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A.P. Kater et al.
port of the data safety and monitoring board, decided to continue part 2 of the trial with the recommended dose level of 7 mg/m2, day 1-7, of chlorambucil (dose level 1) based on toxicity reports of an international phase 3 study.9
Phase 2 patients and study treatment
For the phase 2 part of the trial, 57 patients were includ- ed of whom four were subsequently excluded because they were not eligible in hindsight having been found to have small lymphocytic lymphoma. Combination treat- ment with chlorambucil, rituximab and lenalidomide was started in 53 patients (induction-I). The patients’ disposi- tion through the trial is summarized in Figure 2 and the clinical, biological and cytogenetic characteristics of the patients are reported in Table 1. The median age of the patients was 71 years (range, 60 – 80). Mutational status could be assessed in 39 patients. The IGVH genes were mutated in 20 patients (51%) and unmutated in 19 patients (49%). Deletion of chromosome 17p was found in eight of 51 (17%) patients. Eight of 50 (15%) and 23 of 50 (43%) patients had deletion of chromosome 11q and 13q, respectively.
Forty-seven (89%) patients completed the six planned courses of chlorambucil, rituximab and lenalidomide. Treatment was prematurely discontinued in 11 patients (21%). Reasons for discontinuation were excessive toxic-
ity (n=8: 4 cases of skin toxicity, 1 grade 3 allergic reac- tion, 1 case of neuropathy, 1 acute coronary syndrome and 1 case of mucositis), refusal (n=2) and progression (n=1).
Following combination treatment, lenalidomide monotherapy was initiated in 42 patients (79%) (induc- tion-II). Treatment was prematurely discontinued during induction-II in six patients, due to excessive toxicity (n=5: 3 cases of hematologic toxicity in the form of persistent neutropenia and 2 cases of diarrhea with no improve- ment following dose reductions.) or refusal (n=1). Treatment was completed according to the protocol in 36 (68%) patients.
The full dose of lenalidomide during induction-I was given to 76% of the patients in cycle 1, to 57% of the patients in cycle 2, to 50% in cycle 3, 57% in cycle 4, 53% in cycle 5 and 51% in cycle 6 (Figure 3). During cycle 6 of induction-II, 25 (69%) patients received lenalidomide at the full dose. The median dose of lenalidomide according to the prescribed protocol dosing was 86.7% (range, 10%-101%) and 99.7% (range, 25%-104%) in induction- I and induction-II, respectively.
Response evaluation
On an intention-to-treat basis, response was analyzed in 53 patients at the end of induction-I. The overall response rate was 83% (95% confidence interval: 72%- 92%), which resulted in a positive trial based on the phase 2 design as stated in the protocol. The responding patients all achieved a partial response and no complete responses were observed on induction-I (Figure 4).
Responses at the end of induction-II were evaluated in all patients (n=42) who started this phase of induction. The overall response rate was 93% (95% confidence interval: 79%-98%) and consisted of 14% complete responses (n=6) and 79% partial responses (n=33). The disease remained stable in two (5%) patients and pro-
Figure 3. Lenalidomide dosing: cumulative dose of lenalidomide compared to optimal dose per treatment cycle during induction-I. Lena: Lenalidomide.
Table 1. Patients’ characteristics. Patients’ characteristics
Median age [range], years Age, n. (%)
<65 years
≥65 to ≤70 years
>70 years
Male sex, n. (%)
RAI stage, n. (%) 0-I
II
III
IV
CIRS score − n. (%) ≤6
Number of patients (n=53)
71 [60-80]
1 (2) 25 (47) 27 (51)
29 (55)
11 (21) 10 (19) 22 (42) 10 (19)
47 (87) >6 4(8)
Unknown
Median CIRS [range]
2 (4) 1 [0-9]
33 (62) 18 (34) 2 (4)
3.8 [1.6-10.4]
20 (38) 19 (36) 14 (26)
8 out of 51 (17%) 8 out of 51 (17%) 12 out of 50 (24%) 23 out of 50 (46%)
Lactate dehydrogenase, n. (%)
Lactate dehydrogenase ≤ upper level of normal Lactate dehydrogenase > upper level of normal Unknown
Median β2-microglobulin [range] (n=43)
IGVH mutational status − n. (%) Mutated
Unmutated
Unknown
Cytogenetic abnormalities − n. (%) Del17p
Del11q
Trisomy 12
Del 13q
CRS: Cumulative Illness Rating Scale; IGVH: immunoglobulin variable region heavy chain; del: deletion.
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