Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

Summary

RATIONALE: Giving low doses of chemotherapy before a donor 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. Also, monoclonal antibodies, such as rituximab, can find cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving tacrolimus, sirolimus, and methotrexate after the transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well donor stem cell transplant works in treating patients with high-risk chronic lymphocytic leukemia or small lymphocytic lymphoma.

Further Study Information

OBJECTIVES:

Primary

• To determine if reduced-intensity allogeneic stem cell transplantation can improve 2-year progression-free survival (PFS) of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in the early disease cohort compared to historical controls.

Secondary

• To determine whether 2-year PFS ≥ 50% can be achieved and 2-year PFS ≤ 30% can be excluded in patients with CLL or SLL in the advanced disease cohort.

• To assess objective response rate.

• To assess the incidence of grade 2-4 and 3-4 acute graft-vs-host disease (GVHD).

• To assess the incidence of extensive chronic GVHD.

• To assess the incidence of treatment-related mortality at 100 days and 1 year after transplantation.

• To assess overall survival.

• To assess donor chimerism for CD3+ cells at 1 and 2 years after transplantation.

• To investigate the presence of donor antigen-specific T-cell clones before and after withdrawal of immune suppression.

• To compare the relapse profiles of patients with T-cell responses against CLL to those whose CLL cells are not reactive.

• To prospectively examine the impact of high-risk genomic features and immune-based single nucleotide polymorphisms on response, toxicity, and 2-year PFS.

OUTLINE: This is a multicenter study.

• Preparative regimen: Patients receive 1 of 2 preparative regimens at the discretion of the participating institution.

• Preparative regimen 1: Patients receive rituximab IV on days -7, -1, 7, and 14 and fludarabine phosphate IV over 30 minutes and busulfan IV over 3 hours on days -5 to -2. .

• Preparative regimen 2: Patients receive rituximab IV on days -7, -1, 7, and 14, fludarabine phosphate IV over 30 minutes on days -5 to -2, and cyclophosphamide IV over 1-2 hours on days -5 to -3. Patients with matched unrelated donors also receive anti-thymocyte globulin IV over 4-6 hours on days -6 to -4.

• Graft-vs-host disease (GVHD) prophylaxis: Patients who receive preparative regimen 1 may receive either GVHD prophylaxis regimen 1 or 2; patients who receive preparative regimen 2 may only receive GVHD prophylaxis regimen 2.

• GVHD prophylaxis regimen 1: Patients receive tacrolimus either orally or IV and oral sirolimus beginning on day -2 and continuing until day 60, followed by a taper until day 180. Patients also receive methotrexate IV on days 1, 3, and 6.

• GVHD prophylaxis regimen 2: Patients receive tacrolimus either orally or IV beginning on day -2 and continuing until day 60, followed by a taper until day 180. Patients also receive methotrexate IV on days 1, 3, 6, and 11.

• Transplantation: Patients undergo allogeneic peripheral blood stem cell transplantation on day 0.

• Maintenance therapy: Patients receive rituximab IV at 3, 6, 9, and 12 months after transplantation.

Peripheral blood and bone marrow aspirate samples may be collected periodically for correlative laboratory studies.

After completion of study treatment, patients are followed up periodically for ≥ 5 years.

Eligibility Criteria

DISEASE CHARACTERISTICS:

• Diagnosis of B-cell chronic lymphocytic leukemia or B-cell small lymphocytic lymphoma according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria

• Meets 1 of the following criteria:

• Early disease cohort:

• Meets ≥ 1 of the following criteria:

• FISH showing deletion 17p in ≥ 20% of cells (either at diagnosis or any time before study entry) either alone or in combination with other cytogenetic abnormalities

• FISH showing deletion 11q in ≥ 20% of cells (either at diagnosis or any time before study entry) either alone or in combination with other cytogenetic abnormalities, unless the patient has achieved a complete remission, according to IWCLL 2008 criteria which includes CT scan, bone marrow morphology, and flow cytometry

• Failed to achieve a partial response to initial therapy but lack of disease progression (may receive a second therapy to improve response before transplant)

• Received ≥ 2 courses of induction therapy (it is expected that patients will receive ≥ 4 months of therapy prior to enrollment, but this is not required)

• Suggested regimens include, but are not limited to, the following:

• Fludarabine phosphate and rituximab

• Fludarabine phosphate, cyclophosphamide, and rituximab

• Pentostatin, cyclophosphamide, and rituximab

• Bendmustine and rituximab

• Alemtuzumab alone or in combination with other agents

• Stable disease or better after most recent therapy (i.e., no prior progression), according to the revised IWCLL 2008 criteria

• Nodes ≤ 5 cm

• Advanced disease cohort:

• Meets ≥ 1 of the following criteria:

• First disease progression < 24 months after completing (this includes progression on initial therapy)

• Second or subsequent progression

• Stable disease or better after most recent chemotherapy, according to the revised IWCLL 2008 criteria

• Nodes ≤ 5 cm

• FISH showing deletion of 17p in ≥ 20% of cells (regardless of interval from initial therapy) either alone or in combination with other cytogenetic abnormalities

• Has an HLA-matched related or unrelated donor available

• 6/6 HLA-matched related donor by low-resolution typing at HLA A, B, C, and DR

• 8/8 HLA-matched unrelated donor by molecular typing at both HLA class I and class II (A, B, C, and DR loci)

• No syngeneic donors

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2

• Serum creatinine < 2 mg/dL

• Calculated creatinine clearance ≥ 40 mL/min

• AST < 3 times upper limit of normal

• Total bilirubin < 2 mg/dL (except for patients with Gilbert syndrome)

• DLCO ≥ 40% predicted

• LVEF ≥ 30% by ECHO or MUGA

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• HIV negative

• Hepatitis B surface antigen negative

• Anti-hepatitis B core antigen negative

• Hepatitis C antibody negative

• No uncontrolled diabetes mellitus or active uncontrolled serious infections

• No history of Richter transformation

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• At least 4 weeks after day 1 of the last course since prior cytotoxic chemotherapy or alemtuzumab

Trial Contact Information

Trial Lead Organizations/Sponsors

Cancer and Leukemia Group B

Edwin P. Alyea

Study Chair

U.S.A.
California
	Duarte
	City of Hope Comprehensive Cancer Center
		Robert W Chen	Ph: 800-826-4673
			Email: becomingapatient@coh.org
Delaware
	Lewes
	Tunnell Cancer Center at Beebe Medical Center
		Frank Beardell	Ph: 302-733-6227
	Newark
	Helen F. Graham Cancer Center at Christiana Hospital
		Frank Beardell	Ph: 302-733-6227
Florida
	Orlando
	Florida Hospital Cancer Institute at Florida Hospital Orlando
		Lee M. Zehngebot	Ph: 407-303-5623
	Tampa
	H. Lee Moffitt Cancer Center and Research Institute at University of South Florida
		Marcie R Tomblyn	Ph: 800-456-7121
			Email: canceranswers@moffitt.org
Illinois
	Chicago
	Cancer and Leukemia Group B
		Edwin P. Alyea
			Email: ealyea@partners.org
	University of Chicago Cancer Research Center
		Andrew S Artz	Ph: 773-834-7424
Iowa
	Iowa City
	Holden Comprehensive Cancer Center at University of Iowa
		Daniel A Vaena	Ph: 800-237-1225
Kansas
	Kansas City
	Kansas Masonic Cancer Research Institute at the University of Kansas Medical Center
		Joseph P McGuirk	Ph: 913-588-4709
Maryland
	Elkton MD
	Union Hospital of Cecil County
		Frank Beardell	Ph: 302-733-6227
Massachusetts
	Boston
	Dana-Farber/Brigham and Women's Cancer Center
		Edwin P. Alyea	Ph: 866-790-4500
	Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute
		Edwin P. Alyea	Ph: 866-790-4500
	Massachusetts General Hospital
		Edwin P. Alyea	Ph: 866-790-4500
Missouri
	Saint Louis
	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
		Ravi Vij	Ph: 800-600-3606
			Email: info@siteman.wustl.edu
Nebraska
	Omaha
	UNMC Eppley Cancer Center at the University of Nebraska Medical Center
		Robert Bociek	Ph: 800-999-5465
New Jersey
	Camden
	Cancer Institute of New Jersey at Cooper University Hospital - Camden
		Frank Beardell	Ph: 302-733-6227
New York
	Buffalo
	Roswell Park Cancer Institute
		Philip L. McCarthy	Ph: 877-275-7724
	Lake Success
	Monter Cancer Center of the North Shore-LIJ Health System
		Alla Keyzner	Ph: 516-562-3467
	Manhasset
	Don Monti Comprehensive Cancer Center at North Shore University Hospital
		Alla Keyzner	Ph: 516-562-3467
	New Hyde Park
	Long Island Jewish Medical Center
		Alla Keyzner	Ph: 516-562-3467
	New York
	New York Weill Cornell Cancer Center at Cornell University
		Tsiporah B. Shore	Ph: 212-746-1848
North Carolina
	Winston-Salem
	Wake Forest University Comprehensive Cancer Center
		David Duane Hurd	Ph: 336-713-6771
Ohio
	Cleveland
	Case Comprehensive Cancer Center
		Hillard M. Lazarus	Ph: 800-641-2422
	Cleveland Clinic Taussig Cancer Center
		Matt E Kalaycio	Ph: 866-223-8100
	Columbus
	Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center
		Leslie A Andritsos	Ph: 866-627-7616
			Email: osu@emergingmed.com
Oklahoma
	Oklahoma City
	Oklahoma University Cancer Institute
		Carla Kurkjian	Ph: 405-271-4272
			Email: julie-traylor@ouhsc.edu
Oregon
	Portland
	Knight Cancer Institute at Oregon Health and Science University
		Richard Maziarz	Ph: 503-494-1080
			Email: trials@ohsu.edu

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01027000
Information obtained from ClinicalTrials.gov on February 18, 2013

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