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

NCT ID: NCT00003145

Last Updated: 2020-01-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 18 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 1997-08-31

Brief 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.

Detailed 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.

Conditions

Accelerated Phase of Disease; Childhood Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Chronic Phase of Disease; Recurrent Disease

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment (chemotherapy, TBI, PBSCT, DLI)

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.

Group Type: EXPERIMENTAL

Fludarabine Phosphate

Intervention Type: DRUG

Given IV

Total-Body Irradiation

Intervention Type: RADIATION

Undergo TBI

Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation

Intervention Type: PROCEDURE

Undergo allogeneic PBSCT

Peripheral Blood Stem Cell Transplantation

Intervention Type: PROCEDURE

Undergo allogeneic PBSCT

Cyclosporine

Intervention Type: DRUG

Given PO or IV

Mycophenolate Mofetil

Intervention Type: DRUG

Given PO or IV

Therapeutic Allogeneic Lymphocytes

Intervention Type: BIOLOGICAL

Given IV

Laboratory Biomarker Analysis

Intervention Type: OTHER

Correlative studies

Interventions

Fludarabine Phosphate

Given IV

Intervention Type: DRUG

Total-Body Irradiation

Undergo TBI

Intervention Type: RADIATION

Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation

Undergo allogeneic PBSCT

Intervention Type: PROCEDURE

Peripheral Blood Stem Cell Transplantation

Undergo allogeneic PBSCT

Intervention Type: PROCEDURE

Cyclosporine

Given PO or IV

Intervention Type: DRUG

Mycophenolate Mofetil

Given PO or IV

Intervention Type: DRUG

Therapeutic Allogeneic Lymphocytes

Given IV

Intervention Type: BIOLOGICAL

Laboratory Biomarker Analysis

Correlative studies

Intervention Type: OTHER

Other Intervention Names

2-F-ara-AMP; Beneflur; SH T 586; TBI; Total Body Irradiation; Whole-Body Irradiation; Non-myeloablative allogeneic transplant; Nonmyeloablative Stem Cell Transplantation; NST; PBPC transplantation; Peripheral Blood Progenitor Cell Transplantation; Peripheral Stem Cell Support; Peripheral Stem Cell Transplantation; 27-400; CsA; Neoral; OL 27-400; Sandimmun; Cellcept; MMF; Allogeneic Lymphocytes; ALLOLYMPH; Tumor-Derived Lymphocyte

Eligibility Criteria

Inclusion Criteria

• Patients with Philadelphia chromosome positive (Ph+) CML in first and second chronic and first accelerated phases
• 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

• Maximum Eligible Age: 74 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Fred Hutchinson Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Brenda Sandmaier

Role: PRINCIPAL_INVESTIGATOR

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Locations

City of Hope Medical Center

Duarte, California, United States

Stanford University Hospitals and Clinics

Stanford, California, United States

University of Colorado

Denver, Colorado, United States

Baylor University Medical Center

Dallas, Texas, United States

VA Puget Sound Health Care System

Seattle, Washington, United States

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Seattle, Washington, United States

Universitaet Leipzig

Leipzig, , Germany

University of Torino

Torino, , Italy

Countries

United States; Germany; Italy

References

Cooper JP, Storer BE, Granot N, Gyurkocza B, Sorror ML, Chauncey TR, Shizuru J, Franke GN, Maris MB, Boyer M, Bruno B, Sahebi F, Langston AA, Hari P, Agura ED, Lykke Petersen S, Maziarz RT, Bethge W, Asch J, Gutman JA, Olesen G, Yeager AM, Hubel K, Hogan WJ, Maloney DG, Mielcarek M, Martin PJ, Flowers MED, Georges GE, Woolfrey AE, Deeg JH, Scott BL, McDonald GB, Storb R, Sandmaier BM. Allogeneic hematopoietic cell transplantation with non-myeloablative conditioning for patients with hematologic malignancies: Improved outcomes over two decades. Haematologica. 2021 Jun 1;106(6):1599-1607. doi: 10.3324/haematol.2020.248187.

Reference Type: DERIVED

PMID: 32499241 (View on PubMed)

Other Identifiers

NCI-2012-00579

Identifier Type: REGISTRY

Identifier Source: secondary_id

1209.00

Identifier Type: OTHER

Identifier Source: secondary_id

P30CA015704

Identifier Type: NIH

Identifier Source: secondary_id

View Link

1209.00

Identifier Type: -

Identifier Source: org_study_id