Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation Followed by T Cell Add-Back for Hematological Malignancies - Effect of Peri-transplant Encyclopedic on Chimerism
2 Years
80 Years
Both
Hematologic Malignancies, Bone Marrow Transplant Rejection
Trial Information
Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation Followed by T Cell Add-Back for Hematological Malignancies - Effect of Peri-transplant Encyclopedic on Chimerism
Bone marrow stem cell transplant studies carried out by the National Heart Lung & Blood
Institute (NHLBI) Bone Marrow Transplantation (BMT) Unit have focused on approaches to
optimize the stem cell and lymphocyte dose in order to improve transplant survival and
increase the graft-versus-leukemia effect. The aim is to create the transplant conditions
that permit rapid donor immune recovery without causing graft-versus-host disease (GVHD) by
using reduced post-transplant immunosuppression in conjunction with a transplant depleted of
T cells to a fixed low dose, below the threshold known to be associated with GVHD.
We have found that the outcome from transplant is improved by controlling the stem cell
(CD34+ cell) and T lymphocyte (CD3+ cell) dose. We use the "Nexell Isolex 300i" system to
obtain high CD34+ doses depleted of lymphocytes to a fixed CD3+ T cell dose of 2 x 104/kg.
The use of the cell separator and the monoclonal antibodies is covered by an Investigational
Device Exemption. A persisting problem with these T cell depleted transplants has been the
slow acquisition of full donor T cell engraftment (T cell chimerism). Two previous protocols
have failed to increase the speed of donor T cell chimerism. Patients with mixed
donor-recipient T cell populations are known to be at higher risk for late graft rejection
and leukemic relapse after transplant. Therefore, the achievement of full donor chimerism
remains an important therapeutic goal. In this study we will test whether cyclosporine
given between day -6 and +21 after transplant can significantly improve day 30 T cell
chimerism (the principle end-point). The study also will measure the incidence of acute and
chronic GVHD, day 100 transplant related mortality, cytomegalovirus reactivation, relapse,
and disease-free survival with appropriate safety stopping rules.
This protocol follows closely previous studies in this series. Three additional
modifications will be made however: 1) The first T cell add-back will be delayed until day
60 (instead of day 45) so as to continue to allow a 45 day period without cyclosporine
immunosuppression. 2) No day 100 T cell add-back will be given. (In previous studies many
patients have, for protocol-defined reasons, not received the second transfusion and there
is no evidence that it is required). 3) Patients with high-risk leukemias with a high
relapse probability will receive an additional chemotherapy agent prior to transplant using
etoposide (VP16) 60mg/kg to improve the chance of remaining in remission.
Inclusion Criteria
INCLUSION CRITERIA:
RECIPIENT:
- 1. Ages 10-55 years inclusive (but less than 56)
- 2. Chronic myelogenous leukemia (CML) in chronic phase
- 3. Acute lymphoblastic leukemia (ALL) categories
1. Adults in first remission with high-risk features
2. All second or subsequent remissions, primary induction failure, partially
responding or untreated relapse
- 4. Acute myelogenous leukemia (AML)
1. AML in first remission Except AML with good risk karyotypes
2. All AML in second or subsequent remission, primary induction failure and
resistant relapse
- 5. Myelodysplastic syndromes categories
1. refractory anemia with transfusion dependence
2. refractory anemia with excess of blasts
3. transformation to acute leukemia, chronic myelomonocytic leukemia
- 6. Myeloproliferative disorders in transformation to acute leukemia
- 7. Chronic lymphocytic leukemia refractory to fludarabine treatment and with bulky
progressive disease or with thrombocytopenia (less than or equal to 100,000 /micro L)
or anemia (less than or equal to 10g/dl) not due to recent chemotherapy
- 8. Non-Hodgkin's lymphoma including Mantle cell lymphoma relapsing or refractory to
current chemotherapy and monoclonal antibody treatment and unsuitable for autologous
stem cell transplantation
- 9. No major organ dysfunction precluding transplantation
- 10. Diffusion capacity of lung for carbon monoxide (DLCO) greater than or equal to
60% predicted
- 11. Left ventricular ejection fraction: greater than or equal to 40%
- 12. Eastern Cooperative Oncology Group(ECOG) performance status of 0 or 1
- 13. Able to give informed consent
- 14. Negative pregnancy test for women of childbearing age
INCLUSION CRITERIA:
DONOR
- 1. Human leukocyte antigen (HLA) 6/6 identical family donor
- 2. Weight greater than or equal to 18 kg
- 3. Age greater than or equal to 2 or less than or equal to 80 years old
- 4. Fit to receive granulocyte colony -stimulating factor(G-CSF) and give peripheral
blood stem cells (normal blood count, normotensive, no history of stroke)
EXCLUSION CRITERIA:
RECIPIENT
- 1. Patient pregnant
- 2. Age less than 10 years and 56 years or more
- 3. Patients with CML in chronic phase who are 41 years or over in whom imatinib
mesylate (STI-571)is the treatment of choice
- 4. ECOG performance status of 2 or more
- 5. Severe psychiatric illness
- 6. Major anticipated illness or organ failure incompatible with survival from BMT
- 7. DLCO less than 60% predicted
- 8. Left ventricular ejection fraction: less than 40%
- 9. Serum creatinine greater than 3mg/dl
- 10. Serum bilirubin greater than 4 mg/dl
- 11. HIV positive 12. Debilitation or age making the risk of intensive myeloablative
therapy unacceptable
EXCLUSION CRITERIA:
DONOR
- 1. Pregnant or lactating
- 2. Donor unfit to receive G-CSF and undergo apheresis
- 3. HIV positive
- 4. Weight less than 18 kg
- 5. Age less than 2 or greater than 80 years
- 6. Severe psychiatric illness
Type of Study:
Interventional
Study Design:
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
The Proportion of Patients Who Develop Full Donor T Cell Chimerism at Day 30
Outcome Description:
The proportion of patients who develop full donor CD3+ lymphocyte chimerism by day 30. Full chimerism is defined as >95% donor alleles by molecular profiling (Short Tandem Repeat analysis).
Outcome Time Frame:
Day 30
Safety Issue:
Yes
Principal Investigator
A. John Barrett, MD
Investigator Role:
Principal Investigator
Investigator Affiliation:
NIH National Heart, Lung and Blood Institute
Authority:
United States: Food and Drug Administration
Study ID:
040112
NCT ID:
NCT00079391
Start Date:
January 2004
Completion Date:
September 2011
Related Keywords:
- Hematologic Malignancies
- Bone Marrow Transplant Rejection
- Chronic Myelogenous Leukemia (CML)
- Acute Lymphoblastic Leukemia (ALL)
- Acute Myelogenous Leukemia (AML)
- Chronic Lymphocytic Leukemia (CLL)
- Myelodysplastic Syndromes (MDS)
- Peripheral Blood Stem Cells
- Graft-Versus Leukemia/Myeloma
- Graft-Versus-Host Disease (GVHD)
- Cyclosporine
- Fludarabine
- Leukemia
- Myelodysplastic Syndrome
- Myeloproliferative Syndrome
- Non-Hodgkin Lymphoma
- Neoplasms
- Hematologic Neoplasms
Name | Location |
|---|---|
| National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda, Maryland 20892 |
