Methods to Enhance the Safety and Effectiveness of Stem Cell Transplants
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| ClinicalTrials.gov Identifier: NCT00378534 |
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Recruitment Status :
Completed
First Posted : September 20, 2006
Results First Posted : January 6, 2015
Last Update Posted : June 16, 2021
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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 donors 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.
| Condition or disease | Intervention/treatment | Phase |
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| Chronic Myelogenous Leukemia Acute Myelogenous Leukemia Chronic Lymphocytic Leukemia Acute Lymphoblastic Leukemia Myelodysplastic Syndrome | Device: Miltenyi reagent system Drug: Fludarabine Drug: Cyclosporine Drug: Cyclophosphamide Other: FILGRASTIM (G-CSF) | Phase 2 |
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| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 116 participants |
| Allocation: | Non-Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| 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 |
| Study Start Date : | September 2006 |
| Actual Primary Completion Date : | April 2014 |
| Actual Study Completion Date : | April 2014 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: T Cell Depletion Transplant Participants
Participants with hematological malignancies received a myeloablative conditioning regimen of cyclophosphamide, fludarabine and total body irradiation followed by an infusion of stem cell product prepared using the Miltenyi CliniMacs system for CD34 selection and a delayed T cell depletion add back as donor lymphocyte infusion at day 90.
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Device: Miltenyi reagent system
Miltenyi Clinimax CD34 Reagent System for CD34 selection and delayed T cell depletion add back
Other Name: Miltenyi Clinimax CD34 Reagent System Drug: Fludarabine Therapeutic
Other Name: Fludara Drug: Cyclosporine Therapeutic
Other Name: Neoral Drug: Cyclophosphamide Therapeutic
Other Name: Cytoxan |
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Stem Cell Donors
An HLA 6/6 identical family member will be co-enrolled into this study as a stem cell donor. The stem cell collection aspect of this protocol is not investigational.
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Other: FILGRASTIM (G-CSF)
An HLA 6/6 identical family member will be co-enrolled into this study as a stem cell donor. Stem cell Donors will receive G-CSF for stem cell mobilization. The stem cell collection aspect of this protocol is not investigational.
Other Name: Neupogen |
- Survival and Non-relapse Mortality at Day +200 Using the Miltenyi Reagent System [ Time Frame: Day 200 ]Subjects with hematological malignancies receiving a myeloablative conditioning regimen of cyclophosphamide, fludarabine and total body irradiation followed by an infusion of stem cell product prepared using the Miltenyi CliniMacs system for CD34 selection and a delayed T cell depletion add back as donor lymphocyte infusion at day 90. The subjects receiving allogeneic stem cell transplantation will have stem cell product prepared using Miltenyi CliniMacs system to determine the overall survival and non-relapse mortality at day +200.
- Number of Participants With Relapse of Disease [ Time Frame: Day 200 ]Number of participants with relapse of disease by day 200
- Number of Participants Who Developed Acute GVHD Grades I, II, III, IV [ Time Frame: 100 days ]
Number of participants who developed Acute Graft vs Host Disease (GVHD) Grades I, II, III, IV as defined by CIMBTR criteria for Organ Stages of Acute GVHD.
Grades are defined as:
Grade I: Skin = Maculopapular rash< 25% of body surface area (BSA); Liver = Total Bilirubin 2-3 mg/dL; Lower GI = stool output/day is 500-999 mL/day.
Grade II: Skin = rash on 25-50 percent body surface area; Liver = Total Bilirubin 3.1-6.0 mg/dL; Lower GI = Diarrhea 1001-1500 mL/day.
Grade III: Skin = Rash on >50% of body surface; Liver = Total Bilirubin 6.1 - 15.0 mg/dL; Lower GI = Diarrhea > 1500 mL/day.
Grade IV: Skin = Generalized erythroderma plus bullous formation; Liver = Total Bilirubin >15 mg/dL; Lower GI = Severe abdominal pain with or without ileus.
Grade I GVHD is characterized as mild disease, grade II GVHD as moderate, grade III as severe, and grade IV life-threatening.
- Number of Participants Who Developed Limited Chronic GVHD [ Time Frame: 36 months ]
Number of incidences of participants who developed Limited Chronic Graft vs Host Disease (GVHD).
Limited disease is characterized by localized skin involvement and/or evidence of hepatic dysfunction.
Limited disease is associated with a favorable outcome without systemic therapy, while extensive disease patients have an unfavorable outcome.
- Number of Participants Who Develop Extensive GVHD [ Time Frame: 36 months ]
Number of participants with extensive, Chronic Graft vs Host Disease (GVHD). Extensive chronic GVHD is defined as GVHD occurring after day 100 that did not meet the definition of limited chronic GVHD.
Extensive disease presents either with generalized skin involvement, or with localized skin involvement or hepatic dysfunction plus at least one of the following:
- Liver histology showing chronic progressive hepatitis, bridging necrosis, or cirrhosis
- Involvement of the eye (Schirmer's test with less than 5 mm wetting) (see "Diagnosis and classification of Sjögren's syndrome")
- Involvement of minor salivary glands or oral mucosa (as demonstrated on labial or mucosal biopsy specimen)
- Involvement of any other target organ
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 10 Years to 75 Years (Child, Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
INCLUSION CRITERIA - RECIPIENT:
- Ages 10-75 years inclusive
- Chronic myelogenous leukemia (CML):
- Subjects under the age of 21 in chronic phase
- Subjects ages 10-75 in chronic phase who have failed treatment with imatinib, have intolerance to imatinib, or who did not receive imatinib at therapeutic doses within the first 12 months from diagnosis.
- Subjects ages 10-75 in accelerated phase or blast transformation.
- 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-Hodgkins lymphoma including Mantle cell lymphoma relapsing or refractory to standard of care treatments
- Multiple myeloma, Waldenstrom's 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:
- 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
- Diffusion Capacity of Lung for Carbon Monoxide (DLCO) adjusted for ventilation and hemoglobin less than 65 percent predicted
- Left ventricular ejection fraction less than 40 percent
- Aspartate Aminotransferase (AST)/Serum Glutamate Oxaloacetate Transaminase (SGOT) greater than 10 times upper limit of normal (ULN) (CTCAE grade IV v3.0)
- Bilirubin greater than 5 times upper limit of normal (ULN) (CTCAE grade IV v3.0)
- Creatinine greater than 4.5 times upper limit of normal (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:
- Pregnant. Lactating donors permitted provide breast milk is discarded during the days that G-CSF is given
- 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 donors who are positive for hepatitis B (HBV), hepatitis C (HCV) or human T-cell lymphotropic virus (HTLV-I/II) will be used at the discretion of the investigator following counseling and approval from the recipient
- Severe psychiatric illness. Mental deficiency sufficiently severe as to make compliance with the BMT treatment unlikely, and making informed consent impossible
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00378534
| United States, Maryland | |
| National Institutes of Health Clinical Center, 9000 Rockville Pike | |
| Bethesda, Maryland, United States, 20892 | |
| Principal Investigator: | Minocher M Battiwalla, M.D. | National Heart, Lung, and Blood Institute (NHLBI) |
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | National Heart, Lung, and Blood Institute (NHLBI) |
| ClinicalTrials.gov Identifier: | NCT00378534 |
| Obsolete Identifiers: | NCT00398346 |
| Other Study ID Numbers: |
060248 06-H-0248 ( Other Identifier: NIH National Heart, Lung and Blood Institute ) |
| First Posted: | September 20, 2006 Key Record Dates |
| Results First Posted: | January 6, 2015 |
| Last Update Posted: | June 16, 2021 |
| Last Verified: | December 2014 |
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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 Preleukemia Leukemia, Lymphoid Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphocytic, Chronic, B-Cell Leukemia, Myeloid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid, Acute Myelodysplastic Syndromes Syndrome Disease Pathologic Processes Neoplasms by Histologic Type Neoplasms Bone Marrow Diseases |
Hematologic Diseases Precancerous Conditions Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Leukemia, B-Cell Myeloproliferative Disorders Cyclosporine Cyclophosphamide Fludarabine Cyclosporins Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs |