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A.P. Kater et al.
AB
Figure 5. Survival outcomes after registration. (A) Progression-free survival and (B) overall survival, with the numbers of patients at risk at 1, 2 and 3 years.
Supplementary Table S7. Neutropenic sepsis occurred in two (4%) patients. Grade 3-4 thrombocytopenia was recorded in 15% and 17% of the patients after induction- I and induction-II, respectively. Despite this, no grade 3-4 bleeds occurred. Grade 3-4 anemia was recorded in 2% of the patients during induction-I. Although all patients received thromboembolic prophylaxis, two patients (4%) had a thromboembolic event (i.e. deep vein thrombosis and thrombophlebitis despite prophylactic aspirin).
Grade 3-4 skin and subcutaneous tissue disorders occurred in six patients (11%). Thirteen patients (25%) developed grade 2 skin toxicity. Other grade 3-4 toxicities occurred in 26 patients (49%), of which 23 (44%) during induction-I and eight (19%) during induction-II. The majority of these toxic events were infections (15%), gas- trointestinal disorders (15%), or general disorders and administration site conditions (11%) (Table 2).
Two patients (4%) have died during disease progres- sion. These deaths occurred 19 and 24 months after reg- istration in the study.
Discussion
In this prospective, open label, phase 1/2 study, we investigated the activity of lenalidomide in combination with chlorambucil and rituximab for elderly and FCR- unfit patients with previously untreated CLL.
After a median follow-up of 27 months, the median progression-free survival in our study was 49 months. The 2- and 3-year progression-free survival rates were 58% and 54%, respectively. The corresponding overall survival rates were 98% and 95%. Since this study is the first to investigate triple treatment with chlorambucil, rit- uximab and lenalidomide, direct comparison with other clinical trials is limited.
Recently, novel first-line regimens have been tested in frail, elderly patients: e.g., chlorambucil as a backbone with novel CD20 monoclonal antibodies and novel chemother- apy-free combinations. The CLL11 trial compared treat- ment with chlorambucil monotherapy, chlorambucil and rituximab or chlorambucil and obinutuzumab.1 The medi- an progression-free survival was 16.3 months for patients
treated with chlorambucil and rituximab and 26.7 months for those treated with chlorambucil and obinutuzumab. The COMPLEMENT-1 trial investigated treatment with chlorambucil and ofatumumab, comparing this with chlo- rambucil monotherapy.21 After a median follow-up of 29 months, the median progression-free survival was 22 months and the overall response rate was 82% for patients treated with chlorambucil and ofatumumab.
With regards to chemotherapy-free combinations of lenalidomide with rituximab, an overall response rate of 88% and a median progression-free survival of 20 months were observed in a phase 2 study.14 In the phase 1b/2 PCYC-1102/1103 studies, treatment with ibrutinib result- ed in overall response rates of 87% and 89% in treat- ment-naïve and relapsed/refractory patients, respectively. The overall response rates were 97%, 89% and 79% in relapsed/refractor patients with a del(11q), complex kary- otype and del(17p), respectively. After a median follow- up of 61.5 months, the median progression-free survival had not been reached in treatment-naïve patients and was 51 months in relapsed/refractory patients.22,23
With all the caveats necessary when comparing differ- ent trials, the progression-free survival and overall response rates in the current study seem at least compa- rable to those observed with chlorambucil in combina- tion with novel CD20 monoclonal antibodies and those observed with kinase inhibitors.
The dose of chlorambucil used in our study was 7 mg/m2 on days 1-7 of cycles 1-6. Chlorambucil was administered in combination with rituximab and lenalidomide during six cycles. In the COMPLEMENT-1 trial patients were treated with 10 mg/m2 of chlorambucil on days 1-7 during a minimum of three and a maximum of 12 cycles. In the CLL11 trial, chlorambucil was administered at a dose of 0.5 mg/kg on days 1 and 15 of cycles 1-6.
Lenalidomide was started at a dose of 2.5 mg/day, and was steadily increased to 10 mg/day which was main- tained until cycle 6, provided there were no dose-limiting toxicities. The escalation scheme of lenalidomide was previously described in combination with rituximab in a phase 2 trial.14 However, in that study lenalidomide was administered for 21 days, followed by a period of rest each cycle. The use of a continuous dose of lenalidomide
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haematologica | 2019; 104(1)