Abstract
AbstractWe 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.
Highlights
Waldenstrom macroglobulinemia (WM) is characterized by the malignant accumulation of immunoglobulin M (IgM) that is caused by IgM-secreting lymphoplasmacytic lymphoma cells in bone marrow (BM).[1]
We present the results of a phase 2 study evaluating the combination of obinutuzumab 1 idelalisib in relapsed/refractory (R/R) Waldenstrom macroglobulinemia (WM)
We report a prospective study of the combination of idelalisib 1 obinutuzumab in symptomatic R/R WM patients with a 2-year fixed duration of idelalisib
Summary
Waldenstrom macroglobulinemia (WM) is characterized by the malignant accumulation of immunoglobulin M (IgM) that is caused by IgM-secreting lymphoplasmacytic lymphoma cells in bone marrow (BM).[1]. Mutation of MYD88L265P was described by Treon and colleagues in 90% of WM patients; it is responsible for the proliferation and survival of WM cells by activating the NF-kB pathway via BTK.[5,6] As a result, targeting of BCR kinases is emerging as a new treatment paradigm for numerous B-cell malignancies. A selective BTK inhibitor, has shown high activity and very promising results in patients with WM. Most chemotherapy-free regimen data have been reported in relapsing or refractory (R/R) patients treated with BTK inhibitors, alone or in association with rituximab.[7,8,9,10] lower response rates and longer time to reach a response have been reported in MYD88WT and CXCR4MUT genotype patients treated with ibrutinib.[7,11]
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