Leukemia
Conditions
Keywords
stage 0 chronic lymphocytic leukemia, stage I chronic lymphocytic leukemia, stage II chronic lymphocytic leukemia, B-cell chronic lymphocytic leukemia
Brief summary
RATIONALE: Monoclonal antibodies, such as alemtuzumab and rituximab, 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. Giving alemtuzumab together with rituximab may kill more cancer cells. PURPOSE: This phase II trial is studying the side effects and how well giving alemtuzumab together with rituximab works in treating patients with high-risk, early-stage chronic lymphocytic leukemia.
Detailed description
OBJECTIVES: Primary * Determine the rate of complete and overall response to alemtuzumab and rituximab in patients with high-risk, early-stage chronic lymphocytic leukemia. * Determine the toxicity of this regimen in these patients. Secondary * Determine the overall survival and time to progression of patients treated with this regimen. * Determine time to response and duration of response in patients treated with this regimen. * Correlate prognostic markers 11q-, 17p-, unmutated VH gene, and CD38+ with clinical outcome. * Determine response to this regimen using an expanded definition of response that includes minimal residual disease detected by sensitive flow cytometry in patients in complete clinical remission and single rearranged IgVH gene detected by polymerase chain reaction in patients with no monoclonal population on flow cytometry. * Correlate in vitro response with clinical outcome in patients treated with this regimen. * Determine if alemtuzumab and rituximab are synergistic in vitro. * Determine the mechanism of action of this regimen in vitro. * Determine the effect of this regimen on immune function. * Monitor T-lymphocyte, natural killer cell, and monocyte number during and after treatment in these patients. * Serially evaluate T-lymphocyte immunophenotype and function in patients treated with this regimen. * Monitor recovery of humoral immunity by serial serum protein electrophoresis, immunofixation electrophoresis, and immunoglobulin quantification. OUTLINE: * Dose-escalation (week 1): Patients receive rituximab IV on day 1 and escalating doses of alemtuzumab subcutaneously (SC) on days 3-5 in week 1. * Treatment (weeks 2-5): Patients receive alemtuzumab SC on days 1-3 (at the highest dose administered during week 1) and rituximab IV on day 3 in weeks 2-5 in the absence of disease progression or unacceptable toxicity. Patients undergo blood collection at baseline and periodically during study treatment for pharmacokinetic and prognostic biomarker (11q-, 17p-, unmutated IgVH, and CD38 expression by flow cytometry and fluorescent in-situ hybridization) studies. Immune function (CDR3 T-cell receptor by reverse transcriptase-polymerase chain reaction) and in vitro and in vivo response are also examined. After completion of study therapy, patients are followed periodically for 5 years. PROJECTED ACCRUAL: A total of 33 patients will be accrued for this study.
Interventions
DRUGAlemtuzumab
30 mg Monday, Wednesday, and Friday x 5 weeks
DRUGRituximab
375mg/m2 IV weekly (Wednesday) x 4 weeks (weeks 2-5)
Sponsors
National Cancer Institute (NCI)
Mayo Clinic
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: \* Diagnosis of B-cell chronic lymphocytic leukemia (CLL) \- Early-stage, biologically high-risk disease defined by the following criteria: * Rai stage 0-II (does not meet standard NCI-sponsored Working Group criteria for treatment) * Clinical and phenotypic features manifested in the peripheral blood, including the following: * Minimum threshold peripheral blood lymphocyte count of \> 5,000/mm³ * Small-to-moderate peripheral blood lymphocytes with ≤ 55% prolymphocytes * Monoclonality of B lymphocytes by immunophenotypic evaluation, demonstrating co-expression of CD19, CD5, and CD23 antigens, surface expression of CD20 and CD52, and B-cell monoclonal population defined by light-chain exclusions * Poor prognosis demonstrated by ≥ 1 of the following high-risk parameters: * Unmutated human immunoglobulin variable region heavy chain (IgVH) gene and CD38 expression (≥ 30% cells positive on flow cytometry) OR unmutated IgVH ZAP-70 expression (≥ 20% cells positive on flow cytometry) = 11q- = 17p- PATIENT CHARACTERISTICS: * ECOG performance status 0-2 * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * Creatinine ≤ 1.5 times upper limit of normal (ULN) * Total bilirubin ≤ 3.0 times ULN OR direct bilirubin ≤ 1.5 times ULN * AST ≤ 3.0 times ULN (unless due to hemolysis or CLL) * Hemoglobin ≥ 9.0 g/dL * No New York Heart Association class III-IV heart disease * No myocardial infarction within the past month * No uncontrolled infection * No active HIV infection * No evidence of autoimmune hemolytic anemia, immune thrombocytopenia, or pure red blood cell aplasia * No other active primary malignancy requiring treatment or limiting survival to less than 2 years PRIOR CONCURRENT THERAPY: * No prior treatment for CLL * Prior corticosteroids allowed * No prior radiotherapy * More than 4 weeks since prior major surgery
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Confirmed Response, Defined as Objective Complete Remission or Partial Remission for a Duration of at Least 2 Months | Up to 6 months | Confirmed response is defined as a \> 50% decrease in clinical symptoms from baseline and recovery from blood counts. |
| Number of Participants With Treatment Related Adverse Events | Weekly for first 6 weeks, then monthly for 6 months, then at 9 and 12 months post registration | Adverse events (AE) that are classified as either possibly, probably, or definitely related to study treatment according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE version 3.0). The maximum grade for each type of AE will be recorded for each patient. Grade refers to the severity of the AE.\> \> Grade 1: Mild AE, Grade 2: Moderate AE, Grade 3: Severe AE, Grade 4: Life-threatening or disabling AE, Grade 5: Death related AE |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Response | Registration to first response (up to 5 years) | Calculated from the date of registration until the first date at which the patient's objective status was classified as a response. In patients who do not achieve a response, time to response will be censored at the patient's last evaluation date. Response is defined the same way as in the response primary outcome measure. |
| Duration of Response | Up to 5 years | Duration of response is calculated from the date of documented response until the date of progression in the subset of patients who respond to treatment. In patients who have not yet progressed, duration of response will be censored at the patient's last evaluation date. |
| Survival | Death or last follow-up (up to 5 years) | Survival is calculated from the date of registration to the date of death due to any cause. In patients who are still alive, survival will be censored at the last date when the patient was known to be alive. |
| Time to Disease Progression | Time from registration to progression (up to 5 years) | Calculated from date of registration to date of disease progression. In patients that have not progressed, time to disease progression will be censored at the patient's last evaluation date. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Alemtuzumab + Rituximab Alemtuzumab 30mg Monday, Wednesday, and Friday x 5 weeks, Rituximab 375/mg/m2 IV weekly (Wednesday) x 4 weeks (weeks 2-5) | 30 |
| Total | 30 |
Baseline characteristics
| Characteristic | Alemtuzumab + Rituximab |
|---|---|
| Age Continuous | 61 years |
| Performance Score 0 - Fully Active | 27 participants |
| Performance Score 1 - Ambulatory, restricted strenuous activity | 3 participants |
| Region of Enrollment United States | 30 participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 29 / 30 |
| serious Total, serious adverse events | 1 / 30 |
Outcome results
Primary
Confirmed Response, Defined as Objective Complete Remission or Partial Remission for a Duration of at Least 2 Months
Confirmed response is defined as a \> 50% decrease in clinical symptoms from baseline and recovery from blood counts.
Time frame: Up to 6 months
Population: Number of patients with a confirmed response out of total patients evaluable for response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alemtuzumab + Rituximab | Confirmed Response, Defined as Objective Complete Remission or Partial Remission for a Duration of at Least 2 Months | 27 participants |
Primary
Number of Participants With Treatment Related Adverse Events
Adverse events (AE) that are classified as either possibly, probably, or definitely related to study treatment according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE version 3.0). The maximum grade for each type of AE will be recorded for each patient. Grade refers to the severity of the AE.\> \> Grade 1: Mild AE, Grade 2: Moderate AE, Grade 3: Severe AE, Grade 4: Life-threatening or disabling AE, Grade 5: Death related AE
Time frame: Weekly for first 6 weeks, then monthly for 6 months, then at 9 and 12 months post registration
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alemtuzumab + Rituximab | Number of Participants With Treatment Related Adverse Events | Grade 3-4 Hematologic | 11 participants |
| Alemtuzumab + Rituximab | Number of Participants With Treatment Related Adverse Events | Grade 3-4 Non-hematologic | 3 participants |
Secondary
Duration of Response
Duration of response is calculated from the date of documented response until the date of progression in the subset of patients who respond to treatment. In patients who have not yet progressed, duration of response will be censored at the patient's last evaluation date.
Time frame: Up to 5 years
Population: Patients that responded were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alemtuzumab + Rituximab | Duration of Response | 14.4 Months |
Secondary
Survival
Survival is calculated from the date of registration to the date of death due to any cause. In patients who are still alive, survival will be censored at the last date when the patient was known to be alive.
Time frame: Death or last follow-up (up to 5 years)
Population: At analysis time, only 1 out of 30 patients had died. Thus, median survival was not attainable.
Secondary
Time to Disease Progression
Calculated from date of registration to date of disease progression. In patients that have not progressed, time to disease progression will be censored at the patient's last evaluation date.
Time frame: Time from registration to progression (up to 5 years)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alemtuzumab + Rituximab | Time to Disease Progression | 12.5 Months |
Secondary
Time to Response
Calculated from the date of registration until the first date at which the patient's objective status was classified as a response. In patients who do not achieve a response, time to response will be censored at the patient's last evaluation date. Response is defined the same way as in the response primary outcome measure.
Time frame: Registration to first response (up to 5 years)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alemtuzumab + Rituximab | Time to Response | 8 Days |