Total Body Irradiation/Fludarabine Based Ablative Haploidentical Transplant for Hematologic Diseases
Procedure: Peripheral Blood Stem Cell Transplant
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||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|
- Number of patients experiencing hemorrhagic cystitis post transplant [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]1.1 To estimate the incidence of hemorrhagic cystitis following a TBI-based myeloablative haploidentical HSCT in patients with high risk hematologic malignancies. For this study, HC will be defined as the development of late-onset (post-engraftment) macroscopic hematuria and dysuria, associated with positive urine PCR for BK virus or adenovirus. Asymptomatic viruria, with or without microscopic hematuria, will not be considered an episode of HC.
- Survival [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]To obtain estimates of overall survival (OS), event-free survival (EFS), relapse, non-relapse mortality (NRM), engraftment, acute and chronic graft-versus-host disease (GVHD).
- Toxicity measurement [ Time Frame: 100 days ] [ Designated as safety issue: Yes ]Characterize additional hematologic and non-hematologic toxicities of TBI-based myeloablative haploidentical HSCT.
- Percentage of donor chimerism post-transplant [ Time Frame: Day 100 ] [ Designated as safety issue: Yes ]Characterize donor hematopoietic chimerism in peripheral blood at days ~30, ~60, and ~90 after HSCT.
|Study Start Date:||April 2011|
|Estimated Study Completion Date:||March 2015|
|Primary Completion Date:||December 2014 (Final data collection date for primary outcome measure)|
Experimental: Myeloablative Haploidentical Transplant
Procedure: Peripheral Blood Stem Cell Transplant
Total Body Irradiation 1200cGy (150cGy given in 8 fractions twice a day six hours apart on days -4, -3, -2 and -1.
Fludarabine 30 mg/m2 given once a day for 3 days on days -7, -6 and -5 Cyclophosphamide 50mg/kg given one a day on days +3 and +4
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01336712
|United States, Georgia|
|Atlanta, Georgia, United States, 30342|
|Principal Investigator:||Scott R Solomon, MD||Blood and Marrow Transplant Group of Georgia|