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

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

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.

Study Overview

• Status: Completed
• Conditions: Recurrent Disease; Childhood Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Accelerated Phase of Disease; Chronic Phase of Disease
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Radiation: Total-Body Irradiation; Drug: Fludarabine Phosphate; Drug: Mycophenolate Mofetil; Procedure: Peripheral Blood Stem Cell Transplantation; Drug: Cyclosporine; Biological: Therapeutic Allogeneic Lymphocytes; Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation

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.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Leipzig, Germany, D-04103
    • Universitaet Leipzig
• Italy
  • Torino, Italy, 10126
    • University of Torino
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope Medical Center
    • Stanford, California, United States, 94305
      • Stanford University Hospitals and Clinics
  • Colorado
    • Denver, Colorado, United States, 80217-3364
      • University of Colorado
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
    • Seattle, Washington, United States, 98101
      • VA Puget Sound Health Care System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 74 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 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.

Other: Laboratory Biomarker Analysis; Correlative studies; Radiation: Total-Body Irradiation; Undergo TBI; Other Names: Total Body Irradiation; TBI; Whole-Body Irradiation; Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP; Beneflur; SH T 586; Drug: Mycophenolate Mofetil; Given PO or IV; Other Names: Cellcept; MMF; Procedure: Peripheral Blood Stem Cell Transplantation; Undergo allogeneic PBSCT; Other Names: PBPC transplantation; Peripheral Blood Progenitor Cell Transplantation; Peripheral Stem Cell Support; Peripheral Stem Cell Transplantation; Drug: Cyclosporine; Given PO or IV; Other Names: 27-400; CsA; Neoral; Sandimmun; OL 27-400; Biological: Therapeutic Allogeneic Lymphocytes; Given IV; Other Names: Allogeneic Lymphocytes; Tumor-Derived Lymphocyte; ALLOLYMPH; Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation; Undergo allogeneic PBSCT; Other Names: NST; Non-myeloablative allogeneic transplant; Nonmyeloablative Stem Cell Transplantation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of establishing mixed chimerism using this non-lethal conditioning regimen, in terms of development of GVHD, myelosuppression, infections, and treatment-related mortality	All unexpected toxicities will be summarized and reported.	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	Estimated and corresponding confidence intervals presented. Mixed chimerism is detection of donor T cells (CD3+) and granulocytes (CD33+), as proportion of total T cell and granulocyte population of > 5% and < 95% in peripheral blood. Full donor chimerism is > 95% donor CD3+ T cells. Increasing donor chimerism is absolute increase of 20% of CD3+ T cells over chimerism evaluation of previous month. Decreasing donor chimerism is absolute decrease of 20% of CD3+ T cell chimerism over previous month. Low donor chimerism is < 40% CD3+ T cells after HSCT.	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	Estimated and corresponding confidence intervals presented. Mixed chimerism is detection of donor T cells (CD3+) and granulocytes (CD33+), as proportion of total T cell and granulocyte population of > 5% and < 95% in peripheral blood. Full donor chimerism is > 95% donor CD3+ T cells. Increasing donor chimerism is absolute increase of 20% of CD3+ T cells over chimerism evaluation of previous month. Decreasing donor chimerism is absolute decrease of 20% of CD3+ T cell chimerism over previous month. Low donor chimerism is < 40% CD3+ T cells after HSCT.	Day 56

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients experiencing a complete antileukemic response	Reported in a descriptive manner and confidence intervals will be presented for all estimates.	At 12 weeks after the final DLI
Proportion of patients experiencing GVHD	Reported in a descriptive manner and confidence intervals will be presented for all estimates.	Until day 90 after the last DLI
Proportion of patients experiencing non-relapse mortality	Reported in a descriptive manner and confidence intervals will be presented for all estimates.	Within 65 days of transplant
Incidence of myelosuppression after initial PBSC infusion	Defined as absolute neutrophil count [ANC] < 500 for > 2 days, platelets < 20,000 for > 2 days.	Until 2 months post-transplant
Incidence of aplasia after DLI		Until 2 months post-transplant
Incidence of grades 2-4 acute GVHD after DLI		Until day 90 after the last DLI
Incidence of grades 2-4 acute GVHD after PBSC infusion		Until day 90 after the last DLI
Incidence of grade chronic extensive GVHD after DLI		At 1 year
Dose of CD3+ cells required to convert mixed to full lymphoid chimeras		Day 56

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: National Cancer Institute (NCI)

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: August 1, 1997
• Primary Completion (Actual): March 1, 2005

Study Registration Dates

• First Submitted: November 1, 1999
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Actual): January 10, 2020
• Last Update Submitted That Met QC Criteria: January 7, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Fludarabine; Fludarabine phosphate; Mycophenolic Acid; Cyclosporine; Cyclosporins
• Other Study ID Numbers: 1209.00 (Other Identifier: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium); P30CA015704 (U.S. NIH Grant/Contract); NCI-2012-00579 (Registry Identifier: CTRP (Clinical Trial Reporting Program))