Bone Marrow Transplant Using a Reduced Intensity Regimen That is Given in Two Steps

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

Official Title
-----------------
A Two Step Approach to Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation for Hematologic Malignancies Using Melphalan for T-Cell Tolerization

Conditions
-----------------
Hematologic Malignancies, Acute Leukemia, Myelodysplastic Syndromes (MDS) Other Than RA or RARS Subtypes, Hodgkin's Lymphoma, Non-Hodgkin's Lymphoma, Myeloma, Chronic Myelogenous (or Myeloid) Leukemia (CML) Resistant to STI Therapy

Intervention / Treatment
-----------------
* Drug: Fludarabine
* Drug: Thiotepa
* Radiation: Total Body Irradiation (TBI)
* Biological: Donor Lymphocyte Infusion (DLI)
* Drug: Melphalan
* Device: Hematopoietic stem cell transplantation (HSCT)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Any patient with a high-risk hematologic or oncologic diagnosis in which allogeneic HSCT is thought to be beneficial, and in whom front-line therapy has already been applied. High risk is defined as: Acute leukemia in 3rd or greater CR or with persistent disease Myelodysplastic syndrome (MDS) other than RA or RARS subtypes. Hodgkin's or Non-Hodgkin's lymphoma in 3rd or greater remission or with persistent disease. Myeloma in 3rd or greater remission or with less than PR to most recent therapy. Chronic myelogenous (or myeloid) leukemia (CML) resistant to STI therapy Patients must have a related donor who is at least a 4 antigen match at the HLA-A; B; C; DR loci. Patients must adequate organ function: LVEF of > or = 50% DLCO > or = 50% of predicted corrected for hemoglobin Adequate liver function as defined by a serum bilirubin < or = 1.8, AST or ALT < or = 2.5X upper limit of normal GFR of > or = 60 mL/min/1.73m2 Performance status > or = 80% (TJU Karnofsky) for patients > or = 60 years old or > or = 70% for patients < 60. HCT-CI Score < or = 4 points for patients > or = 60 years old or < or = 5 points for patients < 60. Patients must be willing to use contraception if they have childbearing potential Able to give informed consent Exclusion Criteria: Performance status < 80% (TJU Karnofsky) for patients > or = 60 years old or < 70% for patients < 60. HCT-CI Score > 4 points for patients > or = 60 years old or > 5 points for patients < 60. HIV positive Active involvement of the central nervous system with malignancy Inability to obtain informed consent Pregnancy Patients with life expectancy of < 6 months for reasons other than their underlying hematologic/oncologic disorder Patients who have received alemtuzumab within 8 weeks of the transplant admission, or who have recently received horse or rabbit ant-thymocyte globulin and have an ATG level of > or = 2 ugm/ml Patients with evidence of another malignancy, exclusive of a skin cancer that requires only local treatment, should not be enrolled on this protocol Donor Selection All donors are selected and screened for their ability to provide adequate infection-free apheresis products for the patient in a manner that does not put the donor at risk for negative consequences. Donor selection will be in compliance with 21 CFR 1271 and TJU BMT Program SOP CP: P009.03.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Transplant Treatment Group<br>All patients treated on this research study. | Drug: Fludarabine<br>* Part of the conditioning regimen<br>* Other names: Fludara;Drug: Thiotepa<br>* Part of the conditioning regimen<br>* Other names: N,N'N'-triethylenethiophosphoramide;Radiation: Total Body Irradiation (TBI)<br>* There is one fraction of total body irradiation (2Gy) as part of the conditioning regimen.<br>* Other names: radiotherapy;Biological: Donor Lymphocyte Infusion (DLI)<br>* 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.<br>* Other names: buffy coat fusion;Drug: Melphalan<br>* 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.<br>* Other names: Alkeran;Device: Hematopoietic stem cell transplantation (HSCT)<br>* 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.<br>* Other names: CliniMACS;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Defined Dose of Melphalan (MEL) | To define the dose of MEL required for the establishment of peripheral T cell tolerance with concomitant immune reconstitution. | 100 days post-transplant | 
| Phase 2: Non-Relapse Mortality (NRM) | 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. | 100 days post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relapse Rate | 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. | At 1 and 3 years | 
| GVHD Incidence and Severity | 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. | At 1 and 3 years | 
| Engraftment Rate and Lymphoid Reconstitution | To evaluate engraftment rates and lymphoid reconstitution in patients treated on this trial. | 100 days post-transplant | 
| Overall Survival | To assess overall survival in patients undergoing HSCT treated on this trial. | At 1 and 3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
allogeneic HSCT, Hematopoietic stem cell transplantation