Obinutuzumab and idelalisib in symptomatic patients with relapsed/refractory Waldenström macroglobulinemia

Abstract

We present the results of a phase 2 study evaluating the combination of obinutuzumab + idelalisib in relapsed/refractory (R/R) Waldenström macroglobulinemia (WM). The goal was to determine the safety and efficacy of a fixed-duration chemotherapy-free treatment. During the induction phase, patients received idelalisib + obinutuzumab for 6 cycles, followed by a maintenance phase with idelalisib alone for ≤2 years. Forty-eight patients with R/R WM were treated with the induction combination, and 27 patients participated in the maintenance phase. The best responses, reached after a median of 6.5 months (interquartile range, 3.4-7.1; range, 2.6-22.1 months), were very good partial response in 5 patients, partial response in 27 patients, and minor response in 3 patients, leading to overall response rate and major response rate estimates of 71.4% (95% confidence interval [CI], 56.7-83.4) and 65.3% (95% CI, 50.4-78.3), respectively. With a median follow-up of 25.9 months, median progression-free survival was 25.4 months (95% CI, 15.7-29.0). Univariate analysis focusing on molecular screening found no significant impact of CXCR4 genotypes on responses and survivals but a deleterious impact of TP53 mutations on survival. Although there was no grade 5 toxicity, 26 patients were removed from the study because of side effects; the most frequent were neutropenia (9.4%), diarrhea (8.6%), and liver toxicity (9.3%). The combination of idelalisib + obinutuzumab is effective in R/R WM. Nonetheless, the apparent lack of impact of genotype on outcome could give new meaning to targeting of the phosphatidylinositol 3-kinase pathway in WM. This trial was registered at www.clinicaltrials.gov as #NCT02962401.

Conflict of interest statement

Conflict-of-interest disclosure: C.T. has served on Advisory Boards and received travel support from Roche, Gilead Sciences, Janssen, AbbVie, BeiGene, and Takeda. C.H. has received research funding from Takeda and AbbVie and has received honoraria and nonfinancial support from Roche, Janssen-Cilag, Takeda, and AbbVie. P.M. has served on Advisory Boards for BeiGene, Janssen, and Amgen. O.T. has received honoraria and travel support from AbbVie, Takeda, Gilead Sciences, and Janssen and has received honoraria from Sandoz. O.C. has acted as a consultant for and received honoraria from Roche, Gilead Sciences, Bristol Myers Squibb, Takeda, MSD, and AbbVie and has received research funding from Roche, Gilead Sciences, and Takeda. V.L. has acted as a consultant for and received honoraria from Roche, Gilead Sciences, AbbVie, Eli Lilly and Company, Janssen, and AstraZeneca. The remaining authors declare no competing financial interests.

© 2021 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Study flowchart, patient disposition, and treatment exposure. M8, month 8; PD, progressive disease.

Figure 2.

OS and PFS according to molecular profile. PFS (A), OS (B), PFS according to CXCR4 mutational status and the type of CXCR4 mutation (frameshift vs non-sense) (C), and PFS according to TP53 mutational status (D). (C) Red line, absence of CXCR4 mutation [CXCR4(WT)] (left panel), green line, CXCR4 mutation non-sense [CXCR4(NS)]; blue line, CXCR4 mutation frameshift [CXCR4(FS)]. (D) Red line, absence of TP53 mutation (WT); blue line, TP53 mutation (MUT).

Figure 3.

Best responses according to CXCR4 (left panel) and TP53 (right panel) mutational status (n = 49 and n = 45, respectively).