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

NCT00003145 | Completed Phase 2 DMC

• 3 other identifiers: 1209.00NCI-2012-00579P30CA015704
• Study Type: interventional
• Target: 18
• Locations: 3 countries
• Sites: 8

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.

Conditions

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

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (9)

• Proportion of patients experiencing a complete antileukemic response

  At 12 weeks after the final DLI

• Proportion of patients experiencing GVHD

  Until day 90 after the last DLI

• Proportion of patients experiencing non-relapse mortality

  Within 65 days of transplant

• Incidence of myelosuppression after initial PBSC infusion

  Until 2 months post-transplant

• Incidence of aplasia after DLI

  Until 2 months post-transplant

Study Arms (1)

Treatment (chemotherapy, TBI, PBSCT, DLI)

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.

Drug: Fludarabine Phosphate; Radiation: Total-Body Irradiation; Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation; Procedure: Peripheral Blood Stem Cell Transplantation; Drug: Cyclosporine; Drug: Mycophenolate Mofetil; Biological: Therapeutic Allogeneic Lymphocytes; Other: Laboratory Biomarker Analysis

Interventions

Fludarabine Phosphate DRUG

Given IV

Also known as: 2-F-ara-AMP, Beneflur, SH T 586

Treatment (chemotherapy, TBI, PBSCT, DLI)

Total-Body Irradiation RADIATION

Undergo TBI

Also known as: TBI, Total Body Irradiation, Whole-Body Irradiation

Treatment (chemotherapy, TBI, PBSCT, DLI)

Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation PROCEDURE

Undergo allogeneic PBSCT

Also known as: Non-myeloablative allogeneic transplant, Nonmyeloablative Stem Cell Transplantation, NST

Treatment (chemotherapy, TBI, PBSCT, DLI)

Peripheral Blood Stem Cell Transplantation PROCEDURE

Undergo allogeneic PBSCT

Also known as: PBPC transplantation, Peripheral Blood Progenitor Cell Transplantation, Peripheral Stem Cell Support, Peripheral Stem Cell Transplantation

Treatment (chemotherapy, TBI, PBSCT, DLI)

Cyclosporine DRUG

Given PO or IV

Also known as: 27-400, CsA, Neoral, OL 27-400, Sandimmun

Treatment (chemotherapy, TBI, PBSCT, DLI)

Mycophenolate Mofetil DRUG

Given PO or IV

Also known as: Cellcept, MMF

Treatment (chemotherapy, TBI, PBSCT, DLI)

Therapeutic Allogeneic Lymphocytes BIOLOGICAL

Given IV

Also known as: Allogeneic Lymphocytes, ALLOLYMPH, Tumor-Derived Lymphocyte

Treatment (chemotherapy, TBI, PBSCT, DLI)

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (chemotherapy, TBI, PBSCT, DLI)

Eligibility Criteria

• Age: Up to 74 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Fred Hutchinson Cancer Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (8)

City of Hope Medical Center

Duarte, California, 91010, United States

Location

Stanford University Hospitals and Clinics

Stanford, California, 94305, United States

Location

University of Colorado

Denver, Colorado, 80217-3364, United States

Location

Baylor University Medical Center

Dallas, Texas, 75246, United States

Location

VA Puget Sound Health Care System

Seattle, Washington, 98101, United States

Location

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Seattle, Washington, 98109, United States

Location

Universitaet Leipzig

Leipzig, D-04103, Germany

Location

University of Torino

Torino, 10126, Italy

Location

Related Publications (1)

• 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.

  PMID: 32499241 DERIVED

MeSH Terms

Conditions

Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Recurrence

Interventions

fludarabine phosphate; Whole-Body Irradiation; Peripheral Blood Stem Cell Transplantation; Cyclosporine; Cyclosporins; Mycophenolic Acid

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Radiotherapy; Therapeutics; Investigative Techniques; Hematopoietic Stem Cell Transplantation; Stem Cell Transplantation; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Transplantation; Surgical Procedures, Operative; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins; Caproates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids; Lipids

Study Officials

• Brenda Sandmaier

  Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 1, 1999
• First Posted: January 27, 2003
• Study Start: August 1, 1997
• Primary Completion: March 1, 2005
• Last Updated: January 10, 2020

Record last verified: 2020-01

Locations

IT (1); US (6); DE (1)