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
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
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.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Number of patients experiencing hemorrhagic cystitis post transplant
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.
Scott R Solomon, MD
Blood and Marrow Transplant Group of Georgia
United States: Institutional Review Board
|Northside Hospital||Atlanta, Georgia 30342|