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Methods to Enhance the Safety and Effectiveness of Stem Cell Transplants

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ClinicalTrials.gov Identifier: NCT00378534
Recruitment Status : Completed
First Posted : September 20, 2006
Results First Posted : January 6, 2015
Last Update Posted : October 28, 2015
Sponsor:
Information provided by (Responsible Party):
Minoo Battiwalla, M.D., National Institutes of Health Clinical Center (CC)

September 19, 2006
September 20, 2006
December 22, 2014
January 6, 2015
October 28, 2015
September 2006
April 2014   (Final data collection date for primary outcome measure)
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 infucion at day 90. The subjects receiveing 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.
Not Provided
Complete list of historical versions of study NCT00378534 on ClinicalTrials.gov Archive Site
Standard Transplant Outcome Variables Such as Non-hematologic Toxicity, Incidence and Severity of Acute and Chronic GVHD and Relapse of Disease. [ Time Frame: 3 years maximum ]
Not Provided
Not Provided
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Methods to Enhance the Safety and Effectiveness of Stem Cell Transplants
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

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.

Peripheral blood stem cell transplant research carried out by the National Heart Lung and Blood Institute (NHLBI) Bonne Marrow Transplantation (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. 68 sibling donors will also be recruited. 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.

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.

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.

Interventional
Phase 2
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
  • Chronic Myelogenous Leukemia
  • Acute Myelogenous Leukemia
  • Chronic Lymphocytic Leukemia
  • Acute Lymphoblastic Leukemia
  • Myelodysplastic Syndrome
  • Device: Miltenyi reagent system
    Miltenyi Clinimax CD34 Reagent System for CD34 selectioni 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
Experimental: Miltenyi reagent system

The protocol will evaluate survival at day +200 in subjects with hematological malignancies receiving myeloablative conditioning regimen of cyclophosphamidem fludarabine and total body irradiation followed by an infusion of a stem cell prodict prepared using the Miltenyi CliniMacs system for CD34 selection and a delayed T cell depletion add back as donor lymphocyte infusion (DLI) at day 90.

The objective is to determine the overall survival rate at day +200 following allogeneic peripheral blood stem cell allotransplantation (PBSCT)

Interventions:
  • Device: Miltenyi reagent system
  • Drug: Fludarabine
  • Drug: Cyclosporine
  • Drug: Cyclophosphamide

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
115
68
April 2014
April 2014   (Final data collection date for primary outcome measure)

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, 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:

  • 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 adjusted for ventilation and hemoglobin less than 65 percent predicted
  • Left ventricular ejection fraction less than 40 percent
  • AST/SGOT greater than 10 times ULN (CTCAE grade IV v3.0)
  • Bilirubin greater than 5 times ULN (CTCAE grade IV v3.0)
  • Creatinine greater than 4.5 times 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
Sexes Eligible for Study: All
10 Years to 75 Years   (Child, Adult, Older Adult)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT00378534
060248
06-H-0248 ( Other Identifier: NIH National Heart, Lung and Blood Institute )
No
Not Provided
Not Provided
Minoo Battiwalla, M.D., National Institutes of Health Clinical Center (CC)
National Heart, Lung, and Blood Institute (NHLBI)
Not Provided
Principal Investigator: Minocher M Battiwalla, M.D. National Heart, Lung, and Blood Institute (NHLBI)
National Institutes of Health Clinical Center (CC)
December 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP