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

Fred Hutchinson Cancer Center (FHCC)

Status and phase

Completed

Phase 2

Conditions

Recurrent Disease

Chronic Myelogenous Leukemia, BCR-ABL1 Positive

Accelerated Phase of Disease

Chronic Phase of Disease

Childhood Chronic Myelogenous Leukemia, BCR-ABL1 Positive

Treatments

Biological: Therapeutic Allogeneic Lymphocytes

Procedure: Peripheral Blood Stem Cell Transplantation

Other: Laboratory Biomarker Analysis

Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation

Radiation: Total-Body Irradiation

Drug: Fludarabine Phosphate

Drug: Cyclosporine

Drug: Mycophenolate Mofetil

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT00003145

1209.00 (Other Identifier)

P30CA015704 (U.S. NIH Grant/Contract)

NCI-2012-00579 (Registry Identifier)

Details and patient eligibility

About

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.

Full 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.

Enrollment

18 patients

Sex

All

Ages

Under 74 years old

Volunteers

No Healthy Volunteers

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

Trial design

Primary purpose

Treatment

Allocation

N/A

Interventional model

Single Group Assignment

Masking

None (Open label)

18 participants in 1 patient group

Treatment (chemotherapy, TBI, PBSCT, DLI)

Experimental group

Description:

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.

Treatment: