Final report of a phase II study of ibrutinib and venetoclax in previously untreated Waldenström macroglobulinemia Free

Introduction: BTK inhibitors and BCL2 antagonists are highly active and well-tolerated in Waldenström macroglobulinemia (WM). We initiated a prospective study of the combination of ibrutinib and venetoclax in treatment-naïve patients with WM. This was the first chemotherapy-free, fixed-duration, all-oral regimen to be evaluated in a clinical trial in WM. The accrual goal was 50 patients. Study therapy was stopped on March 31, 2022, after enrolling 45 because of four ventricular arrhythmia events, including two grade 5 events. Study follow-up continued, and we present the final report of this study here.

Methods: This was an investigator-initiated, multicenter, prospective phase II study in symptomatic, treatment-naïve patients with WM (NCT04273139). The study was approved by the IRB of the participating institutions. All patients provided written consent before the commencement of research. Intended therapy consisted of ibrutinib 420 mg/day on cycle 1. Venetoclax was added on cycle 2 at 100 mg/day for one week, 200 mg/day for one week, and 400 mg/day for two weeks. Ibrutinib 420 mg/day and venetoclax 400 mg/day were then given together for cycles 3-24. Study therapy was given in 4-week cycles. All patients underwent tumor lysis syndrome monitoring during the ramp-up of venetoclax. Categorical responses were assessed using modified IWWM6 criteria. Time to events was estimated using the Kaplan-Meier method, and groups were compared using the log-rank test. Events of interest included progression-free survival (PFS), treatment-free survival (TFS), overall survival (OS), and PFS after the end of treatment (EOT). Cox proportional-hazard regression models were fitted to identify predictors of the events of interest. P-values <0.05 were considered significant.

Results: Of the 45 patients, 53% were 65 or older, 67% were male, 73% had hemoglobin ≤11.5 g/dl, 69% had albumin <4 g/dl, 64% had beta-2-microglobulin ≥3 mg/l, 58% had serum IgM ≥4000 mg/dl, 58% had ≥60% bone marrow involvement, 53% had lymphadenopathy ≥1.5 cm, 27% had splenomegaly ≥15 cm, 7% had platelets ≤100 k/ul, and 4% had a high serum LDH. CXCR4 mutations were detected in 38%. The median time on treatment was 10 months (range 2-21). At best response, 42% attained a very good partial response (VGPR), 24% a partial response (PR), and 4% a minor response.

The median follow-up from treatment initiation was 49 months (95% CI 47-53); 27 patients (60%) experienced disease progression, 11 patients (24%) started a new treatment, and four patients (9%) died. The median PFS was 36 months (95% CI 28-42). Median TFS and OS were not reached. The 4-year TFS rate was 73% (95% CI 57-84), and the 4-year OS rate was 91% (95% CI 77-96). Baseline platelets ≤100 K/uL (HR 6.6; 95% CI 1.7-26; p=0.007) and high serum LDH (HR 10.9; 95% CI 2.2-54.9; p=0.004) were associated with inferior PFS in multivariate analysis. A baseline high serum LDH level was associated with inferior TFS (HR 12.8; 95% CI 1.3-123.3; p=0.03) and inferior OS (HR 10.7; 95% CI 1.1-104.7; p=0.04). CXCR4 mutations did not impact PFS, TFS, or OS. The median follow-up from EOT was 39 months (95% CI 38-39), and the median PFS after EOT was 29 months (95% CI 21-37). CXCR4 mutations, VGPR attainment at EOT, or <12 months of treatment did not affect PFS after EOT (p>0.05 for all).

Of 11 patients who initiated a new treatment, four started zanubrutinib monotherapy, one started venetoclax monotherapy, one started bendamustine and rituximab, one started R-CHOP (DLCBL transformation), and four started a clinical trial. All patients responded to the subsequent line of treatment. Of the four patients who died, two died of ventricular arrhythmia while on and responding to therapy, one of amyotrophic lateral sclerosis 32 months after EOT, and one of an unknown cause 25 months after EOT. All deaths occurred in the absence of WM progression.

Conclusion: The combination of ibrutinib and venetoclax, given as a fixed-duration treatment, induced deep and durable responses in previously untreated patients with WM and did not impact the response to subsequent lines of therapy. Despite the deep responses, this regimen is not recommended due high rates of ventricular arrhythmia. CXCR4 mutations, depth of response at EOT, or time on treatment did not affect durability of the response. Results of this study suggest that combination therapy in WM may allow patients a significant treatment-free interval.