Leukemia
Conditions
Keywords
refractory chronic lymphocytic leukemia, B-cell chronic lymphocytic leukemia
Brief summary
RATIONALE: Drugs used in chemotherapy, such as pentostatin, cyclophosphamide, and CAMPATH-1H work in different ways to stop cancer cells from dividing so they stop growing or die. Monoclonal antibodies, such as rituximab can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Combining chemotherapy with monoclonal antibody therapy may kill more tumor cells. PURPOSE: This phase II trial is studying how well pentostatin, cyclophosphamide, rituximab, and CAMPATH-1H work in treating patients with relapsed or refractory B-cell chronic lymphocytic leukemia.
Detailed description
OBJECTIVES: Primary * Determine the objective response rate (complete remission, partial remission \[PR\], or nodular PR) in patients with relapsed or refractory B-cell chronic lymphocytic leukemia (CLL) treated with pentostatin, cyclophosphamide, and rituximab (PCR) followed by CAMPATH-1H . * Determine the presence of minimal residual disease in patients treated with this regimen who achieve a CR or nPR Secondary * Determine the toxicity of this regimen in these patients. * Determine the overall and progression-free survival of patients treated with this regimen. * Evaluate the number of patients who after PCR (or during PCR for PD), only achieve a PR, SD, or PD and who subsequently convert to a higher response category after CAMPATH-1H . Exploratory * Assess the angiogenic profile (i.e., secretion levels of pro- versus anti-angiogenic molecules) of CLL B cell clones as well as bone marrow angiogenesis (i.e., vascular density by immunohistochemistry) at baseline, after PCR, after CAMPATH-1H, every six months (serum only), and at time of response assessment (marrow). * Determine the V\_H gene mutation status and CD38 expression of the B-CLL clones at study entry and at the end of the therapy and assess the association between the VH gene mutation status and CD38 expression and clinical outcome. * Determine surface phenotype (by flow cytometry) and genetic defects (by CLL FISH panel) information on CLL-B cell clones and associate with clinical outcome. * Monitor the T-cell status by repertoire and flow cytometry analysis to determine the nature and extent of T-cell deficiency induced by the PCR and CAMPATH-1H treatment and assess any association with clinical outcome and toxicities.
Interventions
BIOLOGICALrituximab
DRUGcyclophosphamide
DRUGpentostatin
DRUGAlemtuzumab
Sponsors
National Cancer Institute (NCI)
Eastern Cooperative Oncology Group
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of B-cell chronic lymphocytic leukemia (CLL) meeting the following criteria: * Peripheral blood absolute lymphocyte count greater than 5,000/mm\^3 * Lymphocytosis must comprise small to moderate size lymphocytes with no greater than 55% prolymphocytes, atypical lymphocytes, or lymphoblasts morphologically * Phenotypically characterized CLL defined by the following: * Predominant population of cells share B-cell antigens with CD5 in the absence of other pan-T-cell markers (CD3 or CD2) * B cell expresses either kappa or lambda light chains * Surface immunoglobulin with low cell surface density expression * Requires chemotherapy, as indicated by any of the following: * Disease-related symptoms * Weight loss of 10% or more within the past 6 months * Extreme fatigue * Fevers greater than 100.5°F for 2 weeks without evidence of infection * Night sweats without evidence of infection * Evidence of progressive marrow failure manifested by the development of or worsening anemia (hemoglobin no greater than 10 g/dL) and/or thrombocytopenia (platelet count no greater than 100,000/mm\^3) * Massive (i.e., greater than 6 cm below left costal margin) or progressive splenomegaly * Massive nodes or clusters (i.e., greater than 10 cm in longest diameter) or progressive adenopathy * Progressive lymphocytosis with an increase of greater than 50% over a 2-month period OR an anticipated doubling time of less than 6 months * Demonstrated progression after at least 1 course of either an alkylating agent-based or purine nucleoside-based (e.g., fludarabine) regimen OR failed to achieve a meaningful response OR relapsed after prior therapy * Patients who have relapsed after a pentostatin-based regimen are eligible provided the response was greater than 12 months prior to study entry * 18 and over * ECOG Performance Status 0-2 * Bilirubin no greater than 2 mg/dL (unless secondary to tumor, hemolysis, or Gilbert syndrome) * Creatinine no greater than 2.0 mg/dL * Creatinine clearance ≥ 30 mL/min * Negative pregnancy test * Fertile patients must use 2 methods of effective contraception (including 1 barrier method) for at least 28 days before starting lenalidomide, while participating in the study, and for at least 28 days after discontinuation/stopping lenalidomide * At least 8 weeks since prior rituximab * At least 6 weeks since prior chemotherapy * At least 1 year since prior pentostatin, cyclophosphamide, and rituximab (PCR) therapy * PCR therapy at least 1 year prior to study entry allowed
Exclusion criteria
* Bone marrow dysplasia related to prior therapy * New York Heart Association class III or IV heart failure * Prior lenalidomide * Other malignancy within the past 2 years except squamous cell or basal cell skin cancer or carcinoma in situ of the cervix * Pregnant or nursing * Concurrent oral or IV antibiotics for active infection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Molecular Complete Remission (MCR) Rate | 3 months post alemtuzumab | Percent of patients who have MCR (clinical CR with flow negative and RT-PCR negative) |
| Response Rate | 8 weeks after Cycle 6 | Percent with response (CR, nPR, PR) with two-stage 90% confidence interval |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to 5 years from registration | OS is defined as the time from registration until death from any cause. |
| Progression-free Survival (PFS) | Up to 5 years from registration | PFS is defined as the time from registration until induction failure, institution of non-protocol therapy, relapse or death from any cause in the absence of relapse. |
| Number of Patients Who After PCR (or During PCR for PD), Only Achieve a PR, SD, or PD and Who Subsequently Convert to a Higher Response Category After Campath-1H | From re-registration up to 5 years (followed for response until progression) | — |
Countries
United States
Participant flow
Recruitment details
Patients were recruited from ECOG-ACRIN institutions between 12/16/04 and 5/6/13. The first patient was accrued on 4/14/05.
Participants by arm
| Arm | Count |
|---|---|
| Arm A (PCR) Treatment consisted of 6 cycles of pentostatin, cyclophosphamide, and rituximab (PCR) given every 28 days.
Rituximab administered as follows: For the first infusion, all patients receive 100 mg dose (regardless of weight/BSA). For subsequent infusions, all patients receive rituximab 375 mg/m2.
Pentostatin and cyclophosphamide administered as follows: Pentostatin given at 4 mg/m2 either as an IV push or IV over 10-30 minutes in 250 mL NS or D5W on day 1 every 4 weeks of cycles 1-6. Cyclophosphamide given at 600 mg/m2 IV over 30-60 minutes in 250 mL NS on day 1 every 4 weeks of cycle 1-6.
rituximab
cyclophosphamide
pentostatin | 96 |
| Total | 96 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Step 1 | Adverse Event | 32 | 0 | 0 |
| Step 1 | Alternative therapy | 2 | 0 | 0 |
| Step 1 | Death | 6 | 0 | 0 |
| Step 1 | Disease progression | 2 | 0 | 0 |
| Step 1 | Ineligible | 4 | 0 | 0 |
| Step 1 | Never started treatment | 2 | 0 | 0 |
| Step 1 | Other complicating disease | 2 | 0 | 0 |
| Step 1 | Physician Decision | 1 | 0 | 0 |
| Step 1 | Withdrawal by Subject | 7 | 0 | 0 |
| Step 2 | Adverse Event | 0 | 2 | 12 |
| Step 2 | Death | 0 | 0 | 3 |
| Step 2 | Disease progression | 0 | 0 | 5 |
| Step 2 | Ineligible | 0 | 0 | 1 |
| Step 2 | Physician Decision | 0 | 0 | 1 |
| Step 2 | Withdrawal by Subject | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Arm A (PCR) |
|---|---|
| Age, Continuous | 64 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 92 Participants |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 76 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 71 / 100 | 5 / 9 | 23 / 31 |
| other Total, other adverse events | 99 / 100 | 9 / 9 | 31 / 31 |
| serious Total, serious adverse events | 88 / 100 | 8 / 9 | 31 / 31 |
Outcome results
Primary
Molecular Complete Remission (MCR) Rate
Percent of patients who have MCR (clinical CR with flow negative and RT-PCR negative)
Time frame: 3 months post alemtuzumab
Population: Patients who achieved a CR or nPR in Step 1 and were eligible for and began treatment on Step 2
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (PCR) | Molecular Complete Remission (MCR) Rate | 44.4 percentage |
Primary
Response Rate
Percent with response (CR, nPR, PR) with two-stage 90% confidence interval
Time frame: 8 weeks after Cycle 6
Population: Eligible patients who began treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (PCR) | Response Rate | 55.2 percentage |
Secondary
Number of Patients Who After PCR (or During PCR for PD), Only Achieve a PR, SD, or PD and Who Subsequently Convert to a Higher Response Category After Campath-1H
Time frame: From re-registration up to 5 years (followed for response until progression)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A (PCR) | Number of Patients Who After PCR (or During PCR for PD), Only Achieve a PR, SD, or PD and Who Subsequently Convert to a Higher Response Category After Campath-1H | 4 Participants |
Secondary
Overall Survival (OS)
OS is defined as the time from registration until death from any cause.
Time frame: Up to 5 years from registration
Population: Eligible patients who began treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (PCR) | Overall Survival (OS) | 27.6 months |
Secondary
Progression-free Survival (PFS)
PFS is defined as the time from registration until induction failure, institution of non-protocol therapy, relapse or death from any cause in the absence of relapse.
Time frame: Up to 5 years from registration
Population: Eligible patients who began treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (PCR) | Progression-free Survival (PFS) | 12.2 months |