Disclosers Updates: Management of Aplastic Anemia and Congenital Marrow Failure 5/9/2017

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1 2017 Updates: Management of Aplastic Anemia and Congenital Marrow Failure Sachit Patel, MD Department of Pediatrics Division of Hematology-Oncology Blood and Marrow Transplantation Disclosers None 1

2 Objectives: Identify common presenting features of Inherited Bone Marrow Failure Syndromes (IBMFS) Summarize management options for IBMF Summarize useful prognostic features and current outcomes Describe active clinical trails and future initiatives for patients with IBMFS Articulate my message in a way that will combat your innate urge to check Facebook/Twitter/ s in the next 20 minutes. IBMFS Heterogeneous group of disorders Inadequate production of blood forming cells Often presents in childhood, but can go unrecognized Idiopathic aplastic anemia can be a cryptic presentation Bone Marrow Failure Idiopathic (~70%) Aplastic Anemia Inherited (~15%) Aplastic Anemia Fanconi Anemia Schwachman-Diamond Dyskeratosis Congenita Congenital Neutropenia Diamond-Blackfan Pearson CAMT TAR Secondary (~15%) Drugs Virus Immune 2

3 Importance of Recognition? - Progressive marrow failure - Chronic infections - Transfusion dependence - Progressive transfusion-related organ damage - Malignant transformation or clonal evolution - Decreased life-expectancy Where to begin? 3

4 Aplastic Anemia Andrea Bacigalupo Blood 2017;129: Andrea Bacigalupo Blood 2017;129:

5 Andrea Bacigalupo Blood 2017;129: Andrea Bacigalupo Blood 2017;129:

Andrea Bacigalupo Blood 2017;129:1428-1436 ATG: the nature of the beast Scheinberg et al. NEJM.

6 Andrea Bacigalupo Blood 2017;129: ATG: the nature of the beast Scheinberg et al. NEJM Horse is superior to Rabbit ATG as first line IST 3 yr overall survival 96% vs 76% (p=0.04) 6

7 SURVIVAL (%) 5/9/2017 Severe Aplastic Anemia Overall Survival Pediatric Patient Transplantation by Year of Transplant Unrelated Transplants Facilitated by NMDP/Be The Match ( ) (n=121) (n=183) (n=128) (n=175) Log-rank p-value < MONTHS AFTER TRANSPLANT 40 SOURCE: CIBMTR, the research program of NMDP/Be The Match 7

8 Key Considerations for SAA Age at diagnosis Stem cell source Use of ATG Time to transplant Mutation analysis Kulasekararaj et al. Blood 2014 Andrea Bacigalupo Blood 2017;129: Inherited Bone Marrow Failure Syndromes Important points regarding management of IBFS: - Many are under recognized - Malignancy and MDS are not the same animal - Some IBMFS are chemo and radiation sensitive - Non-hematologic abnormalities persist These lead to individualized management with common goals: 1. Limit transfusion exposure 2. Control iron overload 3. Minimize long-term steroid effects 4. Monitor for malignancy and clonal transformation Inherited (~15%) Aplastic Anemia Fanconi Anemia Schwachman-Diamond Dyskeratosis Congenita Congenital Neutropenia Diamond-Blackfan Pearson CAMT TAR 8

9 Fanconi Anemia Gluckman and Colleagues were the first to investigate conditioning regimens in FA ( s) Based on experience in leukemia and SAA they used Cy 200mg/kg 4 out 5 died 30 years of progress Reduced doses of DNA damaging agents Incorporation of antithymocyte globulin (ATG) Incorporation of Fludarabine MSD HSCT without TBI Improved survival of URD HCT Without TBI - Brazil Group Cy/Flu/ATG - US pk adjusted Bu Cy/Flu/ATG Wagner et al. Blood 2007; Ayas et al. BMT Bonfim

Overt Leukemia with >20% blasts or MDS Alter, BP. Prac Res Clin Haematol.

10 Fanconi Anemia Management: - Steroid (50%-70% short term response) - HSCT 1. Persistent Hemoglobin < 8 g/dl 2. Platelets < 30,000/mm 3 3. ANC < 500/mm 3 4. Overt Leukemia with >20% blasts or MDS Alter, BP. Prac Res Clin Haematol HSCT outcomes Fanconi Anemia: - Initial results were dismal - With Fludarabine based regimens, 2 yr OS ~90% Peffault et al. Blood

11 Diamond-Blackfan Anemia (RPL,RPS) First-line steroids have an ~80% transfusion free response However, only ~20% retain the response Severe Congenital Neutropenia (ELA2, HAX1) Validated indications include: GCSF resistance (>20ug/kg/day) GCSF >10ug/kg/dose for > 3 months Fioredda and EBMT reported 136 pts 61 MRD, 14 mismatched 3 year OS 82%, TRM 17% Dyskeratosis Congenita (TERT, TERC, DKC1, TINF2) BMF in ~85% and is the cause of death in ~80% 2 year OS ~90% with matched related donors. Schwachman-Diamond Syndrome (SBDS)** Dilemma: who will have progression? Diagnosis < 3mo and pancytopenia at diagnosis The Future is Bright BMT CTN 1502 Optimizing Cord Blood and Haploidentical Aplastic Anemia Transplantation Dezern et al. BBMT 2016 (Hopkins) Alternative donor with PTCy in SAA 16 pts. All alive and transfusion independent Townsley et al. NEJM 2017 Eltrombopag added to standard IST for 6 months. 33% complete response 80% overall response RACE (NCT ) attempting to confirm this benefit Understanding mixed chimerism 11

References: Bacigalupo, A. Blood. 2017 Dezern et al.

2014 Peffault et al. Blood. 2013 Scheinberg et al.

2011 Wagner et al. Blood 2007. Dokel et al.

12 References: Bacigalupo, A. Blood Dezern et al. BBMT 2016 Alter, BP. Prac Res Clin Haematol Peffault et al. Blood Scheinberg et al. NEJM Morimoto et al. Bone Marrow Research Wagner et al. Blood Dokel et al. Blood Reviews Ayas BMT Frickhofen et al. NEJM Thank You! Bruce Gordon, MD Don Coulter, MD Rebecca Swanson, NP Mandy Arens, RN Amy Brant, NP Pediatric Oncology Adult Oncology/BMT 12

Haploidentical Stem Cell Transplantation with post transplantation Cyclophosphamide for the treatment of Fanconi Anemia

Haploidentical Stem Cell Transplantation with post transplantation Cyclophosphamide for the treatment of Fanconi Anemia Carmem Bonfim Director Pediatric Blood and Marrow Transplantation Program HC Federal