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Chlorambucil, rituximab and lenalidomide in CLL
gressed in one (2%) patient. Improvement of the response after induction-II was observed in eight (15%) of all patients who started induction-I: six patients (11%) had an improvement from a partial to complete response and two patients (4%) had an improvement from stable dis- ease to a partial response in induction-II.
Flow-based minimal residual disease analysis was per- formed on peripheral blood in 41 patients. Of these patients, four (8%) achieved minimal residual disease negativity after induction-I and an additional two (4%) after induction-II.
Survival
After a median follow-up of 27 months, the median pro- gression-free survival was 49 months (Figure 5A). At 2 and 3 years, 58% [standard error (SE)=8%] and 54% (SE=8%) of the patients, respectively, were alive without progres- sion. The 3-year progression-free survival rate of patients with a deletion of chromosome 17p [del(17p); n=8] was lower than that of patients without this deletion (38% ver- sus 59%, respectively). For patients who started induction- II (n=42), the subsequent progression-free survival was 41 months and the 2-year progression-free survival rate was 56% (SE=9%). The median event-free survival was 49 months and the event-free survival rate at 3 years was 53% (SE=8%) with 13% (SE=5%) non-responders and 34% (SE=8%) with progressive disease. Of the patients with progressive disease, one patient started the next treatment before progressing. During follow-up the median overall survival was not reached with 2- and 3-year overall sur- vival rates of 98% (SE=2%) and 95% (SE=3%), respective- ly (Figure 5B). With regard to overall survival following induction-II, no deaths had occurred among the patients who started induction-II.
Safety
Two patients included in the phase 2 part of the trial developed a grade 4 adverse event, consisting of neu- tropenic sepsis. These severe adverse events occurred during induction-I in cycle 2 and cycle 5. No grade 4 adverse events were observed during induction-II. Tumor lysis syndrome did not occur. A tumor flare reaction was reported in five patients (9%) and was ≤ grade 2 in four patients and grade 3 in one patient. Six patients devel- oped a secondary malignancy, which was localized skin cancer in all but one. One patient had a solid tumor.
Grade 3-4 neutropenia occurred in 39 (73%) and 27 (64%) patients during induction-I and induction-II, respectively, which prompted granulocyte colony-stimu- lating factor administration as shown per cycle in Online
Figure 4. Responses after induction-I and -II. PD: progressive disease; SD: sta- ble disease; PR: partial response; CR: complete response.
Table 2. Grade 3-4 toxicities.
Hematologic toxicity
Neutropenia
Thrombocytopenia
Anemia
Other adverse events
Any
Infections and infestations
General disorders and administration site conditions Skin and subcutaneous tissue disorders
Respiratory, thoracic and mediastinal disorders Musculoskeletal and connective tissue disorders Nervous system disorders
Blood and lymphatic disorders
Cardiac disorders
Immune system disorders
Metabolism and nutrition disorders
Renal and urinary disorders
Investigations
Psychiatric disorders
Number of patients (%)
Grade 3
14 (26%)
5 (9%)
Grade 4
25 (47%)
3 (6%)
Grade 3
14 (33%)
5 (12%)
Induction I
Induction II Grade 4
13 (31%)
2 (5%)
-
-
- - - - - - - - - - - - -
1(2%) - -
21 (40%)
5 (9%) 6 (11%) 6 (11%) 3 (6%) 1 (2%) 1 (2%) 1 (2%) 1 (2%) 2 (4%) 2 (4%) 1 (2%) 1 (2%) 1 (2%)
2 (4%)
-
-
-
-
-
-
-
1 (2%) -
-
-
1 (2%) -
8 (19%)
4 (10%) -
3 (7%) -
-
-
-
1 (2%) -
-
-
-
-
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