A Phase II Trial of CD34+ Enriched Transplants From HLA-Compatible Related or Unrelated Donors for Treatment of Patients With Hematologic Malignancies
Overview
- Phase
- Phase 2
- Intervention
- CliniMACS
- Conditions
- Hematologic Diseases
- Sponsor
- Baptist Health South Florida
- Locations
- 1
- Primary Endpoint
- Assess the change of incidence and severity of acute GvHD
- Status
- Withdrawn
- Last Updated
- 3 years ago
Overview
Brief Summary
This is a Phase II trial testing disease-specific myeloablative conditioning regimens for preparatory cytoreduction of patients receiving allogeneic HLA-compatible related or unrelated transplants of GCSF-mobilized peripheral blood stem cells (PBSC) depleted of T-cells by positive selection of CD34+ progenitor cells using the CliniMACS system. The CliniMACS Fractionation system is a method that positively selects CD34+ progenitor cells from PBSC by immunoadsorption of cells binding on anti CD34 monoclonal antibody to paramagnetic beads, which can then be isolated by passage through a magnetized column and released by agitation of beads. Two conditioning regimens have been used successfully with an alternative similar system, isolex, which is no longer being manufactured.
Detailed Description
For this trial, patients will be put into one of two myeloablative conditioning regimens, based on their disease, stage of disease, and dose of radiation accumulated in the course of treatment. Approximately twenty-four to forty-eight hours after completion of each conditioning regimen, patients will receive a transplant of a CD34+ progenitor cell-enriched, T-cell depleted fraction of GCSF-mobilized PBSC after fractionation on the CliniMACS device, from his/her HLA compatible donor. Due to stringent T-cell depletion, no significant Graft-versus-host disease is anticipated. Should Graft-versus-host disease occur, standard treatment would be initiated per the Transplant Service guidelines. The purpose of this trial is to evaluate the potential of T-cell depleted Haploidentical Stem Cell Transplant fractionated by the CliniMACS system, when administered for disease targeted cytoreductive regimens, to secure consistent engraftment and hematopoietic reconstitution in HLA-compatible related or unrelated hosts, and to prevent or abrogate acute and chronic forms of Graft-versus-host disease. This study seeks to validate that these pre-transplant conditioning regimens, when administered with a CD34+ progenitor cell enriched, T-cell depleted graft, fractionated in the CliniMACS system, will be associated with a low incidence of non-leukemic mortality. The sample size is as follows: Regimen A: Hyperfractionated Total Body Irradiation/Thiotepa/Cyclophosphamide: 100 patients Regimen B: Busulfan/Melphalan/Fludarabine: 100 patients It is anticipated that the accrual will last five years. Patients will be followed for two years following transplantation.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Malignant conditions or other life-threatening disorders correctable by transplant for which CD34+ selected, T-cell depleted allogeneic hematopoietic stem cell transplantation is indicated such as:
- •Acute myeloid leukemia (AML) in 1st remission - for patients who is AML does not have 'good risk' cytogenetic features (i.e. t8:21, t 15: 17, inv16).
- •Secondary AML in 1st remission
- •AML in 1st relapse or 2nd remission
- •Acute lymphoblastic leukemia (ALL) / Chronic Lymphocytic Leukemia (CLL) in pt remission clinical or molecular features indicating a high risk for relapse; or ALL/CLL 2nd remission
- •Chronic myelogenous leukemia (CML) failing to respond to or not tolerating Imatinib or Dasatinib in first chronic phase of disease; CML in accelerated phase, second chronic phase, or in CR after accelerated phase or blast crisis.
- •Non-Hodgkin's lymphoma with chemo responsive disease in any of the following categories:
- •Intermediate or high-grade lymphomas who have failed to achieve a first CR or have relapsed following a 1st remission who are not candidates for autologous transplants.
- •Any NHL in remission which is considered not curable with chemotherapy alone and not eligible/appropriate for autologous transplant.
- •Myelodysplastic syndrome (MDS): RA/RARS/RCMA with high-risk cytogenetic features or transfusion dependence, as well as RAEB-1 and RAEB-2 and Acute Myelogenous Leukemia (AML) evolved from MDS.
Exclusion Criteria
- •Subject Exclusion Criteria
- •Female patients who are pregnant or breast-feeding
- •Active viral, bacterial or fungal infection
- •Patient seropositive for HI V-I /II; HTLV -I /II
- •Presence of leukemia in the CNS.
- •Donor Exclusion Criteria
- •If donors do not meet institutional guidelines, exclusion will be considered.
Arms & Interventions
Regimen A
Regimen A: Hyperfractionated Total Body Irradiation/Thiotepa/Cyclophosphamide: Hyperfractionated total body irradiation to dose of 1375cGy fractions at 4-6 hour intervals three times a day for a total of 11 or 12 doses depending on age and disease risk, followed by Thiotepa 5mg/kg/day x 2 (or 10mg/kg/day x 1) and cyclophosphamide 60mg/kg/day x 2 (or Fludarabine 25mg/m2 x 5 if cyclophosphamide is contraindicated)
Intervention: CliniMACS
Regimen A
Regimen A: Hyperfractionated Total Body Irradiation/Thiotepa/Cyclophosphamide: Hyperfractionated total body irradiation to dose of 1375cGy fractions at 4-6 hour intervals three times a day for a total of 11 or 12 doses depending on age and disease risk, followed by Thiotepa 5mg/kg/day x 2 (or 10mg/kg/day x 1) and cyclophosphamide 60mg/kg/day x 2 (or Fludarabine 25mg/m2 x 5 if cyclophosphamide is contraindicated)
Intervention: Bone Marrow Transplant
Regimen A
Regimen A: Hyperfractionated Total Body Irradiation/Thiotepa/Cyclophosphamide: Hyperfractionated total body irradiation to dose of 1375cGy fractions at 4-6 hour intervals three times a day for a total of 11 or 12 doses depending on age and disease risk, followed by Thiotepa 5mg/kg/day x 2 (or 10mg/kg/day x 1) and cyclophosphamide 60mg/kg/day x 2 (or Fludarabine 25mg/m2 x 5 if cyclophosphamide is contraindicated)
Intervention: Hyperfractionated Total Body Irradiation
Regimen A
Regimen A: Hyperfractionated Total Body Irradiation/Thiotepa/Cyclophosphamide: Hyperfractionated total body irradiation to dose of 1375cGy fractions at 4-6 hour intervals three times a day for a total of 11 or 12 doses depending on age and disease risk, followed by Thiotepa 5mg/kg/day x 2 (or 10mg/kg/day x 1) and cyclophosphamide 60mg/kg/day x 2 (or Fludarabine 25mg/m2 x 5 if cyclophosphamide is contraindicated)
Intervention: Thiotepa
Regimen A
Regimen A: Hyperfractionated Total Body Irradiation/Thiotepa/Cyclophosphamide: Hyperfractionated total body irradiation to dose of 1375cGy fractions at 4-6 hour intervals three times a day for a total of 11 or 12 doses depending on age and disease risk, followed by Thiotepa 5mg/kg/day x 2 (or 10mg/kg/day x 1) and cyclophosphamide 60mg/kg/day x 2 (or Fludarabine 25mg/m2 x 5 if cyclophosphamide is contraindicated)
Intervention: Cyclophosphamide
Regimen B
Regimen B: Busulfan/Melphalan/Fludarabine: Busulfan 0.8mg/kg/dose every six hours x 10-12 doses (depending on disease), Melphalan 70mg/m2/day x 2 and Fludarabine 25mg/m2/day x 5.
Intervention: CliniMACS
Regimen B
Regimen B: Busulfan/Melphalan/Fludarabine: Busulfan 0.8mg/kg/dose every six hours x 10-12 doses (depending on disease), Melphalan 70mg/m2/day x 2 and Fludarabine 25mg/m2/day x 5.
Intervention: Bone Marrow Transplant
Regimen B
Regimen B: Busulfan/Melphalan/Fludarabine: Busulfan 0.8mg/kg/dose every six hours x 10-12 doses (depending on disease), Melphalan 70mg/m2/day x 2 and Fludarabine 25mg/m2/day x 5.
Intervention: Busulfan
Regimen B
Regimen B: Busulfan/Melphalan/Fludarabine: Busulfan 0.8mg/kg/dose every six hours x 10-12 doses (depending on disease), Melphalan 70mg/m2/day x 2 and Fludarabine 25mg/m2/day x 5.
Intervention: Melphalan
Regimen B
Regimen B: Busulfan/Melphalan/Fludarabine: Busulfan 0.8mg/kg/dose every six hours x 10-12 doses (depending on disease), Melphalan 70mg/m2/day x 2 and Fludarabine 25mg/m2/day x 5.
Intervention: Fludarabine
Outcomes
Primary Outcomes
Assess the change of incidence and severity of acute GvHD
Time Frame: 6 months, 1 year, 2 years
To assess the incidence and severity of acute GvHD following T cell depleted, CD34+ progenitor cell enriched transplants fractionated by the CliniMACS system.
Assess the change of incidence and severity of chronic GvHD
Time Frame: 6 months, 1 year, 2 years
To assess the incidence and severity of chronic GvHD following T cell depleted, CD34+ progenitor cell enriched transplants fractionated by the CliniMACS system.
Assess the change of incidence of non-relapse mortality
Time Frame: 6 months, 1 year, 2 years
To assess the incidence of non-relapse mortality (transplant-related mortality) following each cytoreduction regimen and a transplant fractionated by the CliniMACS system.
Estimate the probability change of survival and disease-free survival (DFS)
Time Frame: 6 months, 1 year, 2 years
To estimate the probability of survival and disease-free survival (DFS) at 6 months, 1 year and 2 years post-transplant for each disease-targeted cytoreduction regimen when used with a T-cell depleted graft fractionated by the CliniMACS system.
Secondary Outcomes
- Correlate doses of CD34+ progenitors and CD3+ T cells with engraftment(6 months, 1 year, 2 years)
- Determine the proportion of patients receiving optimal CD34+; CD3+(6 months, 1 year, 2 years)