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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

Primary Purpose

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

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
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
Sponsored by
Fred Hutchinson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Accelerated Phase of Disease

Eligibility Criteria

undefined - 74 Years (Child, Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

  • City of Hope Medical Center
  • Stanford University Hospitals and Clinics
  • University of Colorado
  • Baylor University Medical Center
  • VA Puget Sound Health Care System
  • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  • Universitaet Leipzig
  • University of Torino

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (chemotherapy, TBI, PBSCT, DLI)

Arm 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.

Outcomes

Primary Outcome Measures

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.
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.
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.

Secondary Outcome Measures

Proportion of patients experiencing a complete antileukemic response
Reported in a descriptive manner and confidence intervals will be presented for all estimates.
Proportion of patients experiencing GVHD
Reported in a descriptive manner and confidence intervals will be presented for all estimates.
Proportion of patients experiencing non-relapse mortality
Reported in a descriptive manner and confidence intervals will be presented for all estimates.
Incidence of myelosuppression after initial PBSC infusion
Defined as absolute neutrophil count [ANC] < 500 for > 2 days, platelets < 20,000 for > 2 days.
Incidence of aplasia after DLI
Incidence of grades 2-4 acute GVHD after DLI
Incidence of grades 2-4 acute GVHD after PBSC infusion
Incidence of grade chronic extensive GVHD after DLI
Dose of CD3+ cells required to convert mixed to full lymphoid chimeras

Full Information

First Posted
November 1, 1999
Last Updated
January 7, 2020
Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00003145
Brief Title
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
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
Study Type
Interventional

2. Study Status

Record Verification Date
January 2020
Overall Recruitment Status
Completed
Study Start Date
August 1997 (undefined)
Primary Completion Date
March 2005 (Actual)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Accelerated Phase of Disease, Childhood Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Chronic Phase of Disease, Recurrent Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
18 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (chemotherapy, TBI, PBSCT, DLI)
Arm Type
Experimental
Arm 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.
Intervention Type
Drug
Intervention Name(s)
Fludarabine Phosphate
Other Intervention Name(s)
2-F-ara-AMP, Beneflur, SH T 586
Intervention Description
Given IV
Intervention Type
Radiation
Intervention Name(s)
Total-Body Irradiation
Other Intervention Name(s)
TBI, Total Body Irradiation, Whole-Body Irradiation
Intervention Description
Undergo TBI
Intervention Type
Procedure
Intervention Name(s)
Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation
Other Intervention Name(s)
Non-myeloablative allogeneic transplant, Nonmyeloablative Stem Cell Transplantation, NST
Intervention Description
Undergo allogeneic PBSCT
Intervention Type
Procedure
Intervention Name(s)
Peripheral Blood Stem Cell Transplantation
Other Intervention Name(s)
PBPC transplantation, Peripheral Blood Progenitor Cell Transplantation, Peripheral Stem Cell Support, Peripheral Stem Cell Transplantation
Intervention Description
Undergo allogeneic PBSCT
Intervention Type
Drug
Intervention Name(s)
Cyclosporine
Other Intervention Name(s)
27-400, CsA, Neoral, OL 27-400, Sandimmun
Intervention Description
Given PO or IV
Intervention Type
Drug
Intervention Name(s)
Mycophenolate Mofetil
Other Intervention Name(s)
Cellcept, MMF
Intervention Description
Given PO or IV
Intervention Type
Biological
Intervention Name(s)
Therapeutic Allogeneic Lymphocytes
Other Intervention Name(s)
Allogeneic Lymphocytes, ALLOLYMPH, Tumor-Derived Lymphocyte
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Safety of establishing mixed chimerism using this non-lethal conditioning regimen, in terms of development of GVHD, myelosuppression, infections, and treatment-related mortality
Description
All unexpected toxicities will be summarized and reported.
Time Frame
Within the first 65 days
Title
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
Description
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.
Time Frame
Day 28
Title
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
Description
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.
Time Frame
Day 56
Secondary Outcome Measure Information:
Title
Proportion of patients experiencing a complete antileukemic response
Description
Reported in a descriptive manner and confidence intervals will be presented for all estimates.
Time Frame
At 12 weeks after the final DLI
Title
Proportion of patients experiencing GVHD
Description
Reported in a descriptive manner and confidence intervals will be presented for all estimates.
Time Frame
Until day 90 after the last DLI
Title
Proportion of patients experiencing non-relapse mortality
Description
Reported in a descriptive manner and confidence intervals will be presented for all estimates.
Time Frame
Within 65 days of transplant
Title
Incidence of myelosuppression after initial PBSC infusion
Description
Defined as absolute neutrophil count [ANC] < 500 for > 2 days, platelets < 20,000 for > 2 days.
Time Frame
Until 2 months post-transplant
Title
Incidence of aplasia after DLI
Time Frame
Until 2 months post-transplant
Title
Incidence of grades 2-4 acute GVHD after DLI
Time Frame
Until day 90 after the last DLI
Title
Incidence of grades 2-4 acute GVHD after PBSC infusion
Time Frame
Until day 90 after the last DLI
Title
Incidence of grade chronic extensive GVHD after DLI
Time Frame
At 1 year
Title
Dose of CD3+ cells required to convert mixed to full lymphoid chimeras
Time Frame
Day 56

10. Eligibility

Sex
All
Maximum Age & Unit of Time
74 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Brenda Sandmaier
Organizational Affiliation
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
City of Hope Medical Center
City
Duarte
State/Province
California
ZIP/Postal Code
91010
Country
United States
Facility Name
Stanford University Hospitals and Clinics
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Name
University of Colorado
City
Denver
State/Province
Colorado
ZIP/Postal Code
80217-3364
Country
United States
Facility Name
Baylor University Medical Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75246
Country
United States
Facility Name
VA Puget Sound Health Care System
City
Seattle
State/Province
Washington
ZIP/Postal Code
98101
Country
United States
Facility Name
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States
Facility Name
Universitaet Leipzig
City
Leipzig
ZIP/Postal Code
D-04103
Country
Germany
Facility Name
University of Torino
City
Torino
ZIP/Postal Code
10126
Country
Italy

12. IPD Sharing Statement

Citations:
PubMed Identifier
32499241
Citation
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.
Results Reference
derived

Learn more about this trial

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

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