P1105: FINAL RESULTS OF THE PHASE I/II HOVON124/ECWM-R2 STUDY INCLUDING 2-YEAR RITUXIMAB MAINTENANCE AFTER INDUCTION WITH IXAZOMIB, RITUXIMAB AND DEXAMETHASONE IN RELAPSED WALDENSTRÖM’S MACROGLOBULINEMIA

Abstract

Background: In the phase I/II HOVON124/ECWM-R2 trial, induction treatment with the combination of ixazomib, subcutaneous (s.c.) rituximab and dexamethasone (IRd) showed promising efficacy with manageable toxicity in patients with relapsed Waldenström’s Macroglobulinemia (WM). Aims: Here we report the final analysis of the trial after two years of rituximab maintenance and with a median follow-up (FU) on study of 45.6 months (range, 12.4-72.2). Methods: In total, 59 patients were enrolled (median age, 69 years; range, 46-91 years) of which 48 patients completed at least six cycles of induction with IRd; 41 patients (median age 66 years, 66% male) with at least a minimal response (MR) continued to 2 years of rituximab maintenance (1400 mg s.c., q 3 months) starting 3 months after the last induction cycle. The primary endpoint of the study was overall response rate (ORR, ≥ MR)) after 8 induction cycles and was 71% (Kersten/Amaador et al, JCO, 2022). Secondary endpoints included progression-free survival (PFS), overall survival (OS) and ORR after 2 years of rituximab maintenance and improvement of response after maintenance. Results: In total, 22 (54%) out of 41 patients completed 2 years of rituximab maintenance. The median number of cycles was 8 (range, 1-8). Nineteen patients did not complete maintenance treatment due to progression (n=16), excessive toxicity (n=1), non-compliance (n=1), and other unknown reason (n=1). The best ORR after maintenance was 85% (2% complete response [CR], 24% very good partial response [VGPR], 39% partial response [PR], and 20% MR). Improvement of response after maintenance occurred in 9 (22%) patients; VGPR to CR in one (2%), PR to VGPR in 6 (15%), and MR to PR in 2 (5%). A further decrease in IgM levels was seen after 2 years of maintenance (IgM 3.62 g/dl at baseline; 1.3 g/dl after induction and 0.42 g/dl after end of maintenance, p-value<0.001; Figure 1A), accompanied by a further increase in Hb levels (Hb 10.5 to 14.3 g/dl, p-value<0.001; Figure 1B). The median progression-free survival (PFS) was 23.6 months (95% CI, 13.4 to 43.2; Figure 1C), and median overall survival (OS) was not reached; at 45 months, 85% of patients were alive (95% CI, 0.72 to 0.92; Figure 1D). The median time to best response was 7 months, the median duration of response (DOR) was 34.8 months, and the median time to next treatment (TTNT) was 36 months[MM(1]. After a median FU of 45.6 months, 29 patients had received subsequent therapy and the median time to progression after subsequent therapy was 53.7 months[MM(2]. During maintenance, rituximab was administered i.v. instead of s.c. in 7 (17%) patients. None of the patients treated with s.c. rituximab developed systemic hypersensitivity reactions but 2 patients had an injection site reaction (1 grade 1, 1 grade 2). Grade 3/4 toxicity was seen in 10% and 5% of patients, respectively (grade 3/4 neutropenia (n=1 and n=2), grade 3 chronic kidney disease (n=1), and grade 3 elevations of transaminases (n=2)). In the 41 patients who started maintenance, 8 SAEs were reported in 6 patients, of which 4 occurred during maintenance (mostly infections) and 4 (mostly secondary malignancies, considered unrelated to study drug) during FU. Three patients died during maintenance therapy due to progressive disease, intracranial bleeding, and acute myeloid leukemia, respectively. Image:Summary/Conclusion: Rituximab maintenance after IRd induction is feasible and well tolerated. The ORR improved in 22% of patients, confirming the efficacy of this chemo-free regimen in combination with rituximab maintenance in relapsed/refractory WM.