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Onsets of progression and second treatment determine survival of patients with symptomatic Waldenstrom macroglobulinemia.

ABSTRACT: Few reports assess prognosis during follow-up of patients with symptomatic Waldenström macroglobulinemia (WM). In 121 WM patients treated between 1993 and 2016, we analyzed the prognostic role during the clinical course of the initial International Prognostic Scoring System for WM (IPSSWM). Then, we assessed onset of response, progression, and second treatment initiation coded as time-dependent covariates. High-risk IPSSWM was an adverse prognostic factor for survival after first treatment initiation (SAFTI). Nevertheless, the corresponding Dxy concordance index obtained in multiple landmark analyses decreased from 0.24 to 0.08 during the first 6 years, in accordance with a departure from the proportional hazard assumption. By contrast with onset of response (whatever its level), onset of progression and initiation of second-line treatment retained prognostic value for SAFTI (P = .02 and P = .006, respectively). These findings were confirmed in cause-specific Cox models for deaths related to WM, but not for unrelated deaths. Time to progression after first-line treatment and time to initiation of second-line treatment had no prognostic value for survival after these 2 events. These results were confirmed in an independent series of 119 patients homogeneously treated with chemoimmunotherapy. Finally, after second-line and third-line treatment, onset of progression had significant prognostic value for subsequent risk of related death only. Thus, taking initial IPSSWM and delayed response to treatment into account, only onset of progression and second treatment initiation provided additional prognostic information for SAFTI. Therefore, progression-free survival or time to next treatment may be satisfactory surrogate end points of SAFTI in WM.

SUBMITTER: Guidez S

PROVIDER: S-EPMC6258926 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeWe report the long-term findings and final analysis of a pivotal multicenter trial of ibrutinib monotherapy in previously treated patients with Waldenström macroglobulinemia (WM).Patients and methodsSixty-three symptomatic patients with median prior therapies of two (range, one to nine therapies), of whom 40% were refractory to their previous therapy, received ibrutinib at 420 mg/d. Dose reduction was permitted for toxicity.ResultsThe median follow-up was 59 months, and overall and major response rates were 90.5% and 79.4%, respectively. At best response, median serum immunoglobulin M declined from 3,520 to 821 mg/dL, bone marrow disease involvement declined from 60% to 20%, and hemoglobin rose from 10.3 to 14.2 g/dL (P < .001 for all comparisons). Responses were impacted by mutated (Mut) MYD88 and CXCR4 status. Patients with MYD88Mut, wild-type (WT) CXCR4 showed higher major (97.2% v 68.2%; P < .0001) and very good partial (47.2% v 9.1%; P < .01) response rates and a shorter time to major response (1.8 v 4.7 months; P = .02) versus patients with MYD88MutCXCR4Mut. Conversely, four patients who had MYD88WT disease showed no major responses. The median 5-year progression-free survival (PFS) rate for all patients was not reached, and was 70% and 38% for those with MYD88MutCXCR4WT and MYD88MutCXCR4Mut WM, respectively (P = .02). In patients with MYD88WT, the median PFS was 0.4 years (P < .01 for three-way comparisons). The 5-year overall survival rate for all patients was 87%. Grade ≥ 3 adverse events in more than one patient at least possibly related included neutropenia (15.9%), thrombocytopenia (11.1%), and pneumonia (3.2%). Eight patients (12.7%) experienced atrial arrhythmia, and seven of the eight continued therapy with medical management.ConclusionIbrutinib is highly active and produces long-term disease control in previously treated patients with WM. Treatment is tolerable. Response depth, time to major response, and PFS are impacted by MYD88 and CXCR4 mutation status.

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Onsets of progression and second treatment determine survival of patients with symptomatic Waldenstrom macroglobulinemia.

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