Optimizing PTCy Dose and Timing

Summary

Participation Requirements

Description

Background: Post-transplantation cyclophosphamide (PTCy) reduces rates of severe acute and chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) and safely facilitates human leukocyte antigen (HLA)-haploidentical HCT When clinically translated, the dose (...

Background: Post-transplantation cyclophosphamide (PTCy) reduces rates of severe acute and chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) and safely facilitates human leukocyte antigen (HLA)-haploidentical HCT When clinically translated, the dose (50 mg/kg) and timing (days +3 and +4) of PTCy used were partly extrapolated from murine major histocompatibility complex (MHC)-matched skin allografting models and were partly empirical In both MHC-haploidentical and MHC-disparate murine HCT models, a dose of 25 mg/kg/day was superior to 50 mg/kg/day on days +3 and +4 in terms of GVHD severity and mortality In the MHC-haploidentical HCT model, a dose of 25 mg/kg on day +4 was equivalent to 25 mg/kg/day on days +3 and +4 In addition to better GVHD prevention, lower dosing of PTCy is associated with less broad reduction of T-cell numbers after PTCy Objective: -Determine whether a dose of PTCy 25 mg/kg on day +3 and +4 or on day +4 only can maintain adequate protection against grade III-IV acute GVHD. Eligibility: Histologically or cytologically confirmed hematologic malignancy with standard indication for allogeneic hematopoietic cell transplantation including one of the following: Acute myeloid leukemia (AML) of intermediate or adverse risk disease by the 2017 European LeukemiaNet criteria in first morphologic complete remission AML of any risk in second or subsequent morphologic complete remission B-cell acute lymphoblastic leukemia in first or subsequent complete remission T-cell acute lymphoblastic leukemia with minimal residual disease detected after first line therapy and/or adverse genetics Myelodysplastic syndrome of intermediate or higher score by the Revised International Prognostic Scoring System (IPSS-R) Primary myelofibrosis of intermediate-2 or higher risk by the Dynamic International Prognostic Scoring System (DIPSS) Chronic myelomonocytic leukemia Chronic myelogenous leukemia resistant to or intolerant of greater than or equal to 3 tyrosine kinase inhibitors or with prior history of accelerated phase or blast crisis B-cell lymphoma including Hodgkin lymphoma that has relapsed within 1 year of completion of primary treatment Chronic lymphocytic leukemia with 17p deletion and/or unmutated IgHV or refractory to or intolerant of both BTK and PI3K inhibitors Mature T or NK neoplasms as defined in the WHO guidelines of sufficient type and severity for allogeneic HCT based on the Prognostic Index for T- cell lymphoma (PIT) score of low-intermediate risk or higher or on recently published clinical practice guidelines Hematologic malignancy of dendritic cell or histiocytic cell type Multiple myeloma, stage III, relapsing after therapy with both a proteasome inhibitor and an immunomodulatory drug (IMiD) Age 15-65. At least one potentially suitable HLA-haploidentical donor. Karnofsky performance score greater than or equal to 60 Adequate organ function Design: Open-label, single-center, non-randomized, phase I/II study All patients will receive myeloablative conditioning, HLA-haploidentical bone marrow HCT, and GVHD prophylaxis with PTCy, MMF, and sirolimus. A small pilot of 5 evaluable patients will receive the standard PTCy 50 mg/kg on days +3/+4 to obtain a limited amount of comparative pharmacokinetic and T-cell immunophenotyping and repertoire data Then the study will proceed to a small, two-level [1) 25 mg/kg/day on days +3 and +4, 2) 25 mg/kg on day +4 only] phase I dose de-escalation study based on the standard 3+3 approach Patients will be evaluated for development of grade III-IV acute GVHD (aGVHD) at day +60 as the dose-limiting toxicity and then phase II will proceed with the shorter duration of the days of treatment (+3/+4 or +4) which is associated with 0-1 of 6 patients with grade III- IV aGVHD at day +60 and with the least amount of toxicity Simon optimal two-stage phase II trial design, to rule out excess grade III-IV acute GVHD with this decreased PTCy exposure, will be used in the phase II portion of the study which will enroll an additional 14 patients to see if this lower PTCy exposure is associated with a similar rate of grade III-IV acute GVHD as is expected with 50 mg/kg on days +3/+4

Tracking Information