Phase 3 Trial of Ibrutinib plus Rituximab in Waldenström’s Macroglobulinemia
Rituximab monotherapy is frequently used in the treatment of Waldenström’s macroglobulinemia, a B-cell lymphoma. Recently, ibrutinib, a Bruton tyrosine kinase inhibitor, has also been used. In this phase three randomized controlled trial, 150 symptomatic patients were randomized to receive ibrutinib plus rituximab or placebo and rituximab to examine the effect of adding ibrutinib to rituximab on progression-free survival in patients with treatment-naïve or recurrent Waldenström’s macroglobulinemia. Researchers found that the proportion of patients with progression-free survival at 30 months of follow-up was significantly greater amongst those treated with rituximab and ibrutinib compared to those treated with rituximab alone (82% vs. 28%, HR 0.20, 95% CI 0.11 to 0.38, p<0.001). Treatment with rituximab and ibrutinib also led to a significantly higher major response rate (72% vs. 32%, p<0.001) and sustained increases in hemoglobin levels (73% vs. 41%, p<0.001). Combination therapy did, however, lead to increased rates of hypertension (13% vs. 4%) and atrial fibrillation (12% vs. 1%), as compared to rituximab alone. Infusion reactions (6% vs. 1%) and IgM flares (47% vs. 8%), however, were more common in those treated with rituximab alone. Investigators therefore concluded that the addition of ibrutinib to treatment with rituximab results in a significant improvement in progression-free survival rates, as compared to rituximab alone in patients with treatment-naïve or recurrent Waldenström’s macroglobulinemia.
Moderate alcohol consumption has been associated with increased risks of certain cancers and all-cause mortality. In this multicenter case-cohort study, 32,549 patients without any cardiovascular disease were asked to disclose their alcohol consumption, and were subsequently followed up to explore the association between alcohol consumption and coronary heart disease (CHD), both fatal and non-fatal, as well as stroke. The primary outcomes of interest were CHD and stroke. Researchers found an inverse relationship between baseline alcohol intake and non-fatal CHD (per 12 g/day higher intake: HR 0.94, 95% CI 0.92 to 0.96). Non-fatal CHD had a J shaped association with baseline alcohol intake. As compared to those with a baseline intake of 0.1-4.9 g/day of alcohol, the risk of fatal CHD was significantly lower in those consuming 5-14.9 g/day (HR 0.83, 95% CI 0.70 to 0.98) and 15-29.9 g/day (HR 0.65, 95% CI 0.53 to 0.81). There was no significant difference between patients consuming 30-59.9 g/day (HR 0.82, 95% CI 0.65 to 1.03) and 0.1-4.9 g/day. However, increased baseline alcohol consumption was associated with a significantly increased risk of non-fatal stroke (per 12 g/day higher intake: HR 1.04, 95% CI 1.02 to 1.07). No significant difference was seen for fatal stroke (per 12 g/day higher intake: HR 1.05, 95% CI 0.98 to 1.13). Similar results were shown when examining lifetime alcohol consumption instead of consumption at the initiation of the trial. Investigators therefore concluded that alcohol consumption was inversely associated with non-fatal CHD risk, but may confer an increased risk of non-fatal stroke.
Long-term Albumin Administration in Decompensated Cirrhosis (ANSWER): An Open-label Randomized Trial
Reduced serum albumin concentration is frequently seen in patients with advanced cirrhosis. However, the evidence for long-term human albumin administration is limited. In this randomized controlled trial, 431 patients with cirrhosis and uncomplicated ascites treated with anti-aldosteronic drugs and furosemide were randomized to receive either 18 months of standard medical treatment (SMT) or 18 months of SMT plus human albumin (40 grams two times weekly for 2 weeks followed by 40 g weekly) to investigate the use of long-term human albumin on 18-month mortality. Researchers found that survival at 18 months of follow-up was significantly increased in the group treated with albumin compared to the SMT group (HR 0.62, 95% CI 0.40 to 0.95p=0.028). Additionally, treatment with albumin was associated with lower rates of all-cause hospital admission (HR 0.65, 95% CI 0.55 to 0.77, p<0.0001). Similar rates of grade 3-4 non-liver-related adverse events were present in the two groups. Investigators therefore concluded that long-term treatment with human albumin is associated with increased survival at 18 months, has a tolerable side effect profile, and may modify the disease process in decompensated cirrhosis.
Durable Remissions with Ivosidenib in IDH1-mutated Relapsed or Refractory AML
Isocitrate dehydrogenase 1 (IDH1) mutations are frequently implicated in various cancers, including six to ten percent of acute myeloid leukemias (AML). Ivosidenib is an inhibitor of mutant IDH1. In this phase 1 study, safety and efficacy of ivosidenib was assessed in 258 patients with relapsed or refractory AML. Of these patients, 125 received 500 mg of ivosidenib daily with 6 months or more of follow-up. In this population, the rate of complete remission with partial hematologic recovery or complete remission was 30.4% (95% CI 22.5% to 39.3%), with an overall response rate of 41.6% (95% CI 32.9% to 50.8%). Among patients with complete recovery, 21% had no IDH1 mutations detectable using polymerase chain reaction. In all patients with relapsed or refractory AML (n=179), grade 3 adverse effects included QT interval prolongation (7.8% of patients), IDH differentiation syndrome (3.9%), anemia (2.2%), thrombocytopenia or platelet count decline (3.4%), and leukocytosis (1.7%). Investigators therefore concluded that ivosidenib at a dose of 500 mg daily may result in durable remissions in relapsed or refractory AML with IDH1 mutation.
Gastric Residual Volume in Feeding Advancement in Preterm Infants (GRIP Study): A Randomized Trial
Gastric residual volumes are frequently measured as part of guiding the advancement of enteral feeding in preterm infants. In this randomized controlled trial, investigators aimed to evaluate the effects of not routinely measuring gastric volumes to guide advancement on the time to reach full feeds. The study enrolled preterm infants with a birth weight between 1500-2000 grams who were being fed enterally (n=87) and randomized them to have gastric residuals assessed only when indicated (vomiting, abnormal abdominal exam, bloody aspirate) or to be assessed routinely for guiding advancement of feeds. Researchers found no significant difference between the two groups with respect to time to reach full feeds (p=0.82), as the group without routine gastric residual volume measurements reached full feeds in 6 days (95% CI 5.5 days to 6.5 days) while the control group reached full feeds in 5 days (95% CI 4.5 days to 5.5 days). In addition, no significant differences were seen in the incidence of sepsis, time to regain birth weight, or feeding interruptions. Investigators therefore concluded that not routinely measuring gastric volumes was not associated with a decrease in the time to reach full feeds in preterm infants between 1500 and 2000 grams.
Image: PD
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