Knopf, Kevin

Background: Two National Cancer Institute-funded pharmacovigilance programs have identified 49 serious hematology-related ADRs since 1998. The programs, called RADAR (Research on Adverse Drug events and Reports) and then SONAR (Southern Network on Adverse Reactions) involve > 50 institutions and > 75 co-investigators worldwide. The work builds on three prior studies evaluating “Davids and Goliaths” in medical oncology and in cardiology (PLOS One, eClinicalMedicine, and Journal of Scientific and Professional Integrity). Here we review the hematology focused safety investigations of RADAR/SONAR. Methods: Data were based on initial safety signals being identified by a RADAR/SONAR co-investigator. Then, case-series were derived. Collaborations with basic scientists allowed for basic science correlative studies. Results were disseminated primarily as Brief Report in the literature and Black Box warnings on the related drug. In some instances, studies identified hematologic toxicities that prevent FDA from approving a submitted drug application. Results: sADRs were frequently identified based on very small case series, including ticlopidine-and clopidogrel associated thrombotic thrombocytopenic purpura (22 and 10 patients, respectively), thalidomide- and lenalidomide-associated venous thromboembolism (9 and 5 patients, respectively), rituximab-associated progressive multi-focal leukoencephalopathy (22 patients), peginesatide-associated fatal anaphylaxis (5 patients), and COVID-19 vaccine associated immune thrombocytopenia (1 patient). Meta-analyses provided data for epoetin- and darbepoetin-associated mortality among cancer patients and lenalidomide- and thalidomide-associated venous thromboembolism. Following the onset of the COVID-19 pandemic, RADAR/SONAR investigated social media and pre-prints (COVID-19 vaccine associated cerebral vein thrombosis and immune thrombocytopenia). Time from FDA approval to sADR discovery was a median of 5 years (range, 0 months (thalidomide-associated venous thromboembolism) to 34 years (ciprofloxacin-associated neuropsychiatric toxicity). Basic science correlative studies identified ADAMTS13 autoantibodies (ticlopidine), leachates that developed in a multi-dose vial (peginesatide), anti-red blood cell antibodies (epoetin-associated pure red cell aplasia), and high-risk genes (fluoroquinolones and rituximab). Overall, RADAR/SONAR studies are estimated to have saved over 1 million lives and also resulted in overall payments to the Department of Justice of $1.5 billion (related to marketing of unsafe drugs). Discussion: RADAR/SONAR has proven to be a very important adjunct to FDA and pharmaceutical manufacturer-led safety investigations for hematology, paralleling the success in medical oncology and in cardiology. Going forward, independent centers of excellence for safety-focused investigations such as the CERSI network and the SENTINEL network (both are NIH funded) should be broadened to include a hematology-focused safety center.

7091 Background: Mortality in patients with MDS is high, and most require transfusions, emergency department (ED) visits, and hospitalizations. The relationship between these outcomes with the key complications of MDS (anemia, neutropenia, thrombocytopenia) has not been well studied. Methods: Patients who were ≥ 66 years at MDS diagnosis in 2001 or 2002 were identified from SEER registries. Those with both Medicare Part A and B were followed until death or the end of 2005. Mortality, transfusions, ED visits, and hospitalizations were based on Medicare data. The presence of complications was based on diagnosis codes, transfusions, and medication use. Kaplan-Meier incidence was estimated for each outcome. Factors associated with each outcome were based on multivariable Cox models with baseline age, gender, race, co-morbidity level, socio-economic status indicators, and time-varying covariates for each complication. Results: In 1,863 MDS patients, the 3-month incidence of transfusion, ED and hospitalization was 45%, 41%, and 62%, and 3-year incidence was 75%, 87%, and 91% respectively. Median survival was 22 months. The 3-year incidence of anemia, thrombocytopenia and neutropenia was 89%, 37%, and 15% respectively. See table for multivariate results. Conclusions: Starting shortly after diagnosis, MDS patients have high rates of transfusions, ED visits, and hospitalizations. Diagnoses of anemia, neutropenia, and thrombocytopenia are strongly associated with this utilization. The presence of anemia and thrombocytopenia are important independent risk factors for death. [Table: see text] [Table: see text]

Abstract ABSTRACT Background: In 2014, the American Society of Hematology (ASH) established a practice improvement module (PIM) incorporating quality metrics for management of diffuse large B cell lymphoma (DLBCL). Such PIMs have allowed physicians to monitor the quality of care in their practice. We implemented a DLBCL quality improvement initiative (QII) at our institution in January, 2015. In an appraisal of this initiative, we reviewed the ASH PIM metrics and included several others to assess adherence to guidelines for treatment of DLBCL and to examine the need for institutional improvement. Methods: Patients who were newly diagnosed with DLBCL and received treatment at our institution from January 2006 through December 2017 were identified. Electronic medical records were reviewed for documentation of ASH PIM quality measures (e.g., key pathologic features of DLBCL, lymphoma staging, screening for hepatitis B virus (HBV) infection in patients receiving rituximab-based chemotherapy, etc). We also reviewed the proportion of patients who had assessment of prognosis by revised International Prognostic Index (r-IPI) score, testing for hepatitis C (HCV), HIV viral infections, chemotherapy education, and the addition of rituximab in the treatment regimen of CD20+ DLBCL. Results: Following implementation of the QII, our institution saw improvement in most quality metrics. Particularly significant were improvements in reporting of key molecular features (45.45% to 91.6%, P < 0.0001), screening for HBV (41.82% to 91.67%, P < 0.001) and HIV infections (33.94% to 87.5%, P < 0.0001). All patients post-QII had a PET-CT scan for staging of DLBCL and there was a significantly lower use of bone marrow biopsy (61.2% to 33.33%, P = 0.011). Conclusion: Implementation of a quality initiative and employing standardized metrics can aid in improving institutional quality of care for patients with newly diagnosed DLBCL, and allows opportunity to build and ensure better adherence to evolving national and professional patient care guidelines. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

Abstract The study goal was to characterize older chronic lymphocytic leukemia (CLL) patients and to evaluate outcomes in those patients who initiated infused therapy. Patients 66 years of age and older in the Surveillance, Epidemiology, and End Results (SEER) program with a CLL diagnosis were matched to their Medicare Part A and Part B claims for long-term follow-up. Treatment patterns, survival after initiation of infused therapy, and both hematologic and hospitalization outcomes were assessed. There were 6433 CLL patients identified, and 2040 received infused therapy. Treated patients were categorized as receiving rituximab monotherapy (16%), rituximab plus chemotherapy (14%), and chemotherapy alone (70%) based on the initial 60 days after infusion. Rituximab plus chemotherapy compared with chemotherapy alone was associated with a 25% lower risk of overall mortality (95% confidence interval, 9%-38%). Restricting to patients age 70 years and older did not change the risk reduction for rituximab plus chemotherapy. Hematologic interventions were more common with rituximab plus chemotherapy compared with chemotherapy alone, but there was no difference in all-cause hospitalizations. These analyses, based on observational data, suggest that the benefits of initial therapy with rituximab in a heterogeneous group of older CLL patients are comparable with those demonstrated in younger patients.