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Rituximab, Alemtuzumab, and GM-CSF As First-Line Therapy in Treating Patients With Early-Stage Chronic Lymphocytic Leukemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00562328
Recruitment Status : Completed
First Posted : November 22, 2007
Results First Posted : May 8, 2012
Last Update Posted : June 16, 2017
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Mayo Clinic

Brief Summary:

RATIONALE: Monoclonal antibodies, such as rituximab and alemtuzumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Colony-stimulating factors, such as GM-CSF, may increase the number of immune cells found in bone marrow or peripheral blood. Giving monoclonal antibody therapy together with GM-CSF may be an effective treatment for early-stage chronic lymphocytic leukemia.

PURPOSE: This phase II trial is studying the side effects of giving rituximab and alemtuzumab together with GM-CSF and to see how well it works in treating patients with early-stage chronic lymphocytic leukemia.

Condition or disease Intervention/treatment Phase
Leukemia Biological: Alemtuzumab Biological: Rituximab Biological: Sargramostim Phase 2

Detailed Description:



  • To assess the rate of complete and overall response in patients with high-risk, early-stage, chronic lymphocytic leukemia (CLL) treated with alemtuzumab, rituximab, and sargramostim (GM-CSF).
  • To monitor and assess toxicity of this regimen in these patients through clinical evaluation and serial monitoring of cytomegalovirus antigenemia by polymerase chain reaction (PCR).


  • To determine the overall and progression-free survival, time to response, time to next treatment, and duration of response in patients treated with this regimen.
  • To assess the correlation between individual prognostic markers (i.e., 17p-, 11q-, unmutated VH gene, use of VH3-21, ZAP70+, CD38+) and clinical outcome.

Correlative Studies

  • To assess response in these patients using an expanded definition of response, including minimal residual disease (MRD) by sensitive flow cytometry in patients in complete clinical remission.
  • To assess MRD status of responding patients using sensitive flow cytometry and molecular assays (i.e., spectral karyotype analysis of CLL cells) before treatment and at relapse to identify subpopulations that could contribute to disease resistance and relapse.
  • To detail the in vivo effect of this regimen on critical aspects of the immune system in CLL.
  • To determine if GM-CSF, β-glucan, and CpG7909 can increase antibody dependent cellular cytotoxicity to improve efficacy against CLL cells and clinical response to treatment.

OUTLINE: Patients receive rituximab IV over 30 minutes on day 3 of weeks 2-5, alemtuzumab subcutaneously (SC) on days 3, 4, and 5 in week 1 and on days 1, 3, and 5 in weeks 2-5, and sargramostim SC on days 1, 3, and 5 in weeks 1-6. Treatment continues in the absence of disease progression or unacceptable toxicity.

Patients undergo blood sample collection for measurement of serum cytomegalovirus DNA copy number by polymerase chain reaction at baseline, weekly during treatment, and monthly for the 6 months after completion of treatment. Patients also undergo bone marrow biopsy and aspirate at two months and then again at 12 months (if in complete remission). Blood samples are collected periodically during study for evaluation of prognostic biomarkers (i.e., 11q-, 17p-, unmutated IgVH gene, VH3-21 gene segment use, and CD38 and ZAP-70 expression) by fluorescent in situ hybridization (FISH) and for immunophenotyping by flow cytometry. Blood samples are collected from patients at the Mayo Clinic Rochester site at baseline and periodically during study for immunological and other correlative studies, including minimal residual disease (in responding patients only).

After completion of study therapy, patients are followed periodically for up to 5 years.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 33 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Antibody Therapy With Alemtuzumab, Rituximab and GM-CSF for Initial Treatment of High Risk Chronic Lymphocytic Leukemia
Actual Study Start Date : January 2008
Actual Primary Completion Date : August 2010
Actual Study Completion Date : December 18, 2014

Arm Intervention/treatment
Experimental: Alemtuzumab + Rituximab + GM-CSF
Alemtuzumab + Rituximab + GM-CSF
Biological: Alemtuzumab

Week 1 (dose escalation):

Day 3: 3mg subcutaneously; Day 4: 10mg subcutaneously; Day 5 30mg subcutaneously

Weeks 2-5:

30mg subcutaneously three times a week.

Biological: Rituximab

Weeks 2-5:

375 mg/m^2 by IV once weekly

Biological: Sargramostim

Week 1-6:

250 mcg subcutaneously three time as week

Other Name: GM-CSF

Primary Outcome Measures :
  1. Proportion of Confirmed Responses (Complete or Partial Response Noted as the Objective Status for a Duration of at Least 2 Months) at 6 Months [ Time Frame: 6 months ]

    Response, as defined by the National Cancer Institute Working Group (NCIWG), requires the following for a period of at least 2 months:

    • CR: no lymphadenopathy, hepatomegaly, splenomegaly or constitutional symptoms; normal complete blood count; confirmed by bone marrow (BM) aspirate & biopsy
    • PR: 50% decrease in peripheral blood lymphocytes, lymphadenopathy, liver/spleen size, presence/absence of constitutional symptoms; plus ≥1 of the following: ≥1500/μL polymorphonuclear leukocytes, >100,000/μL platelets, >11.0 g/dL hemoglobin or 50% improvement for these parameters without transfusions

Secondary Outcome Measures :
  1. Time to Disease Progression [ Time Frame: Time from registration to progression (up to 5 years) ]
    Time to disease progression (TTP) was defined as the time from registration to the earliest date documentation of disease progression. Participants were followed for a maximum of 5 years from registration. The median OS with 95% confidence interval (CI) was estimated using the Kaplan Meier method.

  2. Time to Response [ Time Frame: time from registration to first documentation of response (up to 5 years) ]
    Time to response (TTR) is defined as the time from registration to first documentation of response (CR or PR). In participants who do not achieve a response, time will be censored at the participants last evaluation (for disease) date. The median TTR with 95% CI was estimated using the Kaplan Meier method.

  3. Duration of Response [ Time Frame: time from start of response to progression (up to 5 years) ]
    Duration of response (DOR) is defined as the time from documentation of response (CR or PR) to disease progression. The median DOR with 95% CI was estimated using the Kaplan Meier method.

  4. Overall Survival [ Time Frame: Time from registration to death (up to 5 years) ]
    Overall Survival (OS) was defined as the time from registration to death of any cause. Participants were followed for a maximum of 5 years from registration. The median OS with 95% CI was estimated using the Kaplan Meier method.

  5. Time to Subsequent Therapy [ Time Frame: time from end of protocol treatment to subsequent treatment (up to 5 years) ]
    Time to subsequent treatment (TTS) was defined as the time from end of active (protocol) treatment to the start of subsequent treatment. The median TTS with 95% CI was estimated using the Kaplan Meier method.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 120 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No


  • Diagnosis of chronic lymphocytic leukemia (CLL) meeting the following criteria:

    • Minimum threshold peripheral blood lymphocyte count 5 x 10^9/L
    • Monoclonality (light chain exclusion) of B lymphocytes detected by immunophenotyping (CD19-positive), demonstrating ≥ 3 of the following characteristics:

      • CD5-positive
      • CD23-positive
      • Dim surface light chain expression
      • Dim surface CD20 expression
    • Negative for IGH/CCND1 translocation AND/OR immunostaining is negative for cyclin D1 expression by fluorescent in-situ hybridization (FISH) analysis
    • Rai stage 0, I, or II disease that does not meet standard NCI-Working Group criteria for treatment of CLL
  • Poor prognosis as defined by ≥ 1 of the following factors:

    • Unmutated IgVH mutation status AND CD38 expression (i.e., ≥ 30% cells positive on flow cytometry)
    • Unmutated IgVH mutation status AND ZAP-70 expression (i.e., ≥ 20% cells positive on flow cytometry)
    • VH3-21 gene segment use irrespective of mutation status AND CD38 expression (≥ 30% cells positive on flow cytometry)
    • VH3-21 gene segment use irrespective of mutation status AND ZAP-70 expression (≥ 20% cells positive on flow cytometry)
    • 11q-negative*
    • 17p-negative* NOTE: *Determination of IgVH mutation status is not required in patients whose eligibility is based on 17p13- or 11q22- deletions


  • ECOG performance status 0- 2
  • Creatinine ≤ 1.5 times upper limit of normal (ULN)
  • Total bilirubin ≤ 3.0 times ULN OR direct bilirubin ≤ 1.5 ULN
  • AST ≤ 3.0 times ULN (unless due to hemolysis or CLL)
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must practice effective contraception
  • Willing to provide mandatory blood samples (for patients at the Mayo Clinic in Rochester only) for research studies as required by the protocol
  • No comorbid conditions, including any of the following:

    • New York Heart Association Class III or IV heart disease
    • Myocardial infarction within the past month
    • Uncontrolled infection
    • HIV infection or AIDS
    • Serological evidence of active hepatitis B infection (i.e., serum antigen or e-antigen positivity) or positive hepatitis C serology
  • No other active primary malignancy requiring treatment or limiting survival to ≤ 2 years
  • No active autoimmune hemolytic anemia, immune thrombocytopenia, or pure red blood cell aplasia


  • More than 4 weeks since prior major surgery
  • No prior chemotherapy or monoclonal antibody treatment for CLL
  • No concurrent corticosteroids

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00562328

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United States, Arizona
Mayo Clinic Scottsdale
Scottsdale, Arizona, United States, 85259-5499
United States, Minnesota
Mayo Clinic Cancer Center
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Mayo Clinic
National Cancer Institute (NCI)
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Study Chair: Clive S. Zent, MD Mayo Clinic

Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Mayo Clinic Identifier: NCT00562328     History of Changes
Other Study ID Numbers: CDR0000574754
P30CA015083 ( U.S. NIH Grant/Contract )
MC0785 ( Other Identifier: Mayo Clinic Cancer Center )
U4449s ( Other Identifier: Genentech )
001.0888 ( Other Identifier: Bayer )
07-002087 ( Other Identifier: Mayo Clinic IRB )
First Posted: November 22, 2007    Key Record Dates
Results First Posted: May 8, 2012
Last Update Posted: June 16, 2017
Last Verified: May 2017
Keywords provided by Mayo Clinic:
stage 0 chronic lymphocytic leukemia
stage I chronic lymphocytic leukemia
stage II chronic lymphocytic leukemia
Additional relevant MeSH terms:
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Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents