T-Cell-Depleted Allogeneic Stem Cell Transplantation After Immunoablative Induction Chemotherapy and Reduced-Intensity Transplantation Conditioning in Treating Patients With Hematologic Malignancies

NCT ID: NCT00080925

Last Updated: 2012-03-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2004-02-29
• Study Completion Date: 2010-12-31

Brief Summary

RATIONALE: Donor peripheral stem cell transplantation may be able to replace bone marrow and immune cells that were destroyed by chemotherapy. Sometimes the transplanted cells from a donor are rejected by the body's normal cells. Eliminating the T cells from the donor cells before transplanting them and giving cyclosporine may prevent this from happening.

PURPOSE: This phase I trial is studying the side effects of T-cell-depleted allogeneic stem cell transplantation after immunoablative induction chemotherapy and reduced-intensity transplantation conditioning (chemotherapy) in treating patients with hematologic malignancies.

Detailed Description

OBJECTIVES:

Primary

• Determine engraftment in patients with hematologic malignancies treated with T-cell-depleted allogeneic stem cell transplantation after immunoablative induction chemotherapy and reduced-intensity transplantation conditioning.

Secondary

• Determine the incidence of acute graft-versus-host disease (GVHD), and nonrelapse mortality (within 100 days after transplantation) in these patients.
• Correlate levels of host immunosuppression before transplantation conditioning, as evaluated by peripheral blood CD4 counts, with graft rejection/failure within 100 days after transplantation and the level of donor hematopoietic chimerism 28 days after transplantation in these patients.
• Correlate donor-versus-recipient natural killer cell alloreactivity with graft rejection/failure, acute GVHD, and relapse of malignant disease in patients treated with this regimen.
• Determine the development of allospecific cytotoxic T-lymphocytes after transplantation in patients with myeloid or lymphoid leukemia.
• Correlate serum interleukin-7 and interleukin-15 levels with in vivo changes in host lymphocyte subpopulations in these patients during sequential immunoablative chemotherapy, before allogeneic stem cell transplantation, and during immune reconstitution after transplantation.

OUTLINE: This is a pilot study.

• Induction chemotherapy: Patients receive 1 of 2 induction chemotherapy regimens according to diagnosis. Patients with partial response or better after prior therapy (i.e., already adequately immune depleted) proceed directly to the transplantation preparative regimen.

• Regimen A (Hodgkin's lymphoma, non-Hodgkin's lymphoma [except lymphoblastic lymphoma], chronic lymphocytic leukemia, prolymphocytic leukemia, or multiple myeloma): Patients receive rituximab IV (if they have CD20+ B-cell malignancies) on day 1; fludarabine IV over 30 minutes on days 1-4; etoposide, doxorubicin, and vincristine IV continuously on days 1-4; cyclophosphamide IV over 30 minutes on day 5; oral prednisone on days 1-5; and filgrastim (G-CSF) subcutaneously (SC) beginning on day 6 and continuing until blood counts recover.
• Regimen B (lymphoblastic lymphoma, acute myeloid leukemia, acute lymphoblastic leukemia, refractory anemia with excess blasts, myeloproliferative disorders, chronic myelomonocytic leukemia, or chronic myelogenous leukemia): Patients receive G-CSF SC beginning 24 hours before initiating induction chemotherapy and continuing until blood counts recover. Patients also receive fludarabine IV over 30 minutes and cytarabine IV over 4 hours on days 1-5.

For both regimens, treatment repeats every 21 days for 1-2 courses. Patients who achieve remission or who have responsive or stable disease after induction chemotherapy then proceed to transplantation preparative regimen chemotherapy.

• Transplantation preparative regimen chemotherapy: Patients receive fludarabine IV over 30 minutes and cyclophosphamide IV over 2 hours on days -6 to -3.
• Graft-versus-host disease (GVHD) prophylaxis: Patients receive cyclosporine IV over 2 hours twice daily beginning on day -1 and continuing IV or orally until day 100. Patients with no acute GVHD at day 100 taper cyclosporine over 12 weeks.
• Allogeneic stem cell transplantation (SCT): Patients undergo T-cell-depleted allogeneic peripheral blood SCT on day 0. Patients receive G-CSF SC beginning on day 0 and continuing until blood counts recover.
• Donor lymphocyte infusion (DLI): Patients with persistent or progressive malignant disease after transplantation or mixed chimerism that does not improve after tapering or discontinuing immunosuppression therapy may receive DLI. DLI may be administered alone or in combination with chemotherapy. DLI repeats every 4 weeks until adequate donor chimerism is achieved or until GVHD develops.

Patients are followed at 28 and 100 days and then at 6, 9, 12, 18, and 24 months.

PROJECTED ACCRUAL: A total of 6-20 patients will be accrued for this study within 2 years.

Conditions

Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms

Study Design

• Primary Study Purpose: TREATMENT

Interventions

filgrastim

Intervention Type: BIOLOGICAL

graft-versus-tumor induction therapy

Intervention Type: BIOLOGICAL

rituximab

Intervention Type: BIOLOGICAL

therapeutic allogeneic lymphocytes

Intervention Type: BIOLOGICAL

cyclophosphamide

Intervention Type: DRUG

cyclosporine

Intervention Type: DRUG

cytarabine

Intervention Type: DRUG

doxorubicin hydrochloride

Intervention Type: DRUG

etoposide

Intervention Type: DRUG

fludarabine phosphate

Intervention Type: DRUG

prednisone

Intervention Type: DRUG

vincristine sulfate

Intervention Type: DRUG

peripheral blood stem cell transplantation

Intervention Type: PROCEDURE

Eligibility Criteria

Inclusion Criteria

• Chronic lymphocytic leukemia

• Treatment failure* after fludarabine, chlorambucil, and at least 1 other salvage regimen
• Prolymphocytic leukemia (PLL), meeting 1 of the following criteria:

• T-PLL

• Treatment failure* after alemtuzumab and at least 1 other regimen
• B-PLL

• Treatment failure* after fludarabine and at least 1 other salvage regimen
• Multiple myeloma, meeting 1 of the following criteria:

• Relapse after autologous SCT
• Plasma cell leukemia
• Adverse cytogenetics, defined as 1 of the following:

• del(13q) = 11q translocation NOTE: *Treatment failure is defined as relapse within 6 months OR failure to achieve remission
• Less than 10% blasts in bone marrow and no circulating blasts in peripheral blood for the following diagnoses:

• Primary or secondary leukemia
• Refractory anemia with excess blasts
• CML
• Other eligible diagnosis in transformation to acute leukemia
• Expected survival of approximately 1 year or less with conventional therapy
• No active CNS involvement by malignancy*

• Prior CNS involvement with no current evidence of CNS malignancy allowed NOTE: *Active CNS malignancy is defined by lymphoma: tumor mass on CT scan or leptomeningeal disease OR leukemia: blasts present on cerebrospinal fluid cytospin
• Availability of a donor who is a sibling, parent, or offspring who shares 1 full haplotype (HLA-A, -B, or -DR)

• Recipient and donor must have at least a 2-antigen disparity in either the host-versus-graft or graft-versus-host direction
• Parent or offspring donor who is mismatched for a single HLA antigen (i.e., 5/6 HLA) is allowed
• No sibling donor who is 6/6 HLA-matched OR mismatched for a single HLA antigen (i.e., 5/6 HLA)
• No unrelated donor identified in a prior or current National Marrow Donor Program registry search

PATIENT CHARACTERISTICS:

Age

• 18 to 55

Performance status

• ECOG 0-2 OR
• Karnofsky 60-100%

Life expectancy

• At least 3 months

Hematopoietic

• See Disease Characteristics
• Absolute neutrophil count ≥ 1,000/mm^3*
• Platelet count ≥ 20,0000/mm^3* (without transfusion) NOTE: *Lower values may be accepted at the discretion of the principal investigator or study chairperson if due to bone marrow involvement by malignancy

Hepatic

• ALT and AST ≤ 2.5 times upper limit of normal (ULN)*
• Bilirubin ≤ 2.5 times ULN*
• Unconjugated hyperbilirubinemia consistent with Gilbert's syndrome allowed
• No chronic active hepatitis B infection

• Hepatitis B core antibody positive allowed provided patient is surface antigen negative and has no evidence of active infection
• No hepatitis C viral infection

• Seronegative for anti-hepatitis C antibody and detectable hepatitis C viral RNA by reverse transcriptase-polymerase chain reaction assay NOTE: *Higher levels may be accepted at the discretion of the principle investigator or study chairperson if such elevations are due to liver involvement by malignancy

Renal

• Creatinine ≤ 1.5 mg/dL OR
• Creatinine clearance ≥ 50 mL/min

Cardiovascular

• LVEF ≥ 45%

Pulmonary

• DLCO ≥ 50% of expected value (corrected for blood hemoglobin level and alveolar volume)

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 1 year after study participation
• HIV negative
• No active infection not responding to antimicrobial therapy
• No psychiatric disorder that would preclude study compliance or informed consent

PRIOR CONCURRENT THERAPY:

Biologic therapy

• See Disease Characteristics
• At least 2 weeks since prior monoclonal antibody therapy

Chemotherapy

• See Disease Characteristics
• At least 2 weeks since prior systemic chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• Not specified

Other

• Recovered from all prior therapy
• No administration of tyrosine kinase (TK) inhibitors, including imatinib mesylate and dasatinib, during the conditioning regimen; TK inhibitor administration may resume 28 days after transplantation

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 55 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

National Institutes of Health Clinical Center (CC)

NIH

Sponsor Role: lead

Principal Investigators

Michael R. Bishop, MD

Role: STUDY_CHAIR

National Cancer Institute (NCI)

Locations

Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office

Bethesda, Maryland, United States

Countries

United States

Other Identifiers

04-C-0116

Identifier Type: -

Identifier Source: secondary_id

CDR0000357432

Identifier Type: -

Identifier Source: secondary_id

040116

Identifier Type: -

Identifier Source: org_study_id