Leukemia
Conditions
Keywords
B-cell chronic lymphocytic leukemia, stage 0 chronic lymphocytic leukemia, stage I chronic lymphocytic leukemia
Brief summary
RATIONALE: Drugs used in chemotherapy, such as fludarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as 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 fludarabine together with rituximab may kill more cancer cells. Sometimes the cancer may not need treatment until it progresses. In this case, observation may be sufficient. It is not yet known whether giving fludarabine together with rituximab early is more effective than giving fludarabine and rituximab after observation in treating chronic lymphocytic leukemia. PURPOSE: This randomized phase III trial is studying fludarabine and rituximab to compare how well they work when given early or after observation in treating patients with previously untreated chronic lymphocytic leukemia.
Detailed description
OBJECTIVES: Primary * To determine if early treatment with chemoimmunotherapy comprising fludarabine phosphate and rituximab extends the time to second treatment in patients with genetically high-risk (unmutated IgV\_H), asymptomatic, previously untreated chronic lymphocytic leukemia (CLL). * To determine the time to disease progression that would warrant second treatment. * To determine overall survival. Secondary * To measure the proportion of patients with asymptomatic, previously untreated CLL who have mutated and unmutated IgV\_H genes. * To determine the differences in acute and chronic toxicity of administering chemoimmunotherapy early to patients with genetically high-risk CLL compared to waiting until symptoms develop. * To determine the effect of select pretreatment clinical and biological characteristics (such as interphase cytogenetic abnormalities, ZAP-70 expression, and p53 dysfunction \[primary and secondary\]) on response, time to second treatment, and overall survival of patients with genetically high-risk CLL randomized to early treatment. * To determine the effect of select pretreatment clinical and biological characteristics (such as interphase cytogenetic abnormalities, ZAP-70 expression, and p53 dysfunction) on response, time to first and second treatments, and overall survival of patients with genetically high-risk CLL randomized to standard treatment (observation until symptoms occur). * To describe the natural history of patients with genetically low-risk (mutated IgV\_H genes), asymptomatic, previously untreated CLL, in terms of time to initial treatment, response, progression, and survival. * To determine the effect of select pretreatment characteristics on time to first treatment, response, progression, and survival of patients with genetically low-risk CLL. * To correlate patterns of resistance that emerge in patients with unmutated IgV\_H genes who have relapsing or refractory CLL following receipt of chemoimmunotherapy with clonal evolution, including acquisition of high-risk karyotype abnormalities, p53 mutations, p53 dysfunction (primary and secondary), altered mRNA and protein expression related to treatment resistance, DNA mutations, microRNA gene expression, and methylation changes. * To determine whether highly sensitive flow cytometry negativity at completion of therapy in patients randomized to early treatment is an effective surrogate marker for prolonged time to second treatment, overall survival, and other clinical benefits. * To collect demographic data on familial CLL in newly diagnosed patients participating on this study. OUTLINE: This is a multicenter study. * Genetically high-risk disease: Patients are stratified according to age (\< 50 years vs 50 to 70 years vs \> 70 years) and presence of the high-risk genetic feature \[del(11)(q22.3) or del(17)(p13.1)\] by FISH (yes vs no). Patients are randomized to 1 of 2 treatment arms. * Arm I: Patients receive rituximab IV over 4 hours on days 1, 3, and 5 of week 1 and then on day 1 of weeks 5, 9, 13, 17, and 21. Patients also receive fludarabine phosphate IV over 30 minutes on days 1-5 of weeks 1, 5, 9, 13, 17, and 21. After completion of chemoimmunotherapy, patients are followed every 3 months until disease progression. At the time of disease progression, patients receive retreatment with chemoimmunotherapy as above or another treatment regimen. * Arm II: Patients are followed every 3 months until disease progression. At the time of disease progression, patients receive rituximab and fludarabine phosphate as in arm I. Patients are then followed every 3 months until second disease progression. Patients with a second disease progression receive retreatment with chemoimmunotherapy as above or another treatment regimen. * Genetically low-risk disease: Patients are followed every 3 months until disease progression. At the time of disease progression, patients receive rituximab and fludarabine phosphate as in arm I. Patients are then followed every 3 months until second disease progression. Patients with a second disease progression receive retreatment with chemoimmunotherapy as above or another treatment regimen. Patients undergo blood sample collection periodically for correlative studies. After finishing treatment, patients are followed periodically.
Interventions
BIOLOGICALrituximab
Given IV over 4 hours
DRUGfludarabine phosphate
Given IV over 30 minutes
Sponsors
National Cancer Institute (NCI)
Alliance for Clinical Trials in Oncology
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Eligibility Criteria for Pre-Registration: 1. Patients must be within 6 months of the initial flow cytometric confirmation of B-cell chronic lymphocytic leukemia (CLL). This interval begins with the initial flow cytometric confirmation of disease. 2. Clinical and immunophenotypic evidence of CLL including: 2.1 An absolute lymphocytosis of \> 5,000/μL * Morphologically, the lymphocytes must appear mature with \< 55% prolymphocytes. * Local institution lymphocyte phenotype must reveal a predominant B-cell monoclonal population sharing a B-cell marker (CD19, CD20, CD23) with the CD5 antigen, in the absence of other pan-T-cell markers. * Additionally, the B-cells must be monoclonal with regard to expression of either κ or λ and have surface immunoglobulin expression of low density. * Patients with bright surface immunoglobulin levels must have CD23 coexpression and absence of t(11;14) on interphase cytogenetics or have negative tumor protein staining for cyclin D1. 2.2 Staging - Patients must be in the low category (i.e., only stages 0 or I) of the modified three-stage Rai staging system as described in the protocol. 3. Patients should not have evidence of active disease as demonstrated by any of the following criteria: * Splenomegaly and/or massive/progressive lymphadenopathy that would require therapy * Presence of weight loss \> 10% over the preceding 6 month period * Grade 2 or 3 fatigue * Fevers \> 100.5°F or night sweats for greater than 2 weeks without evidence of infection * Progressive lymphocytosis with an increase of \> 50% over a 2 month period or an anticipated doubling time of less than 6 months. 4. Prior Treatment: No prior therapy for CLL including corticosteroids for autoimmune complications that have developed since the initial diagnosis of CLL. 5. Age ≥ 18 years 6. Performance Status 0 - 1. 7. No HIV disease. Due to alterations in host immunity, patients known to have HIV infection may not be enrolled. 8. Non-pregnant and non-nursing. Due to the unknown teratogenic potential of chemotherapy, pregnant or nursing women may not be enrolled. Women and men of reproductive potential should agree to use an effective means of birth control. 9. Required Initial Laboratory Values: * Creatinine ≤ 1.5 x upper limit of normal Eligibility Criteria for Registration (to Low-Risk Cohort or High-Risk Cohort Randomization between Early Intervention Versus Observation with Later Treatment) 1. Successful determination of IgVH mutational status by reference laboratory. 2. Absence of progression of CLL, i.e., absence of the following: * Progressive splenomegaly and/or lymphadenopathy on two independent measures spaced two weeks apart. If one assessment notes progression, this should be repeated prior to re-registration. * Development of anemia (hemoglobin \< 11 g/dL) or thrombocytopenia (platelets \< 100,000/μL). * Progressive lymphocytosis with an increase of \> 50% over a 2 month period or an anticipated doubling time of less than 6 months. * Symptoms referable to CLL, including weight loss \> 10% over the preceding 6 month period; grade 2 or 3 fatigue; or fevers \> 100.5°F and/or night sweats for greater than 2 weeks without evidence of infection. 3. Required Laboratory Value: * Creatinine ≤ 1.5 x upper limit of normal
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Second Treatment in High Risk Patients | Up to 72 months | Kaplan-Meier analysis was conducted to estimate the distribution of time from randomization to second treatment or death whichever comes first. Events were defined as the start of second treatment or death. Patients who had not experienced one of these defined events of interest were censored at their last known follow-up. |
| Disease-Free Survival in High Risk Patients | Up to 72 months | Kaplan-Meier analysis was conducted to estimate disease free survival defined as:\> * Arm A: Time from randomization until Second Treatment (first relapse) or death whichever comes first. Events were defined as the start of second treatment or death. Patients who had not experienced one of these defined events of interest were censored at their last known follow-up.\> * Arm B: Time from randomization until First Treatment (first relapse) or death whichever comes first. Events were defined as the start of first treatment or death. Patients who had not experienced one of these defined events of interest were censored at their last known follow-up. |
| Overall Survival (OS) for High Risk Patients | Up to 72 months | Kaplan-Meier analysis was conducted to estimate the distribution of time from randomization to death from any cause. Estimates were not stratified. Patients who did not experience this primary outcome had their survival times censored at their last follow-up. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Mutated and Unmutated IgVH Genes | Once at baseline | Number of patients with mutated and unmutated IgVH genes are reported below. |
| Overall Survival in Low Risk Patients | Up to 72 months | Overall survival in low risk patients (registration to first treatment or death)\> • Events were defined as death from any cause. Low risk Patients who were alive were censored at their last known follow-up. |
| Time to First Treatment Survival in Low Risk Patients | Up to 72 months | Time to First Treatment Survival in low risk patients (registration to first treatment or death)\> • Events were defined as the start of first treatment or death from any cause. Patients who didn't receive their first treatment were censored at their last known follow-up. |
Countries
Canada, United States
Participant flow
Pre-assignment details
The Enrollment number in the Protocol Section does not match the number of participants who started in the Participant Flow due to limited data on one participant (i.e. the participant was registered but was not randomized or classified (high vs. low risk) because the participant withdrew consent for all follow-up the same day of registration).
Participants by arm
| Arm | Count |
|---|---|
| Arm A: High Risk Early Intervention Randomized Patients receive 50, 325, and 375 mg/m\^2 rituximab IV over 4 hours on days 1, 3, and 5 of week 1, respectively; then patients receive 375 mg/m\^2 rituximab IV on day 1 of weeks 5, 9, 13,\> 17, and 21. Patients also receive 25 mg/m\^2/day fludarabine monophosphate IV over 30 minutes on days 1-5 of weeks 1, 5, 9, 13, 17, and 21. After completion of chemoimmunotherapy, patients are followed every 3 months until disease progression. At the time of disease progression, patients receive retreatment with chemoimmunotherapy as above or another treatment regimen. | 17 |
| Arm B: High Risk Observation + Later Treatment Randomized Patients are followed every 3 months until disease progression. At the time of disease progression, patients receive rituximab and fludarabine phosphate as in Arm A. Patients are then followed every 3 months until second disease progression. Patients with a second disease progression receive retreatment with chemoimmunotherapy as above or another treatment regimen. | 11 |
| Arm C: Low Risk Observation + Later Treatment Patients who were registered to the low-risk arm may elect to provide continued follow-up information on their treatment, disease course, and outcome regardless of the medical therapy they and their physician select. Patients are followed every 3 months until disease progression. At the time of disease progression, patients receive rituximab and fludarabine phosphate as in Arm A. Patients are then followed every 3 months until second disease progression. Patients with a second disease progression receive retreatment with chemoimmunotherapy as above or another treatment regimen. | 55 |
| Total | 83 |
Baseline characteristics
| Characteristic | Arm A: High Risk Early Intervention | Arm B: High Risk Observation + Later Treatment | Arm C: Low Risk Observation + Later Treatment | Total |
|---|---|---|---|---|
| Age, Continuous | 60 years | 60 years | 59 years | 60 years |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 23 Participants | 27 Participants |
| Sex: Female, Male Male | 16 Participants | 8 Participants | 32 Participants | 56 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 17 | 2 / 11 | 2 / 55 |
| other Total, other adverse events | 9 / 9 | 11 / 11 | 40 / 40 |
| serious Total, serious adverse events | 0 / 9 | 0 / 11 | 0 / 40 |
Outcome results
Primary
Disease-Free Survival in High Risk Patients
Kaplan-Meier analysis was conducted to estimate disease free survival defined as:\> * Arm A: Time from randomization until Second Treatment (first relapse) or death whichever comes first. Events were defined as the start of second treatment or death. Patients who had not experienced one of these defined events of interest were censored at their last known follow-up.\> * Arm B: Time from randomization until First Treatment (first relapse) or death whichever comes first. Events were defined as the start of first treatment or death. Patients who had not experienced one of these defined events of interest were censored at their last known follow-up.
Time frame: Up to 72 months
Population: Randomized High Risk patients are included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: High Risk Early Intervention | Disease-Free Survival in High Risk Patients | 62.7 months |
| Arm B: High Risk Observation + Later Treatment | Disease-Free Survival in High Risk Patients | 39.2 months |
p-value: 0.0097Log Rank
Primary
Overall Survival (OS) for High Risk Patients
Kaplan-Meier analysis was conducted to estimate the distribution of time from randomization to death from any cause. Estimates were not stratified. Patients who did not experience this primary outcome had their survival times censored at their last follow-up.
Time frame: Up to 72 months
Population: Randomized High Risk patients are included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: High Risk Early Intervention | Overall Survival (OS) for High Risk Patients | NA months |
| Arm B: High Risk Observation + Later Treatment | Overall Survival (OS) for High Risk Patients | NA months |
p-value: 0.4645Log Rank
Primary
Time to Second Treatment in High Risk Patients
Kaplan-Meier analysis was conducted to estimate the distribution of time from randomization to second treatment or death whichever comes first. Events were defined as the start of second treatment or death. Patients who had not experienced one of these defined events of interest were censored at their last known follow-up.
Time frame: Up to 72 months
Population: Randomized High Risk patients are included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: High Risk Early Intervention | Time to Second Treatment in High Risk Patients | 62.7 months |
| Arm B: High Risk Observation + Later Treatment | Time to Second Treatment in High Risk Patients | 56.3 months |
p-value: 0.1521Log Rank
Secondary
Number of Patients With Mutated and Unmutated IgVH Genes
Number of patients with mutated and unmutated IgVH genes are reported below.
Time frame: Once at baseline
Population: All patients are included in this analysis.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: High Risk Early Intervention | Number of Patients With Mutated and Unmutated IgVH Genes | Unmutated | 17 Participants |
| Arm A: High Risk Early Intervention | Number of Patients With Mutated and Unmutated IgVH Genes | Mutated | 0 Participants |
| Arm B: High Risk Observation + Later Treatment | Number of Patients With Mutated and Unmutated IgVH Genes | Mutated | 0 Participants |
| Arm B: High Risk Observation + Later Treatment | Number of Patients With Mutated and Unmutated IgVH Genes | Unmutated | 11 Participants |
| Arm C: Low Risk Observation + Later Treatment | Number of Patients With Mutated and Unmutated IgVH Genes | Unmutated | 0 Participants |
| Arm C: Low Risk Observation + Later Treatment | Number of Patients With Mutated and Unmutated IgVH Genes | Mutated | 55 Participants |
| Total | Number of Patients With Mutated and Unmutated IgVH Genes | Unmutated | 28 Participants |
| Total | Number of Patients With Mutated and Unmutated IgVH Genes | Mutated | 55 Participants |
Secondary
Overall Survival in Low Risk Patients
Overall survival in low risk patients (registration to first treatment or death)\> • Events were defined as death from any cause. Low risk Patients who were alive were censored at their last known follow-up.
Time frame: Up to 72 months
Population: Low Risk patients are included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: High Risk Early Intervention | Overall Survival in Low Risk Patients | 58.1 months |
Secondary
Time to First Treatment Survival in Low Risk Patients
Time to First Treatment Survival in low risk patients (registration to first treatment or death)\> • Events were defined as the start of first treatment or death from any cause. Patients who didn't receive their first treatment were censored at their last known follow-up.
Time frame: Up to 72 months
Population: Low Risk patients are included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: High Risk Early Intervention | Time to First Treatment Survival in Low Risk Patients | 58.1 months |