Objectives

The primary objective was to assess overall survival (OS) at 1-year post-hematopoietic stem cell transplantation (HSCT) from a haploidentical marrow donor in patients with severe aplastic anemia (SAA).

Background

Severe aplastic anemia is a rare bone marrow failure disorder. A major challenge in treating SAA is the management of patients who are resistant to and/or have relapsed after immunosuppressant therapy (IST). At the time of this trial, the only curative option for these patients has been hematopoietic stem cell transplants (HCST) but it is difficult to find suitable donors, especially for certain minority populations. Previously, a single institution showed success with using haploidentical donors. The BMT CTN 1502 clinical trial was created to further test the safety and survival rates of haploidentical donor allogenic bone marrow transplantation with post-transplant cyclophosphamide (PTCy) for relapsed or refractory SAA.

Participants

BMT CTN 1502 enrolled 32 participants and of those, 31 participants underwent bone marrow transplantation.

Enrolled participants were 75 years or younger with a diagnosis of acquired severe aplastic anemia who had not responded to at least one course of immunosuppressive therapy, did not have an available HLA-matched sibling or HLA-matched unrelated donor, but did have a haploidentical marrow donor available. Absence of response to immunosuppressive therapy was defined in the protocol as refractory or relapsed. Exclusions include inherited bone marrow failure syndrome, previous hematopoietic stem cell or solid organ transplant, uncontrolled infection, inadequate organ function, and Karnofsky or Lansky performance score < 60%.

Design

Donors for the trial were defined as a haploidentical relative of the participant. Eligibility for the donor was determined by the following: number of HLA mismatches and typing as well as full haplotype match by being identical at a minimum of one allele based on the typing used. Potential donors were excluded if there was a unidirectional mismatch in either the graft-versus-host or host-versus-graft direction or donor-specific antibodies.

Donor bone marrow was harvested with a target yield of 4 × 10^8 nucleated marrow cells per kg of recipient ideal bodyweight and infused on day 0. Rabbit anti-thymocyte globulin was dosed at 0.5 mg/kg on day −9 and at 2 mg/kg on days −8 and −7, intravenously. Fludarabine was administered at 30 mg/m2 intravenously daily for 5 days, from day −6 to day −2. Cyclophosphamide was given at 14.5 mg/kg intravenously daily for 2 days from day −6 to day −5 and total body irradiation was delivered in a single fraction of 200 cGy on day −1. Filgrastim was given on day 5 at 5 μg/kg per day and continued until absolute neutrophil count was greater than 1.5 × 10^9 cells per L for 3 days. In addition to rabbit anti-thymocyte globulin, GVHD prophylaxis included post-transplantation cyclophosphamide administered at 50 mg/kg per day intravenously on days 3 and 4; mycophenolate mofetil given at a dose of 15 mg/kg orally three times a day up to 1 g from day 5 to day 35; and tacrolimus given orally or intravenously from day 5 to day 180.

Adverse events were assessed at multiple timepoints (day 28, day 56, day 100, day 180, and day 365). Assessment for acute GVHD was done weekly up to day 100 and then monthly to 1-year post-transplantation. Quantitative assessments of peripheral blood CD3, CD4, CD8, and CD56-positive lymphocytes were measured at baseline, day 100, day 180, and day 365 post-transplantation to monitor for immune reconstitution. Health-related quality of life was measured at baseline and then change from baseline at day 100, day 180, and day 365 post-transplantation.

The study was primarily designed to assess overall survival (OS) at 1-year post-hematopoietic stem cell transplantation (HSCT). Secondary outcomes included primary and secondary graft failure, acute GVHD, and chronic GVHD.

Conclusions

The study resulted in excellent overall survival with minimal GVHD in patients who were refractory or relapsed after immunosuppressive therapy. There was an overall 1-year survival rate of 81% and graft-failure-free survival rate of 77%. The study noted that attention to obtaining high cell doses (>2.5×10^8 nucleated marrow cells per kg of recipient ideal bodyweight) from bone marrow harvests is crucial.

DeZern AE, Eapen M, Wu J, et al. Haploidentical bone marrow transplantation in patients with relapsed or refractory severe aplastic anaemia in the USA (BMT CTN 1502): a multicentre, single-arm, phase 2 trial [published correction appears in Lancet Haematol. 2022 Sep;9(9):e641]. Lancet Haematol. 2022;9(9):e660-e669. doi:10.1016/S2352-3026(22)00206-X

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