Methods to Enhance the Safety and Effectiveness of Stem Cell Transplants

The recruitment status of this study is unknown because the information has not been verified recently.
Verified May 2012 by National Institutes of Health Clinical Center (CC).
Recruitment status was  Active, not recruiting
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )
ClinicalTrials.gov Identifier:
NCT00378534
First received: September 19, 2006
Last updated: January 16, 2013
Last verified: May 2012
  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 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Increased rate of survival at day +200. Non-relapse mortality at day +200 will be monitored for safety. [ Time Frame: Day 200 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]

Enrollment: 115
Study Start Date: September 2006
Estimated Study Completion Date: August 2014
Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Intervention Details:
    Device: Miltenyi CliniMACS CD34 Reagent System
    N/A
Detailed Description:

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. 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.

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:   10 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • 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-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 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: (ANY OF THE FOLLOWING)

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

  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00378534

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
Investigators
Principal Investigator: Minocher M Battiwalla, M.D. National Heart, Lung, and Blood Institute (NHLBI)
  More Information

Additional Information:
Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )
ClinicalTrials.gov Identifier: NCT00378534     History of Changes
Obsolete Identifiers: NCT00398346
Other Study ID Numbers: 060248, 06-H-0248
Study First Received: September 19, 2006
Last Updated: January 16, 2013
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
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

Additional relevant MeSH terms:
Myelodysplastic Syndromes
Preleukemia
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia
Syndrome
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms
Neoplasms by Histologic Type
Myeloproliferative Disorders
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Disease
Pathologic Processes

ClinicalTrials.gov processed this record on October 19, 2014