Key Points After hydroxycarbamide therapy in high-risk ET, ruxolitinib showed no improvement for complete or partial response rates compared with BAT. Ruxolitinib significantly improved some disease-related symptoms, but rates of thrombosis, hemorrhage, or transformation were not different.

PURPOSE The CLL14 study has established one-year fixed-duration treatment of venetoclax and obinutuzumab (Ven-Obi) for patients with previously untreated chronic lymphocytic leukemia. With all patients off treatment for at least three years, we report a detailed analysis of minimal residual disease (MRD) kinetics and long-term outcome of patients treated in the CLL14 study. PATIENTS AND METHODS Patients were randomly assigned to receive six cycles of obinutuzumab with 12 cycles of venetoclax or 12 cycles of chlorambucil (Clb-Obi). Progression-free survival (PFS) was the primary end point. Key secondary end points included rates of undetectable MRD and overall survival. To analyze MRD kinetics, a population-based growth model with nonlinear mixed effects approach was developed. RESULTS Of 432 patients, 216 were assigned to Ven-Obi and 216 to Clb-Obi. Three months after treatment completion, 40% of patients in the Ven-Obi arm (7% in the Clb-Obi arm) had undetectable MRD levels < 10−6 by next-generation sequencing in peripheral blood. Median MRD doubling time was longer after Ven-Obi than Clb-Obi therapy (median 80 v 69 days). At a median follow-up of 52.4 months, a sustained significant PFS improvement was observed in the Ven-Obi arm compared with Clb-Obi (median not reached v 36.4 months; hazard ratio 0.33; 95% CI, 0.25 to 0.45; P < .0001). The estimated 4-year PFS rate was 74.0% in the Ven-Obi and 35.4% in the Clb-Obi arm. No difference in overall survival was observed (hazard ratio 0.85; 95% CI, 0.54 to 1.35; P = .49). No new safety signals occurred. CONCLUSION Appearance of MRD after Ven-Obi is significantly slower than that after Clb-Obi with more effective MRD reduction. These findings translate into a superior long-term efficacy with the majority of Ven-Obi–treated patients remaining in remission.

The MURANO trial (ClinicalTrials.gov identifier, NCT02005471) demonstrated superior progression-free survival (PFS) and overall survival (OS) with venetoclax-rituximab treatment vs bendamustine-rituximab in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Patients were randomized to 2 years venetoclax-rituximab (n = 194; rituximab for the first 6 months) or 6 months bendamustine-rituximab (n = 195). Although undetectable minimal residual disease (uMRD) was achieved more often with venetoclax-rituximab, long-term implications of uMRD with this fixed-duration, chemotherapy-free regimen have not been explored. We report MRD kinetics and updated outcomes with 5-years' follow-up. Survival benefits with venetoclax-rituximab vs bendamustine-rituximab were sustained (median PFS [95% confidence interval]: 53.6 [48.4, 57.0] vs 17.0 [15.5, 21.7] months, respectively, P &lt; .0001; 5-year OS [95% confidence interval]: 82.1% [76.4, 87.8] vs 62.2% [54.8, 69.6], respectively, P &lt; .0001). Venetoclax-rituximab was superior to bendamustine-rituximab, regardless of cytogenetic category. Venetoclax-rituximab-treated patients with uMRD at end of treatment (EOT; n = 83) had superior OS vs those with high-MRD+ (n = 12): 3-year post-EOT survival rates were 95.3% vs 72.9%, respectively (P = .039). In those with uMRD at EOT, median time to MRD conversion was 19.4 months. Of 47 patients with documented MRD conversion, 19 developed progressive disease (PD); median time from conversion to PD was 25.2 months. A population-based logistic growth model indicated slower MRD median doubling time post-EOT with venetoclax-rituximab (93 days) vs bendamustine-rituximab (53 days; P = 1.2 x 10−7). No new safety signals were identified. Sustained survival, uMRD benefits and durable responses support 2-year fixed-duration venetoclax-rituximab treatment in R/R CLL.

Background There is no effective intravesical second-line therapy for non-muscle invasive bladder cancer (NMIBC) when bacillus Calmette-Guérin (BCG) fails. Objective To compare disease-free survival time (DFS) between radiofrequency-induced thermo-chemotherapy effect (RITE) and institutional standard second-line therapy (control) in NMIBC patients with recurrence following induction/ maintenance BCG. Design, settings, and participants Open-label, phase III randomised controlled trial accrued across 14 centres between May 2010 and July 2013 [HYMN (ClinicalTrials.gov: NCT01094964)].