Phase II Trial of a Chemotherapy Alone Regimen of IV Busulfan (Busulfex), Melphalan and Fludarabine as Myeloablative Regimen Followed by an Allogeneic T-Cell Depleted Hematopoietic Stem Cell Transplant From an HLA-Identical, or HLA-Non Identical Related or Unrelated Donor For the Treatment of Lymphohematopoietic Disorders
The trial proposed is a single arm, phase II treatment protocol designed to examine the
engraftment, toxicity, graft-versus-host disease and ultimate disease-free survival
following transplants derived from (1) HLA-matched siblings or related donors, (2)
HLA-compatible unrelated donors or (3) HLA haplo-type mismatched related donors using a new
chemotherapeutic cytoreductive regimen. Candidates for transplant will be stratified
according to their donor types.
Candidates for this trial will include patients with high risk forms of ALL, AML or CML,
non-Hodgkin's lymphoma, or myelodysplastic syndrome for whom an allogeneic marrow transplant
is clearly indicated, and patients with aplastic anemia refractory to ATG or cyclosporine
treatment and who are transfusion dependent. All research participants will be conditioned
for transplantation with intravenous busulfan (busulfex®) (0.8- 1.0 mg/Kg/dose Q6H x 10
doses), melphalan (70 mg/m2/dose x 2 doses) and fludarabine (25mg/m2/day x 5 doses). Doses
of busulfan will be adjusted according to plasma levels. All research participants will also
receive ATG (Thymoglobulin®) prior to transplant to promote engraftment. No drug prophylaxis
againstGvHD will be administered post transplant. All research participants will also
receive G-CSF post-transplant to foster engraftment.
The preferred source of stem cells will be peripheral blood stem cells (PBSC) induced and
mobilized by treatment of the donor with G-CSF for 5-6 days. PBSC obtained through 2-3
leukaphereses will be Isolex® 300i separated CD34+ stem cell column selected and E-rosette
depleted (E-). The CD34 + E peripheral blood progenitors will then be administered to the
research participants after they have completed cytoreduction. If the use of CD34 + E- PBSC
is not possible, the alternative graft will consist of bone marrow derived stem cells T-cell
depleted by soybean agglutinin and E-rosetting (SBA-E-).
Research participants will be carefully monitored for engraftment, chimerism, incidence and
severity of acute and chronic GvHD, regimen-related toxicity, characteristics of
hematopoietic and immune reconstitution and ultimate survival and disease-free survival.
This phase II trial is designed to investigate the feasibility and safety of a
chemotherapy-based cytoreductive regimen plus a T-cell depleted peripheral blood stem cell
(PBSC) or bone marrow stem cell transplant (BMT) for the treatment of high risk patients
with advanced stages of hematologic malignancies. The majority of research participants will
receive grafts derived from PBSC and will be the focus of the trial. The study population
will be segmented into three research participant groups based on the type of donors used
for the hematopoietic stem cell graft: (1) HLA-identical sibling or related donor, (2)
HLA-compatible unrelated donor, and (3) HLA-mismatched related donor.
A maximum of 25 PBSC research participants in both related groups will be accrued onto the
study; a maximum of 70 PBSC research participants in the unrelated group will be accrued. In
order to reduce patient risk, the study design includes early termination of any trial group
in the event of excessive graft failure, grade 3-4 acute graft-versus-host disease, or early
transplant related mortality during the accrual period. Excessive failure is defined
differently in the three donor groups. Stopping rules for the three research participant
populations will be utilized. In addition to the 120 PBSC research participants, we
anticipate approximately 25 BMT research participants treated across the three donor groups.
These research participants will be followed and at the conclusion of the trial descriptive
statistics on this subgroup will be recorded.
Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To establish 1-the incidence and quality of engraftment and hematopoietic reconstitution, 2- the early transplant-related severe morbidity and mortality and 3-the incidence and severity of GvHD.
Farid Boulad, MD
Memorial Sloan-Kettering Cancer Center
United States: Food and Drug Administration
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