Overview

This trial is active, not recruiting.

Conditions accelerated phase of disease, childhood chronic myelogenous leukemia, bcr-abl1 positive, chronic myelogenous leukemia, bcr-abl1 positive, chronic phase of disease, recurrent disease
Treatments fludarabine phosphate, total-body irradiation, nonmyeloablative allogeneic hematopoietic stem cell transplantation, peripheral blood stem cell transplantation, cyclosporine, mycophenolate mofetil, therapeutic allogeneic lymphocytes, laboratory biomarker analysis
Phase phase 2
Sponsor Fred Hutchinson Cancer Research Center
Collaborator National Cancer Institute (NCI)
Start date August 1997
End date March 2005
Trial size 18 participants
Trial identifier NCT00003145, 1209.00, NCI-2012-00579, P30CA015704

Summary

This clinical trial studies fludarabine phosphate, low-dose total-body irradiation, and peripheral blood stem cell transplant followed by donor lymphocyte infusion in treating older patients with chronic myeloid leukemia. Giving chemotherapy and total-body irradiation before a donor bone marrow transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil after the transplant may stop this from happening. Once the donated stem cells begin working, the patient's immune system may see the remaining cancer cells as not belonging in the patient's body and destroy them (called graft-versus-tumor effect). Giving an infusion of the donor's white blood cells (donor lymphocyte infusion) may boost this effect.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Endpoint classification safety/efficacy study
Intervention model single group assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
CONDITIONING REGIMEN: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo low-dose TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine PO BID or IV BID or TID on days -3 to 56 with taper to day 77 or 180, and mycophenolate mofetil PO or IV BID on days 0-27. DLI: At least 2 weeks after completion of immunosuppression, patients with > 5% donor CD3+ T cells and no evidence of GVHD receive donor lymphocytes IV over 30 minutes. Patients may receive up to 3 DLIs at increasing cell doses in the absence of GVHD.
fludarabine phosphate 2-F-ara-AMP
Given IV
total-body irradiation TBI
Undergo TBI
nonmyeloablative allogeneic hematopoietic stem cell transplantation Non-myeloablative allogeneic transplant
Undergo allogeneic PBSCT
peripheral blood stem cell transplantation PBPC transplantation
Undergo allogeneic PBSCT
cyclosporine 27-400
Given PO or IV
mycophenolate mofetil Cellcept
Given PO or IV
therapeutic allogeneic lymphocytes Allogeneic Lymphocytes
Given IV
laboratory biomarker analysis
Correlative studies

Primary Outcomes

Measure
Safety of establishing mixed chimerism using this non-lethal conditioning regimen, in terms of development of GVHD, myelosuppression, infections, and treatment-related mortality
time frame: Within the first 65 days
Proportion of patients who successfully establish mixed chimerism (evidence of donor engraftment) and the proportion who convert to full donor chimeras among those who were mixed
time frame: Day 28
Proportion of patients who successfully establish mixed chimerism (evidence of donor engraftment) and the proportion who convert to full donor chimeras among those who were mixed
time frame: Day 56

Secondary Outcomes

Measure
Proportion of patients experiencing a complete antileukemic response
time frame: At 12 weeks after the final DLI
Proportion of patients experiencing GVHD
time frame: Until day 90 after the last DLI
Proportion of patients experiencing non-relapse mortality
time frame: Within 65 days of transplant
Incidence of myelosuppression after initial PBSC infusion
time frame: Until 2 months post-transplant
Incidence of aplasia after DLI
time frame: Until 2 months post-transplant
Incidence of grades 2-4 acute GVHD after DLI
time frame: Until day 90 after the last DLI
Incidence of grades 2-4 acute GVHD after PBSC infusion
time frame: Until day 90 after the last DLI
Incidence of grade chronic extensive GVHD after DLI
time frame: At 1 year
Dose of CD3+ cells required to convert mixed to full lymphoid chimeras
time frame: Day 56

Eligibility Criteria

Male or female participants up to 74 years old.

Inclusion Criteria: - Patients with Philadelphia chromosome positive (Ph+) CML in first and second chronic and first accelerated phases - Patients =< 65 years old who are at high risk of regimen related toxicity through pre-existing chronic disease affecting liver, lungs, and/or heart, or others who wish to be treated on this protocol, will be considered on a case-by-case basis; transplants should be approved for these inclusion criteria by both the participating institutions' patient review committees such as the Patient Care Conference (PCC) at the Fred Hutchinson Cancer Research Center (FHCRC) and by the principal investigators at the collaborating centers; patients =< 65 years of age who have received previous high-dose transplantation do not require patient review committee approvals; all children < 12 years must be discussed with the FHCRC principal investigator (PI) (Brenda Sandmaier, MD 206-667-4961) prior to registration - HLA genotypically identical related donor willing to undergo leukapheresis initially for collection of peripheral blood stem cell (PBSC) and subsequently for collection of peripheral blood mononuclear cell (PBMC) - Patients treated with alpha interferon must have discontinued drug at least 1 month prior to transplant - DONOR: HLA genotypically identical family member (excluding identical twins) - DONOR: Donor must consent to filgrastim (G-CSF) administration and leukapheresis - DONOR: Donor must have adequate veins for leukapheresis or agree to placement of central venous catheter (femoral, subclavian) Exclusion Criteria: - Patients who are human immunodeficiency virus positive (HIV+) - GROUP 1: (PATIENTS AGED > 65 AND < 75 YEARS) - Patients unwilling to use contraceptive techniques during and for 12 months following treatment - Presence of circulating leukemic blasts (in the peripheral blood) detected by standard pathology for patients with CML - Patients in an interferon induced complete or partial cytogenetic remission - Organ dysfunction: - Patients with renal failure are eligible, however patients with renal compromise (Serum creatinine greater than 2.0) will likely have further compromise in renal function and may require hemodialysis (which may be permanent) due to the need to maintain adequate serum cyclosporine levels - Cardiac ejection fraction < 40%; ejection fraction is required if the patient has a history of anthracyclines or history of cardiac disease - Diffusing capacity of the lung for carbon monoxide (DLCO) < 50% of predicted - Liver function tests including total bilirubin, serum glutamic pyruvate transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT) > 2x the upper limit of normal unless proven to be due to the malignancy - Karnofsky score < 70 - Patients with poorly controlled hypertension - GROUP 2 (PATIENTS AGED =< 65) - Patients who are HIV+ - Presence of circulating leukemic blasts (in the peripheral blood) detected by standard pathology for patients with CML - Females who are pregnant - Patients unwilling to use contraceptive techniques during and for 12 months following treatment - Patients in an interferon induced complete or partial cytogenetic remission - Organ dysfunction: - Patients with renal failure are eligible, however patients with renal compromise (Serum creatinine greater than 2.0) will likely have further compromise in renal function and may require hemodialysis (which may be permanent) due to the need to maintain adequate serum cyclosporine levels - Cardiac ejection fraction < 40% or a history of congestive heart failure; ejection fraction is required if the patient has a history of anthracyclines or history of cardiac disease - Severe defects in pulmonary function testing as defined by the pulmonary consultant (defects are currently categorized as mild, moderate and severe) or receiving supplementary continuous oxygen; DLCO < 50% of predicted - Liver function tests: total bilirubin > 2x the upper limit of normal, SGPT and SGOT 4x the upper limit of normal - Karnofsky score < 50 - Patients with poorly controlled hypertension - DONOR: Age less than 12 years - DONOR: Pregnancy - DONOR: Infection with HIV - DONOR: Inability to achieve adequate venous access - DONOR: Known allergy to G-CSF - DONOR: Current serious systemic illness

Additional Information

Official title Induction of Mixed Hematopoietic Chimerism Using Fludarabine, Low Dose TBI , PBSC Infusion and Post-Transplant Immunosuppression With Cyclosporine and Mycophenolate Mofetil to be Followed by Donor Lymphocyte Infusion In Patients With Chronic Myeloid Leukemia in Chronic and Accelerated Phases: A Multi-center Study
Principal investigator Brenda Sandmaier
Description PRIMARY OBJECTIVES: I. To determine if mixed hematopoietic chimerism can be safely established using a non-myeloablative conditioning regimen in patients > 65 years of age with chronic myeloid leukemia (CML) in chronic or accelerated phase who have human leukocyte antigen (HLA) identical related donors. II. To determine if mixed chimerism, established with non-myeloablative conditioning regimens, can be converted to full donor hematopoietic chimerism by infusions of donor lymphocytes (DLI), and thereby produce an immunologic cure of the malignancy. OUTLINE: CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2 and undergo low-dose total-body irradiation (TBI) on day 0. TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation (PBSCT) on day 0. IMMUNOSUPPRESSION: Patients receive cyclosporine orally (PO) twice daily (BID) or IV BID or thrice daily (TID) on days -3 to 56 with taper to day 77 or 180, and mycophenolate mofetil PO or IV BID on days 0-27. DLI: At least 2 weeks after completion of immunosuppression, patients with > 5% donor cluster of differentiation (CD)3+ T cells and no evidence of graft-versus-host disease (GVHD) receive donor lymphocytes IV over 30 minutes. Patients may receive up to 3 DLIs at increasing cell doses in the absence of GVHD. After completion of study treatment, patients are followed up periodically for 5 years.
Trial information was received from ClinicalTrials.gov and was last updated in January 2016.
Information provided to ClinicalTrials.gov by Fred Hutchinson Cancer Research Center.