Two National Clinical Trials Poised to Expand the Role of Bone Marrow Transplant in Newly Diagnosed Severe Aplastic Anemia

STUDY TITLE: A Phase III Randomized Trial Comparing Unrelated Donor Bone Marrow Transplantation With Immune Suppressive Therapy for Newly Diagnosed Pediatric and Young Adult Patients With Severe Aplastic Anemia (TransIT, BMT CTN 2202)

CLINICALTRIALS.GOV IDENTIFIER: NCT05600426

PARTICIPATING CENTERS: Open to centers participating in one of the following consortia: the North American Pediatric Aplastic Anemia Consortium (NAPAAC), Pediatric Transplantation and Cellular Therapy Consortium (PTCTC NMD2201), Blood and Marrow Transplant Clinical Trials Network (BMT CTN 2202)

ACCRUAL GOAL: 234 participants

STUDY DESIGN: In this multicenter randomized phase III clinical trial, patients age 25 years and younger with newly diagnosed severe aplastic anemia (SAA) who lack a known human leukocyte antigen (HLA)-matched sibling donor will be randomized 1:1 to receive either immunosuppressive therapy (IST) with cyclosporin and horse antithymocyte globulin (ATG) or an unrelated donor bone marrow transplantation (BMT) with non-myeloablative conditioning (ATG/fludarabine/cyclophosphamide/TBI 2 Gy) and cyclosporine/methotrexate (MTX) as graft-versus-host disease prophylaxis. The primary endpoint is the time from randomization to treatment failure (defined as a recommendation to begin second-line definitive therapy) or death from any cause. A multitude of secondary clinical objectives including assessments of immune reconstitution and gonadal function, along with interesting correlative exploratory objectives focused on germline mutations and clonal hematopoiesis, are included.

STUDY TITLE: CUREAA: Clinical Trial of Upfront Haploidentical or Unrelated Donor BMT to REstore Normal Hematopoiesis in Aplastic Anemia

CLINICALTRIALS.GOV IDENTIFIER: Pending

PARTICIPATING CENTERS: Open to centers participating in the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 2207)

ACCRUAL GOAL: 60 participants

STUDY DESIGN: For this multicenter phase II single-arm clinical trial, patients over 25 years old (or younger if TransIT not open at the site) with newly diagnosed SAA who lack a known HLA-matched sibling donor but have either an appropriate unrelated donor (HLA-matched or -mismatched) or haploidentical relative will be eligible to participate. Patients will receive treatment with the Baltimore regimen, consisting of non-myeloablative conditioning (ATG/fludarabine/cyclophosphamide/TBI 4 Gy) followed by bone marrow infusion and combined treatment with cyclophosphamide, tacrolimus, and mycophenolate mofetil as graft-versus-host disease (GVHD) prophylaxis. The primary endpoint is GVHD-failure-free survival (GFFS) at one year following BMT. Enrollment is intended to include equal numbers of patients receiving bone marrow from unrelated or haploidentical donors. Secondary endpoints include metrics that may allow some clinical comparisons of the results to those achieved using up-front IST in this age group.

RATIONALE: For decades, the treatment paradigm for newly diagnosed acquired SAA has relied on immunosuppressive therapy (IST), with bone marrow transplant (BMT) limited to the relatively rare patient who happens to be both young (<40 years old) and to have an available HLA-identical sibling donor.¹  The standard IST regimen of antithymocyte globulin (ATG) and cyclosporine has undergone modest improvements over time (most notably with the addition of eltrombopag, which enhances rapidity and depth of response in adults only and does not provide an overall survival advantage^2-4 ); however, approximately half of children and adults treated with IST will experience treatment failure over or disease refractoriness over time,⁵  and an additional 10 to 15% will develop clonal hematopoiesis with resultant myelodysplastic syndromes/acute myeloid leukemia.⁶  In contrast, up-front non-myeloablative BMT using an HLA-identical sibling results in failure-free survival in over 90% of younger patients with SAA, with fewer than 10% experiencing GVHD. However, BMT was historically too toxic to offer as up-front therapy for older patients with SAA and those who lacked an HLA-identical sibling donor.

The TransIT and CUREAA studies seek to shatter these traditional treatment paradigms for SAA. Building on retrospective studies and pilot data demonstrating feasibility and excellent outcomes with modern-day BMT for SAA using unrelated donors, the North American Pediatric Aplastic Anemia Consortium and the Pediatric Transplantation and Cellular Therapy Consortium have partnered with the Blood and Marrow Transplant Clinical Trials Network to launch TransIT, a randomized phase III trial evaluating IST versus unrelated donor (URD) BMT in younger patients (≤25 years old) with newly diagnosed SAA. The trial investigators aim to detect a 20% improvement in two-year failure-free survival with BMT versus IST and to examine several important secondary and exploratory outcomes between the study arms, including rates of gonadal failure and clonal hematopoiesis. Importantly, the pediatric consortium has completed an initial pilot study,⁷  which demonstrated patient willingness to undergo randomization and helped inform “best practices” for operationalizing this successor phase III trial.

The CUREAA trial, led by the BMT Clinical Trials Network (BMT CTN 2207), incorporates the latest innovation in BMT, post-transplant cyclophosphamide (PTCy)⁸ , into up-front BMT for patients with SAA without HLA-identical sibling donors. This multicenter trial expands previous single-center experiences with the Baltimore regimen in SAA^9,10  and will test this approach in patients with either unrelated or haploidentical donor options. The trial also capitalizes on the investigators’ experiences with increasing TBI from 2 to 4 Gy to facilitate deeper engraftment without greater toxicity. The primary endpoint, GVHD-relapse-free survival, along with key secondary survival and immune reconstitution endpoints, will establish the safety and efficacy of this approach in patients with newly diagnosed SAA.

COMMENT: These exceptional clinical trials, focused on both children and adults with SAA, highlight important breakthroughs in the field of BMT, as well as the critical role that focused research and multicenter consortia play in establishing new standards for rare diseases. The TransIT trial, if successful, will expand BMT options for many children and young adults with newly diagnosed SAA with HLA-matched or -mismatched (9/10) URD donors. The CUREAA trial, in addition to testing a new BMT platform (PTCy), extends up-front BMT access even further via the inclusion of HLA-mismatched (>7/10) unrelated and haploidentical donors. In addition to answering critical questions on SAA, these protocols provide an opportunity to improve equity in accessing curative therapies among patients from underrepresented racial/ethnic backgrounds, who in the past have been commonly excluded from BMT due to lack of HLA-matched donors. In fact, in a recently published multicenter trial evaluating haploidentical BMT as treatment for relapsed/refractory SAA (BMT CTN 1502), 61% of the study population self-reported as belonging to underrepresented minority groups.¹¹  This is a win for patients and for hematology, and the results will be further strengthened by ongoing efforts to improve enrollment of diverse populations in BMT clinical trials.¹²  In summary, the TransIT and CUREAA trials signify an evolving era of disease management, highlighting the promise of a cure for more patients with SAA.