Ibrutinib followed by ofatumumab consolidation in previously untreated patients with chronic lymphocytic leukemia (CLL): GELLC-7 trial from the Spanish group of CLL (GELLC).

Background: BTK inhibitors have been concurrently administered with anti-CD20 monoclonal antibodies (mAbs) in chronic lymphocytic leukemia (CLL). However, the optimal regimen for combining these two drugs remains pending. Methods: This multi-center phase 2 study aimed to analyze whether consolidation with ofatumumab improved the response in patients with CLL receiving front-line treatment with ibrutinib. Patients received 12 cycles of ibrutinib monotherapy. Those who achieved CR after this induction were maintained on ibrutinib. Conversely, those who did not attain CR continued with ibrutinib in addition to a consolidation, which involved 7 doses of ofatumumab. The primary objective was the complete response (CR) rate at cycle 20. This study is registered within the EU Clinical Trials Register (EudraCT 2016-004937-26). Findings: Between September 8, 2017, and May 21, 2018, 84 patients (median age, 69 years) were included. After completion of 12 cycles of ibrutinib (n = 80), 4 patients (5%) were in CR, 67 (84%) in partial response (PR), and 6 patients (7%) had a PR with lymphocytosis (PRL). After consolidation with ofatumumab, 20 patients improved the response from PR to CR and 6 patients with PRL obtained a PR. Seventy-one patients (85%) completed 20 cycles of treatment, with a CR rate of 24/71 (34%). According to the intention-to-treat analysis at cycle 20, the ORR was 69/84 (82.2%), with a CRR of 24/84 (28.6%). Progression-free survival and overall survival at 48-months were 89.9% (CI: 82.4-95.5) and 92.2% (CI: 85.3-97.1), respectively. Interpretation: These findings underscore the potential for a consolidation strategy in CLL, wherein the addition of a mAb in patients with low tumor burden might enhance the quality of the response. Funding: The study was funded by Janssen that also supplied ibrutinib, whereas ofatumumab was supplied by Novartis.

Fixed-Duration Ibrutinib-Venetoclax in Patients with Chronic Lymphocytic Leukemia and Comorbidities.

BACKGROUND: GLOW is a phase 3 trial evaluating the efficacy and safety of ibrutinib-venetoclax in older patients and/or those with comorbidities with previously untreated chronic lymphocytic leukemia (CLL). METHODS: We randomly assigned (1:1) patients 65 years of age or older or those 18 to 64 years of age who also had a Cumulative Illness Rating Scale (CIRS) score greater than 6 (CIRS scores range from 0 to 56, with higher scores indicating more impaired function of organ systems) or creatinine clearance of less than 70 ml/min, to ibrutinib-venetoclax (3 cycles ibrutinib lead-in, then 12 cycles ibrutinib-venetoclax) or chlorambucil-obinutuzumab (6 cycles). The primary end point was progression-free survival (PFS) assessed by an independent review committee. Secondary end points included undetectable minimal residual disease (uMRD), response rates, and safety. RESULTS: This study enrolled 211 patients, with 106 randomly assigned to ibrutinib-venetoclax and 105 to chlorambucil-obinutuzumab. With a median follow-up of 27.7 months, there were 22 PFS events for ibrutinib-venetoclax and 67 events for chlorambucil-obinutuzumab. PFS was significantly longer for ibrutinib-venetoclax than for chlorambucil-obinutuzumab (hazard ratio, 0.216; 95% confidence interval [CI], 0.131 to 0.357; P<0.001). The improvement in PFS with ibrutinib-venetoclax was consistent across predefined subgroups, including patients 65 years of age or older or with a CIRS score greater than 6. The best uMRD rate in bone marrow by next-generation sequencing was significantly higher for ibrutinib-venetoclax (55.7%) than for chlorambucil-obinutuzumab (21.0%; P<0.001). The proportion of patients with sustained uMRD in peripheral blood from 3 to 12 months after end of treatment was 84.5% for ibrutinib-venetoclax and 29.3% for chlorambucil-obinutuzumab. Four patients treated with ibrutinib-venetoclax required subsequent therapy compared with 27 patients receiving chlorambucil-obinutuzumab (hazard ratio, 0.143; 95% CI, 0.050 to 0.410). Adverse events grade 3 or greater occurred for 80 (75.5%) and 73 (69.5%) patients receiving ibrutinib-venetoclax and chlorambucil-obinutuzumab, respectively, with neutropenia being most common in both arms (37 [34.9%] and 52 [49.5%]). There were 11 (10.4%) and 12 (11.4%) all-cause deaths in the ibrutinib-venetoclax and chlorambucil-obinutuzumab arms, respectively. CONCLUSIONS: Ibrutinib-venetoclax, an all-oral, once-daily, fixed-duration combination, demonstrated superior PFS and deeper and better sustained responses versus chlorambucil-obinutuzumab as first-line CLL treatment in older patients and/or those with comorbidities. (Funded by Janssen Research & Development, LLC, and Pharmacyclics; ClinicalTrials.gov number, NCT03462719.)

Nitric oxide, prostaglandins and angiotensin II in the regulation of renal medullary blood flow during volume expansion

Regulation of medullary blood flow (MBF) is essential in maintaining renal function and blood pressure. However, it is unknown whether outer MBF (OMBF) and papillary blood flow (PBF) are regulated independently when extracellular volume (ECV) is enhanced. The aim of this study was to determine whether OMBF and PBF are differently regulated and whether there is an interaction between nitric oxide (NO), prostaglandins (PGs) and angiotensin II (Ang II) in regulating OMBF and PBF when ECV is enhanced. To achieve these goals, OMBF and PBF were measured by laser-Doppler in volume-expanded rats treated with a cyclooxygenase inhibitor (meclofenamate, 3 mg/kg) and/or a NO synthesis inhibitor (L-nitro-arginine methyl ester (L-NAME), 3 μg/kg/min) and/or Ang II (10 ng/kg/min). OMBF was unchanged by NO or PGs synthesis inhibition but decreased by 36 % (P < 0.05) when L-NAME and meclofenamate were infused simultaneously. PBF was similarly reduced by L-NAME (12 %), meclofenamate (17 %) or L-NAME + meclofenamate (19 %). Ang II did not modify OMBF, but it led to a similar decrease (P < 0.05) in OMBF when it was administered to rats with reduced NO (32 %), PGs (36 %) or NO and PGs (37 %) synthesis. In contrast, the fall in PBF induced by Ang II (12 %) was enhanced (P < 0.05) by the simultaneous PGs (30 %) or PGs and NO (31 %) synthesis inhibition but not in L-NAME-treated rats (20 %). This study presents novel findings suggesting that blood flows to the outer medulla and renal papilla are differently regulated and showing that there is a complex interaction between NO, PGs and Ang II in regulating OMBF and PBF when ECV is enhanced (AU)