Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

Fludarabine and Total-Body Irradiation Followed By Donor Peripheral 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

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase II, Phase I Treatment Active 70 and under NCI FHCRC-1581.00 NCI-H02-0087, NCT00036738

Objectives

Primary

1. Determine whether the rate of leukemic relapse can be decreased for patients with imatinib mesylate, dasatinib, or nilotinib-responsive Philadelphia chromosome-positive acute lymphoblastic leukemia or chronic myelogenous leukemia in blast crisis treated with a non-myeloablative conditioning regimen comprising fludarabine and total body irradiation followed by allogeneic peripheral blood stem cell (PBSC) transplantation, compared to historical controls treated with high-dose conventional chemotherapy followed by allogeneic PBSC transplantation.
2. Determine whether the rate of transplant-related mortality can be decreased in patients treated with this regimen.

Secondary

1. Evaluate whether donor lymphocyte infusions can be safely used in patients with mixed or full donor chimerism treated with this regimen as preemptive therapy to eliminate minimal residual disease.

Entry Criteria

Disease Characteristics:

• Diagnosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) or chronic myelogenous leukemia in blast crisis
  • Less than 15% blasts on morphologic bone marrow evaluation after receiving imatinib mesylate, dasatinib, or nilotinib
    • Patients with no detectable Ph+ ALL by morphologic or molecular assay (i.e., complete remission) after treatment with imatinib mesylate, dasatinib, or nilotinib are eligible
    • Patients who initially respond to imatinib mesylate, dasatinib, or nilotinib and then progress are ineligible for nonmyeloablative stem cell transplantation on this protocol



• No CNS involvement with leukemia refractory to intrathecal chemotherapy



• Availability of an HLA-matched related or unrelated peripheral blood stem cell donor
  • Related donors HLA genotypically identical for at least 1 haplotype and may be genotypically or phenotypically identical for HLA-A, -B, -C, -DRB1, and -DQB1 alleles
    • No identical twin

    OR

  • Unrelated donors meeting the following criteria:
    • Matched for HLA-A, -B, -C, -DRB1, and -DQB1 by high-resolution typing
    • Only a single allele disparity allowed for HLA-A, -B, or -C by high-resolution typing
  • No bone marrow donors

Prior/Concurrent Therapy:

Biologic therapy:

• See Disease Characteristics
• No concurrent growth factors until after day 21 post-transplantation

Chemotherapy:

• See Disease Characteristics

Endocrine therapy:

• Not specified

Radiotherapy:

• Not specified

Surgery:

• Not specified

Patient Characteristics:

Age:

• 70 and under
• Patients age 12 and under are allowed at the discretion of the protocol investigator

Performance status:

• Karnofsky 60-100%
• Lansky play performance score 40-100% (for pediatric patients)

Life expectancy:

• Not specified

Hematopoietic:

• See Disease Characteristics

Hepatic:

• No fulminant liver failure
• No cirrhosis of the liver with evidence of portal hypertension
• No alcoholic hepatitis
• No esophageal varices
• No history of bleeding esophageal varices
• No hepatic encephalopathy
• No uncorrectable hepatic synthetic dysfunction, evidenced by prolongation of PT
• No ascites related to portal hypertension
• No bacterial or fungal liver abscess
• No biliary obstruction
• No chronic viral hepatitis (with bilirubin greater than 3 mg/dL)
• No symptomatic biliary disease

Renal:

• Creatinine ≤ 2 times upper limit of normal

Cardiovascular:

• No poorly controlled hypertension despite multiple antihypertensives
• No grade IV cardiac disease

  OR

• Cardiac ejection fraction ≥ 35%*

   [Note: *Required for patients > 50 years of age with a history of cardiac disease or prior anthracycline exposure]

• QTc prolongation ≤ 450 msec for patients receiving dasatinib or nilotinib

Pulmonary:

• DLCO ≥ 30% predicted
• Total lung capacity ≥ 30%
• FEV1 ≥ 30%
• No requirement for continuous supplementary oxygen

Other:

• Not pregnant or nursing
• Fertile patients must use effective barrier-method contraception during and for 1 year after study completion of study treatment
• HIV negative

Expected Enrollment

A total of 25 patients will be accrued for this study within 5 years.

Outcomes

Relapse-free survival < 40% at 1 year
Transplant related mortality < 40% at 1 year

Outline

This is a multicenter study.

Patients receive oral imatinib mesylate, dasatinib, or nilotinib once daily beginning before study and continuing until day -2 of study. Patients resume oral imatinib mesylate, dasatinib, or nilotinib once daily beginning on day 14 or when blood counts recover after peripheral blood stem cell (PBSC) transplantation.

• Transplantation: Patients receive a non-myeloablative conditioning regimen comprising fludarabine IV on days -4 to -2 and total body irradiation followed by filgrastim (G-CSF)-mobilized allogeneic PBSC transplantation on day 0.



• Graft-versus-host-disease (GVHD) prophylaxis: Patients receiving related PBSC receive oral mycophenolate mofetil (MMF) twice daily on days 0-27 without tapering. Patients receiving unrelated PBSC receive oral MMF three times daily on days 0-40 followed by a taper on days 41-96 in the absence of GVHD or disease progression. Adults receiving related PBSC receive cyclosporine (CYSP) orally twice daily on days -3 to 56 followed by a taper on days 57-100. Children receiving related donor PBSC receive CYSP IV twice or three times daily on days -3 to 56 followed by a taper on days 57-100. Adults receiving unrelated donor PBSC receive oral CYSP twice daily on days -3 to 100 followed by a taper on days 101-177. Children receiving unrelated donor PBSC receive CYSP IV twice or three times daily on days -3 to 100 followed by a taper on days 101-177.



• CNS prophylaxis: Patients receive six doses of intrathecal methotrexate or cytarabine beginning on day 32 after PBSC transplantation or when there is no evidence of gross systemic leukemia. Patients who have a history of CNS leukemia at any time and have not received prior cranio-spinal irradiation (CSI) before study entry receive CSI for 11 days after PBSC transplantation when there is no evidence of gross systemic leukemia.

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.

Patients are followed at 6, 9, 12, 18, and 24 months and then annually for 5 years.

Norasetthada L, Maris MB, Sandmaier BM, et al.: Feasibility and toxicity of nonmyeloablative hematopoietic cell transplantation (HCT) with or without imatinib for Philadelphia chromosome (Ph+) acute lymphoblastic leukemia (ALL). [Abstract] Blood 104 (11): A-5056, 2004.

Trial Contact Information

Trial Lead Organizations

Fred Hutchinson Cancer Research Center

George Georges, MD, Protocol chair		Ph: 206-667-6886 Email: ggeorges@fhcrc.org

U.S.A.
Colorado
	Denver
	Rocky Mountain Cancer Centers - Denver Midtown
		Michael Maris, MD	Ph:  303-388-4876
Washington
	Seattle
	Fred Hutchinson Cancer Research Center
		George Georges, MD	Ph:  206-667-6886
			Email: ggeorges@fhcrc.org
	Seattle Cancer Care Alliance
		Clinical Trials Office - Seattle Cancer Care Alliance	Ph:  800-804-8824
	Veterans Affairs Medical Center - Seattle
		Thomas R. Chauncey, MD, PhD	Ph:  206-764-2709 800-329-8387

Registry Information
Official Title		Allogeneic Nonmyeloablative Hematopoietic Stem Cell Transplant for Patients with BCR-ABL Tyrosine Kinase Inhibitor Responsive PH+ Acute Leukemia - A Multi-Center Trial
Trial Start Date		2001-07-13
Trial Completion Date		2010-07-13 (estimated)
Registered in ClinicalTrials.gov		NCT00036738
Date Submitted to PDQ		2002-02-27
Information Last Verified		2008-09-22
NCI Grant/Contract Number		CA18029, CA15704, CA92058