Donor Stem Cell Transplant in Treating Patients With High-Risk Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Phase II Study of Reduced-Intensity Allogeneic Stem Cell Transplant for High-Risk Chronic Lymphocytic Leukemia (CLL)

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.

Study Overview

• Status: Completed
• Conditions: Lymphoma; Leukemia
• Intervention / Treatment: Drug: cyclophosphamide; Drug: methotrexate; Drug: fludarabine phosphate; Drug: busulfan; Biological: rituximab; Drug: tacrolimus; Drug: sirolimus; Procedure: allogeneic stem cell transplant

Detailed Description

OBJECTIVES:

Primary

• To determine if this treatment can improve 2-year current progression-free survival (PFS) in the early disease cohort compared to historical controls. Specifically, we plan to study whether we can achieve 2-year PFS ≥ 70% and to exclude 2 year PFS ≤ 50%

Secondary

• To determine whether in the advanced disease cohort we can achieve 2-year current PFS ≥ 50% and to exclude 2-year PFS ≤ 30%
• 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
• 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 to reduced intensity allogeneic stem cell transplant

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.

Patients are followed up periodically for a maximum of 5 years from study entry.

• Study Type: Interventional
• Enrollment (Actual): 68
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010-3000
      • City of Hope Comprehensive Cancer Center
  • Delaware
    • Lewes, Delaware, United States, 19958
      • Tunnell Cancer Center at Beebe Medical Center
    • Newark, Delaware, United States, 19713
      • CCOP - Christiana Care Health Services
  • Florida
    • Orlando, Florida, United States, 32803-1273
      • Florida Hospital Cancer Institute at Florida Hospital Orlando
    • Tampa, Florida, United States, 33612-9497
      • H. Lee Moffitt Cancer Center and Research Institute at University of South Florida
  • Illinois
    • Chicago, Illinois, United States, 60637-1470
      • University of Chicago Cancer Research Center
  • Iowa
    • Iowa City, Iowa, United States, 52242-1002
      • Holden Comprehensive Cancer Center at University of Iowa
  • Maryland
    • Elkton, Maryland, United States, 21921
      • Union Hospital of Cecil County
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber/Brigham and Women's Cancer Center
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
  • Nebraska
    • Omaha, Nebraska, United States, 68198-6805
      • UNMC Eppley Cancer Center at the University of Nebraska Medical Center
  • New Jersey
    • Voorhees, New Jersey, United States, 08043
      • Cancer Institute of New Jersey at Cooper - Voorhees
  • New York
    • Buffalo, New York, United States, 14263-0001
      • Roswell Park Cancer Institute
    • Lake Success, New York, United States, 11042
      • Monter Cancer Center of the North Shore-LIJ Health System
    • Manhasset, New York, United States, 11030
      • CCOP - North Shore University Hospital
    • Manhasset, New York, United States, 11030
      • Don Monti Comprehensive Cancer Center at North Shore University Hospital
    • New Hyde Park, New York, United States, 11040
      • Long Island Jewish Medical Center
    • New York, New York, United States, 10065
      • Memorial Sloan-Kettering Cancer Center
    • New York, New York, United States, 10021
      • New York Weill Cornell Cancer Center at Cornell University
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157-1096
      • Wake Forest University Comprehensive Cancer Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Taussig Cancer Center
    • Columbus, Ohio, United States, 43210-1240
      • Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Oklahoma University Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 69 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Patient Eligibility:

1. Diagnosis of B-cell chronic lymphocytic leukemia or B-cell small lymphocytic lymphoma.

   Diagnosis should be according to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 Criteria

   1. Early Disease Cohort - Patients in the early disease cohort must include one or more of the following:

      • FISH showing deletion 17p in ≥ 20% of cells (either at diagnosis or any time prior to study entry) either alone or in combination with other cytogenetic abnormalities
      • FISH showing del 11q in ≥ 20% of cells (either at diagnosis or any time prior to study entry) either alone or in combination with other cytogenetic abnormalities, unless the patient has achieved a complete remission by IWCLL 2008 which includes CT scan, bone marrow morphology and flow cytometry
      • Failure to achieve a partial response with initial chemotherapy, but with lack of progression. These patients may receive a second therapy to improve their response prior to transplant.
      • Patients who, at the time of first progression, have a 17p deletion by FISH in ≥ 20% of cells, either alone or in combination with other cytogenetic abnormalities.

      The duration of the first progression is not specified.

      • In addition, patients in the early disease cohort must have all of the following:

        • Received at least 2 cycles of induction therapy. It is expected that most patients will receive at least 4 months of therapy prior to enrollment, but this is not required. Suggested regimens include but are not limited to the following: fludarabine plus rituximab, fludarabine, cyclophosphamide plus rituximab, pentostatin, cyclophosphamide plus rituximab, bendumustine plus rituximab, or alemtuzumab alone or in combination with other agents. Patients may receive no more than 2 different regimens prior to proceeding to transplantation.
        • Nodes ≤ 5 cm

   2. Advanced Disease Cohort - Patients in the advanced disease cohort must include one or more of the following:

      • FISH showing deletion 17p in ≥ 20% of cells (regardless of interval from initial therapy) either alone or in combination with other cytogenetic abnormalities
      • First progression < 24 months after completing therapy. This includes progression on initial therapy.
      • Second or subsequent progression

      • In addition, patients in the advanced disease cohort must have all of the following:

        • Stable disease or better by the Revised IWCLL 2008 NCI Criteria to their most recent chemotherapy
        • Nodes ≤ 5 cm
2. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
3. Age Requirement - Patients must be between ≥ 18 and < 70 years of age
4. Cytotoxic Chemotherapy or Alemtuzamab - There must be at least 4 weeks after day 1 of the last cycle of cytotoxic chemotherapy, or alemtuzamab.

5. Human Immunodeficiency Virus (HIV) Status - Patients must have no HIV infection.

   Allogeneic transplantation in the HIV patient population is not well-defined and there are likely to be requirements for concomitant anti-HIV therapy and anti-GVHD therapy that would create potentially dangerous pharmacokinetic interactions among the different agents that could constrain therapeutic options for controlling both HIV and GVHD.

6. Hepatitis B and C - Patients must have no Hepatitis B sAg, anti-HBc or HCV.
7. Diffusion capacity of carbon monoxide DLCO must be ≥ 40% predicted
8. Left ventricular ejection fraction (LVEF) by Echocardiogram (ECHO) or Multiple gated acquisition (MUGA) must be ≥ 30%
9. Diabetes or Serious Infection - Patients must have no uncontrolled diabetes mellitus or active uncontrolled serious infections

10. Pregnancy and Nursing Status - Patients must be non-pregnant and non-nursing. Treatment under this protocol would expose a fetus to significant risks. Women of childbearing potential should have a negative pregnancy test prior to study entry.

    Women and men of reproductive potential should agree to use an appropriate method of birth control throughout their participation in this study due to the teratogenic potential of the therapy utilized in this trial. Appropriate methods of birth control include oral contraceptives, implantable hormonal contraceptives (Norplant®), or double barrier method (diaphragm plus condom).

11. Richter's Transformation - Patients must have no history of Richter's transformation.

12. Initial Required Laboratory Values:

    • Serum Creatinine < 2 mg/dL
    • Calculated Creatinine Clearance ≥ 40 mL/min
    • AST < 3 x ULN
    • Total Bilirubin < 2 mg/dL (except for Gilbert's syndrome)

Donor Eligibility:

1. Donors may be either a 6/6 HLA-matched related donor by low-resolution typing at HLA A, B, DR.
2. Donors may be an 8/8 HLA-matched unrelated donor at HLA A, B, C, DR. Unrelated donors will be analyzed by molecular typing at both HLA Class I and Class II (A, B, C, DR loci).
3. Syngeneic donors are not eligible
4. Donors must be healthy and must be an acceptable donor as per institutional standards for stem cell donation.
5. There will be no donor age restriction.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (Combination of chemotherapy and transplant); See detailed description	Drug: cyclophosphamide; Drug: methotrexate; Drug: fludarabine phosphate; Drug: busulfan; Biological: rituximab; Drug: tacrolimus; Drug: sirolimus; Procedure: allogeneic stem cell transplant

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
2-year Progression-free Survival in Early Disease Participants	Percentage of participants who were alive and progression free at 2 years for participants with early disease stage. The 2 year progression free survival, with 95% confidence interval, was estimated using the Kaplan Meier method. A progression is defined as one of the following events: >= 50% increase in the products of at least two lymph nodes on two consecutive determinations two weeks apart (at least one lymph node must be >= 2 cm); appearance of new palpable lymph nodes.; >= 50% increase in the size of the liver and/or spleen as determined by measurement below the respective costal margin; appearance of palpable hepatomegaly or splenomegaly, which was not previously present.; > 50% increase in peripheral blood lymphocytes with an absolute increase > 5000/μL.; Transformation to a more aggressive histology (i.e., Richter's syndrome or prolymphocytic leukemia with >= 56% prolymphocytes).	2 years post-registration

Secondary Outcome Measures

Outcome Measure	Time Frame
Response	5 years post-registration
Acute Graft-vs-host Disease (GVHD)	5 years post-registration
Chronic GVHD	5 years post-registration
Treatment-related Mortality	6 months post-transplant
Overall Survival	5 years post-registration
Chimerism for CD3	5 years post-registration

Collaborators and Investigators

• Sponsor: Alliance for Clinical Trials in Oncology
• Collaborators: National Cancer Institute (NCI); Genentech, Inc.; Biologics, Inc.

Study record dates

Study Major Dates

• Study Start: February 1, 2010
• Primary Completion (Actual): January 1, 2016
• Study Completion (Actual): April 1, 2023

Study Registration Dates

• First Submitted: December 4, 2009
• First Submitted That Met QC Criteria: December 4, 2009
• First Posted (Estimate): December 7, 2009

Study Record Updates

• Last Update Posted (Estimate): May 4, 2023
• Last Update Submitted That Met QC Criteria: April 10, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: B-cell chronic lymphocytic leukemia; stage I chronic lymphocytic leukemia; noncontiguous stage II small lymphocytic lymphoma; recurrent small lymphocytic lymphoma; stage I small lymphocytic lymphoma; stage III small lymphocytic lymphoma; stage IV small lymphocytic lymphoma; contiguous stage II small lymphocytic lymphoma; refractory chronic lymphocytic leukemia; stage II chronic lymphocytic leukemia; stage III chronic lymphocytic leukemia; stage IV chronic lymphocytic leukemia
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, B-Cell; Lymphoma; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Calcineurin Inhibitors; Cyclophosphamide; Rituximab; Fludarabine; Fludarabine phosphate; Methotrexate; Tacrolimus; Sirolimus; Busulfan
• Other Study ID Numbers: CALGB 100701; U10CA031946 (U.S. NIH Grant/Contract); CDR0000660555 (Registry Identifier: Physician Data Query); NCI-2011-01995 (Registry Identifier: NCI Clinical Trials Reporting Office)