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

• Sponsor: Fred Hutchinson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00036738
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 28
• Locations: 3
• Arm: 1
• Actual Duration (Months): 201.6
• Patients Per Site: 9.3
• Patients Per Site Per Month: 0

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
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	Drug: Cyclosporine; Drug: Dasatinib; Drug: Fludarabine Phosphate; Drug: Imatinib Mesylate; Drug: Mycophenolate Mofetil; Drug: Nilotinib; Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation; Procedure: Peripheral Blood Stem Cell Transplantation; Biological: Therapeutic Allogeneic Lymphocytes; Radiation: Total-Body Irradiation	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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.

2. 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:

1. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 28 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Allogeneic Nonmyeloablative Hematopoietic Stem Cell Transplant for Patients With BCR-ABL Tyrosine Kinase Inhibitor Responsive Ph+ Acute Leukemia ? A Multi-center Trial
• Actual Study Start Date: Jul 13, 2001
• Actual Primary Completion Date: Jul 1, 2014
• Actual Study Completion Date: May 1, 2018

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (allogeneic nonmyeloablative HSCT) See Detailed Description

Drug: Cyclosporine; Given IV or PO; Other Names: 27-400 Ciclosporin CsA Cyclosporin Cyclosporin A Gengraf Neoral OL 27-400 Sandimmun Sandimmune SangCya ; Drug: Dasatinib; Given PO; Other Names: BMS-354825 Sprycel ; Drug: Fludarabine Phosphate; Given IV; Other Names: 2-F-ara-AMP 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)- Beneflur Fludara SH T 586 ; Drug: Imatinib Mesylate; Given PO; Other Names: CGP 57148 CGP57148B Gleevec Glivec STI 571 STI-571 STI571 ; Drug: Mycophenolate Mofetil; Given PO; Other Names: Cellcept MMF ; Drug: Nilotinib; Given PO; Other Names: AMN 107 Tasigna ; Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation; Undergo nonmyeloablative allogeneic PBSC transplantation; Other Names: Non-myeloablative allogeneic transplant Nonmyeloablative Stem Cell Transplantation NST ; Procedure: Peripheral Blood Stem Cell Transplantation; Undergo allogeneic PBSC transplantation; Other Names: PBPC transplantation PBSCT Peripheral Blood Progenitor Cell Transplantation Peripheral Stem Cell Support Peripheral Stem Cell Transplant Peripheral Stem Cell Transplantation ; Biological: Therapeutic Allogeneic Lymphocytes; Given IV; Other Names: Allogeneic Lymphocytes ; Radiation: Total-Body Irradiation; Undergo TBI; Other Names: Total Body Irradiation Whole-Body Irradiation

Outcome Measures

Primary Outcome Measures

1. Relapse Free Survival [Assessed up to 1 year]

   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

1. Leukemia-free Survival [Assessed up to 5 years]

   Number of patients surviving in CR up to five years post-transplant.

2. Overall Survival [Assessed up to 5 years]

   Number of patients surviving up to five years post-transplant.

3. Transplant-related Mortality [At day 100]

   Number of patients with TRM within 100 days post-transplant.

4. Transplant-related Mortality [At 1 year]

   Number of patients with TRM within one year post-transplant.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 A0101 and the donor is A0102, 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Presbyterian - Saint Lukes Medical Center - Health One	Denver	Colorado	United States	80218
2	VA Puget Sound Health Care System	Seattle	Washington	United States	98101
3	Fred Hutch/University of Washington Cancer Consortium	Seattle	Washington	United States	98109

Sponsors and Collaborators

• Fred Hutchinson Cancer Center
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: George Georges, Fred Hutch/University of Washington Cancer Consortium

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Fred Hutchinson Cancer Center
• ClinicalTrials.gov Identifier: NCT00036738
• Other Study ID Numbers: 1581.00; NCI-2010-00131; 1581.00; P01CA078902; P30CA015704
• First Posted: Jan 27, 2003
• Last Update Posted: Jan 29, 2020
• Last Verified: Dec 1, 2019

• Additional relevant MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Recurrence; Cyclosporine; Mycophenolic Acid; Fludarabine; Fludarabine phosphate; Imatinib Mesylate; Dasatinib; Cyclosporins

Study Results

Participant Flow

Arm/Group Title	Treatment (Allogeneic Nonmyeloablative HSCT)
Arm/Group Description	See Detailed Description Cyclosporine: Given IV or PO Dasatinib: Given PO Fludarabine Phosphate: Given IV Imatinib Mesylate: Given PO Mycophenolate Mofetil: Given PO Nilotinib: Given PO Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation: Undergo nonmyeloablative allogeneic PBSC transplantation Peripheral Blood Stem Cell Transplantation: Undergo allogeneic PBSC transplantation Therapeutic Allogeneic Lymphocytes: Given IV Total-Body Irradiation: Undergo TBI
Period Title: Overall Study
STARTED	28
COMPLETED	28
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment (Allogeneic Nonmyeloablative HSCT)
Arm/Group Description	See Detailed Description Cyclosporine: Given IV or PO Dasatinib: Given PO Fludarabine Phosphate: Given IV Imatinib Mesylate: Given PO Mycophenolate Mofetil: Given PO Nilotinib: Given PO Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation: Undergo nonmyeloablative allogeneic PBSC transplantation Peripheral Blood Stem Cell Transplantation: Undergo allogeneic PBSC transplantation Therapeutic Allogeneic Lymphocytes: Given IV Total-Body Irradiation: Undergo TBI
Overall Participants	28
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	26 92.9%
>=65 years	2 7.1%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	57.6
Sex: Female, Male (Count of Participants)
Female	9 32.1%
Male	19 67.9%
Region of Enrollment (participants) [Number]
United States	28 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Allogeneic Nonmyeloablative HSCT)
Arm/Group Description	See Detailed Description Cyclosporine: Given IV or PO Dasatinib: Given PO Fludarabine Phosphate: Given IV Imatinib Mesylate: Given PO Mycophenolate Mofetil: Given PO Nilotinib: Given PO Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation: Undergo nonmyeloablative allogeneic PBSC transplantation Peripheral Blood Stem Cell Transplantation: Undergo allogeneic PBSC transplantation Therapeutic Allogeneic Lymphocytes: Given IV Total-Body Irradiation: Undergo TBI
Measure Participants	28
Count of Participants [Participants]	3 10.7%

2. Secondary Outcome

Title	Leukemia-free Survival
Description	Number of patients surviving in CR up to five years post-transplant.
Time Frame	Assessed up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Allogeneic Nonmyeloablative HSCT)
Arm/Group Description	See Detailed Description Cyclosporine: Given IV or PO Dasatinib: Given PO Fludarabine Phosphate: Given IV Imatinib Mesylate: Given PO Mycophenolate Mofetil: Given PO Nilotinib: Given PO Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation: Undergo nonmyeloablative allogeneic PBSC transplantation Peripheral Blood Stem Cell Transplantation: Undergo allogeneic PBSC transplantation Therapeutic Allogeneic Lymphocytes: Given IV Total-Body Irradiation: Undergo TBI
Measure Participants	28
6 Months	19 67.9%
1 Year	17 60.7%
2 Years	13 46.4%
3 Years	11 39.3%
4 Years	11 39.3%
5 Years	10 35.7%

3. Secondary Outcome

Title	Overall Survival
Description	Number of patients surviving up to five years post-transplant.
Time Frame	Assessed up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Allogeneic Nonmyeloablative HSCT)
Arm/Group Description	See Detailed Description Cyclosporine: Given IV or PO Dasatinib: Given PO Fludarabine Phosphate: Given IV Imatinib Mesylate: Given PO Mycophenolate Mofetil: Given PO Nilotinib: Given PO Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation: Undergo nonmyeloablative allogeneic PBSC transplantation Peripheral Blood Stem Cell Transplantation: Undergo allogeneic PBSC transplantation Therapeutic Allogeneic Lymphocytes: Given IV Total-Body Irradiation: Undergo TBI
Measure Participants	28
6 Months	26 92.9%
1 Year	24 85.7%
2 Years	19 67.9%
3 Years	17 60.7%
4 Years	16 57.1%
5 Years	13 46.4%

4. Secondary Outcome

Title	Transplant-related Mortality
Description	Number of patients with TRM within 100 days post-transplant.
Time Frame	At day 100

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Allogeneic Nonmyeloablative HSCT)
Arm/Group Description	See Detailed Description Cyclosporine: Given IV or PO Dasatinib: Given PO Fludarabine Phosphate: Given IV Imatinib Mesylate: Given PO Mycophenolate Mofetil: Given PO Nilotinib: Given PO Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation: Undergo nonmyeloablative allogeneic PBSC transplantation Peripheral Blood Stem Cell Transplantation: Undergo allogeneic PBSC transplantation Therapeutic Allogeneic Lymphocytes: Given IV Total-Body Irradiation: Undergo TBI
Measure Participants	28
Count of Participants [Participants]	1 3.6%

5. Secondary Outcome

Title	Transplant-related Mortality
Description	Number of patients with TRM within one year post-transplant.
Time Frame	At 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Allogeneic Nonmyeloablative HSCT)
Arm/Group Description	See Detailed Description Cyclosporine: Given IV or PO Dasatinib: Given PO Fludarabine Phosphate: Given IV Imatinib Mesylate: Given PO Mycophenolate Mofetil: Given PO Nilotinib: Given PO Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation: Undergo nonmyeloablative allogeneic PBSC transplantation Peripheral Blood Stem Cell Transplantation: Undergo allogeneic PBSC transplantation Therapeutic Allogeneic Lymphocytes: Given IV Total-Body Irradiation: Undergo TBI
Measure Participants	28
Count of Participants [Participants]	3 10.7%

Adverse Events

Time Frame	AEs: Conditioning through Day 100; SAEs: Conditioning through Day 200
Arm/Group Title	Treatment (Allogeneic Nonmyeloablative HSCT)
Arm/Group Description	See Detailed Description Cyclosporine: Given IV or PO Dasatinib: Given PO Fludarabine Phosphate: Given IV Imatinib Mesylate: Given PO Mycophenolate Mofetil: Given PO Nilotinib: Given PO Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation: Undergo nonmyeloablative allogeneic PBSC transplantation Peripheral Blood Stem Cell Transplantation: Undergo allogeneic PBSC transplantation Therapeutic Allogeneic Lymphocytes: Given IV Total-Body Irradiation: Undergo TBI
All Cause Mortality
	Treatment (Allogeneic Nonmyeloablative HSCT)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Allogeneic Nonmyeloablative HSCT)
	Affected / at Risk (%)	# Events
Total	2/28 (7.1%)
Investigations
Blood bilirubin increased	1/28 (3.6%)	1
Nervous system disorders
Encephalopathy	1/28 (3.6%)	1
Intracranial hemorrhage	1/28 (3.6%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Allogeneic Nonmyeloablative HSCT)
	Affected / at Risk (%)	# Events
Total	8/28 (28.6%)
Blood and lymphatic system disorders
Febrile neutropenia	1/28 (3.6%)	1
Cardiac disorders
Atrial flutter	1/28 (3.6%)	1
Gastrointestinal disorders
Diarrhea	1/28 (3.6%)	1
Immune system disorders
Anaphylaxis	1/28 (3.6%)	1
Investigations
Blood bilirubin increased	3/28 (10.7%)	3
Nervous system disorders
Transient ischemic attacks	1/28 (3.6%)	1
Respiratory, thoracic and mediastinal disorders
Bronchopulmonary hemorrhage	1/28 (3.6%)	1
Pneumonitis	1/28 (3.6%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.