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
- 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.
- 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
- 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.
Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Proportion of Confirmed Responses (Complete or Partial Response Noted as the Objective Status for a Duration of at Least 2 Months) at 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
Clive S. Zent, MD
United States: Food and Drug Administration
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