Experimental Bone Marrow Transplant Protocol
| Status: | Completed |
|---|---|
| Conditions: | Blood Cancer, Blood Cancer, Blood Cancer, Blood Cancer, Blood Cancer, Hematology, Hematology |
| Therapuetic Areas: | Hematology, Oncology |
| Healthy: | No |
| Age Range: | 10 - 55 |
| Updated: | 9/28/2018 |
| Start Date: | May 19, 2003 |
| End Date: | June 14, 2017 |
Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation Followed by T Cell Add-Back for Hematological Malignancies - Effect of Irradiated Donor Lymphocytes on Chimerism
Bone marrow transplantation (BMT) is a risky procedure. If doctors could reduce the
complications, BMT would be safer to use for a wider range of conditions. The purposes of
this study are
- to prevent graft rejection by increasing the amount of immunosuppression and by giving
some lymphocytes from the donor before transplant;
- to prevent graft-versus-host disease (GVHD) by transplanting T-cell depleted stem cells;
- to improve the immune effect against residual leukemia by the add-back of donor
lymphocytes before transplant and six or more weeks after transplant.
Beyond the standard transplant protocol, study participants will undergo additional
procedures. First, along with total body irradiation, patients will receive two drugs (a high
dose of cyclophosphamide and fludarabine) to suppress immunity and prevent rejection of the
transplant. Second, four days before the transplant, patients will be given donor lymphocytes
that have been irradiated to make them incapable of causing GVHD. On the day of the
transplant, patients will receive an infusion of T-cell depleted bone marrow stem cells.
Finally, patients will receive two doses of add-back donor T-cells (45 and 100 days post
transplant) and the immunosuppressive drug cyclosporine starting on day 44 until about six
months after transplant.
Study participants must be between the ages of 10 and 56 and have a family member who is a
suitable stem cell donor match.
complications, BMT would be safer to use for a wider range of conditions. The purposes of
this study are
- to prevent graft rejection by increasing the amount of immunosuppression and by giving
some lymphocytes from the donor before transplant;
- to prevent graft-versus-host disease (GVHD) by transplanting T-cell depleted stem cells;
- to improve the immune effect against residual leukemia by the add-back of donor
lymphocytes before transplant and six or more weeks after transplant.
Beyond the standard transplant protocol, study participants will undergo additional
procedures. First, along with total body irradiation, patients will receive two drugs (a high
dose of cyclophosphamide and fludarabine) to suppress immunity and prevent rejection of the
transplant. Second, four days before the transplant, patients will be given donor lymphocytes
that have been irradiated to make them incapable of causing GVHD. On the day of the
transplant, patients will receive an infusion of T-cell depleted bone marrow stem cells.
Finally, patients will receive two doses of add-back donor T-cells (45 and 100 days post
transplant) and the immunosuppressive drug cyclosporine starting on day 44 until about six
months after transplant.
Study participants must be between the ages of 10 and 56 and have a family member who is a
suitable stem cell donor match.
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. The aim is to create the transplant conditions that
permit rapid donor immune recovery without causing graft-versus-host disease (GVHD) by using
no 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. In the last study, in this series, we used
the Nexell Isolex 300i system to obtain high CD34+ doses depleted of lymphocytes to a fixed
CD3+ T cell dose of 2 x 10(4)/kg. The use of the cell separator and the monoclonal antibodies
was covered by IDE 8139. The study measured the incidence of acute GVHD and used chimerism
assays to determine the percentage of donor and recipient cells circulating at different
time-points after transplant. We found that in the first six weeks donor T cell chimerism
varied widely reaching 100% only in 10/22 patients. Thus the goal or rapid donor immune
recovery was achievable only in about half the patients. 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 is an important
therapeutic goal.
To improve donor T cell chimerism we will test whether the addition of irradiated donor
lymphocytes during the preparative regimen of the transplant can increase the chance of
achieving 100% donor T cell chimerism within six weeks of transplant. It is known that
irradiated lymphocytes do not cause GVHD and that they can suppress residual host immunity,
thus promoting donor lymphocyte engraftment. The end point of the study will be the
proportion of patients achieving full donor chimerism six weeks after transplant. Apart from
this addition of irradiated lymphocytes and some minor modifications, this protocol will be
identical to the predecessor protocol 02-H-0111. This involves the continued use of the
Isolex 300i cell separator and the monoclonal antibodies provided by CTEP (anti CD 6, anti
CD2, anti CD7). This is covered by a continuing IND for the selection of CD34+ and CD3+ cells
for T cell depleted peripheral blood stem cell transplantation.
optimize the stem cell and lymphocyte dose in order to improve transplant survival and
increase the graft-vs.-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
no 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. In the last study, in this series, we used
the Nexell Isolex 300i system to obtain high CD34+ doses depleted of lymphocytes to a fixed
CD3+ T cell dose of 2 x 10(4)/kg. The use of the cell separator and the monoclonal antibodies
was covered by IDE 8139. The study measured the incidence of acute GVHD and used chimerism
assays to determine the percentage of donor and recipient cells circulating at different
time-points after transplant. We found that in the first six weeks donor T cell chimerism
varied widely reaching 100% only in 10/22 patients. Thus the goal or rapid donor immune
recovery was achievable only in about half the patients. 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 is an important
therapeutic goal.
To improve donor T cell chimerism we will test whether the addition of irradiated donor
lymphocytes during the preparative regimen of the transplant can increase the chance of
achieving 100% donor T cell chimerism within six weeks of transplant. It is known that
irradiated lymphocytes do not cause GVHD and that they can suppress residual host immunity,
thus promoting donor lymphocyte engraftment. The end point of the study will be the
proportion of patients achieving full donor chimerism six weeks after transplant. Apart from
this addition of irradiated lymphocytes and some minor modifications, this protocol will be
identical to the predecessor protocol 02-H-0111. This involves the continued use of the
Isolex 300i cell separator and the monoclonal antibodies provided by CTEP (anti CD 6, anti
CD2, anti CD7). This is covered by a continuing IND for the selection of CD34+ and CD3+ cells
for T cell depleted peripheral blood stem cell transplantation.
- INCLUSION CRITERIA FOR RECIPIENTS:
Recipient
Ages 10-55 years inclusive (but less than 56)
Chronic myelogenous leukemia in chronic phase
A) Patients not treated with STI 571 under the age of 41 (subject to regular DSMB review).
B) 10-55 age limits patients in chronic phase who have failed treatment with STI-571.
C) 10-55 age limits patients in 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, t19, 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/ml) or anemia (less than or
equal to 10g/dl) not due to recent chemotherapy.
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.
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: Ability to comprehend the investigational nature of the study and provide
informed consent. 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.
Negative pregnancy test for women of childbearing age.
INCLUSION CRITERIA FOR DONORS:
HLA 6/6 identical family donor
Weight greater than or equal to 18 kg
Age greater than or equal to 2 or less than or equal to 80 years old
Fit to receive G-CSF and give peripheral blood stem cells (normal blood count,
normotensive, no history of stroke)
For adults: Ability to comprehend the investigational nature of the study and provide
informed consent. For minors: Written informed consent from one parent or guardian and
informed assent: The process will be explained to the minor on a level of complexity
appropriate for their age and ability to comprehend.
EXCLUSION CRITERIA FOR RECIPIENTS (any of the following):
Patient pregnant
Age less than 10 years and 56 years or more
Patients with CML in chronic phase who are 41 years or over in whom STI 571 is the
treatment of choice
ECOG performance status of 2 or more
Severe psychiatric illness. Mental deficiency sufficiently severe as to make compliance
with the BMT treatment unlikely, and making informed consent impossible.
Major anticipated illness or organ failure incompatible with survival from BMT
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 3 times the upper limit of normal
HIV positive
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 in
eligibility criteria for this protocol, but where debility or age makes the risk of
intensive myeloablative therapy unacceptable. This includes patients who have received
busulfan treatment for more than 6 months continuously. These patients will be considered
for a non-myeloablative allogeneic transplantation protocols.
EXCLUSION CRITERIA:
Donor (any of the following)
Pregnant or lactating
Donor unfit to receive G-CSF and undergo apheresis. (Uncontrolled hypertension, history of
congestive heart failure or unstable angina, thrombocytopenia)
HIV positive. Donors who are positive for HBV, HCV or HTLV-1 may be used if the
risk-benefit ratio is considered acceptable by the patient and investigator.
Weight less than 18 kg
Age less than 2 or greater than 80 years
Severe psychiatric illness. Mental deficiency sufficiently severe as to make compliance
with the BMT treatment unlikely, and making informed consent impossible
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
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