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235 Long-Term Outcomes after Unrelated Marrow Transplantation for Aplastic Anemia with Optimized Cyclophosphamide Dose (BMT CTN 0301)

Program: Oral and Poster Abstracts
Type: Oral
Session: 723. Allogeneic Transplantation: Long-Term Follow-Up and Disease Recurrence: Long-Term Survival and Survivorship From Clinical Trials And Observations
Hematology Disease Topics & Pathways:
Research, clinical trials, Clinical Research
Saturday, December 9, 2023: 2:00 PM

Mary Eapen, MBBS, MS1, Joseph Antin, MD2*, Jakub Tolar, MD, PhD3, Sally Arai, MD4, Mitchell Horwitz, MD5, Jainqun Kou, MPH6*, Eric Leifere, PhD7*, John M. McCarty, MD8, Ryotaro Nakamura, MD9, Michael A. Pulsipher, MD10*, Mary M. Horowitz, MD6 and H Joachim Deeg, MD11*

1Department of Medicine, The Medical College of Wisconsin Inc, Milwaukee, WI
2Dana-Farber Cancer Institute, Boston, MA
3University of Minnesota, Minneapolis, MN
4Stanford University Medical Center, Palo Alto, CA
5Duke University Medical Center, Durham, NC
6Center for International Blood and Marrow Transplant Research, Milwaukee, WI
7National Heart Lung and Blood Institute, Bethesda, MD
8Virginia Commonwealth University Medical Center, Richmond, VA
9Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Comprehensive Cancer Center, Duarte, CA
10University of Utah School of Medicine, Salt Lake City, UT
11Fred Hutchinson Cancer Center, Seattle, WA

Background: Seventy-nine patients (aged ≤65 years) with aplastic anemia received HLA-matched or single locus mismatched unrelated donor marrow transplantation (BMT) on a clinical trial (BMT CTN 0301; NCT00326417) between 02/2006 and 12/2013 (Lancet Haematol. 2015, 2:e367-75). The median ages of patients enrolled on the cyclophosphamide (Cy) 50 mg/kg and 100 mg/kg strata were 25 and 18 years, respectively, and 80% were Caucasians. That trial determined the minimum dose of Cy required for engraftment when added to total body irradiation (TBI 2 Gy), anti-thymocyte globulin (rabbit-ATG 9 mg/kg) and fludarabine (120 mg/m2). Graft versus host disease (GVHD) prophylaxis was cyclosporine and methotrexate. Although Cy at 50 mg/kg (n=38) and 100 mg/kg (n=41) were both effective for day 100 and 1-year outcomes, the computed optimum Cy dose by Bayesian method was 50 mg/kg. Early results showed a 1-year incidence of graft failure after Cy 50 mg/kg and 100 mg/kg of 12% and 15%, respectively. The corresponding probabilities of 1-year survival were 92% and 76%.

Methods: Thirty-seven patients who received Cy at 50 mg/kg and 31 patients who received Cy at 100 mg/kg were alive ≥1 year after BMT. These patients now have median follow ups of 7 and 8.7 years, respectively. The incidence of graft failure and chronic GVHD was calculated using the cumulative incidence estimator and the probability of survival using the Kaplan-Meier estimator.

Results: In the trial cohort, 31 of 38 patients (82%) who received Cy 50 mg/kg were HLA-matched to their donor at HLA-A, B, C and DRB1, compared to 27 of 41 (66%) receiving Cy 100 mg/kg. Table 1 shows outcomes of the 38 and 41 patients who received Cy at 50 mg/kg and Cy at 100 mg/kg. With Cy 50 mg/kg there was 1 late graft failure at 4 years (cumulative total 5). Five deaths occurred at 1.5, 1.8, 4.2, 5.2 and 12.2 years after BMT (cumulative total 6). All chronic GVHD occurred within 2 years. Late toxicities (n=8; 22%) included liver cirrhosis (n=1, 1.25 years), myocardial infarction (n=1, 3.8 years), congestive heart failure (n=1, 8.7 years), acute renal failure requiring dialysis (n=1, 3.8 years), avascular necrosis (n=1, 9 years), gonadal dysfunction in pre-pubertal children at BMT (n=2, 1.4 and 3.9 years), and secondary cancer (n=1, pancreatic adenocarcinoma 3.1 years). The 8-year survival among the 38 patients receiving Cy 50 mg/kg was 85% despite late toxicities, including death, being more common beyond the first year after BMT. With Cy 100 mg/kg, there were no late graft failures. There was 1 death at 8.6 years (in a patient with underlying dyskeratosis congenita (cumulative total 11). One patient was diagnosed with chronic GVHD at 7 years. Late toxicities (n=6; 19%) included pulmonary (n=2, ARDS 8 years and restrictive airway disease 1.9 years), chronic renal failure requiring dialysis (n=1, 15 years), avascular necrosis (n=1, 1.5 years), gonadal dysfunction (n=1, 2.6 years), and secondary cancer (n=1, myelodysplastic syndrome 8.9 years). The 8-year survival among the 41 patients receiving Cy 100 mg/kg was 76% and all except 1 death occurred within the 1st year after BMT. Causes of death after the first year of BMT are shown in Table 2.

Conclusion: Eight-year survival ≥75% and sustained engraftment confirm both Cy at 50 mg/kg and Cy at 100 mg/kg with TBI 2 Gy, ATG and fludarabine are effective conditioning for unrelated BMT for aplastic anemia but life-long surveillance for late complications is required. Chronic GVHD was common and proved fatal in several patients despite most donor-recipient pairs who received Cy at 50 mg/kg being HLA-matched at the allele-level.

Disclosures: Horwitz: AbbVie: Consultancy; CareDx: Consultancy; Kadmon: Consultancy; Magenta: Consultancy; GamidaCell: Research Funding. Nakamura: Omeros: Consultancy; Blue Bird: Consultancy; BMT CTN Steering Committee: Membership on an entity's Board of Directors or advisory committees; Mt. Sinai: Other: Acute GVHD; International Consortium: Other: consortium chair; Sanofi: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: research collaboration; Napajen: Consultancy; NCCN: Other: guideline panel for HCT; Miyarisan: Research Funding; Leukemia & Lymphoma Society: Other: grant reviewer; NCTN Lymphoma Steering Committee: Membership on an entity's Board of Directors or advisory committees. Pulsipher: Adaptive Biotechnologies: Research Funding; GentiBio: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; CARGO Therapeutics: Membership on an entity's Board of Directors or advisory committees; Vertex Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotec: Research Funding.

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