Phase I/II Study to Reduce Post-transplantation Cyclophosphamide Dosing for Older or Unfit Patients Undergoing Bone Marrow Transplantation for Hematologic Malignancies

Background:

With novel therapies for hematologic malignancies, an increasing number of older and/or less fit patients are achieving remissions, but these new therapies are not curative, making consolidation approaches with curative intent such as allogeneic transplantation necessary.

Frailty is a phenotype that predicts a patient s intolerance of physiologic stressors and may predict a patient s tolerance of intensive consolidative strategies.

Frailty phenotype, though increasing in incidence in older patients, can occur in younger patients and may predict poor survival after allogeneic transplantation.

We have yet to define the ideal allogeneic transplantation regimen for older patients or those with frailty or pre-frail phenotypes.

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)-matched-related, HLA-matched-unrelated, HLA-mismatched-unrelated, and HLA-haploidentical HCT; it has become the most widely adopted change to transplantation platforms over the last decade.

When clinically translated, the dose (50 mg/kg/day) of PTCy used was partly extrapolated from murine major histocompatibility complex (MHC)-matched skin allografting models and was 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. Lower dosing of PTCy also was associated with less broad reductions of T-cell numbers after PTCy and lower toxicity than higher dosing.

In patients on an NIH study using myeloablative conditioning, a dose of 25 mg/kg/day has been associated with more rapid engraftment and potentially better immune function without an increase in severe acute GVHD.

Objectives:

Determine whether PTCy 25 mg/kg on days +3 and +4 can maintain adequate protection against grade III-IV acute GVHD and reduce toxicity associated with transplantation in older and/or unfit transplant recipients receiving reduced intensity conditioned allogeneic HCT.

Determine the frailty measures associated with outcomes after allogeneic transplantation.

Eligibility:

Histologically or cytologically confirmed hematologic malignancy with standard indication for allogeneic hematopoietic cell transplantation.

Age 60-85 years, or age 18-60 years and unfit for myeloablative conditioning (MAC).

At least one potentially suitable HLA-matched related, HLA-haploidentical donor, HLA-matched unrelated, or >=5/10 HLA-mismatched unrelated donor.

Karnofsky performance score >=60

Adequate organ function

Design:

Open-label, multi-center, non-randomized, phase I/II study

There will be four separate arms: HLA-matched elderly, HLA-matched young/infirm, HLA-partially matched elderly, and HLA-partially matched young/infirm

All subjects will receive nonmyeloablative conditioning consisting of fludarabine, cyclophosphamide, and total body irradiation; GVHD prophylaxis with PTCy 25 mg/kg on days +3 and +4, MMF, and sirolimus; and bone marrow as the stem cell source

Subjects will be evaluated for development of grade III-IV acute GVHD (aGVHD) at day +60 as the dose-limiting toxicities for the Simon two-stage design. Dose escalation of PTCy will be permitted within each arm if stopping rules are met at the 25 mg/kg/day on days +3 and +4 dose.

Frailty assessments will be performed prior to transplantation conditioning and serially after allogeneic transplantation.