Bone Marrow Transplant Using a Reduced Intensity Regimen That is Given in Two Steps
This is a research study involving the treatment of patients with hematological cancers with allogeneic (cells from a donor) hematopoietic stem cell transplant (HSCT). HSCT is often referred to as bone marrow transplant. Patients who are not expected to have long term survival after conventional therapy will undergo HSCT as a curative therapy after receiving front line therapy for their disease. This project is based on an HSCT approach that has been used at TJU since 2006 with the goal of optimizing this type of treatment further. In this new study, the investigators will substitute the chemotherapy agent, Melphalan (Mel), for cyclophosphamide (CY). Cyclophosphamide was used in the original trial. The research question is whether side effects are less using Mel and if donor T cells can be made tolerant to the recipient with the use of Mel. The proposed study is also more specific in terms of performance status and organ function entry criterion. The investigators observed in the original trial that patients with poor performance upon admission for transplant did not have as good outcomes.
Because many older patients are treated according to this type of transplant, the chemotherapy and radiation used are less intensive than other types of transplant. The name for this in the transplant field is a reduced intensity hematopoietic stem cell transplant. The abbreviations most used in this document are RIC for reduced intensity conditioning, HSCT which refers to the transplant itself, and MEL which refers to the drug, Melphalan.
Myelodysplastic Syndromes (MDS) Other Than RA or RARS Subtypes
Chronic Myelogenous (or Myeloid) Leukemia (CML) Resistant to STI Therapy
Radiation: Total Body Irradiation (TBI)
Biological: Donor Lymphocyte Infusion (DLI)
Device: Hematopoietic stem cell transplantation (HSCT)
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Two Step Approach to Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation for Hematologic Malignancies Using Melphalan for T-Cell Tolerization|
- Phase 1: Defined Dose of Melphalan (MEL) [ Time Frame: 100 days post-transplant ] [ Designated as safety issue: Yes ]To define the dose of MEL required for the establishment of peripheral T cell tolerance with concomitant immune reconstitution.
- Phase 2: Non-Relapse Mortality (NRM) [ Time Frame: 100 days post-treatment ] [ Designated as safety issue: No ]To evaluate the 100 day non-relapse mortality (NRM) rate in patients undergoing HSCT treated on this successor TJU 2 Step RIC haploidentical regimen and compare it with that of the initial regimen.
- Relapse Rate [ Time Frame: At 1 and 3 years ] [ Designated as safety issue: No ]To compare relapse rates in patients undergoing HSCT treated on this successor TJU 2 Step RIC haploidentical regimen and compare it with that of the initial regimen.
- GVHD Incidence and Severity [ Time Frame: At 1 and 3 years ] [ Designated as safety issue: Yes ]To determine the incidence and severity of graft-versus-host disease (GVHD) in patients undergoing treatment on this regimen using MEL for T cell tolerization as well as tacrolimus and mycophenolate mofetil (MMF) as GVHD prophylaxis.
- Engraftment Rate and Lymphoid Reconstitution [ Time Frame: 100 days post-transplant ] [ Designated as safety issue: Yes ]To evaluate engraftment rates and lymphoid reconstitution in patients treated on this trial.
- Overall Survival [ Time Frame: At 1 and 3 years ] [ Designated as safety issue: No ]To assess overall survival in patients undergoing HSCT treated on this trial.
|Study Start Date:||April 2011|
|Study Completion Date:||August 2012|
|Primary Completion Date:||May 2012 (Final data collection date for primary outcome measure)|
Experimental: Transplant Treatment Group
All patients treated on this research study.
Part of the conditioning regimen
Other Names:Drug: Thiotepa
Part of the conditioning regimen
Other Name: N,N'N'-triethylenethiophosphoramideRadiation: Total Body Irradiation (TBI)
There is one fraction of total body irradiation (2Gy) as part of the conditioning regimen.
Other Name: radiotherapyBiological: Donor Lymphocyte Infusion (DLI)
Immediately following the conditioning regimen of fludarabine, thiotepa, and TBI, the patient receives a set dose of their donor's T cells (DLI), After the DLI, the donor's T cells will react with the remaining parts of the recipients immune system.
Other Name: buffy coat fusionDrug: Melphalan
Two days after the DLI, Melphalan will be given to eliminate the reacting T cells to avoid graft versus host disease. Non-activated T cells should not be affected by the Melphalan and remain to help fight infection.
Other Names:Device: Hematopoietic stem cell transplantation (HSCT)
One day after the Melphalan ends, the patient will receive their donor's stem cells. This is the actual day of transplant.
The CliniMACS® Plus Instrument will be used for the selection of human CD34+ hematopoietic stem and progenitor cells in human allogeneic hematopoietic stem cell transplantation.
Other Name: CliniMACS
Twenty-nine patients in the Thomas Jefferson University (TJU) Blood and Marrow Transplantation Program have been treated on the research protocol, A Two Step Approach To Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation for Hematologic Malignancies from HLA Partially-Matched Related Donors (TJU 2 Step RIC, TJU IRB# 06U.328) as of July, 2010. While treatment on this protocol has resulted in durable responses for many older patients and younger, heavily pretreated patients with hematological malignancies, poor performance status at the time of transplant and morbidities related to cyclophosphamide (CY) administration in the regimen have contributed to decreased survival. In addition, disease relapse after hematopoietic stem cell transplantation (HSCT) has been a major cause of mortality for those patients with disease at the time of transplant.
The objective of this research is to improve patient outcomes after treatment on the TJU 2 Step RIC protocol by refining the approach based on outcomes observed in the initial trial. More thorough assessment of performance status prior to HSCT and the substitution of the alkylating agent Melphalan (MEL) for CY to decrease CY-related toxicity while strengthening the anti-leukemic intensity of the regimen for patients with poor-risk disease will be the major strategies used to increase the efficacy of the regimen. MEL has shown efficacy against myeloid malignancies when used in conditioning in RIC HSCT. Patients with AML and MDS were the most common group treated on the initial TJU 2 Step RIC trial and also comprise the largest patient group treated in the TJU Medical Oncology Program.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01350258
|United States, Pennsylvania|
|Thomas Jefferson University|
|Philadelphia, Pennsylvania, United States, 19107|
|Principal Investigator:||Dolores Grosso, DNP, CRNP||Thomas Jefferson University|
|Principal Investigator:||Neal Flomenberg, MD||Thomas Jefferson University|