2 Minute Medicine Rewind December 7, 2015

Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia

Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma (CLL/SLL) is a spectrum of indolent malignant blood disorders characterized by progressive immune suppression and myelosuppression. While many patients are observed instead of given active therapy given low-grade disease, CLL is incurable and the timing of therapy depends on having a repertoire of well tolerated treatments. In this multicenter randomized, controlled trial of 269 patients over the age of 65 with previously untreated CLL/SLL, participants were randomized to ibrutinib, a covalent inhibitor of Bruton’s tyrosine kinase, or chlorambucil, a cytotoxic oral alkylating agent. At 24 month follow-up, 2% of patients who received ibrutinib vs. 15% of patients who received chlorambucil had underwent disease progression or death (HR 0.16, p = 0.001). The median progression-free survival has not been met for the ibrutinib arm, compared to 18.9 months for the chlorambucil arm. There were minimal adverse side effects for ibrutinib, including diarrhea, fatigue, cough, and nausea, and 87% of patients who were in the ibrutinib arm are continuing to take ibrutinib at the time of article submission. This clinical trial shows the continued efficacy of ibrutinib for the treatment of CLL/SLL, and is the first trial to show such clinical efficacy in the first line setting.

Effect of Metformin Added to Insulin on Glycemic Control Among Overweight/Obese Adolescents With Type 1 Diabetes

Type 1 diabetics undergo autoimmune destruction of insulin-producing beta cells in the pancreas and are exogenous insulin dependent. Metformin, which suppresses gluconeogenesis, is commonly used in type 2 diabetics to minimize hyperglycemia and improve glycemic control. In this multicenter randomized controlled trial of 140 adolescents between 12 and 20 with type 1 diabetes and mean body mass index (BMI) at the 94^th percentile, patients were randomized to up to 2000mg daily of metformin or placebo and evaluated for change in hemoglobin A1c, weight, insulin use, and blood lipid levels. At 26 week follow-up, mean hemoglobin A1c went from 8.8% in each group to 9.0% in each group (difference between groups 0.0%, 95% CI -0.3% to 0.3%, p = 0.92). Daily total insulin decreased by more than 25% in 23% of patients who received metformin vs. 1% of patients who received placebo (difference 21%, 95% CI 11% to 32%, p = 0.003). 24% of participants in the metformin arm had a 10% or greater decrease in BMI, compared to 7% of participants in the placebo arm (difference 17%, 95% CI 5% to 29%, p = 0.01). In this study of obese adolescents with type 1 diabetes, the addition of metformin did not improve long term glycemic control, however modestly reduced BMI and decreased total insulin usage.

Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia—TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial

Patients with sickle cell anemia are at higher risk of cerebrovascular events and often are given frequent blood transfusions to prevent primary stroke. The frequency, duration, and alternatives to regular transfusion for children with sickle cell anemia is relatively poorly studied. Hydroxyurea has been used to minimize cerebrovascular events and some think can be used to minimize blood transfusions. In this multinational randomized, open label trial of 121 patients between 4 to 16 years of age with sickle cell anemia and abnormal transcranial doppler (TCD) ultrasound flow velocities, patients were randomized to hydroxyurea or regular monthly blood transfusions. TCD velocities were 143 cm/s in the standard transfusions arm and 138 cm/s in the hydroxyurea arm (difference 4.54, 95% CI 0.10 to 8.98, p < 0.001 for non-inferiority  and p=0·023 for superiority). Three transient ischemic attacks occurred in each group. Patients who received hydroxyurea had more frequent vaso-occlusive pain (11 events in five [8%] patients with hydroxurea and three events in one [2%] patient with transfusions). For patients with high-risk sickle cell anemia and high TCD velocities, hydroxyurea is effective primary prevention for cerebrovascular events compared to regular blood transfusions.

Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia

BCL2 is a critical anti-apoptotic regulator protein characterized in a variety of cancers including Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma (CLL/SLL). Venetoclax is a novel inhibitor of BCL2 that induces apoptosis of CLL cells in vivo and have shown efficacy previously in mouse xenograft models. In this phase I dose-escalation trial, 116 patients with relapsed CLL/SLL received treatment with venetoclax with doses ranging from 150mg to up 1200mg per day. In the initial 56 patient dose-escalation cohort, tumor lysis syndrome occurred in 3 patients, with one resulting death. The trial protocol was subsequently changed and 60 additional patients underwent a weekly dose-escalation scheme with a maximum dose of 400mg per day. In total, 92 (79%) patients had clinical response and 23 (20%) of patients had a complete remission. 6 (5%) patient had no residual disease on flow cytometry. Side effects to venetoclax included diarrhea (52%), upper respiratory infections (48%), nausea (47%), and neutropenia (41%). There was a durable response for multiple subsets of the participants, including subsets of patients with poor prognosis with resistance to fludarabine and chromosome 17p deletions. This clinical trial was a first in man trial of venetoclax for selective inhibition of BCL2 as a treatment strategy of CLL/SLL.

Association of Fitness in Young Adulthood With Survival and Cardiovascular Risk The Coronary Artery Risk Development in Young Adults (CARDIA) Study

Cardiovascular health and response to exercise is associated with decreased cardiovascular event and morbidity in older adults. There have been few long term studies assessing whether the same relationship is true for younger adults. In this prospective study of 4872 adults initially between the ages of 18 to 30, serial exercise treadmill tests were performed and correlated with incident obesity, echocardiographic findings, coronary artery calcification, and cardiovascular disease. During the study period, 273 (5.6%) of study participants died and 193 (4.0%) developed cardiovascular disease. Improved baseline exercise treadmill test duration was associated with decreased risk of death (HR 0.85 for each increased minute on treadmill test, 95% CI 0.80 to 0.91, p < 0.001) and decreased risk of cardiovascular disease (HR 0.88, 95% CI 0.81 to 0.96, p = 0.002). At seven year follow-up, 2472 (50.7%) participants underwent repeat exercise treadmill test. At this follow-up treadmill test, each minute decrease and reduction in fitness was associated with higher death (HR 1.21, 95% CI 1.07 to 1.37, p = 0.002) and higher rates of cardiovascular disease (HR 1.20, 95% CI 1.06 to 1.37, p = 0.006). Higher baseline and maintained cardiovascular health was associated with lower risks of death and long term cardiovascular disease.

Image: PD

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