Protocol Number: 06-H-0248

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

Number:

06-H-0248

Summary:

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.

Sponsoring Institute:

National Heart, Lung and Blood Institute (NHLBI)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility 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 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

Special Instructions:

Currently Not Provided

Keywords:

Chronic Myelogenous Leukemia (CML)

Acute Myelogenous Leukemia (AML)

Chronic Lymphocytic Leukemia (CLL)

Acute Lymphoblastic Leukemia (ALL)

Myelodysplastic Syndrome (MDS)

Recruitment Keyword(s):

Leukemia

Chronic Myelogenous Leukemia

CML

Acute Myeloid Leukemia

AML

Chronic Lymphocytic Leukemia

CLL

Acute Lymphoblastic Leukemia

ALL

Myelodysplasia Syndrome

Condition(s):

Chronic Myelogenous Leukemia

Acute Myelogenous Leukemia

Chronic Lymphocytic Leukemia

Acute Lymphoblastic Leukemia

Myelodysplastic Syndrome

Investigational Drug(s):

None

Investigational Device(s):

Miltenyi CliniMACS CD34 Reagent System

Intervention(s):

Device: Miltenyi CliniMACS CD34 Reagent System

Supporting Site:

National Heart, Lung and Blood Institute

Contact(s):

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citation(s):

Appelbaum FR. Haematopoietic cell transplantation as immunotherapy. Nature. 2001 May 17;411(6835):385-9. Review.

Armitage JO. Bone marrow transplantation. N Engl J Med. 1994 Mar 24;330(12):827-38. Review. No abstract available.

Balaguer H, Galmes A, Ventayol G, Bargay J, Besalduch J. Splenic rupture after granulocyte-colony-stimulating factor mobilization in a peripheral blood progenitor cell donor. Transfusion. 2004 Aug;44(8):1260-1. No abstract available.

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