OPTIMIZE A Phase II Study of Reduced Dose Post Transplantation Cyclophosphamide as GvHD Prophylaxis in Adult Patients with Hematologic Malignancies Receiving HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation

Summary:

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative therapy for many hematologic disorders. ​The best outcomes are associated with the use of an HLA-matched sibling donor or 8/8 HLA-matched unrelated donor. Availability of HLA-matched sibling donors ranges from 13 to 51% while an unrelated donor is largely dependent upon race and ethnicity. ​The probability of finding an 8/8 HLA-matched unrelated donor is 76% for White and 29% for Black people. However, the probability of finding an at least a 7 out of 8 HLA-matched unrelated donor is >99% for all races.​ While HCT with a mismatched donor is possible, survival is historically inferior with increased graft-versus-host disease (GvHD) and graft failure. ​Fifty mg/kg of post-transplant cyclophosphamide (PTCy) on day 3 and 4 effectively overcomes the barriers associated with multiple HLA-mismatches, has significantly better outcomes than the previous standard of care (tacrolimus and methotrexate), and as a result has become the new standard of care, regardless of donor type (match OR mismatch).​ PTCy can cause significant acute and potential long-term side effects, including mucositis, organ toxicities, and infections. Infections were higher than the previous standard of care. Additionally, there is an increased risk for secondary malignancy with its use. ​Preliminary and small studies of reduced dose PTCy (25 mg/kg on day 3 and 4) have shown to be effective in protecting against GvHD while resulting in fewer early post-transplant toxicities and faster engraftment. However, larger multicenter studies are needed.​ This phase II study will assess the safety and the rate at which adult patients with hematologic malignancies develop a moderate to severe infection within 100-days after a mismatched unrelated donor stem cell transplantation and treatment with reduced dose PTCy in combination with other immunosuppressive agents as GvHD prophylaxis. ​If successful, OPTIMIZE will enable >99% of patients access to HCT regardless of ancestry while reducing side effects and toxicities.

Trial Registration: ClinicalTrials.gov Identifier: NCT06001385