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

Lymphoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01027000
• Other study ID #: CALGB 100701
• Secondary ID: CDR0000660555U10
• Status: Completed
• Phase: Phase 2
• Start date: February 2010
• Est. completion date: April 2023

Study information

• Verified date: April 2023
• Source: Alliance for Clinical Trials in Oncology
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 68
• Est. completion date: April 2023
• Est. primary completion date: January 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 69 Years

Eligibility

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.

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Lymphoma

Intervention

Biological:
• rituximab

Drug:
• busulfan

• cyclophosphamide

• fludarabine phosphate

• methotrexate

• sirolimus

• tacrolimus

Procedure:
• allogeneic stem cell transplant

Locations

Country	Name	City	State
United States	Dana-Farber/Brigham and Women's Cancer Center	Boston	Massachusetts
United States	Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	University of Chicago Cancer Research Center	Chicago	Illinois
United States	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio
United States	Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	Union Hospital of Cecil County	Elkton	Maryland
United States	Holden Comprehensive Cancer Center at University of Iowa	Iowa City	Iowa
United States	Monter Cancer Center of the North Shore-LIJ Health System	Lake Success	New York
United States	Tunnell Cancer Center at Beebe Medical Center	Lewes	Delaware
United States	CCOP - North Shore University Hospital	Manhasset	New York
United States	Don Monti Comprehensive Cancer Center at North Shore University Hospital	Manhasset	New York
United States	Long Island Jewish Medical Center	New Hyde Park	New York
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	New York Weill Cornell Cancer Center at Cornell University	New York	New York
United States	CCOP - Christiana Care Health Services	Newark	Delaware
United States	Oklahoma University Cancer Institute	Oklahoma City	Oklahoma
United States	UNMC Eppley Cancer Center at the University of Nebraska Medical Center	Omaha	Nebraska
United States	Florida Hospital Cancer Institute at Florida Hospital Orlando	Orlando	Florida
United States	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri
United States	H. Lee Moffitt Cancer Center and Research Institute at University of South Florida	Tampa	Florida
United States	Cancer Institute of New Jersey at Cooper - Voorhees	Voorhees	New Jersey
United States	Wake Forest University Comprehensive Cancer Center	Winston-Salem	North Carolina

Sponsors (4)

Lead Sponsor	Collaborator
Alliance for Clinical Trials in Oncology	Biologics, Inc., Genentech, Inc., National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Response		5 years post-registration
Secondary	Acute Graft-vs-host Disease (GVHD)		5 years post-registration
Secondary	Chronic GVHD		5 years post-registration
Secondary	Treatment-related Mortality		6 months post-transplant
Secondary	Overall Survival		5 years post-registration
Secondary	Chimerism for CD3		5 years post-registration