Key Points Ibrutinib increases the incidence of AF in patients with hematologic malignancies treated on or off a clinical trial. Patients with a history of AF and those with a high FHS-AF risk score are at highest risk for developing AF while on ibrutinib.

No abstract

No abstract

Purpose There are limited data regarding the clinical use of decitabine for the treatment of acute myeloid leukemia in patients with a serum creatinine of 2 mg/dL or greater. Methods We retrospectively evaluated 111 patients with acute myeloid leukemia who had been treated with decitabine and compared the development of toxicities during cycle 1 in those with normal renal function (creatinine clearance greater than or equal to 60 mL/min) to those with renal dysfunction (creatinine clearance less than 60 mL/min). Results Notable differences in the incidence of grade ≥3 cardiotoxicity (33% of renal dysfunction patients vs. 16% of normal renal function patients, p = 0.042) and respiratory toxicity (40% of renal dysfunction patients vs. 14% of normal renal function patients, p = 0.0037) were observed. The majority of heart failure, myocardial infarction, and atrial fibrillation cases occurred in the renal dysfunction group. The odds of developing grade ≥3 cardiotoxicity did not differ significantly between patients with and without baseline cardiac comorbidities (OR 1.43, p = 0.43). Conclusions This study noted a higher incidence of grade ≥3 cardiac and respiratory toxicities in decitabine-treated acute myeloid leukemia patients with renal dysfunction compared to normal renal function. This may prompt closer monitoring, regardless of baseline cardiac comorbidities. Further evaluation of decitabine in patients with renal dysfunction is needed.

Background/rationale Romiplostim is a thrombopoietin receptor agonist recommended as a second-line therapy for immune thrombocytopenia. An initial dose of 1 mcg/kg/week subcutaneously with weekly 1 mcg/kg dose escalation is recommended per package labeling. Optimizing romiplostim dosing for hospitalized, corticosteroid- and intravenous immunoglobulin-refractory patients with severe thrombocytopenia secondary to immune thrombocytopenia may be critical for improving platelet responses, reducing the risk of bleeding, and decreasing hospital length of stay. Limited data are available evaluating the efficacy and safety of higher initial doses. Objective The primary objective of this study was to compare the time to platelet ≥ 10 × 10/L between patients who received an initial romiplostim dose of ≥2 mcg/kg/week compared to the standard initial dose of 1 mcg/kg/week. Secondary objectives included time to platelet response ≥ 30 × 10/L and ≥50 × 10/L, percentage of patients achieving platelet responses, hospital length of stay, and incidence of adverse events and bleeding complications. Methods This was a retrospective, single-center, cohort study including hospitalized adults with corticosteroid- and intravenous immunoglobulin-refractory immune thrombocytopenia. A baseline platelet < 10 × 10/L was required. Patients were stratified by their initial romiplostim dose into Cohort 1 (1 mcg/kg/week) and Cohort 2 (≥2 mcg/kg/week). A review of electronic medical records and descriptive statistics generated findings. Results A total of 18 patients were included, 4 in Cohort 1 and 14 in Cohort 2. Patients in Cohort 2 had a median initial dose of 4.5 mcg/kg/week. Patients in Cohort 2 achieved a platelet ≥ 10 × 10/L in a median of 2 days versus 4.5 days for Cohort 1. More patients in Cohort 2 achieved a platelet ≥ 30 × 10/L (42.9% vs. 25%) and platelet ≥ 50 × 10/L (28.6% vs. 25%). The median hospital length of stay was shorter in Cohort 2 (13.5 vs. 20 days). Clinically relevant nonmajor bleeding was noted less frequently in Cohort 2 (28.6% vs. 75%), while major bleeding was more frequent in Cohort 2 (14.3% vs. 0%). No thrombotic events occurred. Conclusion Our study suggests that higher initial romiplostim doses may be safe for hospitalized patients with treatment-refractory immune thrombocytopenia. Compared to Food and Drug Administration-approved dosing, higher initial doses may shorten time to platelet responses and hospital length of stay. Further large-scale studies are needed to confirm these findings.

BACKGROUND: Ibrutinib is an irreversible inhibitor of Burton's tyrosine kinase (BTK) in the B-cell receptor (BCR) signaling cascade and is a practice changing treatment for chronic lymphocytic leukemia (CLL) and other B-cell malignancies. Ibrutinib also inhibits Interleukin-2 Inducible Kinase (ITK) in T-cells and has demonstrated immunomodulatory effects. Recently, cases of opportunistic infections (OI) have been reported during ibrutinib treatment including pneumocystis jirovecii pneumonia (PJP), cryptococcus, and fusarium. To date there are no reports on OI in large unselected cohorts of patients taking ibrutinib. We conducted a single-institution retrospective study to determine the incidence and type of OI during ibrutinib treatment as well as outcomes and characteristics associated with risk. METHODS: We reviewed medical records of all patients treated with ibrutinib at the Ohio State University between June 1st 2010 and March 31st 2016. Patients who received ibrutinib for graft versus host disease were excluded. All charts were initially reviewed by one of the investigators and patients with OI were independently reviewed by a second investigator. Baseline patient and disease characteristics were captured at time of starting ibrutinib. All OI occurring after the first dose of ibrutinib were recorded. Onset of OI was considered as the time of first presentation for a complaint related to OI. Time to OI was calculated from the date of starting ibrutinib until the onset of OI or censored at the last assessment date, discontinuation of ibrutinib, or death prior to OI as competing risks. The cumulative incidence of OI was estimated and the Fine and Gray regression models were used to examine the association between patient characteristics and risk of OI. Covariates with significance level of p&lt;0.20 from univariable analyses were further evaluated in a multivariable analysis using a stepwise selection procedure, retaining those with p&lt;0.05 in the final model. RESULTS: The cohort included 566 patients. Median age was 65 (range 23-89) and 70.1% (397/566) were men. The majority of patients had CLL (73.7%, 417/566). Other diagnoses included mantle cell lymphoma (9.9%, 56/566), indolent B-cell malignancies (8.1%, 46/566; 11 Waldenström's Macroglobulinemia, 13 Hairy Cell Leukemia, 15 Follicular Lymphoma, 6 Marginal Zone Lymphoma, and 1 Prolymphocytic Leukemia), and aggressive lymphoma (8.3%, 47/566; 35 diffuse large B-cell or transformed lymphoma and 12 Richter's syndrome). Median number of prior treatments was 3 (range 0-18) and 6.5% (37/566) of patients were treatment naïve. Ibrutinib was prescribed on clinical trial for 80.9% (458/566) of patients with the rest receiving it as standard of care. A second agent was given with ibrutinib in 30.9% (175/566) of cases and was most often a monoclonal antibody (81.7%, 143/175). Use of antiviral prophylaxis was common (78.6%, 445/566) with fewer patients receiving PJP (44.9%, 254/566) or fungal (11.5%, 65/566) prophylaxis. The most utilized prophylactic antifungal agent was fluconazole (70.8%, 46/65). Total ibrutinib exposure for the cohort was 1,225 person-years with a median exposure of 1.98 (range 0.008-6.40) years. Median duration of follow-up was 2.69 (range 0.03-6.40) years. Twenty-three of 566 (4.1%) patients developed an OI at a median of 0.39 (range 0.03-4.33) years after starting ibrutinib. The cumulative incidence of OI was 2.3% (95% CI: 1.3-3.8%) at 0.5 years and increased to 4.7% (95% CI: 3.0-7.0-%) at 5 years. Types of OI and outcomes are detailed in Table 1. Median survival of the entire cohort was not reached. Among 23 OI patients, the median survival after infection was 1.39 years. Univariable analysis revealed ≥3 prior treatments (HR 2.61), diabetes (HR 3.03), pulmonary disease (HR 2.81), chronic kidney disease (HR 2.56), and liver disease (HR 6.42) were associated with an increased risk for OI (p&lt;0.05). In a multivariable analysis ≥3 prior treatments (HR 2.87, 95% CI: 1.12-7.35; p=0.028), diabetes (HR 3.63, 95% CI: 1.50-8.77; p=0.004), and liver disease (HR 7.53, 95% CI: 2.14-26.49; p=0.002) retained independent association with OI development. CONCLUSIONS: The cumulative incidence of OI during ibrutinib treatment was low (4.7% at 5 years) and the most common type was invasive fungal (61%) with no PJP cases. Three or greater prior treatments, diabetes, and liver disease were independently associated with risk for OI. Disclosures Byrd: Janssen: Research Funding; The Ohio State University: Patents & Royalties: OSU-2S; Genentech: Research Funding; Acerta Pharma: Research Funding; Pharmacyclics: Research Funding.

Background Ibrutinib (IB) is Food and Drug Administration approved for chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenström's macroglobulinemia (WM). High overall response rates, extended progression free survival, and an acceptable adverse event profile make IB an impactful therapy for these malignancies. Atrial fibrillation (AF) has been identified as a less common but serious adverse effect of IB with reported incidence ranging from 2-16% in clinical trials and post-marketing experience. AF can be associated with significant morbidity and mortality, including congestive heart failure and embolic events such as stroke. Data regarding the management of AF in this patient population is thus far limited. Embolic stroke prevention poses a particular clinical challenge as IB carries an inherent bleeding risk that may be increased by antiplatelet therapy and therapeutic anticoagulation. We report the management and outcomes of a large cohort of patients who developed AF while on IB therapy. Methods Patients with hematological malignancies and incident or recurrent AF while on IB therapy at the Ohio State University were identified retrospectively. Incident AF was defined as new onset AF in patients without a history AF and recurrent AF as an AF event requiring new intervention in patients with a prior history of AF. Data pertaining to patient demographics, comorbid conditions, AF events, AF management, stroke prevention strategies, and complications of AF therapy were collected. AF events were graded according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0 andcongestive heart failure, hypertension, age, diabetes mellitus, stroke (CHADs2) scores were calculated. Major bleeding was defined as a decrease in hemoglobin of 2g/dL or more, requiring a transfusion of 2 or more units of packed red blood cells or whole blood, occurring in a critical site, or contributing to death. Clinically relevant non-major bleeding events were graded according to CTCAE criteria. Management strategies and outcomes are summarized. Results Seventy-two patients with incident or recurrent AF were identified. Fifty-nine patients developed incident AF while 13 patients developed recurrent AF while on IB. Baseline characteristics are presented in Table 1.Patients with recurrent AF were older, had worse baseline ECOG performance status, and longer baseline PR interval on electrocardiogram assessment.Patients were followed for a median of 4.3 years from the start of ibrutinib and 1.7 years from AF event.Ninety-three percent of the AF events were grade 1-2 and 7% were grade 3. First-line therapy forAF included rate-control for 54 (75%) patients, interventional procedural strategies for 8 (11.1%), and rhythm-control for 3 (4.2%). Seven (9.7%) patients required no intervention. Twenty-two patients (30.5%) required a second and 4 (5.5%) required third-line AF management intervention. Among those with a secondary AF management strategy, rhythm control was the most frequently utilized (n=10, 45.5%). During the AF events, 31 (43.1%) patients continued IB, 35 (48.6%) temporarily held IB, 5 (6.9%) discontinued IB, and one patient had the dose reduced. Stroke prevention strategies are described in Table 2. Patients with recurrent AF were less likely to be treated with anticoagulation when compared to patients with incident AF. Six (8.3%) patients had a major bleeding event and 2 of these patients went on to have a second major bleed. Of the 8 major bleeding events, 3 occurred with concomitant antiplatelet therapy and no patients were on anticoagulation therapy at the time of bleeding. Eighteen (25%) patients developed a total of 25 clinically relevant non-major bleeding events (9 grade 1 events, 13 grade 2 events, 2 grade 3 events, and 1 could not be graded). Only one potential embolic event occurred in a patient with a CHADs2 score of 1 on aspirin 325mg who developed symptoms consistent with stroke. Conclusions AF events in patients being treated with IB are generally manageable and in the majority of cases did not result in IB discontinuation. Clinically relevant bleeding events are common, and caution must be exercised when initiating routine antiplatelet therapy and/or anticoagulation in patients with IB. Risk of ischemic stroke was low in our patient population, though follow up was limited. The optimum strategy for stroke prophylaxis in patients with concurrent IB is unclear. Disclosures Christian: Pharmacyclics: Research Funding; Janssen: Research Funding. Porcu:miRagen: Other: Investigator in a clinical trial; Innate Pharma: Other: Investigator in a clinical trial; celgene: Other: Investigator in a clinical trial; Millenium: Other: investigator in a clinical trial. Woyach:Morphosys: Research Funding; Karyopharm: Research Funding; Acerta: Research Funding. Jones:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding. Awan:Innate Pharma: Research Funding; Novartis Oncology: Consultancy; Pharmacyclics: Consultancy.

The purpose of this retrospective chart review was to determine the correlation between full weight-based enoxaparin use and the frequency of anti-Xa concentrations within the defined therapeutic range; to ascertain if anti-Xa monitoring is being appropriately ordered in relation to the timing of enoxaparin dose (after 3 consistent therapeutic doses and 3-5 hours post-dose); to establish if the evidence-based recommended dose adjustment protocol that was studied in the pediatric population was utilized; and if this yielded anti-Xa concentrations within the target range (0.6 -1.1 IU/mL) for an adult population. The data may suggest a lack of correlation between BMI and whether or not the anti-Xa concentration is within the therapeutic range. Further prospective studies are needed to confirm this finding, and to determine the utility of the available dose adjustment nomogram.