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Fludarabine Phosphate and Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Acute Lymphoblastic Leukemia or Chronic Myelogenous Leukemia That Has Responded to Treatment With Imatinib Mesylate, Dasatinib, or Nilotinib

Primary Purpose

Adult Acute Lymphoblastic Leukemia in Remission, Adult B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1, Blastic Phase

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Cyclosporine
Dasatinib
Fludarabine Phosphate
Imatinib Mesylate
Mycophenolate Mofetil
Nilotinib
Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation
Peripheral Blood Stem Cell Transplantation
Therapeutic Allogeneic Lymphocytes
Total-Body Irradiation
Sponsored by
Fred Hutchinson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Adult Acute Lymphoblastic Leukemia in Remission

Eligibility Criteria

undefined - 70 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Patients =< 12 years of age must be approved by Fred Hutchinson Cancer Research Center (FHCRC) principal investigator (PI) in advance Patients with a history of Ph+ ALL or CML-BC who, after receiving imatinib mesylate, (or either dasatinib or nilotinib) have < 15% blasts on morphologic marrow evaluation; patients with no detectable Ph+ ALL by morphologic or molecular assays (complete remission) will be accepted An appropriately human leukocyte antigen (HLA) matched related or unrelated donor must be prospectively identified who will be available to donate filgrastim (G-CSF) mobilized stem cells RELATED DONOR: Related donor who is HLA genotypically identical at least at one haplotype and may be genotypically or phenotypically identical at the allele level at HLA-A, -B, -C, -DRB1, and -DQB1; Donor must consent to G-CSR administration and leukapheresis; Donor must have adequate veins for leukapheresis or agree to placement of central venous catheter (femoral, subclavian) HLA-MATCHED UNRELATED DONOR: FHCRC matching allowed will be grades 1.0 to 2.1; unrelated donors who are prospectively matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing; only a single allele disparity will be allowed for HLA-A, B, or C as defined by high resolution typing A positive anti-donor cytotoxic crossmatch is an absolute donor exclusion; donors are excluded when preexisting immunoreactivity is identified that would jeopardize donor hematopoietic cell engraftment; this determination is based on the standard practice of the individual institution; the recommended procedure for patients with 10 of 10 HLA allele level (phenotypic) match is to obtain a panel reactive antibody (PRA) screens to class I and class II antigens for all patients before HCT; if the PRA shows >10% activity, then flow cytometric or B and T cell cytotoxic cross matches should be obtained; the donor should be excluded if any of the cytotoxic cross match assays are positive; for those patients with an HLA class I allele mismatch, flow cytometric or B and T cell cytotoxic cross matches should be obtained regardless of the PRA results Patient and donor pairs homozygous at a mismatched allele in the graft rejection vector are considered a two-allele mismatch, i.e., the patient is A*0101 and the donor is A*0102, and this type of mismatch is not allowed Only G-CSF mobilized PBSC only will be permitted as a HSC source on this protocol Exclusion Criteria: Central nervous system (CNS) involvement with leukemia refractory to intrathecal chemotherapy; prior to HSCT (all patients must receive a diagnostic lumbar puncture (LP) with intrathecal (IT) chemotherapy as per standard practice) Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment Patients with active non-hematologic malignancies (except non-melanoma skin cancers); this exclusion does not apply to patients with non-hematologic malignancies that do not require therapy Patients with a history of non-hematologic malignancies (except non-melanoma skin cancers) currently in a complete remission, who are less than 5 years from the time of complete remission, and have a > 20% risk of disease recurrence; this exclusion does not apply to patients with non-hematologic malignancies that do not require therapy Females who are pregnant or breastfeeding Patients who are human immunodeficiency virus (HIV)-positive Patients with poorly controlled hypertension despite multiple antihypertensives Adults: Karnofsky score < 60 Pediatrics: Lansky play-performance score < 40 Patients with cardiac ejection fraction < 35% (or, if unable to obtain ejection fraction, shortening fraction of < 26%); ejection fraction is required if age > 50 years or there is a history of anthracycline exposure or history of cardiac disease; patients with a shortening fraction < 26% may be enrolled if approved by a cardiologist Diffusing capacity of the lungs for carbon monoxide (DLCO) < 30% Total lung capacity (TLC) < 30% Forced expiratory volume in one second (FEV1) < 30% and/or receiving supplementary continuous oxygen; the FHCRC PI of the study must approve enrollment of all patients with pulmonary nodules Patients with clinical or laboratory evidence of liver disease would be evaluated for the cause of liver disease, its clinical severity in terms of liver function, and the degree of portal hypertension; patients will be excluded if they are found to have fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evinced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dL, or symptomatic biliary disease Creatinine levels more than 2.2 X's the upper limit of normal (ULN) at the laboratory where the analysis was performed Patients with active bacterial or fungal infections unresponsive to medical therapy For patients receiving dasatinib or nilotinib, baseline corrected QT interval (QTc) (Fridericia's method) prolongation greater than 500 msec RELATED DONORS: Identical twin Infection with HIV Inability to achieve adequate venous access Known allergy to G-CSF Current serious system illness Bone marrow (BM) donors HLA-MATCHED UNRELATED DONORS: BM donors Donors who are HIV-positive and/or, medical conditions that would result in increased risk for G-CSF mobilization and harvest of PBSC

Sites / Locations

  • Presbyterian - Saint Lukes Medical Center - Health One
  • VA Puget Sound Health Care System
  • Fred Hutch/University of Washington Cancer Consortium

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (allogeneic nonmyeloablative HSCT)

Arm Description

See Detailed Description

Outcomes

Primary Outcome Measures

Relapse Free Survival
Number of patients with relapsed disease within 1 Year post-transplant. Relapse is defined as the detection of > 5% blasts after a documented complete remission.

Secondary Outcome Measures

Leukemia-free Survival
Number of patients surviving in CR up to five years post-transplant.
Overall Survival
Number of patients surviving up to five years post-transplant.
Transplant-related Mortality
Number of patients with TRM within 100 days post-transplant.
Transplant-related Mortality
Number of patients with TRM within one year post-transplant.

Full Information

First Posted
May 13, 2002
Last Updated
January 17, 2020
Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00036738
Brief Title
Fludarabine Phosphate and Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Acute Lymphoblastic Leukemia or Chronic Myelogenous Leukemia That Has Responded to Treatment With Imatinib Mesylate, Dasatinib, or Nilotinib
Official Title
Allogeneic Nonmyeloablative Hematopoietic Stem Cell Transplant for Patients With BCR-ABL Tyrosine Kinase Inhibitor Responsive Ph+ Acute Leukemia ? A Multi-center Trial
Study Type
Interventional

2. Study Status

Record Verification Date
December 2019
Overall Recruitment Status
Completed
Study Start Date
July 13, 2001 (Actual)
Primary Completion Date
July 2014 (Actual)
Study Completion Date
May 2018 (Actual)

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 phase II trial is studying how well fludarabine phosphate and total-body irradiation followed by donor peripheral blood stem cell transplant work in treating patients with acute lymphoblastic leukemia or chronic myelogenous leukemia that has responded to previous treatment with imatinib mesylate, dasatinib, or nilotinib. Giving low doses of chemotherapy, such as fludarabine phosphate, and total-body irradiation (TBI) before a donor peripheral blood stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune system and help destroy any remaining cancer cells (graft-versus-tumor effect). Giving an infusion of the donor's T cells (donor lymphocyte infusion) after the transplant may help increase this effect. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving mycophenolate mofetil and cyclosporine after the transplant may stop this from happening.
Detailed Description
PRIMARY OBJECTIVES: I. To determine whether the rate of leukemia relapse can be decreased for patients with chronic myelogenous leukemia in blast crisis (CML-BC) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) responsive to imatinib mesylate (or either dasatinib or nilotinib for patients who have imatinib-resistant disease or who are intolerant of imatinib) followed by nonmyeloablative hematopoietic stem cell transplantation (HSCT) compared to historical controls given high-dose conventional allogeneic HSCT or chemotherapy. II. To determine whether the rate of transplantation-related mortality (TRM) can be decreased for patients with CML-BC and Ph+ ALL responsive to imatinib mesylate (or dasatinib or nilotinib) followed by nonmyeloablative HSCT compared to historical controls given high-dose conventional allogeneic HSCT or chemotherapy. SECONDARY OBJECTIVES: I. To evaluate whether donor lymphocyte infusion (DLI) can be safely used in patients with mixed or full donor chimerism as preemptive therapy to eliminate minimal residual disease. OUTLINE: INDUCTION THERAPY: Patients continue to receive imatinib mesylate orally (PO), dasatinib PO, or nilotinib PO once or twice daily until day -2 and resume on day 14 or when blood counts recover after peripheral blood stem cell (PBSC) transplantation. NONMYELOABLATIVE CONDITIONING: Patients receive fludarabine intravenously (IV) on days -4 to -2; and undergo TBI on day 0. TRANSPLANTATION: Patients undergo allogeneic PBSC transplantation on day 0. GRAFT-VERSUS-HOST-DISEASE (GVHD) PROPHYLAXIS: Patients receive mycophenolate mofetil (MMF) PO every 12 hours on days 0-27 (related donor recipients) or every 8 hours on days 0-96 with taper on day 40 (unrelated donor recipients). Patients also receive cyclosporine IV or PO every 12 hours on days -3 to 56, followed by taper on days 57-180 (related donor recipients) or on days -3 to 100, followed by taper on days 101-177 (unrelated donor recipients). DONOR LYMPHOCYTE INFUSION: Patients with persistent disease and no GVHD after stopping GVHD prophylaxis receive donor lymphocyte infusion IV over 30 minutes once every 28 days for 3 doses. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients are followed up periodically for 2 years and then annually thereafter for 5 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Adult Acute Lymphoblastic Leukemia in Remission, Adult B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1, Blastic Phase, Childhood Acute Lymphoblastic Leukemia in Remission, Childhood B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1, Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Chronic Phase of Disease, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Childhood Acute Lymphoblastic Leukemia, 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
28 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (allogeneic nonmyeloablative HSCT)
Arm Type
Experimental
Arm Description
See Detailed Description
Intervention Type
Drug
Intervention Name(s)
Cyclosporine
Other Intervention Name(s)
27-400, Ciclosporin, CsA, Cyclosporin, Cyclosporin A, Gengraf, Neoral, OL 27-400, Sandimmun, Sandimmune, SangCya
Intervention Description
Given IV or PO
Intervention Type
Drug
Intervention Name(s)
Dasatinib
Other Intervention Name(s)
BMS-354825, Sprycel
Intervention Description
Given PO
Intervention Type
Drug
Intervention Name(s)
Fludarabine Phosphate
Other Intervention Name(s)
2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Imatinib Mesylate
Other Intervention Name(s)
CGP 57148, CGP57148B, Gleevec, Glivec, STI 571, STI-571, STI571
Intervention Description
Given PO
Intervention Type
Drug
Intervention Name(s)
Mycophenolate Mofetil
Other Intervention Name(s)
Cellcept, MMF
Intervention Description
Given PO
Intervention Type
Drug
Intervention Name(s)
Nilotinib
Other Intervention Name(s)
AMN 107, Tasigna
Intervention Description
Given PO
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 nonmyeloablative allogeneic PBSC transplantation
Intervention Type
Procedure
Intervention Name(s)
Peripheral Blood Stem Cell Transplantation
Other Intervention Name(s)
PBPC transplantation, PBSCT, Peripheral Blood Progenitor Cell Transplantation, Peripheral Stem Cell Support, Peripheral Stem Cell Transplant, Peripheral Stem Cell Transplantation
Intervention Description
Undergo allogeneic PBSC transplantation
Intervention Type
Biological
Intervention Name(s)
Therapeutic Allogeneic Lymphocytes
Other Intervention Name(s)
Allogeneic Lymphocytes
Intervention Description
Given IV
Intervention Type
Radiation
Intervention Name(s)
Total-Body Irradiation
Other Intervention Name(s)
Total Body Irradiation, Whole-Body Irradiation
Intervention Description
Undergo TBI
Primary Outcome Measure Information:
Title
Relapse Free Survival
Description
Number of patients with relapsed disease within 1 Year post-transplant. Relapse is defined as the detection of > 5% blasts after a documented complete remission.
Time Frame
Assessed up to 1 year
Secondary Outcome Measure Information:
Title
Leukemia-free Survival
Description
Number of patients surviving in CR up to five years post-transplant.
Time Frame
Assessed up to 5 years
Title
Overall Survival
Description
Number of patients surviving up to five years post-transplant.
Time Frame
Assessed up to 5 years
Title
Transplant-related Mortality
Description
Number of patients with TRM within 100 days post-transplant.
Time Frame
At day 100
Title
Transplant-related Mortality
Description
Number of patients with TRM within one year post-transplant.
Time Frame
At 1 year

10. Eligibility

Sex
All
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients =< 12 years of age must be approved by Fred Hutchinson Cancer Research Center (FHCRC) principal investigator (PI) in advance Patients with a history of Ph+ ALL or CML-BC who, after receiving imatinib mesylate, (or either dasatinib or nilotinib) have < 15% blasts on morphologic marrow evaluation; patients with no detectable Ph+ ALL by morphologic or molecular assays (complete remission) will be accepted An appropriately human leukocyte antigen (HLA) matched related or unrelated donor must be prospectively identified who will be available to donate filgrastim (G-CSF) mobilized stem cells RELATED DONOR: Related donor who is HLA genotypically identical at least at one haplotype and may be genotypically or phenotypically identical at the allele level at HLA-A, -B, -C, -DRB1, and -DQB1; Donor must consent to G-CSR administration and leukapheresis; Donor must have adequate veins for leukapheresis or agree to placement of central venous catheter (femoral, subclavian) HLA-MATCHED UNRELATED DONOR: FHCRC matching allowed will be grades 1.0 to 2.1; unrelated donors who are prospectively matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing; only a single allele disparity will be allowed for HLA-A, B, or C as defined by high resolution typing A positive anti-donor cytotoxic crossmatch is an absolute donor exclusion; donors are excluded when preexisting immunoreactivity is identified that would jeopardize donor hematopoietic cell engraftment; this determination is based on the standard practice of the individual institution; the recommended procedure for patients with 10 of 10 HLA allele level (phenotypic) match is to obtain a panel reactive antibody (PRA) screens to class I and class II antigens for all patients before HCT; if the PRA shows >10% activity, then flow cytometric or B and T cell cytotoxic cross matches should be obtained; the donor should be excluded if any of the cytotoxic cross match assays are positive; for those patients with an HLA class I allele mismatch, flow cytometric or B and T cell cytotoxic cross matches should be obtained regardless of the PRA results Patient and donor pairs homozygous at a mismatched allele in the graft rejection vector are considered a two-allele mismatch, i.e., the patient is A*0101 and the donor is A*0102, and this type of mismatch is not allowed Only G-CSF mobilized PBSC only will be permitted as a HSC source on this protocol Exclusion Criteria: Central nervous system (CNS) involvement with leukemia refractory to intrathecal chemotherapy; prior to HSCT (all patients must receive a diagnostic lumbar puncture (LP) with intrathecal (IT) chemotherapy as per standard practice) Fertile men or women unwilling to use contraceptive techniques during and for 12 months following treatment Patients with active non-hematologic malignancies (except non-melanoma skin cancers); this exclusion does not apply to patients with non-hematologic malignancies that do not require therapy Patients with a history of non-hematologic malignancies (except non-melanoma skin cancers) currently in a complete remission, who are less than 5 years from the time of complete remission, and have a > 20% risk of disease recurrence; this exclusion does not apply to patients with non-hematologic malignancies that do not require therapy Females who are pregnant or breastfeeding Patients who are human immunodeficiency virus (HIV)-positive Patients with poorly controlled hypertension despite multiple antihypertensives Adults: Karnofsky score < 60 Pediatrics: Lansky play-performance score < 40 Patients with cardiac ejection fraction < 35% (or, if unable to obtain ejection fraction, shortening fraction of < 26%); ejection fraction is required if age > 50 years or there is a history of anthracycline exposure or history of cardiac disease; patients with a shortening fraction < 26% may be enrolled if approved by a cardiologist Diffusing capacity of the lungs for carbon monoxide (DLCO) < 30% Total lung capacity (TLC) < 30% Forced expiratory volume in one second (FEV1) < 30% and/or receiving supplementary continuous oxygen; the FHCRC PI of the study must approve enrollment of all patients with pulmonary nodules Patients with clinical or laboratory evidence of liver disease would be evaluated for the cause of liver disease, its clinical severity in terms of liver function, and the degree of portal hypertension; patients will be excluded if they are found to have fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evinced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dL, or symptomatic biliary disease Creatinine levels more than 2.2 X's the upper limit of normal (ULN) at the laboratory where the analysis was performed Patients with active bacterial or fungal infections unresponsive to medical therapy For patients receiving dasatinib or nilotinib, baseline corrected QT interval (QTc) (Fridericia's method) prolongation greater than 500 msec RELATED DONORS: Identical twin Infection with HIV Inability to achieve adequate venous access Known allergy to G-CSF Current serious system illness Bone marrow (BM) donors HLA-MATCHED UNRELATED DONORS: BM donors Donors who are HIV-positive and/or, medical conditions that would result in increased risk for G-CSF mobilization and harvest of PBSC
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
George Georges
Organizational Affiliation
Fred Hutch/University of Washington Cancer Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
Presbyterian - Saint Lukes Medical Center - Health One
City
Denver
State/Province
Colorado
ZIP/Postal Code
80218
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 Hutch/University of Washington Cancer Consortium
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States

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
PubMed Identifier
21508120
Citation
Ram R, Storb R, Sandmaier BM, Maloney DG, Woolfrey A, Flowers ME, Maris MB, Laport GG, Chauncey TR, Lange T, Langston AA, Storer B, Georges GE. Non-myeloablative conditioning with allogeneic hematopoietic cell transplantation for the treatment of high-risk acute lymphoblastic leukemia. Haematologica. 2011 Aug;96(8):1113-20. doi: 10.3324/haematol.2011.040261. Epub 2011 Apr 20.
Results Reference
derived

Learn more about this trial

Fludarabine Phosphate and Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Acute Lymphoblastic Leukemia or Chronic Myelogenous Leukemia That Has Responded to Treatment With Imatinib Mesylate, Dasatinib, or Nilotinib

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