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| Sponsored by: |
National Heart, Lung, and Blood Institute (NHLBI) |
|---|---|
| Information provided by: | National Institutes of Health Clinical Center (CC) |
| ClinicalTrials.gov Identifier: | NCT00378534 |
Purpose
Bone marrow stem cell transplants (otherwise called bone marrow transplants) from healthy donors are sometimes the only means of curing hematological malignant diseases such as acute and chronic leukemias, myelodysplastic syndrome, myeloproliferative diseases and lymphomas. Before transplant the patient receives chemotherapy and radiation treatment to reduce the malignancy to low levels and to prevent rejection of the transplant. The transplant restores the blood counts to normal and replaces the patients immunity with that of the donor. The donor's immune cells increase the effect of the transplant by attacking remaining malignant cells. Donor immune cells (especially those called T lymphocytes) also attack healthy non-cancerous cells and tissues of the recipient causing "graft-versus-host-disease" (GVHD). Strong GVHD reactions occurring within weeks after the transplant can be life-threatening . In this study we remove most of the T lymphocytes from the transplant to minimize the risk of GVHD. However to improve immunity against residual malignant cells and boost immunity to infections, donor T cells (stored frozen at time of transplant) are given back around 90 days after the transplant when they have a reduced risk of causing serious GVHD.
Any patient between 10 and 75 years of age with acute or chronic leukemia, myelodysplastic syndrome, myeloproliferative syndromes or lymphoma, who have a family member who is a suitable stem cell donor may be eligible for this study. Candidates are screened with a medical history and various tests and examinations.
Participants undergo apheresis to collect lymphocytes for research studies. This procedure involves collecting blood through a needle in the arm, extracting the lymphocytes through a cell separator machine and returning the rest of the blood through a needle in the other arm. Before treatment begins, patients have a central intravenous line (plastic tube) placed in a vein in the neck. This line remains in place during the transplant and recovery period for drawing and transfusing blood, giving medications, and infusing the donated cells.
To prepare patients for transplantation their immune system is suppressed by a combination of chemotherapy and radiation which will also help to fight remaining malignant cells. The chemotherapy consists of two anti-cancer drugs (fludarabin and cyclophosphamide) and will be infused over the central line starting eight days before the transplant. Patients will receive eight doses of total body irradiation, administered in two 30-minute sessions per day for 4 days. Patients above 55 years of age who tolerate transplants less well than younger individuals will receive a lower dose of radiation. One day after the preparative treatment is finished, patients receive the transplant of donors' stem cells as an infusion through the central line.
Patients receive cyclosporine, an immune-suppressing drug starting 6 days before the transplant until 21 days post-transplant. This helps prevent both transplant rejection and GVHD. The drug is stopped to allow the donor immunity to function and is restarted on day 89 to prevent GVHD from the infusion of T lymphocytes on day 90.
Patients are followed with various tests, treatments and examinations periodically for the first 3 years and then yearly thereafter.
| Condition | Intervention | Phase |
|---|---|---|
|
Chronic Myelogenous Leukemia Acute Myelogenous Leukemia Chronic Lymphocytic Leukemia Acute Lymphoblastic Leukemia Myelodysplastic Syndrome |
Device: Miltenyi CliniMACS CD34 Reagent System |
Phase II |
| Study Type: | Interventional |
| Study Design: | Treatment, Non-Randomized, Open Label, Historical Control, Single Group Assignment, Safety/Efficacy Study |
| Official Title: | Peripheral Blood Stem Cell Allotransplantation for Hematological Malignancies Using a Positive Stem Cell Selection Technique for T Cell Depletion, Followed by Delayed T Cell Add-Back |
| Estimated Enrollment: | 68 |
| Study Start Date: | September 2006 |
Peripheral blood stem cell transplant research carried out by the NHLBI BMT Unit focus on transplant techniques designed to decrease graft versus host disease (GVHD), increase the graft-versus-leukemia (GVL) effect and reduce the risk of post-transplant graft rejection.
We have found that by controlling the stem cell (CD34+ cell) and T lymphocyte (CD3+ cell) dose severe GVHD can be reduced whilst beneficial GVL effects can be preserved by postponed donor lymphocyte infusion (DLI). We found that T cell depleted transplants using the Nexell/Baxter Isolex 300i system to obtain high CD34+ doses depleted of lymphocytes were safe to administer and associated with less severe acute GVHD and promising response rates and overall survival, when combined with a delayed T cell add-back (DLI). This protocol is designed to evaluate safety and efficacy of an improved T cell depletion procedure using the Miltenyi CliniMACs system (CD34 reagent system) with a delayed T cell add back in the HLA-matched peripheral blood stem cell transplant setting.
The protocol will accrue up to 68 subjects ages 10-75 with a hematological malignancy, in whom allogeneic stem cell transplantation from an HLA-matched sibling would be routinely indicated. Diagnostic categories will include acute and chronic leukemia, myelodysplastic syndrome, lymphoma, multiple myeloma and myeloproliferative syndromes.
Subjects will receive a myeloablative conditioning regimen of cyclophosphamide, fludarabine and total body irradiation, followed by an infusion of a stem cell product prepared using the Miltenyi CliniMacs system for CD34 selection, and a delayed T-cell add back as donor lymphocyte infusion (DLI) at day 90.
Older subjects will receive a lower dose of irradiation to reduce the regimen intensity.
Primary endpoint will be overall survival at day +200. Non-relapse mortality at day +200 will be monitored for safety. Secondary endpoints will be standard transplant outcome variables such as non-hematologic toxicity, incidence and severity of acute and chronic GVHD and relapse of disease.
Eligibility| Ages Eligible for Study: | 2 Years to 80 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Ages 10-75 years inclusive
Chronic myelogenous leukemia (CML):
Acute lymphoblastic leukemia (ALL): any of these categories: ALL 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 (MDS): any of these categories - refractory anemia with transfusion dependence, refractory anemia with excess of blasts, transformation to acute leukemia, chronic myelomonocytic leukemia, atypical MDS/myeloproliferative syndromes
Myeloproliferative disorders including atypical (Ph negative) chronic myeloid and neutrophilic leukemias, progressing myelofibrosis, and polycythemia vera, essential thrombocythemia in transformation to acute leukemia or with progressive transfusion requirements or pancytopenia.
Chronic lymphocytic leukemia refractory to fludarabine treatment and with bulky progressive disease or with thrombocytopenia (less than or equal to 100,000 /microl) 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 standard of care treatments
Multiple myeloma, Waldenstroms macroglobulinemia, unresponsive or relapsed following standard of care treatments.
HLA identical (6/6) related donor
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.
EXCLUSION CRITERIA - RECIPIENT: (ANY OF THE FOLLOWING)
Estimated probability of surviving less than three months
Major anticipated illness or organ failure incompatible with survival from transplant
Severe psychiatric illness. Mental deficiency sufficiently severe as to make compliance with the transplant treatment unlikely and making informed consent impossible.
Positive pregnancy test for women of childbearing age.
HIV positive
DLCO less than 65% predicted
Left ventricular ejection fraction less than 40%
AST/SGOT greater than 20 x ULN (CTCAE grade IV v3.0)
Bilirubin greater than 10 x ULN (CTCAE grade IV v3.0)
Creatinine greater than 6 x ULN (CTCAE grade IV v 3.0)
Prior allogeneic stem cell transplantation.
INCLUSION CRITERIA - DONOR:
Related donor, HLA identical (6/6) with recipient
Weight greater than or equal to 18 kg
Age greater than or equal to 2 or less than or equal to 80 years old
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 - DONOR: (ANY OF THE FOLLOWING)
Pregnant or lactating
Unfit to receive filgrastim (G-CSF) and undergo apheresis (abnormal blood counts, history of stroke, uncontrolled hypertension)
Sickling hemoglobinopathies including HbSS, HbAS, HbSC
HIV positive
Severe psychiatric illness. Mental deficiency sufficiently severe as to make compliance with the BMT treatment unlikely, and making informed consent impossible
Contacts and Locations| Contact: Patient Recruitment and Public Liaison Office | (800) 411-1222 | prpl@mail.cc.nih.gov |
| Contact: TTY | 1-866-411-1010 |
| United States, Maryland | |
| National Institutes of Health Clinical Center, 9000 Rockville Pike | Recruiting |
| Bethesda, Maryland, United States, 20892 | |
More Information
| Responsible Party: | National Institutes of Health ( A. John Barrett, M.D./National Heart, Lung, and Blood Institute ) |
| Study ID Numbers: | 060248, 06-H-0248 |
| Study First Received: | September 19, 2006 |
| Last Updated: | October 6, 2008 |
| ClinicalTrials.gov Identifier: | NCT00378534 History of Changes |
| Health Authority: | United States: Federal Government |
|
Chronic Myelogenous Leukemia (CML) Acute Myelogenous Leukemia (AML) Chronic Lymphocytic Leukemia (CLL) Acute Lymphoblastic Leukemia (ALL) Myelodysplastic Syndrome (MDS) Leukemia Chronic Myelogenous Leukemia CML |
Acute Myeloid Leukemia AML Chronic Lymphocytic Leukemia CLL Acute Lymphoblastic Leukemia ALL Myelodysplasia Syndrome |
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Leukemia, Lymphoid Immunoproliferative Disorders Precursor Cell Lymphoblastic Leukemia-Lymphoma Precancerous Conditions Hematologic Diseases Myelodysplastic Syndromes Myeloproliferative Disorders Leukemia, Myeloid Leukemia, Myeloid, Acute Leukemia Lymphatic Diseases Chronic Lymphocytic Leukemia |
Acute Myelocytic Leukemia Preleukemia Acute Myeloid Leukemia, Adult Leukemia, Lymphocytic, Chronic, B-Cell Leukemia, Myelogenous, Chronic, BCR-ABL Positive Chronic Myelogenous Leukemia Leukemia, B-cell, Chronic Bone Marrow Diseases Leukemia, B-Cell Lymphoproliferative Disorders Lymphoma Acute Lymphoblastic Leukemia |
|
Leukemia, Lymphoid Disease Immunoproliferative Disorders Precursor Cell Lymphoblastic Leukemia-Lymphoma Neoplasms by Histologic Type Precancerous Conditions Immune System Diseases Hematologic Diseases Myelodysplastic Syndromes Myeloproliferative Disorders Leukemia, Myeloid Leukemia, Myeloid, Acute |
Lymphatic Diseases Leukemia Preleukemia Neoplasms Pathologic Processes Leukemia, Lymphocytic, Chronic, B-Cell Syndrome Leukemia, Myelogenous, Chronic, BCR-ABL Positive Bone Marrow Diseases Lymphoproliferative Disorders Leukemia, B-Cell |
