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Antibody Therapy With Alemtuzumab, Rituximab and GM-CSF for Initial Treatment of High Risk Chronic Lymphocytic Leukemia

Phase 2
18 Years
Open (Enrolling)

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Trial Information

Antibody Therapy With Alemtuzumab, Rituximab and GM-CSF for Initial Treatment of High Risk Chronic Lymphocytic Leukemia



- 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

- 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.

Inclusion Criteria


- 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

- 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

- 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

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Proportion of Confirmed Responses (Complete or Partial Response Noted as the Objective Status for a Duration of at Least 2 Months) at 6 Months

Outcome Description:

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

Outcome Time Frame:

6 months

Safety Issue:


Principal Investigator

Clive S. Zent, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Mayo Clinic


United States: Food and Drug Administration

Study ID:




Start Date:

January 2008

Completion Date:

December 2012

Related Keywords:

  • Leukemia
  • stage 0 chronic lymphocytic leukemia
  • stage I chronic lymphocytic leukemia
  • stage II chronic lymphocytic leukemia
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid



Mayo Clinic Scottsdale Scottsdale, Arizona  85259
Mayo Clinic Cancer Center Rochester, Minnesota  55905