ASH Clinical News ACN_5.1_Digital - Page 28

CLINICAL NEWS On Location 2018 ASH Annual Meeting TABLE 1. Grade ≥3-5 Treatment-Related Adverse Events Adverse Event Ibrutinib plus Rituximab (n=352) Fludarabine, Cyclophosphamide, Rituximab (n=158) p Value Neutropenia 22.7% 43.7% <0.001 Anemia 2.6% 12% <0.001 Thrombocytopenia 2.9% 13.9% <0.001 Infection 7.1% 19% <0.001 Atrial fibrillation 2.9% 0% 0.04 Bleeding 1.1% 0% 0.32 Hypertension 7.4% 1.9% 0.01 Diarrhea 2.6% 0.6% 0.19 and 58 in the FCR group (ranges not provided). After a median follow-up of 33.4 months (range not reported), the researchers recorded a total of 77 PFS events – 37 in the ibrutinib group and 40 in the FCR group. Fourteen patients died – four in the ibrutinib group and 10 in the FCR group. This translated to a 65-percent reduction in the risk of disease pro- gression or death (primary endpoint) with ibrutinib compared with FCR (hazard ratio [HR] = 0.35; 95% CI 0.22-0.5; p<0.001). There also was an OS advantage with ibrutinib (secondary endpoint; HR=0.17; 95% CI 0.05-0.54; p<0.003). The improvement in PFS was seen across subgroups, Dr. Shanafelt noted. For example, for the 329 patients with IGHV mutation status available, 71.1 percent had IGHV-unmutated disease; within this group, ibrutinib lowered the risk of disease progression or death by 74 percent, compared with FCR (HR=0.26; 95% CI 0.14-0.5; p<0.0001). However, the impact of treatment did not differ significantly in the patients with IGHV-mutated disease (HR=0.44; 95% CI 0.14-1.36; p=0.07). Dr. Shanafelt commented that the ibrutinib-rituximab regimen was “less toxic than our historical therapy,” with more patients in the FCR group experiencing a grade ≥3 treatment-related adverse event (72% vs. 58%; p=0.0042; TABLE 1 ). Together, these results “establish ibrutinib-based therapy as the most effective treatment … for untreated patients,” Dr. Shanafelt concluded. “In cancer trials, [we want] to improve the effectiveness of treatment or reduce its side effects. This trial is one of the rare circumstances where we’ve done both.” The younger age of this patient group represents a potential limita- tion of this finding, as these results may not be generalizable to the larger CLL population, which generally consists of patients older than 65 years. The results of this trial also should be interpreted in light of results from the ALLIANCE trial presented as a plenary abstract at the ASH annual meeting, which showed that ibrutinib alone was superior to che- moimmunotherapy with bendamustine and rituximab in older patients with treatment-naïve CLL. Adding rituximab to ibrutinib did not result in improved outcomes. When asked if rituximab was necessary in this setting, Dr. Shanafelt advised caution about cross-trial comparisons – adding that the ECOG-E1912 trial enrolled a younger population. Each trial demonstrated ibrutinib’s superiority over standard che- moimmunotherapy, however, and the results represent “a paradigm shift from a six-month course of intravenous chemotherapy to chronic treat- ment with a pill,” which raises questions about the pharmaco-economics of long-term targeted therapy. The authors report financial relationships with Celgene, GlaxoSmith- Kline, Roche, Genentech, Janssen, and Pharmacyclics. REFERENCE Shanafelt TD, Wang V, Kay NE, et al. A randomized phase III study of ibrutinib (PCI-32765)-based therapy vs. standard fludara- bine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy in untreated younger patients with chronic lymphocytic leukemia (CLL): a trial of the ECOG-ACRIN Cancer Research Group (E1912). Abstract # LBA-4. Presented at the 2018 ASH Annual Meeting, December 4, 2018; San Diego, CA. New Tool Provides Simple Approach to Interrupting Direct Oral Anticoagulants for Surgery Researchers have developed a “simple, standardized, easy-to-use” strategy to guide decisions about interrupting direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF) scheduled to undergo an elective surgery or procedure. The approach was safe and associated with a low incidence of perioperative major bleeding and arterial thromboembolism. “This is a common clinical problem that occurs in one in six patients with atrial fibrillation each year, or six million patients worldwide, and it is increasing in prevalence as the population ages,” report- ed James Douketis, MD, from McMaster University in Ontario, who presented the results of the late-breaking trial at the 2018 ASH Annual Meeting. However, “since the DOACs were introduced nearly 10 years ago, few studies have looked at how to manage these patients, [lead- ing to] a lot of variability in clinical practice and inconsistency in guideline recommendations.” The aim of the Perioperative Anti- coagulant Use for Surgery Evaluation (PAUSE) study, Dr. Douketis said, was to establish a simple tool that did not require perioperative anticoagulant bridging or coagulation function testing. Interruption and resumption of DOACs was dictated by the bleeding risk associated with the planned procedure and the type of DOAC: For procedures with low bleeding risk (e.g., colonoscopy or hernia repair), DOACs were inter- rupted for one day before and one day after surgery; for procedures with high bleeding risk (e.g., major cancer, heart, or orthopedic surgery), DOACs were inter- rupted for two days before and two days after surgery. Patients on dabigatran with a creatine clearance <50 mL/min and who were planned for a procedure with a high bleeding risk stopped the drug four days before and two days after surgery. Researchers evaluated the approach in 3,007 patients with AF receiving apixa- ban (n=1,257), dabigatran (n=668), or rivaroxaban (n=1,082). Approximately one-third of patients in the trial were scheduled to undergo a high-bleeding-risk surgery, and the median CHADS 2  scores (a 1- to 5-point scale measuring stroke risk based on congestive heart failure, hypertension, age, diabetes, and previous TABLE 2. ASH Clinical News stroke) were 2.1, 2.2, and 2.0 in the apixa- ban, dabigatran, and rivaroxaban groups, respectively. Participants were followed weekly for 30 days post-procedure to measure incidence of major bleeding and arterial thromboembolism (primary endpoint). The researchers expected arterial thromboembolism (including stroke, sys- temic embolism, and transient ischemic attack) to occur in 0.5 percent of patients and major bleeding in 1 percent. They reported lower-than-expected rates for arterial thromboembolism in the entire cohort, but the rates were higher than expected in the apixaban and rivaroxaban groups ( TABLE 2 ). An analysis of preoperative blood samples indicated that more than 90 percent of patients treated per the PAUSE protocol had minimal or no residual DOAC levels. Nearly all patients (98.9%) undergoing a high-bleeding-risk proce- dure had DOAC levels <50 ng/L, prompt- ing the investigators to select 50 ng/L as “a clinically safe threshold to allow a surgery to proceed.” “This is the first study to demonstrate the safety of a standardized perioperative management approach in patients with AF who are taking a DOAC, and we hope it will establish a standard and will have an effect on clinical practice guidelines,” Dr. Douketis concluded. The authors report financial relation- ships with Pfizer, Janssen, Merck, Aniara- Hyphen Biomed, and Sanofi. ● REFERENCE Douketis J, Spyropoulos AC, Duncan JM, et al. Perioperative anticoagulant use for surgery evaluation (PAUSE) study: a perioperative management plan for patients with atrial fibrillation who are receiving a direct oral an- ticoagulant. Abstract LBA-5. Presented at the 2018 ASH Annual Meeting, December 4, 2018; San Diego, CA. Primary Outcomes Apixaban (n=1,257) Dabigatran (n=668) Arterial thromboembolism 2 (0.16%) 4 (0.60%) 4 (0.37%) Major bleeding 17 (1.35%) 6 (0.90%) 20 (1.85%) Outcome 26 James Douketis, MD Rivaroxaban (n=1,082) January 2019