Leukemia
Conditions
Keywords
B-cell chronic lymphocytic leukemia, stage I chronic lymphocytic leukemia, stage II chronic lymphocytic leukemia, stage III chronic lymphocytic leukemia, stage IV chronic lymphocytic leukemia
Brief summary
This randomized phase III trial is studying fludarabine, cyclophosphamide, and rituximab to see how well they work compared to fludarabine and cyclophosphamide in treating patients with B-cell chronic lymphocytic leukemia.
Interventions
DRUGRituximab
Intravenous repeating dose
DRUGCyclophosphamide
Intravenous repeating dose
DRUGFludarabine Phosphate
Intravenous repeating dose
Sponsors
German CLL Study Group
Hoffmann-La Roche
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
DISEASE CHARACTERISTICS: * Diagnosed B-cell chronic lymphocytic leukemia (CLL) defined by the National Cancer Institute (NCI) Working Group criteria * Meets 1 of the following criteria: * Binet stage C disease * Binet stage B disease AND ≥ 1 of the following signs or symptoms\*: * B symptoms (night sweats, weight loss ≥ 10% within the previous 6 months, fevers \> 38°C or 100.4°F for ≥ 2 weeks without evidence of infection), or constitutional symptoms (fatigue) * Continuous progression (doubling of peripheral lymphocyte count within the past 6 months and absolute lymphocyte count \> 50 G/I) * Evidence of progressive marrow failure as manifested by the development/worsening of anemia and/or thrombocytopenia * Massive, progressive or painful splenomegaly or hypersplenism * Massive lymph nodes or lymph node clusters (\> 10 cm in longest diameter), danger of organ complications through large lymphoma (e.g., vascular compression or tracheal narrowing), or progressive lymphadenopathy * Occurrence of symptomatic hyperviscosity problems at leukocyte counts \> 200 G/I (symptomatic leukostasis) NOTE: \* Marked hypogammaglobulinemia or the development of a monoclonal protein in the absence of any of the above criteria for active disease is not sufficient for eligibility * No Binet stage A disease * No transformation to an aggressive B-cell malignancy (e.g., diffuse large cell lymphoma, Richter's syndrome, or prolymphocytic leukemia) PATIENT CHARACTERISTICS: * Eastern Cooperative Oncology Group (ECOG) performance status 0-1 * Cumulative Illness Rating Scale (CIRS) score \> 6 * Life expectancy \> 6 months * Bilirubin ≤ 2 times upper limit of normal (ULN) * Alkaline phosphatase and transaminases ≤ 2 times ULN * Creatinine clearance ≥ 70 mL/min * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception during and for 2 months after study treatment * No known hypersensitivity with anaphylactic reaction to humanized monoclonal antibodies or any of the study drugs * No cerebral dysfunction that precludes chemotherapy * No active bacterial, viral, or fungal infection * No clinically significant autoimmune cytopenia or Coombs-positive hemolytic anemia * No other active malignancy requiring concurrent treatment except basal cell carcinoma or tumors treated curatively by surgery * No medical or psychological condition that would preclude study therapy * No concurrent disease that requires prolonged (\> 1 month) therapy involving glucocorticoids PRIOR CONCURRENT THERAPY: * No previous treatment of CLL by chemotherapy, radiotherapy, or immunotherapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Median observation time at time of analysis was approximately 21 months | Progression-free survival (PFS) was defined as the time between randomization and the date of first documented disease progression, relapse or death by any cause, whichever came first. |
| Final Analysis: Time to Progression-free Survival Event | Median observation time was approximately 66.4 months | Progression-free survival was defined as the time between randomization and the date of first documented disease progression, relapse or death by any cause, whichever came first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease-free Survival (DFS) of Patients With Confirmed Complete Response (CR). | Median observation time at time of analysis was approximately 21 months | CR is defined by at least 8 weeks of: 1)Absence of lymphadenopathy 2)No hepatomegaly or splenomegaly 3)Absence of B-symptoms 4)Normal blood count 5)Bone marrow aspirate and biopsy 8 weeks after the clinical and laboratory results demonstrated that a CR was achieved. A marrow sample had to be normocellular for age with less than 30% lymphocytes. Lymphoid nodules had to be absent. If marrow was hypocellular,a repeat biopsy was taken 4 weeks later and samples were re-reviewed in conjunction with the prior pathology. DFS was calculated from time of CR to relapse or death. Median DFS was not reached. |
| Final Analysis: Time to Overall Survival Event | Median observation time was approximately 66.4 months | Overall survival (OS) was defined as the time between randomization and the date of death due to any cause. |
| Final Analysis: Time to Event-free Survival Event | Median observation time was approximately 66.4 months | Event-free survival was defined as the time between randomization and the date of disease progression, relapse, start of new Chronic Lymphocytic Leukemia treatment or death by any cause. |
| Event-free Survival (EFS) | Median observation time at time of analysis was approximately 21 months | Event-free survival (EFS) was defined as the time between randomization and the date of disease progression, relapse, start of new CLL treatment or death by any cause. |
| Final Analysis: Duration of Response | Median observation time was approximately 66.4 months | Duration of response was defined as the time from the first documented Complete Response, Partial Response to disease progression or death by any cause. |
| Final Analysis: Percentage of Participants With Complete Response (CR) and Partial Response | Median observation time was approximately 66.4 months | CR is defined by at least 8 weeks of: 1)Absence of lymphadenopathy 2)No hepatomegaly or splenomegaly 3)Absence of B-symptoms 4)Normal blood count 5)Bone marrow aspirate and biopsy 8 weeks after the clinical and laboratory results demonstrated that a CR was achieved. A marrow sample had to be normocellular for age with less than 30% lymphocytes. Lymphoid nodules had to be absent. If marrow was hypocellular,a repeat biopsy was taken 4 weeks later and samples were re-reviewed in conjunction with the prior pathology. Partial response is defined as a decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment. |
| Final Analysis: Time to New Treatment for Chronic Lymphocytic Leukemia(CLL) | Median observation time was approximately 66.4 months | The time from randomization to the start of a new treatment. |
| Final Analysis: Time to Disease-free Survival (DFS) Event in Participants With Complete Response (CR) | Median observation time was approximately 66.4 months | CR is defined by at least 8 weeks of: 1)Absence of lymphadenopathy 2)No hepatomegaly or splenomegaly 3)Absence of B-symptoms 4)Normal blood count 5)Bone marrow aspirate and biopsy 8 weeks after the clinical and laboratory results demonstrated that a CR was achieved. A marrow sample had to be normocellular for age with less than 30% lymphocytes. Lymphoid nodules had to be absent. If marrow was hypocellular,a repeat biopsy was taken 4 weeks later and samples were re-reviewed in conjunction with the prior pathology. DFS was calculated from time of CR to relapse or death |
| Overall Survival (OS) | Median observation time at time of analysis was approximately 21 months | Overall survival (OS) was defined as the time between randomization and the date of death due to any cause. Median OS was not reached. |
Countries
Australia, Austria, Belgium, Czechia, Denmark, France, Germany, Israel, Italy, New Zealand, Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Fludarabine+Cyclophosphamide (FC) Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles. | 407 |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) Rituximab intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: 375 mg/m² IV on Day 0; Cycles 2-6: 500 mg/m² IV on Day 1. FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles. | 403 |
| Total | 810 |
Baseline characteristics
| Characteristic | Fludarabine+Cyclophosphamide (FC) | Fludarabine+Cyclophosphamide+Rituximab (FCR) | Total |
|---|---|---|---|
| Age Continuous | 59.3 years STANDARD_DEVIATION 8.55 | 59.6 years STANDARD_DEVIATION 8.7 | 59.5 years STANDARD_DEVIATION 8.62 |
| Sex: Female, Male Female | 105 Participants | 105 Participants | 210 Participants |
| Sex: Female, Male Male | 302 Participants | 298 Participants | 600 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 122 / 398 | 185 / 402 |
| serious Total, serious adverse events | 164 / 398 | 186 / 402 |
Outcome results
Primary
Final Analysis: Time to Progression-free Survival Event
Progression-free survival was defined as the time between randomization and the date of first documented disease progression, relapse or death by any cause, whichever came first.
Time frame: Median observation time was approximately 66.4 months
Population: Participants from the Intent-to-treat population, that included all randomized participants, with PFS events.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fludarabine+Cyclophosphamide (FC) | Final Analysis: Time to Progression-free Survival Event | 998.0 Days |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) | Final Analysis: Time to Progression-free Survival Event | 1703.0 Days |
p-value: <0.000195% CI: [0.48, 0.67]Log Rank
Primary
Progression-free Survival (PFS)
Progression-free survival (PFS) was defined as the time between randomization and the date of first documented disease progression, relapse or death by any cause, whichever came first.
Time frame: Median observation time at time of analysis was approximately 21 months
Population: The Intent-to-treat (ITT) population was comprised of all patients randomized in the study, irrespective of whether they received treatment or not. Informed consent was unavailable at the time of analysis for 2 patients in the FC group and 5 patients in the FCR group. ITT population: FC = 407; FCR = 403.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fludarabine+Cyclophosphamide (FC) | Progression-free Survival (PFS) | 981.0 Days |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) | Progression-free Survival (PFS) | 1212.0 Days |
p-value: <0.0001Log Rank
Secondary
Disease-free Survival (DFS) of Patients With Confirmed Complete Response (CR).
CR is defined by at least 8 weeks of: 1)Absence of lymphadenopathy 2)No hepatomegaly or splenomegaly 3)Absence of B-symptoms 4)Normal blood count 5)Bone marrow aspirate and biopsy 8 weeks after the clinical and laboratory results demonstrated that a CR was achieved. A marrow sample had to be normocellular for age with less than 30% lymphocytes. Lymphoid nodules had to be absent. If marrow was hypocellular,a repeat biopsy was taken 4 weeks later and samples were re-reviewed in conjunction with the prior pathology. DFS was calculated from time of CR to relapse or death. Median DFS was not reached.
Time frame: Median observation time at time of analysis was approximately 21 months
Population: The ITT population was comprised of all patients randomized in the study, irrespective of whether they received treatment or not. Informed consent was unavailable at the time of analysis for 2 patients in the FC group and 5 patients in the FCR group. ITT population: FC = 407; FCR = 403.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fludarabine+Cyclophosphamide (FC) | Disease-free Survival (DFS) of Patients With Confirmed Complete Response (CR). | Minimum number of days to an event | 84 Days to an event |
| Fludarabine+Cyclophosphamide (FC) | Disease-free Survival (DFS) of Patients With Confirmed Complete Response (CR). | Maximum number of days to an event | 1164 Days to an event |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) | Disease-free Survival (DFS) of Patients With Confirmed Complete Response (CR). | Minimum number of days to an event | 91 Days to an event |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) | Disease-free Survival (DFS) of Patients With Confirmed Complete Response (CR). | Maximum number of days to an event | 1226 Days to an event |
p-value: 0.7882Log Rank
Secondary
Event-free Survival (EFS)
Event-free survival (EFS) was defined as the time between randomization and the date of disease progression, relapse, start of new CLL treatment or death by any cause.
Time frame: Median observation time at time of analysis was approximately 21 months
Population: The ITT population was comprised of all patients randomized in the study, irrespective of whether they received treatment or not. Informed consent was unavailable at the time of analysis for 2 patients in the FC group and 5 patients in the FCR group. ITT population: FC = 407; FCR = 403.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fludarabine+Cyclophosphamide (FC) | Event-free Survival (EFS) | 947.0 Days |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) | Event-free Survival (EFS) | 1212.0 Days |
p-value: <0.0001Log Rank
Secondary
Final Analysis: Duration of Response
Duration of response was defined as the time from the first documented Complete Response, Partial Response to disease progression or death by any cause.
Time frame: Median observation time was approximately 66.4 months
Population: Participants from the Intent-to-treat population, all randomized participants, with complete response or partial response who experienced an event (disease progression or death due to any cause).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fludarabine+Cyclophosphamide (FC) | Final Analysis: Duration of Response | 1102.0 Days |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) | Final Analysis: Duration of Response | 1718.0 Days |
p-value: <0.000195% CI: [0.48, 0.71]Log Rank
Secondary
Final Analysis: Percentage of Participants With Complete Response (CR) and Partial Response
CR is defined by at least 8 weeks of: 1)Absence of lymphadenopathy 2)No hepatomegaly or splenomegaly 3)Absence of B-symptoms 4)Normal blood count 5)Bone marrow aspirate and biopsy 8 weeks after the clinical and laboratory results demonstrated that a CR was achieved. A marrow sample had to be normocellular for age with less than 30% lymphocytes. Lymphoid nodules had to be absent. If marrow was hypocellular,a repeat biopsy was taken 4 weeks later and samples were re-reviewed in conjunction with the prior pathology. Partial response is defined as a decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment.
Time frame: Median observation time was approximately 66.4 months
Population: Intent-to-treat population included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fludarabine+Cyclophosphamide (FC) | Final Analysis: Percentage of Participants With Complete Response (CR) and Partial Response | 72.4 Percentage of participants |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) | Final Analysis: Percentage of Participants With Complete Response (CR) and Partial Response | 85.8 Percentage of participants |
p-value: <0.000195% CI: [1.62, 3.28]Chi-squared
Secondary
Final Analysis: Time to Disease-free Survival (DFS) Event in Participants With Complete Response (CR)
CR is defined by at least 8 weeks of: 1)Absence of lymphadenopathy 2)No hepatomegaly or splenomegaly 3)Absence of B-symptoms 4)Normal blood count 5)Bone marrow aspirate and biopsy 8 weeks after the clinical and laboratory results demonstrated that a CR was achieved. A marrow sample had to be normocellular for age with less than 30% lymphocytes. Lymphoid nodules had to be absent. If marrow was hypocellular,a repeat biopsy was taken 4 weeks later and samples were re-reviewed in conjunction with the prior pathology. DFS was calculated from time of CR to relapse or death
Time frame: Median observation time was approximately 66.4 months
Population: Participants from the Intent-to-treat population, all randomized participants, with complete response who experienced a disease free survival event (disease relapse or death).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fludarabine+Cyclophosphamide (FC) | Final Analysis: Time to Disease-free Survival (DFS) Event in Participants With Complete Response (CR) | 1488.0 Days |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) | Final Analysis: Time to Disease-free Survival (DFS) Event in Participants With Complete Response (CR) | 1854.0 Days |
p-value: 0.052395% CI: [0.52, 1.02]Log Rank
Secondary
Final Analysis: Time to Event-free Survival Event
Event-free survival was defined as the time between randomization and the date of disease progression, relapse, start of new Chronic Lymphocytic Leukemia treatment or death by any cause.
Time frame: Median observation time was approximately 66.4 months
Population: Participants from the Intent-to-treat population, that included all randomized participants, with disease progression, relapse, start of new Chronic Lymphocytic Leukemia treatment or death.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fludarabine+Cyclophosphamide (FC) | Final Analysis: Time to Event-free Survival Event | 951.0 Days |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) | Final Analysis: Time to Event-free Survival Event | 1666.0 Days |
p-value: <0.000195% CI: [0.48, 0.67]Log Rank
Secondary
Final Analysis: Time to New Treatment for Chronic Lymphocytic Leukemia(CLL)
The time from randomization to the start of a new treatment.
Time frame: Median observation time was approximately 66.4 months
Population: Participants from the Intent-to-treat population, that included all randomized participants, who started a new CLL treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fludarabine+Cyclophosphamide (FC) | Final Analysis: Time to New Treatment for Chronic Lymphocytic Leukemia(CLL) | 1455.0 Days |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) | Final Analysis: Time to New Treatment for Chronic Lymphocytic Leukemia(CLL) | 2082.0 Days |
p-value: <0.000195% CI: [0.49, 0.72]Log Rank
Secondary
Final Analysis: Time to Overall Survival Event
Overall survival (OS) was defined as the time between randomization and the date of death due to any cause.
Time frame: Median observation time was approximately 66.4 months
Population: Participants from the Intent-to-treat population, that included all randomized participants who died.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fludarabine+Cyclophosphamide (FC) | Final Analysis: Time to Overall Survival Event | 2613.0 Days |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) | Final Analysis: Time to Overall Survival Event | NA Days |
p-value: 0.00195% CI: [0.54, 0.86]Log Rank
Secondary
Overall Survival (OS)
Overall survival (OS) was defined as the time between randomization and the date of death due to any cause. Median OS was not reached.
Time frame: Median observation time at time of analysis was approximately 21 months
Population: The ITT population was comprised of all patients randomized in the study, irrespective of whether they received treatment or not. Informed consent was unavailable at the time of analysis for 2 patients in the FC group and 5 patients in the FCR group. ITT population: FC = 407; FCR = 403.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fludarabine+Cyclophosphamide (FC) | Overall Survival (OS) | Minimum number of days to an event | 5 Days |
| Fludarabine+Cyclophosphamide (FC) | Overall Survival (OS) | Maximum number of days to an event | 1373 Days |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) | Overall Survival (OS) | Minimum number of days to an event | 4 Days |
| Fludarabine+Cyclophosphamide+Rituximab (FCR) | Overall Survival (OS) | Maximum number of days to an event | 1372 Days |
p-value: 0.0427Log Rank