Trial in Progress: Cureaa - a Clinical Trial of Upfront Haploidentical or Unrelated Donor BMT to Restore Normal Hematopoiesis in Aplastic Anemia, Blood and Marrow Transplant Clinical Trials Network (BMT CTN) #2207

Background: Immunosuppressive therapy (IST) is considered the standard front-line treatment for acquired severe aplastic anemia (SAA) for pts >40 years. For pts aged <40 years who have a suitable human leukocyte antigen (HLA)-matched sibling donor (MSD), hematopoietic stem cell transplantation (HSCT) is recommended. This recommendation is based on the toxicity associated with alternative donors; haploidentical (HAPLO) and unrelated donor (URD) HSCT for patients who lack a MSD. However, the hematopoietic response after IST is ~ 70-80%, even after augmentation with eltrombopag in the front-line setting, and failure-free survival (FFS, defined as patients alive and in remission without clonal disease more than 10 years after IST) remains < 40%. HSCT is often employed as a second line salvage therapy for those who do not respond to IST or have disease recurrence. However, outcomes after HSCT are often compromised because of IST-related complications such as clonal evolution, development of donor specific antibodies, infectious adverse events and organ dysfunction. In contrast, a successful allogeneic HSCT leads to relatively prompt hematopoietic and immune reconstitution and mitigates the risk of secondary clonal disease. Innovations in recent decades, such as improved graft versus host disease (GVHD) prophylaxis and supportive care, have steadily reduced the morbidity and mortality of adults undergoing HSCT from unrelated or mismatched donors and expanded the donor pool such that almost all pts with SAA have a potential donor available. The use of post-transplant cyclophosphamide (PTCy) is now a well-established approach to facilitate engraftment and mitigate the risk of GVHD. It was successfully used in relapsed/refractory SAA pts using HAPLO donors in the multi-center BMT CTN #1502 trial (NCT02918292). Similar PTCy based approaches have been effective in the upfront setting with HAPLO and URD in small single center studies. Opened in July 2024, the CureAA trial (NCT06517641), seeks to increase donor options for SAA pts who have not yet received IST by using PTCy based GVHD prophylaxis for HSCT using HAPLO or URD.

Study Design and Methods: This BMT CTN study (#2207) is a prospective multi-center phase II trial to assess efficacy of HSCT using HAPLO or URD bone marrow with a reduced intensity, thymoglobulin (ATG)-containing preparative regimen and PTCy GVHD prophylaxis in previously untreated SAA pts. This trial has two parallel cohorts for each donor type, HAPLO and URD, with an accrual goal of 30 participants in each cohort. All will receive ATG (0.5mg/kg on day -9 and 2mg/kg on days -8 and -7), cyclophosphamide (14.5mg/kg on days -6 and -5), fludarabine (30mg/m² on days -6 to -2), 400 cGy total body irradiation (day -1 in a single fraction), a marrow graft (goal >2.5 x 10⁸ nucleated cells per kg of recipient) on day 0 and PTCy (50mg/kg on days +3 and +4). Additionally, participants receive tacrolimus (until day +180) and mycophenolate mofetil days +5-35. The primary objective of the trial is to estimate the GVHD-free failure-free survival (GFFS) rate at 1 year after initiation of conditioning. GFFS is a composite endpoint of survival without grade III-IV acute GVHD, chronic GVHD requiring immunosuppression, or primary or secondary graft failure requiring second definitive therapy within 1 year after initiation of conditioning. Secondary objectives will evaluate patient survival, engraftment, transfusion dependence, cumulative incidence of GVHD and hematologic response. Health related quality of life, healthcare utilization and financial toxicity data will also be collected. These endpoints will allow clinical comparison with current results achieved with upfront IST in other studies. We hypothesize that this HSCT approach will improve survival without significant transplant-associated morbidity by using a low toxicity regimen that reduces rates of GVHD and provides rapid hematologic recovery without graft failure, thereby making HAPLO and URD HSCT a viable option for initial upfront treatment of SAA. The ability to use mismatched donors will also ensure that a HSCT option is more widely available to all racial/ethnic groups.

This collaborative study was funded by grants U10HL069294, U24HL138660 to the BMT CTN from the NHLBI/ NCI, along with funding from Sanofi. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Sharma:Vertex Pharmaceuticals: Consultancy, Other: Clinical Trial site-PI; CRISPR Therapeutics: Other: Clinical Trial site-PI, Research Funding; Novartis: Other: Clinical Trial site-PI; Beam Therapeutics: Other: Clinical Trial site-PI; Editas Medicine: Consultancy; Sangamo Therapeutics: Consultancy; Medexus Inc.: Consultancy. Mangaonkar:BMS: Research Funding; Incyte: Research Funding; Novartis: Research Funding. Fritz:Emmes Corporation: Current Employment. Patel:Kite: Honoraria; Sanofi: Honoraria. Devine:National Marrow Donor Program: Current Employment. Horowitz:Sobi: Research Funding; Xenikos: Research Funding; Bristol-Myers Squibb: Research Funding; Astellas: Research Funding; CSL Behring: Research Funding; Gamida Cell: Research Funding; Incyte: Research Funding; Janssen: Research Funding; Medac: Research Funding; Novartis: Research Funding; Sanofi: Research Funding. DeZern:Appellis: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Keros: Membership on an entity's Board of Directors or advisory committees; geron: Other: dsmb; Bristol Myers Squibbs: Membership on an entity's Board of Directors or advisory committees; servier: Membership on an entity's Board of Directors or advisory committees.