The Role of Cyclosporine in Blood Cell Transplants With T-Cell Add-Back for Blood Cancers
| Status: | Completed |
|---|---|
| Conditions: | Cancer, Blood Cancer, Blood Cancer, Orthopedic, Hematology, Hematology, Hematology |
| Therapuetic Areas: | Hematology, Oncology, Orthopedics / Podiatry |
| Healthy: | No |
| Age Range: | 10 - 55 |
| Updated: | 9/28/2018 |
| Start Date: | February 22, 1999 |
| End Date: | June 13, 2017 |
Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation Followed by T-Cell Add-Back for Hematological Malignancies - Role of Cyclosporine
Cancers of the blood, sometimes referred to as hematologic malignancies, are disorders of
bone marrow cells that lead to the failure of the normal function of bone marrow and the
uncontrolled growth of cancerous cells in the bone marrow. These cancerous cells can spill
over into the bloodstream and affect other organs causing widespread symptoms. The disease is
life threatening because it blocks the normal function of the marrow, which is to produce red
cells (preventing anemia), white cells (preventing infection), and platelets (preventing
progression).
Bone marrow transplants are a potential form of therapy for patients with hematologic
malignancies. However, BMT is a complicated procedure and can be associated with dangerous
side effects.
In this study researchers are attempting to find ways to reduce the complications of BMT, so
that it would be possible to use it more safely and can be offered more patients. In order to
do this, researchers are developing new techniques to make BMT safer. It requires making
small changes to the standard procedure, which may improve the outcome.
The experimental procedures researchers are evaluating are:
1.T-cell depleted peripheral blood progenitor cell (PBPC) transplantation
2. Cyclosporine given immediately after the transplant
3.Add-back of donor lymphocytes
Patients undergoing these experimental techniques must be monitored closely to see if any
benefit or harmful effects will occur. Information gathered from this study can be used to
develop further research studies and potential new therapies for hematologic malignancies.
bone marrow cells that lead to the failure of the normal function of bone marrow and the
uncontrolled growth of cancerous cells in the bone marrow. These cancerous cells can spill
over into the bloodstream and affect other organs causing widespread symptoms. The disease is
life threatening because it blocks the normal function of the marrow, which is to produce red
cells (preventing anemia), white cells (preventing infection), and platelets (preventing
progression).
Bone marrow transplants are a potential form of therapy for patients with hematologic
malignancies. However, BMT is a complicated procedure and can be associated with dangerous
side effects.
In this study researchers are attempting to find ways to reduce the complications of BMT, so
that it would be possible to use it more safely and can be offered more patients. In order to
do this, researchers are developing new techniques to make BMT safer. It requires making
small changes to the standard procedure, which may improve the outcome.
The experimental procedures researchers are evaluating are:
1.
2.
3.
Patients undergoing these experimental techniques must be monitored closely to see if any
benefit or harmful effects will occur. Information gathered from this study can be used to
develop further research studies and potential new therapies for hematologic malignancies.
Bone marrow stem cell transplant studies carried out by the NHLBI BMT Unit have focused on
approaches to optimize the stem cell and lymphocyte dose in order to improve transplant
survival and increase the graft-vs.-leukemia effect. A CD34 stem cell dose of greater than 3
x 10(6)/kg was found to increase survival and reduce relapse, while a CD3+ lymphocyte dose of
less than 1 x 10(5)/kg was associated with a very low incidence of GVHD. Although processing
of 2 peripheral blood progenitor cell (PBPC) collections with the CellPro immunoabsorption
method (combined CD34-positive selection and CD2-negative selection) provided an improvement
over previous methods, the system did not always achieve these optimal cell doses. A recent
preclinical evaluation by the Department of Transfusion Medicine of a new immunomagnetic cell
selection system available from Nexell, Inc. has demonstrated improved recovery of CD34+
cells and increased depletion of T lymphocytes, compared to the CellPro method. Incorporation
of the Nexell system (Isolex 300i) into this clinical protocol will allow us to more
consistently achieve CD34+ cell doses above the threshold of 3 x 10(6)/kg and CD3+ lymphocyte
dosing in the region of 0.5 x 10(5)/kg. This will make it possible to test (1) the potential
benefit of optimized transplant cell doses, (2) elimination of post transplant
immunosuppression to enhance immune recovery.
In this study, we will use the Nexell Isolex 300i system to obtain more data on the
relationship between CD34+ stem cell dose and outcome. In recipients who receive a T cell
dose less than 0.5 x 10(5) CD3+ cells/kg the effect of withdrawing cyclosporine on
development of GVHD will be evaluated in a cohort study: 20 patients will receive low dose
cyclosporine. If the incidence of grade II or worse GVHD is 10% or less, no post transplant
immunosuppression will be given to the next cohort and the incidence and severity of acute
GVHD again assessed. Stopping rules for unacceptable GVHD severity will be applied. Two match
groups HLA 6/6 and 5/6 donor-recipient pairs will be separately studied using this approach.
In a second phase of the study we will continue to accumulate data on T lymphocyte add-back
given on day 45 and day 100 after transplant. For this phase, cyclosporine will be
reintroduced on day 44 and continued until day 120 to accelerate immune recovery.
Up to 70 patients aged between 10 and 55 years will be studied in each subset (HLA 6/6 and
5/6 matched cohorts). The major endpoint of the study is acute GVHD after transplant. We will
also measure engraftment, acute and chronic GVHD, leukemic relapse, transplant-related and
all causes of mortality, cytomegalovirus reactivation and leukemia-free survival. Patients
will be followed for a minimum of 5 years.
approaches to optimize the stem cell and lymphocyte dose in order to improve transplant
survival and increase the graft-vs.-leukemia effect. A CD34 stem cell dose of greater than 3
x 10(6)/kg was found to increase survival and reduce relapse, while a CD3+ lymphocyte dose of
less than 1 x 10(5)/kg was associated with a very low incidence of GVHD. Although processing
of 2 peripheral blood progenitor cell (PBPC) collections with the CellPro immunoabsorption
method (combined CD34-positive selection and CD2-negative selection) provided an improvement
over previous methods, the system did not always achieve these optimal cell doses. A recent
preclinical evaluation by the Department of Transfusion Medicine of a new immunomagnetic cell
selection system available from Nexell, Inc. has demonstrated improved recovery of CD34+
cells and increased depletion of T lymphocytes, compared to the CellPro method. Incorporation
of the Nexell system (Isolex 300i) into this clinical protocol will allow us to more
consistently achieve CD34+ cell doses above the threshold of 3 x 10(6)/kg and CD3+ lymphocyte
dosing in the region of 0.5 x 10(5)/kg. This will make it possible to test (1) the potential
benefit of optimized transplant cell doses, (2) elimination of post transplant
immunosuppression to enhance immune recovery.
In this study, we will use the Nexell Isolex 300i system to obtain more data on the
relationship between CD34+ stem cell dose and outcome. In recipients who receive a T cell
dose less than 0.5 x 10(5) CD3+ cells/kg the effect of withdrawing cyclosporine on
development of GVHD will be evaluated in a cohort study: 20 patients will receive low dose
cyclosporine. If the incidence of grade II or worse GVHD is 10% or less, no post transplant
immunosuppression will be given to the next cohort and the incidence and severity of acute
GVHD again assessed. Stopping rules for unacceptable GVHD severity will be applied. Two match
groups HLA 6/6 and 5/6 donor-recipient pairs will be separately studied using this approach.
In a second phase of the study we will continue to accumulate data on T lymphocyte add-back
given on day 45 and day 100 after transplant. For this phase, cyclosporine will be
reintroduced on day 44 and continued until day 120 to accelerate immune recovery.
Up to 70 patients aged between 10 and 55 years will be studied in each subset (HLA 6/6 and
5/6 matched cohorts). The major endpoint of the study is acute GVHD after transplant. We will
also measure engraftment, acute and chronic GVHD, leukemic relapse, transplant-related and
all causes of mortality, cytomegalovirus reactivation and leukemia-free survival. Patients
will be followed for a minimum of 5 years.
- INCLUSION CRITERIA - Patient:
Ages 10-55 years.
Chronic myelogenous leukemia, any of these categories: chronic phase, accelerated phase or
blast transformation.
Acute lymphoblastic leukemia, any of these categories: Adults (greater than 18 years) in
first remission with high-risk features (presenting leukocyte count greater than 100,000/cu
mm, karyotypes t9; 22, t4, t11, biphenotypic leukemia) All second or subsequent remissions,
primary induction failure, partially responding or untreated relapse.
Acute myelogenous leukemia (AML): AML in first remission except AML with good risk
karyotypes: AML M3 (t15; 17), AML M4Eo (inv 16), AML t (8;21). All AML in second or
subsequent remission, primary induction failure and resistant relapse.
Myelodysplastic syndromes, any of these categories: refractory anemia with transfusion
dependence, refractory anemia with excess of blasts, transformation to acute leukemia,
chronic myelomonocytic leukemia.
Myeloproliferative disorders (myelofibrosis, polycythemia vera, essential thrombocythemia)
in transformation to acute leukemia.
Chronic lymphocytic leukemia refractory to fludarabine treatment and with bulky progressive
disease or with thrombocytopenia (less than or equal to 100,000 / mcl) or anemia (less than
or equal to 10g/dl) not due to recent chemotherapy.
No major organ dysfunction precluding transplantation.
DLCO greater than or equal to 60% predicted.
Left ventricular ejection fraction: greater than or equal to 40% predicted.
ECOG performance status of 0 or 1.
For adults: Written informed consent given by adults. For minors: Written informed consent
from one parent or guardian. Informed oral consent from minors: The process will be
explained to the minor on a level of complexity appropriate for their age and ability to
comprehend.
Women of childbearing age with a negative pregnancy test may participate.
EXCLUSION CRITERIA - Recipient (any of the following):
Patient pregnant.
Age less than 10 and greater than 55 years.
ECOG performance status of 2 or more.
Severe psychiatric illness in the patient or donor. Mental deficiency sufficiently severe
as to make compliance with the treatment unlikely, and making informed consent impossible.
Major anticipated illness or organ failure incompatible with survival from transplant.
DLCO less than 60% predicted.
Left ventricular ejection fraction: less than 40% predicted.
Serum creatinine greater than 3mg/dl.
Serum bilirubin greater than 4 mg/dl.
Transaminases greater than 3x upper limit of normal.
HIV positive (donor or recipient).
History of other malignancies except basal cell or squamous carcinoma of the skin, positive
PAP smear and subsequent negative follow up.
Individuals with diseases listed above as eligible for this protocol, but where debility or
age makes the risk of intensive myeloablative therapy unacceptable. These patients will be
considered for a non-myeloablative allogeneic transplantation protocol (97-H-0202,
99-H-0050).
INCLUSION CRITERIA - Donor:
HLA 6/6 identical or 5/6 (one antigen mismatched) family donor.
Fit to receive G-CSF and give peripheral blood stem cells (normal blood count,
normotensive, no history of stroke).
For adults: Written informed consent given by adults. For minors: Written informed consent
from one parent or guardian. Informed oral consent from minors: The process will be
explained to the minor on a level of complexity appropriate for their age and ability to
comprehend.
EXCLUSION CRITERIA - Donor (any of the following):
Pregnant or lactating.
Severe psychiatric illness. Mental deficiency sufficiently severe as to make compliance
with the BMT treatment unlikely, and making informed consent impossible.
HIV positive.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
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