Leukemia
Conditions
Keywords
stage 0 chronic lymphocytic leukemia, stage I chronic lymphocytic leukemia, stage II chronic lymphocytic leukemia
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.
Detailed description
OBJECTIVES: Primary * 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). Secondary * 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.
Interventions
BIOLOGICALAlemtuzumab
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.
BIOLOGICALRituximab
Weeks 2-5: 375 mg/m\^2 by IV once weekly
BIOLOGICALSargramostim
Week 1-6: 250 mcg subcutaneously three time as week
Sponsors
National Cancer Institute (NCI)
Mayo Clinic
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * 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 PATIENT CHARACTERISTICS: * 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 PRIOR CONCURRENT THERAPY: * More than 4 weeks since prior major surgery * No prior chemotherapy or monoclonal antibody treatment for CLL * No concurrent corticosteroids
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Confirmed Responses (Complete or Partial Response Noted as the Objective Status for a Duration of at Least 2 Months) at 6 Months | 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
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | Time from registration to progression (up to 5 years) | Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to the standard NCI-WG96 criteria. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator. |
| Duration of Response | 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.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 |
| Time to Next Treatment | time from end of protocol treatment to subsequent treatment (up to 5 years) | Time to next treatment was defined as the time from end of active (protocol) treatment to the start of subsequent treatment. The median and 95% CI was estimated using the Kaplan Meier method. |
| Overall Survival | 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. |
Countries
United States
Participant flow
Recruitment details
Thirty-three (33) participants were recruited at Mayo Clinic (Rochester and Arizona) between January 2008 and February 2010.
Pre-assignment details
All patients were deemed eligible.
Participants by arm
| Arm | Count |
|---|---|
| Alemtuzumab + Rituximab + GM-CSF Alemtuzumab + Rituximab + GM-CSF | 33 |
| Total | 33 |
Baseline characteristics
| Characteristic | Alemtuzumab + Rituximab + GM-CSF |
|---|---|
| Age, Continuous | 60 years |
| CD38 Expression Status Negative (<30%) | 18 participants |
| CD38 Expression Status Positive (>=30%) | 15 participants |
| Immunoglobulin Variable Heavy Chain (IGVH) Mutation Status Mutated | 3 participants |
| Immunoglobulin Variable Heavy Chain (IGVH) Mutation Status Unmutated | 30 participants |
| Rai Stage Stage 0 | 2 participants |
| Rai Stage Stage 1 | 27 participants |
| Rai Stage Stage 2 | 4 participants |
| Region of Enrollment United States | 33 participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 23 Participants |
| ZAP-70 Expression Negative (<20%) | 7 participants |
| ZAP-70 Expression Positive (>=20%) | 25 participants |
| ZAP-70 Expression Unknown | 1 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 33 / 33 |
| serious Total, serious adverse events | 1 / 33 |
Outcome results
Primary
Number 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
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Alemtuzumab + Rituximab + GM-CSF | Number of Confirmed Responses (Complete or Partial Response Noted as the Objective Status for a Duration of at Least 2 Months) at 6 Months | 31 Participants |
Secondary
Duration of Response
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.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
Time frame: time from start of response to progression (up to 5 years)
Population: Only patients who responded to treatment are included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alemtuzumab + Rituximab + GM-CSF | Duration of Response | 14.9 months |
Secondary
Overall Survival
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.
Time frame: Time from registration to death (up to 5 years)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alemtuzumab + Rituximab + GM-CSF | Overall Survival | NA months |
Secondary
Progression Free Survival
Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to the standard NCI-WG96 criteria. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.
Time frame: Time from registration to progression (up to 5 years)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alemtuzumab + Rituximab + GM-CSF | Progression Free Survival | 13.0 months |
Secondary
Time to Next Treatment
Time to next treatment was defined as the time from end of active (protocol) treatment to the start of subsequent treatment. The median and 95% CI was estimated using the Kaplan Meier method.
Time frame: time from end of protocol treatment to subsequent treatment (up to 5 years)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alemtuzumab + Rituximab + GM-CSF | Time to Next Treatment | 33.5 months |