for patients with primary immune deficiencies treated in the last 10 years to previous decades, and examine differences in choice of conditioning regimens among patients with different primary immune deficiency disease categories. • To examine the covariates which may impact overall and event free survival of patients with primary immune deficiencies including decade of transplant, conditioning regimen intensity, age, HLA match, graft source, development of grades II-IV and III-IV acute GVHD, and underlying diagnosis.

Scientific justification: There are no recent large non-European studies of outcomes for patients with primary immune deficiencies (PID) treated with allogeneic HCT. In particular, there are only very limited studies which compare the outcomes of patients with different PID disorders, or compare the outcomes of different conditioning regimen intensity approaches for PIDs. This information is critical for clinicians to consider when making decisions regarding proceeding to transplant, ad regarding conditioning intensity. This information is also vital for patients and parents who are being counseled about expected outcomes. Data from Europe regarding PID patients treated between 1968 and 2005 (Gennery et al, 2010) suggests that outcomes have improved over time in Europe. Only smaller series of patients from North America exist to suggest the same, particularly with regard to WAS (Moratto et al, 2011, Shin et al, 2012). Indeed, a 2008 workshop sponsored by the Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases, and the Office of Rare Diseases at the National Institutes of Health published a summary stating that there is a “…critical need for evaluation of the North American experience of different HCT approaches for these diseases” (Griffith et al, 2008). Series of patients in North America demonstrate that a variety of conditioning approaches are undertaken for PID patients, even for patients within a uniform diagnostic category such as SCID (Pai et al, 2014). A recent CIBMTR study (Eapen et al, 2012) analyzed long term outcomes of patients with non-malignant disorders that included PID patients, but only included patients who had survived at least 2 years following HCT. The report did not detail outcomes between PID diagnostic groups or analyze the outcomes of different conditioning approaches for PID patients in general or for patients within different disease groups.

We hypothesize that allogeneic HCT practice patterns have changed in the last 10 years for patients with PIDs and that outcomes have improved. We hypothesize that decade of transplant, conditioning regimen choice, donor HLA match, source of graft, development of grades III-IV acute GVHD, and underlying diagnosis impact outcomes. Analysis of the CIBMTR data regarding outcomes for PID

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patients treated over the last 10 years and comparison to earlier patients will allow us to test these hypotheses. These data will contribute a summary of the current “state of the art” of allogeneic HCT for patients with PID, and will serve as a ready historical reference for future prospective studies of PID HCT outcomes.

Patient eligibility population: We have familiarized ourselves with existing CIBMTR data collection forms. We will include all patients with a primary immune deficiency diagnosis transplanted at an age of 29 years or less and transplanted in the year 2014 or earlier. We will include all donor and graft types and transplant regimens. We will categorize patients by diagnosis group and categorize and transplant regimen intensity (and receipt of serotherapy or not if the sample sizes allow) prior to analyses.

Data requirements: Recipient Baseline Data o Hematopoietic Stem Cell Transplant (HCT) Infusion o Immune Deficiencies Pre-HSCT Data o X-Linked Lymphoproliferative Syndrome Pre-HCT Data o Hemophagocytic Lymphohistiocytosis Pre-HCT Data o 100 Day Post-HSCT Data • Six Months to Two Years Post-HSCT Data • Yearly Follow-Up for Greater than Two Years Post-HSCT Data

Variables to be analyzed/described: • Date of HCT • Date of repeat HCT • Diagnosis • Genetic Diagnosis if reported • Age • HLA Match • Relation • Graft Source • Conditioning Regimen • GVHD Prophylaxis • Engraftment (ANC and PLT) • Survival/death, last follow up • Cause of Death • Acute GVHD grades II-IV • Acute GVHD grades III-IV • Chronic GVHD limited • Chronic GVHD extensive • Graft modification (T cell depletion/CD34+ selection) • History of mechanical ventilation prior to HCT (surrogate for significant illness) • History of HLH prior to HCT (patients transplanted October 2013 and later) • Active HLH or not at the time of HCT (patients transplanted October 2013 and later) • SCID Phenotype: CD4+ T cell, CD8+T cell, NK, and B cell #s as reported

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Study design (scientific plan) • To compare the choice of conditioning regimen intensity for patients with primary immune deficiencies treated in the last 10 years to previous decades, and examine differences in choice of conditioning regimens among patients with different primary immune deficiency disease categories. This aim will be addressed by summarizing the CIBMTR data regarding patient underlying diagnosis and choice of conditioning regimen by categories including myeloablative, reduced intensity but myeloblative, non-myeloablative reduced intensity, and immune suppression or none, and the diagnostic categories of HLH, XLP, SCID, CID/CVID, CGD, WAS, HIgM, IPEX, and Other. If the sample sizes are large enough, we may create additional diagnosis categories and create serotherapy categories. This information would be summarized in a Table in a manuscript. • To examine the covariates which may impact overall and event free survival of patients with primary immune deficiencies including decade of transplant, conditioning regimen intensity, receipt of serotherapy or not, age, HLA match and relation, graft source, T cell depletion or not, development of grades II-IV and III-IV acute GVHD, chronic extensive GVHD, and underlying diagnosis. This aim would be addressed with the following. We would create Kaplan Meier survival and event-free survival curves of all primary immune deficiency patients categorized by decade, with the last decade including patients treated from 2004-2014 (assuming it is a year until the data analysis actually begins at the University of Wisconsin). Groups would be compared using the log-rank test. We would then analyze the following for the patients as a whole and just within the last 10 year group: conditioning regimen intensity, serotherapy, T cell depletion, underlying patient diagnosis group, age at HCT (divided by quartiles), HLA match and relation (MSD, MUD, MMUD, haploidentical), graft source (bone marrow, PBSC, cord blood), development of acute GVHD grades II-IV or III-IV, and development of chronic extensive GVHD. If the number of patients allows, we will also compare patients based on graft+conditioning groupings to allow analysis of outcomes in groups of patients treated with haploidentical T cell depleted grafts with and without conditioning (most relevant for SCID). If applicable within each transplant regimen intensity category, we will also analyze outcomes based on receipt of alemtuzumab, ATG, or neither. If the sample sizes are large enough, we will examine history of mechanical ventilation prior to HCT (as a surrogate for significant illness prior to HCT), examine the presence of HLH/active or not on outcome in patients with HLH and XLP diagnoses, and examine SCID outcomes based on SCID phenotype. We will also repeat the discussed analyses within each disease subgroup (HLH, SCID, etc). We will create cumulative incidence curves and competing risk curves if applicable to analyze the cumulative incidences of other outcomes of interest including acute GVHD Grades II-IV and III-IV, chronic GVHD, chronic extensive GVHD, and repeat allogeneic HCT. The analyses will be summarized in several figures in a manuscript. • Multivariate survival and event-free survival (survival without re-transplantation) analyses will then be performed using Cox Hazard Regression and we will examine the effects of the covariates of decade of transplantation, conditioning regimen intensity, age (continuous variable), HLA match, graft source, serotherapy, underlying diagnosis, year of HCT, development of acute GVHD grades II-IV and III-IV, and chronic extensive GVHD. We will perform additional multivariate analyses to determine if conditioning regimen intensity impacts survival specifically for patients within each diagnosis category. If applicable within each transplant regimen intensity category- we will also perform subset analyses based on receipt of alemtuzumab, ATG, or neither. If the sample sizes are large enough, we will examine history of mechanical ventilation prior to HCT (as a surrogate for significant illness prior to HCT), examine the presence

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of HLH/active or not on outcome in patients with HLH and XLP diagnoses, and examine SCID outcomes based on SCID phenotype. We will also perform multivariate analyses to analyze the other outcomes of interest including acute GVHD Grades II-IV and III-IV, chronic GVHD, chronic extensive GVHD, and repeat allogeneic HCT. This information will be summarized in a table or several tables in a manuscript.

References: 1. Griffith LM, Cowan MJ, Kohn DB, et al. Allogeneic hematopoietic cell transplantation for primary immune deficiency diseases: current status and critical needs. J Allergy Clin Immunol. 2008;122(6):1087- 1096. 10.1016/j.jaci.2008.09.045. 2. Gennery AR, Slatter MA, Grandin L, et al. Transplantation of hematopoietic stem cells and long-term survival for primary immunodeficiencies in Europe: entering a new century, do we do better? J Allergy Clin Immunol. 2010;126(3):602-610 e601-611. 10.1016/j.jaci.2010.06.015. 3. Moratto D, Giliani S, Bonfim C, et al. Long-term outcome and lineage-specific chimerism in 194 patients with Wiskott-Aldrich syndrome treated by hematopoietic cell transplantation in the period 1980-2009: an international collaborative study. Blood. 2011;118(6):1675-1684. 10.1182/blood-2010- 11-319376. 4. Shin CR, Kim MO, Li D, et al. Outcomes following hematopoietic cell transplantation for Wiskott- Aldrich syndrome. Bone Marrow Transplant. 2012;47(11):1428-1435. 10.1038/bmt.2012.31. 5. Pai SY, Logan BR, Griffith LM, et al. Transplantation outcomes for severe combined immunodeficiency, 2000-2009. N Engl J Med. 2014;371(5):434-446. 10.1056/NEJMoa1401177. 6. Eapen M, DeLaat CA, Baker KS, et al. Hematopoietic cell transplantation for Chediak-Higashi syndrome. Bone Marrow Transplant. 2007;39(7):411-415. Prepublished on 2007/02/13 as DOI 1705600 [pii]

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Characteristics of patients who underwent an allogeneic HCT for Primary Immune Deficiencies registered to the CIBMTR from 1980 to 2014

Variable 1980-1989 1990-1999 2000-2009 2010-2014 Disease SCID ADA deficiency 35 (10) 66 ( 6) 64 ( 4) 51 ( 4) SCID absence of T and B cells 74 (22) 121 (10) 122 ( 7) 89 ( 7) SCID absence of T, normal B cell SCID 103 (30) 182 (15) 162 ( 9) 94 ( 8) Wiskott Aldrich syndrome 52 (15) 257 (22) 305 (17) 146 (12) Hemophagocytosis 4 ( 1) 197 (17) 506 (29) 406 (33) Langerhans Cell Histiocytosis 0 19 ( 2) 49 ( 3) 23 ( 2) X-linked lymphoproliferative syndrome 2 ( 1) 23 ( 2) 79 ( 4) 47 ( 4) Combined immunodeficiency disorder 23 ( 7) 86 ( 7) 29 ( 2) 0 Chronic granulomatous disease 7 ( 2) 33 ( 3) 134 ( 8) 203 (16) Ommen syndrome 8 ( 2) 63 ( 5) 83 ( 5) 44 ( 4) Reticular dysgenesis 5 ( 1) 6 ( 1) 7 (<1) 2 (<1) Bare lymphocyte syndrome 8 ( 2) 18 ( 2) 47 ( 3) 36 ( 3) Chediak-Higashi syndrome 8 ( 2) 41 ( 3) 49 ( 3) 23 ( 2) Common variable ID 10 ( 3) 15 ( 1) 44 ( 2) 33 ( 3) Leukocyte adhesion deficiencies 0 48 ( 4) 50 ( 3) 24 ( 2) CD40 ligand deficiency 0 4 (<1) 35 ( 2) 28 ( 2)

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Proposal 1511-44

Title: Pulmonary complications of hematopoietic cell transplantation in sickle cell disease.

Joshua, John, Dill, D.O, University of Arizona Health Sciences- Arizona Respiratory Center, [email protected] Christian, Bime , M.D., M.Sc., University of Arizona Health Sciences - Arizona Respiratory Center [email protected]

Hypotheses: • Number of hematopoietic cell transplants (HCT) performed on a yearly basis for both children and adults with sickle cell disease (SCD) has progressively increased over the past 10 years. • Older age, baseline pulmonary function test (PFT) abnormalities and a history of acute chest syndrome are associated with increased pulmonary complications following HCT in SCD.

Specific aims: • Describe the yearly trend in number of HCT performed for both children and adults in SCD patients. • Describe the types of pulmonary complications after HCT for both children and adults in the SCD patient population in the first 100 days, 1 year and 2 years after transplantation. • Assess the effect of age, gender, baseline PFT abnormality, HCT and product type, and history of acute chest syndrome prior to transplant with the risk of post-transplant pulmonary complications. • Compare the rates of pulmonary complications among patients undergoing HCT for SCD versus those undergoing HCT for other indications, such as hematologic malignancy, that have been previously reported in the literature.

Scientific justification: SCD is a genetic disorder that leads to significant morbidity throughout the life of patients with this disease. This includes pulmonary hypertension, which has been reported to be present in 10% of SCD patients in a recent study population, as well as silent brain infarcts which are present in 37% of children by age 14 and are associated with decline in global intellectual function.1,2 In addition, it leads to early mortality with a mean age at death of 39.3 Historically, there have been no curative therapies, but in the past two decades hematopoietic cell transplantation (HCT) has emerged as a viable option for the treatment and only potential cure for SCD.4,5,6 While HCT has been studied extensively in patients with various types of cancer, much less research has been done in regards to HCT in SCD. Current literature describes only 1238 patients having received transplantation for SCD as of 2013.7 Several limitations for the wide spread adoption of HCT in SCD have been reported in recent reviews, including treatment related toxicity from condition regimens, a paucity of human leukocyte antigen- identical donors and the higher potential risk associated with older SCD patients with more advanced chronic organ damage.8,9 That said, some in the field are advocating for aggressively screening all homozygous SCD patients with matched sibling donors for suitability of HCT.10,11 As increased screening and eligibility along with advances in the field lead to an increase in the number of HCT for SCD, it will be imperative to have a better understanding of the short and long-term complications. Specifically, the pulmonary complications of HCT in SCD are not well understood. Several small studies of pediatric SCD patients who underwent HCT described a trend toward stability in pre and

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post PFTs but did not perform a detailed analysis for pulmonary complications.12,13 The aim of this study is to evaluate recent trends in the number of patients with SCD undergoing HCT with curative intent and also to assess the pulmonary complications associated with HCT in this patient population.

Patient eligibility population: • Ages range: All ages • Disease: Sickle cell disease • Disease stage: n/a • Year of transplant: 2002-2012 • Graft and donor type: HCT: allogeneic- related, allogeneic- unrelated. o Product type: marrow, PBSC, cord blood • Prior treatments: none • Specific transplant regimens: none • Other restrictions: none

Data requirements: Independent variables: • Age (at time of transplant) • Gender • HCT Type: allogeneic- related, allogeneic- unrelated. (2100 R1-3, IBMTR/ABMTR Reporting Form 002CORE) • Product type: marrow, PBSC, cord blood (2100 R1-3, IBMTR/ABMTR Reporting Form 002CORE) • History of acute chest syndrome, total number of episodes of acute chest syndrome, pulmonary hypertension, intubation, other pulmonary problems (2030 R1-2, IBMTR/ABMTR Reporting Form 095-SCA) • Pre HCT PFT results, if done [normal or stage of disease] (2030 R1-2 and IBMTR/ABMTR Reporting Form 095-SCA) o Copies of all PFTs available. Dependent outcome variables: • Death (100 days form 2100 R1-3, IBMTR/ABMTR Reporting Form 002CORE) (1 year, 2 years form 2200 R 1-3 and IBMTR/ABMTR Follow-up Form 002COREFU) • Acute chest syndrome post HCT (100 days, 1 year, 2 years) (2130 R1-2, IBMTR/ABMTR Reporting Form 095-SCAFU) • Total number of acute chest syndrome episodes since last report (100 days, 1 year, 2 years) (2130 R1-2, IBMTR/ABMTR Reporting Form 095-SCAFU) • Treatment given for acute chest syndrome: • Intubation/mechanical ventilation (100 days, 1 year, 2 years) (2130 R1-2, IBMTR/ABMTR Reporting Form 095-SCAFU) • Did acute GVHD occur or persist from prior HCT/DCI (100 days form 2100 R1-3, IBMTR/ABMTR Reporting Form 002CORE) (1 year, 2 years form 2200 R 1-3 and IBMTR/ABMTR Follow-up Form 002COREFU) • Maximum grade of acute GVHD: 1, 2, 3, 4 (100 days form 2100 R1-3, IBMTR/ABMTR Reporting Form 002CORE) (1 year, 2 years form 2200 R 1-3 and IBMTR/ABMTR Follow-up Form 002COREFU) • Lung involvement of acute GVHD based on bx? (100 days form 2100 R1-3, IBMTR/ABMTR Reporting Form 002CORE) (1 year, 2 years form 2200 R 1-3 and IBMTR/ABMTR Follow-up Form 002COREFU)

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• Chonic GVHD occur: yes, no, chronic GVHD persists from prior HSCT/DCI (100 days form 2100 R1-3, IBMTR/ABMTR Reporting Form 002CORE) (1 year, 2 years form 2200 R 1-3 and IBMTR/ABMTR Follow-up Form 002COREFU) • Overall severity of chronic GVHD: mild, moderate, severe (100 days form 2100 R1-3, IBMTR/ABMTR Reporting Form 002CORE) (1 year, 2 years form 2200 R 1-3 and IBMTR/ABMTR Follow-up Form 002COREFU) • Organ involvement for chronic GVHD • Bronchiolitis obliterans? (100 days form 2100 R1-3, IBMTR/ABMTR Reporting Form 002CORE) (1 year, 2 years form 2200 R 1-3 and IBMTR/ABMTR Follow-up Form 002COREFU) • Other lung involvement? (100 days form 2100 R1-3, IBMTR/ABMTR Reporting Form 002CORE) (1 year, 2 years form 2200 R 1-3 and IBMTR/ABMTR Follow-up Form 002COREFU) • Develop interstitial pneumonitis (IPn or ARDS)/Idiopathic pneumonia syndrome (IPS)? (100 days form 2100 R1-3, IBMTR/ABMTR Reporting Form 002CORE) (1 year, 2 years form 2200 R 1-3 and IBMTR/ABMTR Follow-up Form 002COREFU) • Did develop non-infectious pulmonary abnormalities (other than IPn/IPS/ARDS) after the preparative regimen? (100 days form 2100 R1-3, IBMTR/ABMTR Reporting Form 002CORE) (1 year, 2 years form 2200 R 1-3 and IBMTR/ABMTR Follow-up Form 002COREFU) • Did the recipient develop bronchiolitis obliterans after the start of preparative regimen? (100 days form 2100 R1-3, IBMTR/ABMTR Reporting Form 002CORE) (1 year, 2 years form 2200 R 1-3 and IBMTR/ABMTR Follow-up Form 002COREFU) • Did patient develop pulmonary hemorrhage? (100 days form 2100 R1-3, IBMTR/ABMTR Reporting Form 002CORE) (1 year, 2 years form 2200 R 1-3 and IBMTR/ABMTR Follow-up Form 002COREFU) • Did the recipient develop any other non-infectious pulmonary abnormalities? (100 days form 2100 R1-3, IBMTR/ABMTR Reporting Form 002CORE) (1 year, 2 years form 2200 R 1-3 and IBMTR/ABMTR Follow-up Form 002COREFU) • Specify other pulmonary abnormality (100 days form 2100 R1-3, IBMTR/ABMTR Reporting Form 002CORE) (1 year, 2 years form 2200 R 1-3 and IBMTR/ABMTR Follow-up Form 002COREFU) • Total number of inpatient days in first 100 days post transplant (100 days form 2100 R1-3, IBMTR/ABMTR Reporting Form 002CORE) (1 year, 2 years form 2200 R 1-3 and IBMTR/ABMTR Follow-up Form 002COREFU)

Study design: The analysis would be a retrospective study of all SCD patients who underwent HCT to evaluate for pulmonary complications and assess if any independent variables were associated with increased risk of specific complications (i.e. increasing stage of baseline lung disease present is associated with increased risk of developing idiopathic pneumonia syndrome). We will use binary and multinomial logistic regression to evaluate dependent variables in relation to independent variables. We will use descriptive statistics in the form of odds ratios for dependent variables that are found to be statistically significant in logistic regression analysis.

References: 1. Mehari A, Gladwin MT, TianX, Machado RF, Kato GJ. Mortality in adults with sickle cell disease and pulmonary hypertension. JAMA 2012, Mar 28;307(12):1254-6. 2. DeBaun, M.R. & Telfair, J. Transition and sickle cell disease. Pediatrics 2012 Nov;130(5):926-35. Hassell, K.L. Population estimates of sickle cell disease in the US. Am J Prev Med 2010, Apr;38(4 Suppl):S512-21.

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3. Johnson FL, Look AT, Gockerman J, Ruggiero MR, Dalla-Pozza L, Billings FT 3rd. Bone-marrow transplantation in a patient with sickle-cell anemia. N Engl J Med 1984;311:780–3. 4. Walters MC, Patience M, leisenring W, Eckman JR, Scott JP, Mentzer WC, et al. Bone marrow transplantation for sickle cell disease. N Engl J Med 1996;335:369–76. 5. Locatelli F, Kabbara N, Ruggeri A, Ghavamzadeh A, Roberts I, Li CK, et al. Outcome of patients with hemoglobinopathies given either cord blood or bone marrow transplantation from an HLA-identical sibling. Blood 2013;122:1072–8. 6. Gluckman E. Allogeneic transplantation strategies including haploidentical transplantation in sickle cell disease. Hematology Am Soc Hematol Educ Program 2013; 2013:370–376. 7. Walters M. Update of hematopoietic cell transplantation for sickle cell disease. Curr Opin Hematol 2015 May;22(3):227-33. 8. Talano JA, Cairo MS. Hematopoietic stem cell transplantation for sickle cell disease: state of the science. Eur J Haematol 2015 May;94(5):391-9. 9. Bhatia M, Sheth S. Hematopoietic stem cell transplantation in sickle cell disease: patient selection and special considerations. Journal Blood Med 2015 Jul 10;6:229-38. 10. Hsieh MM, Fitzhugh CD, Tisdale JF. Allogeneic hematopoietic stem cell transplantation for sickle cell disease: the time is now. Blood 2011 Aug 4;118(5):1197-207. 11. Walters MC, Patience M, Leisenring W, Rogers ZR, Aquino VM, Buchanan GR, et al. Stable mixed hematopoietic chimerism after bone marrow transplantation for sickle cell anemia. Biology of Blood and Marrow Transplantation 2001;7,665–673. 12. Walters MC, Hardy K, Edwards S, Adamkiewicz T, Barkovich J, Bernaudin F, et al. Pulmonary, Gonadal, and Central Nervous System Status after Bone Marrow Transplantation for Sickle Cell Disease. Biol Blood Marrow Transplant 2010 Feb;16(2):263-72.

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Table 1. Characteristics of patients who underwent first allo HCT for Sickle Cell Anemia and reported to the CIBMTR, 2002-2012 Variable N (%) Number of patients 170 Recipient age < 10 87 (51) 10 - 19 73 (43) 20 - 29 8 (5) 30 - 39 2 (1) Indication for HCT Stroke 32 (19) Acute chest syndrome 12 (7) Recurrent vaso-occlusive pain 33 (19) Recurrent priapism 1 (<1) Excessive transfusion requirements 21 (12) Not reported 71 (41) Donor type HLA-identical sibling 101 (59) Other related 7 (4) Unrelated 62 (36) Graft type BM 108 (64) PB 8 (5) UCB 54 (32)

Table 2. Pulmonary complication Day-100 1 Year 2 Year Q350: Ipn/ARDS/IPS Yes 6 (4) 2 (1) 2 (1) No 162 (95) 113 (67) 103 (61) Unknown 2 (1) 55 (32) 65 (38) Q373: Noninfectious pulmonary abnormalities Yes 2 (1) 2 (1) 2 (1) No 166 (98) 113 (67) 103 (61) Unknown 2 (1) 55 (32) 65 (38) Q403: Intubation or ventilation Yes 12 (7) 3 (2) 4 (3) No 154 (91) 112 (66) 101 (59) Unknown 4 (2) 55 (32) 65 (38) Acute Chest Syndrome Yes 1 (1) 2 (1) 1 (1) No 157 (92) 131 (77) 121 (71) Unknown 12 (7) 37 (22) 48 (28)

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Proposal 1511-71

Title: The effect of Conditioning Regimen on Clinical Outcomes of Allogeneic Hematopoietic Cell Transplantation in Severe Aplastic Anemia

Nelli Behanyan, MD, Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota Natasha Kekre, MD, The Ottawa Hospital, Ottawa, ON, Canada Daniel Weisdorf, MD, Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota Joseph Antin, MD, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA

Hypothesis: Clinical outcomes of allogeneic hematopoietic cell transplantation (alloHCT) for severe aplastic anemia (SAA) can be best informed by conditioning regimen

Specific aims: Primary endpoint: • To study the effect of conditioning regimen on overall survival (OS) of adult allograft recipients with SAA. Secondary endpoints: • To study neutrophil recovery, platelet recovery, treatment-related mortality (TRM). • To study the late complications of alloHCT including secondary malignancies, late infections, late organ impairment/disorders • To study acute GVHD, chronic GVHD and delayed transfusion dependence (RBC and/or platelets).

Scientific justification: AlloHCT with HLA-identical related donor (MRD) is the treatment of choice in younger patients (<40 years) with newly diagnosed severe aplastic anemia (SAA) and in adults with relapsed/refractory disease after immunosuppressive therapy.1-4 Since MRD is only available for the 1/3 of patients undergoing transplantation;5 large number of patients who lack suitable sibling donor are being considered for adult matched unrelated donor (MUD) transplant. Despite improvement in survival of allograft recipients for SAA in the past decade,1, 6 high risks of graft failure and late complications of transplant still remain the major challenges of alloHCT in SAA. The choice of conditioning regimen and the development of chronic GVHD have been recognized to play a key role in development of late complications after transplantation.7 The addition of TBI in conditioning regimen helped to minimize the risk of graft failure in one report, but unfortunately it led to increased risks of long-term morbidity and mortality after alloHCT.8 Similarly, despite improvement in hematopoietic engraftment with the use of peripheral blood stem cell source for transplantation in SAA, the rates of chronic GVHD and subsequent mortality were reported to be excessive in some studies.9, 10 ATG in combination with Cytoxan at total dose of 200mg/kg has been demonstrated in few reports to provide successful hematopoietic engraftment and encouraging long-term outcomes in younger patients with SAA after MRD alloHCT.1-3 Although various conditioning regimens have been studied in recent years to further improve the transplant outcomes for SAA particularly in older patients11 and in those receiving graft from MUD,12-15 till now no uniformly accepted conditioning regimen has been identified for alloHCT in SAA. Therefore, we propose using

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CIBMTR’s large dataset to identify the preferred conditioning regimen for alloHCT in SAA that is associated with most favorable clinical outcomes across patient age groups, donor types and graft types.

Patient eligibility population: Inclusion Criteria: • Patients with SAA who underwent alloHCT at participating CIBMTR centers between 2001 and 2013 • Both MA and RIC transplants • Both MRD and MUD donor types Exclusion Criteria: • SAA patients who had disease progression to MDS or AML prior to alloHCT

Data requirements: All necessary study data are available for extraction from the disease‐specific CIBMTR data collection forms Demographic and clinical characteristics (Supplementary Table 1) will be abstracted from the CIBMTR data forms. As possible, data sets utilized will include already analyzed (and/or published) HCT outcomes to minimize the need for subsequent data re-review and cleanup.

Study design: We propose an observational retrospective study of recipients of alloHCT with SAA. Chi-square test for categorical variables and the Wilcoxon test for continuous variables will be used to compare patient, disease and transplant related characteristics between types of conditioning regimens. Cumulative incidence estimator will be used to calculate probabilities of neutrophil engraftment, platelet engraftment, acute and chronic GVHD and TRM. The Kaplan-Meier method will be used to estimate OS probabilities and other secondary endpoints. Cox proportional hazards regression model would be used to study the association between conditioning groups and outcomes. Multivariate models will be built using the forward step-wise selection process considering variables in Table 1. The conditioning groups will be included in all steps of model building (reference group; Cy/ATG), regardless of level of significance. The Cox regression model will be used to estimate adjusted probability of OS.

References: 1. Scheinberg P, Young NS. How I treat acquired aplastic anemia. Blood 2012; 120(6): 1185-96. 2. Storb R, Etzioni R, Anasetti C, Appelbaum FR, Buckner CD, Bensinger W et al. Cyclophosphamide combined with antithymocyte globulin in preparation for allogeneic marrow transplants in patients with aplastic anemia. Blood 1994; 84(3): 941-9. 3. Storb R, Leisenring W, Deeg HJ, Anasetti C, Appelbaum F, Bensinger W et al. Long-term follow-up of a randomized trial of graft-versus-host disease prevention by methotrexate/cyclosporine versus methotrexate alone in patients given marrow grafts for severe aplastic anemia. Blood 1994; 83(9): 2749- 50. 4. Gupta V, Eapen M, Brazauskas R, Carreras J, Aljurf M, Gale RP et al. Impact of age on outcomes after bone marrow transplantation for acquired aplastic anemia using HLA-matched sibling donors. Haematologica 2010; 95(12): 2119-25. 5. Alousi AM, Le-Rademacher J, Saliba RM, Appelbaum FR, Artz A, Benjamin J et al. Who is the better donor for older hematopoietic transplant recipients: an older-aged sibling or a young, matched unrelated volunteer? Blood; 121(13): 2567-73.

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6. Champlin RE, Perez WS, Passweg JR, Klein JP, Camitta BM, Gluckman E et al. Bone marrow transplantation for severe aplastic anemia: a randomized controlled study of conditioning regimens. Blood 2007; 109(10): 4582-5. 7. Tichelli A, Rovo A, Passweg J, Schwarze CP, Van Lint MT, Arat M et al. Late complications after hematopoietic stem cell transplantation. Expert review of hematology 2009; 2(5): 583-601. 8. Deeg HJ, O'Donnell M, Tolar J, Agarwal R, Harris RE, Feig SA et al. Optimization of conditioning for marrow transplantation from unrelated donors for patients with aplastic anemia after failure of immunosuppressive therapy. Blood 2006; 108(5): 1485-91. 9. Schrezenmeier H, Passweg JR, Marsh JC, Bacigalupo A, Bredeson CN, Bullorsky E et al. Worse outcome and more chronic GVHD with peripheral blood progenitor cells than bone marrow in HLA-matched sibling donor transplants for young patients with severe acquired aplastic anemia. Blood 2007; 110(4): 1397-400. 10. Bacigalupo A, Socie G, Schrezenmeier H, Tichelli A, Locasciulli A, Fuehrer M et al. Bone marrow versus peripheral blood as the stem cell source for sibling transplants in acquired aplastic anemia: survival advantage for bone marrow in all age groups. Haematologica 2012; 97(8): 1142-8. 11. Maury S, Bacigalupo A, Anderlini P, Aljurf M, Marsh J, Socie G et al. 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(9): 1312-5. 12. Marsh JC, Gupta V, Lim Z, Ho AY, Ireland RM, Hayden J et al. Alemtuzumab with fludarabine and cyclophosphamide reduces chronic graft-versus-host disease after allogeneic stem cell transplantation for acquired aplastic anemia. Blood 2011; 118(8): 2351-7. 13. Deeg HJ, Amylon ID, Harris RE, Collins R, Beatty PG, Feig S et al. Marrow transplants from unrelated donors for patients with aplastic anemia: minimum effective dose of total body irradiation. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 2001; 7(4): 208-15. 14. Bacigalupo A, Locatelli F, Lanino E, Marsh J, Socie G, Maury S et al. Fludarabine, cyclophosphamide and anti-thymocyte globulin for alternative donor transplants in acquired severe aplastic anemia: a report from the EBMT-SAA Working Party. Bone marrow transplantation 2005; 36(11): 947-50. 15. Bacigalupo A, Socie G, Lanino E, Prete A, Locatelli F, Locasciulli A et al. Fludarabine, cyclophosphamide, antithymocyte globulin, with or without low dose total body irradiation, for alternative donor transplants, in acquired severe aplastic anemia: a retrospective study from the EBMT- SAA Working Party. Haematologica 2010; 95(6): 976-82.

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Table 1. Baseline characteristics of patients undergoing their first alloHCT with an HLA identical sibling donor for Severe Aplastic Anemia from 2001-2013

Variable N (%) Number of patients 855 Age at HCT, years Median (range) 19 (1-69) < 10 yrs 150 (18) 10-19 yrs 312 (36) 20-29 yrs 181 (21) 30-39 yrs 100 (12) 40-49 yrs 67 (8) 50-59 yrs 34 (4) ≥ 60 yrs 11 (1) Conditioning regimen Cy alone 95 (11) Cy + ATG 492 (58) Bu + Cy 103 (12) Cy + Flud 165 (19) Year of HCT 2001-2004 423 (49) 2005-2008 343 (40) 2009-2013 89 (10)

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Table 2. Baseline characteristics of patients undergoing their first alloHCT with an unrelated donor for Severe Aplastic Anemia from 2001-2013

Variable N (%) Number of patients 495 Age at HCT, years Median (range) 19 (<1-67) < 10 yrs 112 (23) 10-19 yrs 150 (30) 20-29 yrs 99 (20) 30-39 yrs 60 (12) 40-49 yrs 26 (5) 50-59 yrs 36 (7) ≥ 60 yrs 12 (2) Conditioning regimen TBI 200 + Cy + ATG 115 (23) TBI 200 + Cy + Flud + ATG 142 (29) TBI ≥ 1000 + Cy 43 (9) Bu + Cy 27 (5) Cy + Flud + ATG 75 (15) Cy + Flud (No ATG) 28 (6) Cy + ATG 30 (6) Mel + Flud 23 (5) Bu + Flud 12 (2) Year of HCT 2001-2004 117 (24) 2005-2008 223 (45) 2009-2013 155 (31)

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Proposal 1511-82

Title: Second Allogeneic Hematopoietic Cell Transplantation (HCT) for Hemoglobin Disorders

Nahal Rose Lalefar, MD, UCSF Benioff Children’s Hospital Oakland, [email protected] Mark C Walters, MD, UCSF Benioff Children’s Hospital Oakland, [email protected]

Hypothesis: It is possible to accomplish disease-free survival in recipients with hemoglobin disorders after graft rejection by rescue transplantation. A review of current trends in utilization might indicate how to select the optimal donor and conditioning regimen before second transplant. We hypothesize that having a back-up plan in the event of graft rejection will optimize disease-free survival after HCT for hemoglobin disorders.

Specific aims: There is increased utilization of reduced intensity hematopoietic stem cell transplantation with alternate donors that has expanded the therapeutic application of HCT for hemoglobin disorders. This practice includes the treatment of more heavily treated patients who can be sensitized to donors as a consequence of transfusion exposures. Thus, we aim to:

Determine the rate of graft failure in patients with hemoglobin disorders. Identify patients who have received multiple allogeneic hematopoietic cell transplants for sickle cell anemia or β-thalassemia major and describe their pre-transplant characteristics (donor, HLA matching, stem cell source, cell dose, T-cell depletion, conditioning regimen, GVHD prophylaxis) and the rescue/second transplant characteristics including donor, conditioning regimen and transplant complications (GVHD, infections, organ toxicities such as VOD/SOS). Evaluate survival, disease-free survival and functional status in patients with hemoglobin disorders who undergo multiple hematopoietic cell transplants.

Scientific justification: Fewer than 18% of patients with sickle cell anemia have suitable HLA-matched siblings (1, 2). Fewer than 25% of thalassemia patients have an unaffected HLA-matched sibling (3). To accommodate the majority of individuals who lack a suitable sibling donor, transplant options have been expanded to include alternative sources of hematopoietic donors such as volunteer unrelated donors, umbilical cord blood, or mobilized peripheral blood stem cells from haploidentical donors. However, these options often utilize reduced intensity conditioning regimens which carry higher risks of graft rejection, graft-versus- host disease and transplant-related mortality, particularly in heavily pre-treated patients who can be sensitized to donors as a consequence of transfusion exposures. In addition to pre-transplant transfusion exposures, a hyperproliferative marrow can interfere with donor engraftment. Graft failure accompanied by marrow aplasia after hematopoietic cell transplantation (HCT) for hemoglobin disorders is a potentially life-threatening complication. This contrasts with the more frequent complication of graft rejection accompanied by autologous reconstitution, which follows immunological rejection of the donor cells after an initial wave of donor engraftment (4-6). Given the significant risk of graft failure after alternate donor HCT, having a strategic approach to treat graft failure might improve the likelihood of a curative outcome. We intend to identify methods that elicit curative outcomes despite an initial graft rejection. After first quantifying the problem with graft rejection and the type of transplants associated with graft rejection

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treated by subsequent transplantation, we can describe strategies to optimize donor selection and conditioning regimens. This could be useful in the future for treating older patients where graft rejection rates may be higher. For the purposes of this study, engraftment will be defined as achieving a peripheral blood neutrophil count >500 per microliter (The first of three consecutive days) with > 5% donor cells. Graft failure is defined as the absence of donor cell engraftment with or without marrow aplasia. Primary graft failure will be defined as the failure to achieve an absolute neutrophil count (ANC) of 500 by 42 days after transplantation. Secondary graft failure will be defined as a decrease in ANC to less than 500 per after having achieved neutrophil engraftment with the loss of donor cells. Primary graft rejection with autologous reconstitution will be defined as less than 5% donor cell engraftment (7).

Patient eligibility population: All patients with Hb SS, Hb SC, Hb S-B thalassemia, or B-thalassemia major who have undergone more than one allogeneic bone marrow transplant 1998-2015.

Data requirements: Forms Recipient Variables 2400-Transplant Essential data Age, gender, ethnicity, primary disease, height/weight, Pre-HCT conditioning and GVHD prophylaxis for all HCTs, stem cell source for all HCTs, reason for current HCT, date of graft failure, product manipulation, clinical status of recipient, comorbid conditions of recipient 2000- Recipient Baseline data Pre-HCT conditioning regimen and total doses for all HCTs 2006- HCT Infusion HCT date, Product type, donor source, TNC (with CD34+ cell count, if available), product manipulation 2100 - Post HCT data (100 days) Neutrophil recovery (First of 3 consecutive days that ANC >500/mm3), date ANC decline <500 for >3 consecutive days, platelet recovery, date of last PRBC transfusion, Date/indication/source of subsequent HCT, grading/severity/organ involvement of acute and chronic GVHD, chimerism study analysis (lineage specific chimerism should be queried if possible), immune reconstitution, donor lymphocyte infusions, survival and functional status 2200 – Post HCT data (6mo, 1year, 2years) Date/indication/source of subsequent HCT, 2300 – Post HCT data (>2years) grading/severity/organ involvement of acute and chronic GVHD, chimerism study analysis (lineage specific chimerism should be queried if possible), immune reconstitution, donor lymphocyte infusions, survival and functional status, evidence of new malignancy

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2030 - Sickle cell anemia Pre HCT data HCT type/source, sickle cell disease genotype, date of first transfusion, alloimmunization history, type of alloantibodies, iron chelation history, disease symptoms prior to preparative regimen, Hydroxyurea start/stop dates, hemoglobin electrophoresis results prior to preparative regimen, primary indication for HCT 2130 - Sickle cell anemia Post HCT data (day Disease status, iron chelation therapy, 100, 6months, 1 year, 2 years, >2 years) hemoglobin electrophoresis results, ferritin level results, sickle cell disease related complications

We also request permission to contact the participating institutions in order to determine if patients who developed graft failure were tested for donor specific antibodies and what the results showed.

Study design: Obtain the total number of patients with Hb SS, Hb SC, Hb S-B thalassemia, or B-thalassemia major who have received hematopoietic stem cell transplants. Obtain the total number of patients who have undergone at least two allogeneic transplants for sickle cell anemia, sickle cell/B-thalassemia, B-thalassemia major. Characterize patients by age, disease type, gender, transfusion history and history of red cell alloimmunization, indication for transplant, iron overload and chelation history, pre-transplant complications, hydroxyurea use prior to first HCT. This data will be collected from transplant essential data (2400) and sickle cell anemia Pre HCT data (2030). Characterize transplants (both initial and rescue transplants) by: conditioning regimen, graft type, donor type, GVHD prophylaxis, duration until neutrophil/platelet engraftment, acute/chronic GVHD, chimerism status following both transplants (lineage specific chimerism should be queried if possible), whether or not patients received donor lymphocyte infusions, and interval between transplants. This information will be retrieved from recipient baseline data (2000), HCT infusion data (2006) as well as data collection forms at day 100 (2100, 2130), 6 months, 1 year, 2 years (2130, 2200) and >2 years post HCT (2130, 2300). Evaluate functional status post HCT and probability of survival using Kaplan-Meier estimator.

References: 1. Brodsky RA, Luznik L, Bolanos-Meade J, Leffell MS, Jones RJ, Fuchs EJ. Reduced intensity HLA- haploidentical BMT with post transplantation cyclophosphamide in nonmalignant hematologic diseases. Bone marrow transplantation. 2008;42(8):523-7. doi: 10.1038/bmt.2008.203. PubMed PMID: 18622413; PMCID: 3086163. 2. Walters MC, Patience M, Leisenring W, Eckman JR, Scott JP, Mentzer WC, Davies SC, Ohene-Frempong K, Bernaudin F, Matthews DC, Storb R, Sullivan KM. Bone marrow transplantation for sickle cell disease. The New England journal of medicine. 1996;335(6):369-76. doi: 10.1056/NEJM199608083350601. PubMed PMID: 8663884. 3. Fleischhauer K, Locatelli F, Zecca M, Orofino MG, Giardini C, De Stefano P, Pession A, Iannone AM, Carcassi C, Zino E, La Nasa G. Graft rejection after unrelated donor hematopoietic stem cell transplantation for thalassemia is associated with nonpermissive HLA-DPB1 disparity in host-versus-graft direction. Blood. 2006;107(7):2984-92. doi: 10.1182/blood-2005-08-3374. PubMed PMID: 16317094.

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4. Stepensky P, Or R, Shapira MY, Revel-Vilk S, Stein J, Resnick IB. Second bone marrow transplantation for patients with thalassemia: risks and benefits. Haematologica. 2009;94(9):1329-30. doi: 10.3324/haematol.2009.006817. PubMed PMID: 19734431; PMCID: 2738733. 5. Sabloff M, Chandy M, Wang Z, Logan BR, Ghavamzadeh A, Li CK, Irfan SM, Bredeson CN, Cowan MJ, Gale RP, Hale GA, Horan J, Hongeng S, Eapen M, Walters MC. HLA-matched sibling bone marrow transplantation for beta-thalassemia major. Blood. 2011;117(5):1745-50. doi: 10.1182/blood-2010-09- 306829. PubMed PMID: 21119108; PMCID: 3056598. 6. Gaziev J, Sodani P, Lucarelli G, Polchi P, Marktel S, Paciaroni K, Marziali M, Isgro A, Simone MD, Roveda A, Montuoro A, Lanti A, Alfieri C, De Angelis G, Gallucci C, Ciceri F, Roncarolo MG. Second hematopoietic SCT in patients with thalassemia recurrence following rejection of the first graft. Bone marrow transplantation. 2008;42(6):397-404. doi: 10.1038/bmt.2008.175. PubMed PMID: 18574445. 7. Rondon G, Saliba RM, Khouri I, Giralt S, Chan K, Jabbour E, McMannis J, Champlin R, Shpall E. Long- term follow-up of patients who experienced graft failure postallogeneic progenitor cell transplantation. Results of a single institution analysis. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2008;14(8):859-66. doi: 10.1016/j.bbmt.2008.05.005. PubMed PMID: 18640568; PMCID: PMC4548938.

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Characteristics of Patients Who Received a Second Allogeneic Hematopoietic Cell Transplant for Hemoglobin Disorders Variable 1st TX 2nd TX Number of patients 26 26 Number of centers 18 18 Age in decades, years Median (range) 10 (3-17) 11 (3-18) < 10 13 (50) 12 (46) 10-19 13 (50) 14 (54) Graft source Bone marrow 15 (58) 8 (31) Peripheral blood 6 (23) 9 (35) Umbilical cord blood 5 (19) 8 (31) Missing1 0 1 (4) Donor type HLA-identical sibling 13 (50) 13 (50) Unrelated donor 4 (15) 10 (38) HLA-mismatch relative 3 (12) 3 (12) HLA-matched unrelated 1 (4) 0 HLA-mismatched. unrelated 4 (15) 0 Missing2 1 (4) 0 Same donor for 1st and 2nd transplant No 0 5 (19) Yes 0 15 (58) Missing3 0 6 (23) Year of transplant 1994-1999 4 (15) 3 (12) 2000-2005 7 (27) 8 (31) 2006-2011 9 (35) 7 (27) 2012-2015 6 (23) 8 (31) Median interval between 1st and 2nd transplant - 6 (<1-101) 1. Missing graft source information for second HCT but reported peripheral blood as the graft source for their first HCT 2. Missing donor type information for their first HCT but reported HLA-identical sibling as donor type for their second HCT 3. HLA-matched unrelated donor 1st HCT then unrelated donor 2nd HCT (n=5); HLA mismatch relative 1st HCT then HLA mismatch relative 2nd HCT (n=1)

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Proposal 1511-101

Title: Evaluation of the impact of changing clinical profile, transplant conditioning regimens and stem cell source on clinical outcome in patients with Thalassemia major.

Vikram Mathews , MD, DM, Department of Haematology, Christian Medical College, India [email protected] Biju George, MD, DM, Department of Haematology, Christian Medical College, India [email protected]

Hypothesis: Significant changes have happened over the last 5 years in the clinical profile, conditioning regimens and stem cell source being used in allogeneic stem cell transplantation for Thalassemia major. Increasingly, larger number of patients in developing economies and older patients are being transplanted; newer conditioning regimens have been utilized with reported reduction in graft rejection rates and less toxicity. As a result there is lack of clarity as to what are best variables with regard to suitable age at which to do the transplant, conditioning regimen to be used and stem cell source for these transplants. Only a large registry based analysis can clarify these issues

Specific aims: Describe the demographic profile of patients who have had an allogeneic stem cell transplant over the last 10 years and compare the changes that have happened in the last 5 years. Evaluate the impact of baseline demographic variables on clinical outcome Evaluate the impact of Treosulfan based conditioning regimens in comparison to a conventional busulfan based conditioning regimen on clinical outcomes. Evaluate the impact of different donor pools and stem cell sources on clinical outcomes

Scientific justification: An allogeneic stem cell transplant remains the only curative option for patients with β thalassemia major. Significant advances have been made over the last decade to improve the clinical outcome for patients with this disorder undergoing such a procedure. Currently in patients with good risk features it is reasonable to anticipate a greater than 90% chance of a successful transplant outcome1. Parameters for risk stratification prior to an allogeneic stem cell transplant for this disorder are unique and distinct. The conventional risk stratification system has limitations and alternative systems are being explored to better identify subsets that require innovative approaches to improve their outcome. A previous CIBMTR analysis suggested that age ≥7years and hepaomegaly were significant adverse risk factors1. However, a similar and more recently reported analysis done on the EBMT registry data suggested that age up to 14 years was associated with good clinical outcomes2. The earlier CIBMTR analysis was done in an era when only a conventional myeloablative busulfan based regimen was used. A number of novel regimens3,4 have been evaluated in an effort to reduce treatment related morbidity and mortality, prominent and widely used among these is a treosulfan based regimen5. Additionally some groups have reported an improvement in clnical outcomes in high risk group of patients with a peripheral blood stem cell transplant6. With the increase in the donor pool by the use of matched unrelated donors, cord blood stem cells and haploidentical donors more patients can potentially access this curative therapy and the data on these strategies have been mostly reported from single centers7. In the current scenario their is lack of clarity as to the optimal age at which to transplant these patients, optimal conditioning regimen,

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stem cell source and role of alternate donor stem cell sources for transplant. These issues will be best and probably only be addressed by analysis of large registry based data.

Patient eligibility population: All patients who underwent an allogeneic stem cell transplant for a diagnosis of thalassemia major.

Data requirements: Additional data that will be required include: • Presence of hepatomegaly at time of transplant. • Serum Ferritin level at time of transplant • Presence of liver fibrosis pre-transplant (if liver biopsy was done) • If MRI T2* scores of cardiac and liver iron overload are available pre-transplant.

Study design: This will be a descriptive retrospective analysis of all patients with thalassemia major who underwent an allogeneic stem cell transplant with data reported to CIBMTR over a period of 10 years.

Non-CIBMTR data source: EBMT has about 1200 transplants thalassemia major transplants done over this period that was recently analyzed in the context of prognostic factors. It would be useful if the CIBMTR and EBMT data were combined for this analysis. Large transplant cohorts are also available in China and Thailand which do not currently report to CIBMTR and an effort can be made to get data from these groups as well.

References: 1. Sabloff, M., et al. HLA-matched sibling bone marrow transplantation for beta-thalassemia major. Blood 117, 1745-1750 (2010). 2. Angelucci, E., et al. Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel. Haematologica 99, 811-820 (2014). 3. Li, C., et al. A novel conditioning regimen improves outcomes in beta-thalassemia major patients using unrelated donor peripheral blood stem cell transplantation. Blood 120, 3875-3881 (2012). 4. Anurathapan, U., et al. Pretransplant immunosuppression followed by reduced-toxicity conditioning and stem cell transplantation in high-risk thalassemia: a safe approach to disease control. Biol Blood Marrow Transplant 19, 1259-1262 (2013). 5. Bernardo, M.E., et al. Allogeneic hematopoietic stem cell transplantation in thalassemia major: results of a reduced-toxicity conditioning regimen based on the use of treosulfan. Blood 120, 473-476 (2012). 6. Mathews, V., et al. Improved clinical outcomes of high risk beta thalassemia major patients undergoing a HLA matched related allogeneic stem cell transplant with a treosulfan based conditioning regimen and peripheral blood stem cell grafts. PLoS One 8, e61637 (2013). 7. Locatelli, F., et al. Outcome of patients with hemoglobinopathies given either cord blood or bone marrow transplantation from an HLA-identical sibling. Blood 122, 1072-1078 (2013).

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Baseline characteristics of patients with Beta Thalassemia Major reported to the CIBMTR from 2004-2014 - supplemental data required Variable N (%) Number of patients 197 Number of centers 52 Number of research cases 119 Age at HCT, in years Median (range) 6 (1-25) < 10 yrs 158 (80) 18-19 yrs 37 (19) 18-29 yrs 2 (1) Sex Male 116 (59) Female 81 (41) Donor HLA-identical sibling 128 (65) Unrelated donor 41 (20) HLA-matched other relative 23 (12) HLA-mismatched relative 4 (2) Missing 1 (<1) Graft type Bone marrow 119 (60) Peripheral blood 49 (24) Umbilical cord blood 28 (15) Missing 1 (<1) CCN region US 60 (30) Canada 6 (3) Europe 26 (13) Asia 81 (41) Australia/New Zealand 1 (<1) Mideast/Africa 22 (11) Central/South America 1 (<1) Year of HCT 2004-2009 14 (7) 2010-2014 183 (93) Median follow-up of survivors (range), months 10 (1-121)

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Proposal 1511-110

Title: Unrelated donor marrow transplantation for children, adolescents and young adults with relapsed or refractory severe aplastic anemia

Staci D. Arnold, MD, MBA, MPH Children’s Healthcare of Atlanta, Emory University John T. Horan, MD, MPH, Children’s Healthcare of Atlanta, Emory University Phillip Scheinberg, MD, Hematology Branch, NHLBI Danielle Townsley, MD, MSc, Hematology Branch, NHLBI Neal S. Young, MD, Chief, Hematology Branch, NHLBI Regis Peffault de la Tour, MD, Istituto Giannina Gaslini Carlo DuFour, MD, Istituto Giannina Gaslini

Specific aim: To compare immunosuppressive treatment strategies to unrelated donor bone marrow transplant for patients with relapsed/refractory severe aplastic anemia.

Scientific justification: For patients with severe aplastic anemia (SAA) and an HLA matched related donor (MRD), the role of allogeneic hematopoietic cell transplantation (HCT) is well defined. Here, the evidence from clinical studies supports the use of HCT over immune suppression therapy (IST) at diagnosis in patients under 40 years. Because the risk for transplant related mortality (TRM) rises with recipient age, initial treatment with IST is generally recommended for patients older than this.1-3 For patients lacking a MRD, on the other hand, the role of the role HCT is not well defined.

However, advances in unrelated donor (URD) transplant warrant reinvestigation of this approach. Outcomes with URD transplantation for SAA had long been inferior to outcomes with MRD4, until recently the use of URD HCT has been largely reserved for patients whose SAA has failed to respond to multiple courses of IST. With advances in HLA matching, supportive care and pre-transplant conditioning since the 1990s, however, the difference in survival after URD and MRD transplantation for SAA has narrowed considerably4. As such, the optimal role of URD HCT at present remains to be defined. In URD HCT for SAA, the relative benefit of transplantation is likely to vary depending not only on recipient age (as in MRD HCT), but also on the degree of donor-recipient HLA matching5.

Data sources: Immune Suppression Therapy: Data would be drawn from NHLBI SAA database. Patients less than 40 years treated between 2000 and 2015 would be included. Data would be derived from patients receiving treatment for newly diagnosed SAA using horse ATG based immune suppression and also from patients receiving treatment for recurrent or refractory disease. This database includes over 100 eligible patients treated for recurrent or refractory SAA. Transplantation: Data would be drawn from the EBMT and CIBMTR registries. Only patients less than 40 years who received T cell replete unrelated bone marrow transplants from HLA matched or single mismatched donors (defined by allele level matching at the A, B, C, DRB1, ± DPB1 and DQB1) following one failed course of IST between 2000 and 2015 would be included. Only patients who received pre- transplant conditioning regimens containing both fludarabine and cyclophosphamide, but no other chemotherapies would be included. Patients may have also received total body irradiation, total

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lymphoid irradiation, or any lymphocyte depleting antibody. Only patients who received cyclosporine or tacrolimus (+/- others) for GVHD prophylaxis would be included.

It is estimated that almost 300 patients with URD transplant will be available for analysis from both the CIBMTR and EBMT databases. Of that, approximately 20% of patients will have had a mismatched URD transplant.

Analysis: Patient, disease and treatment related characteristics will be described. Outcomes (OS, graft failure, DFS, TRM, and GVHD) for IST and URD transplantation will be compared. Multivariate analysis will be performed with the main effect being the impact of treatment type on outcome. Secondary analyses will be performed as feasible for subgroups defined by recipient age and degree of HLA matching.

References: 1. Gupta V, Eapen M, Brazauskas R, et al. Impact of age on outcomes after bone marrow transplantation for acquired aplastic anemia using HLA-matched sibling donors. Haematologica 2010;95:2119-25. 2. Passweg JR, Marsh JC. Aplastic anemia: firstline treatment by immunosuppression and sibling marrow transplantation. ASH Education Program 2010;2010:36-42. 3. Scheinberg P, Young NS. How I treat acquired aplastic anemia. Blood 2012;120:1185-96. 4. https://bethematchclinical.org/resources-and-education/hct-presentation-slides. 5. Horan J, Wang T, Haagenson M, et al. Evaluation of HLA matching in unrelated hematopoietic stem cell transplantation for nonmalignant disorders. Blood 2012;120:2918-24. 6. Lee SJ, Kuntz KM, Horowitz MM, et al. Unrelated donor bone marrow transplantation for chronic myelogenous leukemia: a decision analysis. Annals of internal medicine 1997;127:1080-8. 7. Cutler CS, Lee SJ, Greenberg P, et al. A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood 2004;104:579-85. 8. Kurosawa S, Yamaguchi T, Miyawaki S, et al. A Markov decision analysis of allogeneic hematopoietic cell transplantation versus chemotherapy in patients with acute myeloid leukemia in first remission. Blood 2011;117:2113-20.

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Characteristics of < 40 years patients who underwent a 7/8 or 8/8 HLA match unrelated bone marrow allogeneic HCT reported to the CIBMTR from 2000 to 2015

Variable N (%) Number of patients 149 Number of centers 57 Age at transplant, years <10 40 (27) 10-19 56 (38) 20-29 39 (26) 30-39 14 ( 9) HLA match 7/8 40 (27) 8/8 109 (73) Conditioning regimen Cy + Fludarabine + TBI + ATG 100 (67) Cy + Fludarabine + ATG 31 (21) Cy + Fludarabine + TBI 10 ( 7) Cy + Fludarabine 8 ( 5) Year of HCT 2000-2007 43 (29) 2008-2015 106 (71)

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Proposal 1511-131

Title: Results of transplants from genetically-identical twin donors in persons with aplastic anaemia

Robert Peter Gale, MD, PhD, DSc(hc), FACP, FRSM, Imperial College London, [email protected]

Hypothesis: About one-half of cases of aplastic anaemia are caused by defective haematopoietic stem or progenitor cells

Specific aims: Determine the proportion of persons with aplastic anaemia receiving an infusion of bone marrow or blood cells from a genetically-identical twin recover normal bone marrow function after no pretransplant conditioning and, if this fails, after pretransplant conditioning. Results will estimate the proportion of cases of aplastic anaemia resulting from absent or defective haematopoietic stem or progenitor cells versus other mechanisms such as immune-dysfunction.

Scientific justification: We previously reported about one-half of twins recover after infusing bone marrow cells from a normal genetically-identical twin suggesting absent or defective haematopoietic stem or progenitor cells as the likely aetiology. This notion is being challenged by others claiming all cases of acquired aplastic anaemia are immune-mediated. Importance of the intended study: Fundamental to understanding the aetiology(ies) of bone marrow failure. Please include a statement regarding the scientific impact on the field: Major.

Subject eligibility population: Subjects: Recipients of bone marrow or blood cell transplants for aplastic anaemia with or with pretransplant conditioning.

Data requirements: All ages, all years, only 1st transplants from genetically-identical twins given without pretransplant conditioning. Prior non-transplant therapies not important. Include a list of variables from the existing CIBMTR data collection forms that need to be analyzed, and desired outcome variables. Age, gender, aetiology of aplastic anaemia (if known), prior therapies (if known), bone marrow recovery (granulocytes, platelets).

Study design (scientific plan): Observational database

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References: 1. Results of transplanting bone marrow from genetically identical twins into patients with aplastic anemia. Hinterberger W, Rowlings PA, Hinterberger-Fischer M, Gibson J, Jacobsen N, Klein JP, Kolb HJ, Stevens DA, Horowitz MM, Gale RP. Ann Intern Med. 1997 Jan 15;126(2):116-22. 2. Case problems in bone marrow transplantation. I. Graft failure in aplastic anemia: its biology and treatment.Champlin RE, Feig SA, Gale RP.Exp Hematol. 1984 Oct;12(9):728-33. 3. Bone marrow transplants for paroxysmal nocturnal haemoglobinuria. Saso R, Marsh J, Cevreska L, Szer J, Gale RP, Rowlings PA, Passweg JR, Nugent ML, Luzzatto L, Horowitz MM, Gordon-Smith EC. Br J Haematol. 1999 Feb;104(2):392-6. 4. Current results of bone marrow transplantation in patients with acquired severe aplastic anemia. Report of the European Group for Blood and Marrow transplantation. On behalf of the Working Party on Severe Aplastic Anemia of the European Group for Blood and Marrow Transplantation. Bacigalupo A, Oneto R, Bruno B, Socié G, Passweg J, Locasciulli A, Van Lint MT, Tichelli A, McCann S, Marsh J, Ljungman P, Hows J, Marin P, Schrezenmeier H. Acta Haematol. 2000;103(1):19-25.

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Characteristics of Patients Who Underwent an Allogeneic Hematopoietic Cell Transplant from a Genetically Identical Twin Donor in Persons with Aplastic Anemia Variable N (%) Number of patients 139 Number of centers 110 Age in decades, years Median (range) 18 (2-76) < 10 20 (14) 10-19 57 (41) 20-29 27 (19) 30-39 20 (14) 40-49 9 (6) 50-59 2 (1) > 60 4 (3) Graft source Bone marrow 104 (75) Peripheral blood 35 (25) Conditioning Regimen None 37 (24) Yes 102 (69) CY alone 24 (41) BuCy 7 (7) ATG + CY 34 (32) TBI + CY 4 (4) CY ± Others(no ATG,TBI) 7 (8) ATG ± Others (Flud=2) 4 (4) TBI + Others (no ATG,TBI, CY) 1 (1) Others 3 (2) Year of transplant 1960-1979 6 (4) 1980-1999 70 (50) 2000-2014 63 (45)

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Proposal 1512-01

Title: Combined EBMT/CIBMTR retrospective Study of Allogeneic Stem Cell Transplant Outcomes in Older Patients (age > 50 years) with Severe Aplastic Anaemia (SAA)

Carmel Rice Victor Potter Ghulam Mufti Judith Marsh

Introduction: Severe aplastic anaemia (SAA) is a rare disorder with a biphasic incidence in patients 10-25 years and >60 years. Although treatment algorithms are well characterised for younger patients (1, 2), guidelines relating to older patients are limited. There is a paucity of data describing outcomes of older patients with SAA following allogeneic stem cell transplantation from both sibling and unrelated donors

HSCT is not recommended first line in older patients without a sibling donor but is considered on an individual basis in patients who fail immunosuppressive therapy (3,4). Since outcomes after HSCT in general continue to improve over time, and with an increased ageing population globally, demand for HSCT in older patients is likely to increase further.

In recent years, improvements in supportive care and new transplant protocols, including the introduction of Alemtuzumab and reduced intensity conditioning, have demonstrated benefits in older patients undergoing HSCT for other haematological disorders (5,6). It is likely that similar findings may be observed in older SAA patients but little published data exist for patients aged > 50 years. Of two previous studies in older patients with SAA, a CIBMTR study compared outcomes of patients aged <20, 20-40 and > 40 years, transplanted from HLA matched sibling donors. Compared to patients aged < 20 years, patients > 40 years had a lower chance of platelet recovery, and higher risk of mortality (7). The second study from Seattle evaluated 23 patients aged 40-68 years undergoing matched sibling BMT using high dose cyclophosphamide 200mg/kg and ATG conditioning. Overall survival was 65%, acute grade II, III, IV GVHD was 30%, 4% and 0% and chronic GVHD 26% (8).

Short description of the study: This protocol will: • Examine number of HSCT performed in older patients (> 50 years) for SAA performed annually worldwide since 1980, for each age cohort of 50-60, 60-70 and >70yr. • Examine outcomes of patients aged >50 years receiving HSCT for SAA since 2000. We will stratify older patients into: o Different age groups (50-60 yr, 60-70 and > 70yr) o Year of transplant: 2000-2005, 2005-2010, 2010-2015 • We will describe the mortality and morbidity for each group with particular focus on graft failure, GVHD and infection. • We will analyse the impact of key factors, including HCT-CI score/Karnovsky status, previous courses of immunosuppression, stem cell source, donor type, specific conditioning regimens, and use of ATG versus Alemtuzumab (Campath).

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Research design: Retrospective analysis of the EBMT and CIBMTR database.

Study population: Inclusion criteria: • all patients > 50yrs requiring allogeneic HSCT for SAA/vSAA • either as first line treatment or following failure of • immunosuppresive therapy (e.g. ATG+CSA) • from sibling donor or matched unrelated donor (9/10 • or 10/10) by high resolution HLA typing • HSCT source (BM, PB) Exclusion Criteria: • previous HSCT • haploidentical, as defined by 4/8 or 5/10 or 6/12 antigen mis-matched. Transplant procedure: • VUD/SIB • ATG/Campath based protocols

Data to be collected/analysed: Outcomes of interest are: • event free survival; GVHD-free survival; overall survival; time to engraftment; late graft failure; incidence of II-IV aGvHD and cGvHD • Data will be reported after consent to the EBMT and CIBMTR • Data will be analyzed retrospectively. • Data reporting is covered through the EBMT and CIBMTR guidelines and consent rules as well as ethics approval for data reporting.

References: 1. Killick S et al. Guidelines for the diagnosis and management of adult aplastic anaemia. BCSH guidelines. BJH 2015 in press. 2. Scheinberg P. et al. How I treat acquired aplastic anaemia. Blood 2012. 120(6):1185-96. 3. Marsh JC et al. Alemtuzumab with fludarabine and cyclophosphamide reduces chronic graft-versus- host disease after allogeneic stem cell transplantation for acquired aplastic anaemia. Blood 2011; 118: 2351-2357. 4. Maury S et al. Unrelated stem cell transplantation for severe acquired aplastic anaemia: improved outcome in the era of high resolution HLA matching between donor and recipient. Haematologica 2007; 92(5):589-96. 5. McClune BL et al Effect of age on outcome of reduced intensity haematopoietic stem cell transplantation for older patients with AML in first complete remission or MDS. JCO 2010; 28(11):1878- 87 6. Lim Z. et al. Allogeneic hematopoietic stem-cell transplanattion for patients 50 years or older with MDS or secondary AML. JCO 2010; 8(3):405-11.. 7. Gupta V et al. Impact of age on outcomes after bone marrow transplantation for acquired aplastic anemia using HLA-matched sibling donors. Haematologica. 2010; 95: 2119-25. 8. Sangiolo D et al. 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: 1411-8.

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Table 1. Characteristics of ≥ 50 years patients who underwent an HLA-identical sibling alloHCT for severe aplastic anemia registered to the CIBMTR from 2000-2014 in USA, Canada and South America

TED only CrF Total Variable N (%) N (%) N (%) Number of patients 109 45 154 Number of centers 61 31 75 Country US 91 (83) 41 (91) 132 (86) Canada 7 ( 6) 1 ( 2) 8 ( 5) South America 11 (10) 3 ( 7) 14 ( 9) Argentina 1 0 1 Brazil 5 2 7 Uruguay 0 1 1 Columbia 5 0 5 Age at HCT, years Median 58 (50-77) 55 (50-82) 57 (50-82) 50-59 74 (68) 31 (69) 105 (68) 60-69 32 (29) 13 (29) 45 (29) 70-79 3 ( 3) 0 3 ( 2) 80-89 0 1 ( 2) 1 ( 1) Sex Male 62 (57) 25 (56) 87 (56) Female 47 (43) 20 (44) 67 (44) Graft type Bone marrow 64 (58) 22 (49) 86 (56) Peripheral blood 45 (42) 23 (51) 68 (44) Year of HCT 2000 2 ( 2) 2 ( 4) 4 ( 3) 2001 2 ( 2) 4 ( 9) 6 ( 4) 2002 7 ( 6) 1 ( 2) 8 ( 5) 2003 8 ( 7) 2 ( 4) 10 ( 6) 2004 7 ( 6) 1 ( 2) 8 ( 5) 2005 3 ( 3) 0 3 ( 2) 2006 6 ( 6) 3 ( 7) 9 ( 6) 2007 5 ( 5) 2 ( 4) 7 ( 5) 2008 2 ( 2) 10 (22) 12 ( 8) 2009 10 ( 9) 9 (20) 19 (12) 2010 23 (21) 0 23 (15) 2011 8 ( 7) 0 8 ( 5) 2012 13 (12) 1 ( 2) 14 ( 9) 2013 10 ( 9) 2 ( 4) 12 ( 8) 2014 3 ( 3) 8 (18) 11 ( 7)

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Table 2. Characteristics of ≥ 50 years patients who underwent an unrelated alloHCT for severe aplastic anemia registered to the CIBMTR from 2000-2014 in USA, Canada and South America

TED only CrF Total Variable N (%) N (%) N (%) Number of patients 68 72 140 Number of centers 42 43 64 Country US 63 (93) 71 (99) 134 (96) Canada 5 ( 7) 1 ( 1) 6 ( 4) South America 0 0 0 Argentina 0 0 0 Brazil 0 0 0 Uruguay 0 0 0 Columbia 0 0 0 Age at HCT, years Median 60 (50-77) 58 (50-71) 58 (50-77) 50-59 33 (49) 47 (65) 80 (57) 60-69 32 (47) 24 (33) 56 (40) 70-79 3 ( 4) 1 ( 1) 4 ( 3) 80-89 0 0 0 Sex Male 30 (44) 35 (49) 65 (46) Female 38 (56) 37 (51) 75 (54) Graft type Bone marrow 36 (53) 42 (58) 78 (56) Peripheral blood 32 (47) 30 (42) 62 (44) Year of HCT 2001 2 ( 3) 3 ( 4) 5 ( 4) 2002 0 1 ( 1) 1 ( 1) 2003 0 2 ( 3) 2 ( 1) 2004 1 ( 1) 4 ( 6) 5 ( 4) 2005 0 4 ( 6) 4 ( 3) 2006 0 8 (11) 8 ( 6) 2007 2 ( 3) 11 (15) 13 ( 9) 2008 2 ( 3) 9 (13) 11 ( 8) 2009 5 ( 7) 6 ( 8) 11 ( 8) 2010 11 (16) 4 ( 6) 15 (11) 2011 12 (18) 1 ( 1) 13 ( 9) 2012 18 (26) 2 ( 3) 20 (14) 2013 10 (15) 6 ( 8) 16 (11) 2014 5 ( 7) 11 (15) 16 (11)

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