Page 160 - 2022_02-Haematologica-web

S. Rule et al.
Figure 1. Study design. aWaldenström macroglobulinemia/lymphoplasmacytic lymphoma or marginal zone lymphoma. bChemotherapy options included bendamus- tine, CHOP, CVP, FCM, MCP, CHVP-IFN, chlorambucil, fludarabine-containing regimen or GIFOX. cMaintenance started within 8–12 weeks of completion of induction. R/R: relapsed or refractory; FL: follicular lymphoma; Gr: grade; NHL: non-Hodgkin lymphoma; R: rituximab; Cs: cycles; PD: disease progression; CR: complete response; PR: partial response; SD: stable disease; SC: subcutaneous; IV: intravenous; CHOP: cyclophosphamide, doxorubicin, vincristine and prednisone; CVP: cyclophosphamide, vincristine and prednisone; FCM: fludarabine, cyclophosphamide and mitoxantrone; MCP: mitoxantrone, chlorambucil and prednisone; CHVP-IFN: cyclophosphamide, doxorubicin, etoposide and prednisone + interferon-α; GIFOX: gemcitabine, ifosfamide and oxaliplatin.
follow-up (4; 0.6%), death (2; 0.3%) or other reasons (20; 2.9%) (Online Supplementary Figure S1A, B, Online Supplementary Table S2). A further 39 patients withdrew after Induction and before Maintenance I because of disease progression (16; 2.3%), adverse events (6; 0.9%), patients’ request (2; 0.3%), investigators’ request (2; 0.3%), death (1; 0.1%), loss to follow-up (1; 0.1%) or other reasons (11; 1.6%, all with stable disease).
Of the 505 patients who continued to Maintenance I, 494 were treated (ITT population for Maintenance I; treatment was not given because of adverse events in 5 patients, dis- ease progression in 2, investigator’s request or death in 1 each, and other reasons in 2). During Maintenance I, 188 patients (38.1%) discontinued study treatment because of disease progression (82; 16.6%), adverse events (66; 13.4%), patients’ request (20; 4.0%), investigators’ request (8; 1.6%), death (3; 0.6%), loss to follow-up (2; 0.4%) or other reasons (7; 1.4%: 2 with stable disease) (Online Supplementary Figure S1C). A further 28 patients (5.7%) completed Maintenance I but discontinued before Maintenance II. Reasons were patients’ request (12; 2.4%), disease progression (9; 1.8%), adverse events (4; 0.8%), investigator’s request (1; 0.2%) and other reasons (2; 0.4%). Two other patients (0.4%) failed to meet randomization cri- teria; the remaining 276 patients were randomized to Maintenance II (Figure 2).
The median durations of the Induction and Maintenance I periods were 8.2 (range 0–18) months and 22.1 (range 0– 31) months, respectively.
The primary ITTrand population included 276 patients who were randomized into Maintenance II (138 each in the rit- uximab and observation arms). Two further patients were initially planned for randomization but were subsequently found to be ineligible: one had disease progression and one had stable disease. Just over half of all patients were male and approximately two-thirds had Ann Arbor stage IV dis- ease (Table 1). Patients were evenly distributed across FLIPI score categories in both arms. Approximately 40% of patients had bone marrow involvement, and just over half of all patients had FL. Nearly 60% overall had received rit- uximab plus bendamustine at Induction. Of the ITT popu-
lation for Induction (n=692), patients receiving bendamus- tine were older than those receiving CHOP or CVP, and a greater proportion had a high FLIPI score and Ann Arbor stage III/IV disease at screening (Online Supplementary Table S3). More patients receiving bendamustine and CHOP had FL compared with those receiving CVP.
Six of 138 patients in the Maintenance II rituximab arm discontinued before the start of treatment (Figure 2). Maintenance II was completed thereafter by 109 patients randomized to rituximab and 111 randomized to observa- tion; 23 patients (16.7%) randomized to rituximab and 27 (19.6%) randomized to observation discontinued during Maintenance II (Figure 2). The median follow-up time was 28.1 (range, 0–46) months. A single patient had progressive disease at the end of Maintenance I but was randomized to rituximab in error. This was subsequently recorded as a protocol violation.
Rituximab exposure
The median duration of exposure to rituximab during Induction was 6.4 (range, 0–11) months. The median num- ber of rituximab cycles was 8.0 (range, 1–9); 522 patients (75.4%) received the planned eight cycles.
In Maintenance I, the median duration of exposure to rit- uximab was 20.3 (range, 0–28) months, with a median of 12.0 (range, 1–12) cycles being given. Of the 494 patients, 295 (59.7%) received the planned maximum 12 injections every 8 weeks for 24 months.
The median duration of exposure during Maintenance II treatment was 24.8 (range, 0–43) months, and the median number of rituximab cycles was 14.0 (range, 1–24).
Three patients received the highest number of rituximab treatments (44 cycles across the entire study), while two received the lowest (21 cycles).
Safety and tolerability
Induction
Treatment-emergent adverse events and serious adverse events were reported during Induction in 89.0% (616/692) and 30.1% (208/692) of patients, respectively. Half of all patients experienced at least one treatment-emergent
502
haematologica | 2022; 107(2)