A Phase II Trial of Total Body Irradiation-Based Myeloablative Conditioning and Transplantation of Partially HLA-Mismatched Peripheral Blood Stem Cells for Patients With Hematologic Malignancies

Status
Active
Cancer Type
Hematologic Malignancies
Trial Phase
Phase II
Eligibility
18 to 60, Male and Female
Study Type
Treatment
NCD ID
NCT01336712
Protocol IDs
NSH 922 (primary)
Study Sponsor
Northside Hospital Cancer Center

Summary

In this study, patients will receive a myeloablative preparative regimen consisting of fludarabine and total body irradiation (TBI), followed by a T cell replete, mobilized peripheral blood stem cell (PBSC) allograft from a partially matched related donor. All patients will receive post-transplant Cy in addition to standard post transplant immunosuppression with tacrolimus and MMF. The treatment protocol will be essentially identical to the prior study, with the exception of the substitution of TBI for Busulfan. The investigators hypothesize that this change will significantly reduce the risk of HC, while maintaining the efficacy of the transplant.

Objectives

Historically, haploidentical HSCT has been associated with significant risks of graft rejection and severe graft versus host disease (GVHD), leading to high treatment related mortality and poor outcomes. The risk of engraftment failure and GVHD may be reduced in intensively conditioned recipients of grafts that have been rigorously depleted of T cells, but the risks of serious infection and death from prolonged immune compromise in these patients remains high. Recently, investigators from Johns Hopkins University demonstrated a new approach to haploidentical transplantation, utilizing a nonmyeloablative preparative regimen, followed by a T cell-replete bone marrow infusion and post-transplantation immunosuppression with high dose Cyclophosphamide (Cy), tacrolimus, and MMF. Clinical studies have shown this approach to be safe and effective with a low incidence of graft rejection, GVHD, and treatment-related mortality. Relapse represents the major cause of treatment failure in these patients, particularly with high-risk myeloid malignancies.

In order to decrease this relapse risk in high-risk patients, the investigators initiated a myeloablative haploidentical HSCT study in January 2009 utilizing Busulfan-based conditioning, post-transplant Cy, and PBSC, instead of BM, as the stem cell source. Outcomes of the 15 patients transplanted to date have been promising with 100% engraftment, low rates of treatment-related mortality, relapse and GVHD, and excellent survival rates. An unexpected outcome of the study was a higher-than-expected rate of BK virus-induced hemorrhagic cystitis (HC) occurring in 7 of 14 evaluable patients. Although there were no deaths attributable to HC, it was associated with significant morbidity in some patients.

HC is a recognized complication of allogeneic transplant therapy. Late onset HC, occurring after engraftment, is due almost exclusively to reactivation of the polyoma BK virus (BKV). Other important risk factors associated with HC include Busulfan-based conditioning, acute GVHD, HLA mismatched transplants, and use of bone marrow as the stem cell source. TBI-based conditioning, prior to myeloablative allogeneic transplant, has been associated with significantly less HC than Busulfan-based conditioning in both retrospective and prospective randomized trials.

Eighteen patients will be accrued to this study. The primary end point of this study is the incidence of HC. The investigators will also examine the incidence of acute and chronic GVHD, engraftment, degree of donor-host chimerism, transplant related morbidity and mortality, as well as disease-free and overall survival. Stopping rules will minimize the risk of untoward or unexpected side effects.