Background Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia mediated by IgM autoantibodies that trigger hemolysis via classical complement pathway. Increased incidence of thrombotic events (TEs) has been reported in patients with other forms of hemolysis. The incidence of TEs in patients with CAD is unknown. Objective Evaluate TE risk in patients with CAD. Patients/Methods This is a matched cohort comparison study evaluating the risk of TEs in patients with CAD and without CAD over a 10‐year period. A total of 608 patients with CAD were identified in the Optum Claims–Clinical data set by reviewing clinical notes for CAD terms and matched with up to 10 patients without CAD (N = 5873). TEs were defined as the first medical claim for a TE using International Classification of Diseases, Ninth and Tenth Revision codes. Cox regression models were used to estimate time to first TE. Sensitivity analyses were conducted to estimate TE risk among patients with primary CAD. Results At least 1 TE occurred in 29.6% of patients with CAD and 17.6% of patients without CAD. The proportion of patients experiencing venous, arterial, and cerebral TEs were each higher among CAD patients. The overall risk of having TEs was higher in patients with CAD (adjusted hazard ratio [aHR], 1.94; 95% confidence interval [CI], 1.64‐2.30). Patients with presumed primary CAD also demonstrated an increased risk of TEs (aHR, 1.80; 95% CI, 1.46‐2.22). Patients with CAD with the fewest comorbidities had 2.44‐fold higher risk of having a TE (95% CI, 1.70‐3.52). Conclusions Patients with CAD have an increased risk of TEs when compared with a matched non‐CAD population.
Introduction: Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia (AIHA) with a prevalence of approximately 16 patients per million. CAD accounts for less than 20% of all AIHA and is characterized by immunoglobulin M (IgM) mediated agglutination of erythrocytes and subsequent activation of the classical complement pathway. In addition to hemolysis, which can vary from mild to severe, clinical manifestations of CAD have been reported to include livedo reticularis, acrocyanosis, circulatory symptoms and cutaneous necrosis (Swiecicki, P Et al Blood 2013). The rarity of this disease has resulted in a lack of data regarding its natural history. Thromboembolic events (TEs) are a known complication of other hemolytic disorders, however, little is known about its incidence and severity in CAD. We evaluated the largest cohort of CAD patients to date and compared them to a matched non-CAD cohort to evaluate clinical characteristics and occurrence rate of TEs. Methods: Patients were identified from the Optum-Humedica database, containing de-identified information on claims, medications, lab results, diagnoses, procedures and clinical notes for individuals from all 50 states. The presence of "cold agglutinin disease" must have appeared in their medical record on at least 3 separate dates from 2006-2016. Patients with "cold agglutinin disease" documented on 1 or 2 dates were included only after an independent review and agreement by 2 hematologists. A comparison cohort was identified from the database and matched on gender, race, region, overall follow-up time, age, and entry date into the health plan. Patient characteristics, TEs, treatment with rituximab, and lab parameters [hemoglobin (Hgb), bilirubin, lactate dehydrogenase (LDH)] were evaluated. LDH and bilirubin were included as they represent hemolysis and indirect measures of complement activity in CAD. TEs in both cohorts were identified from claims submitted. Results: 814 patients with CAD and 7,960 comparisons were identified. Median follow-up time for CAD patients was 75.6 months (0-125 months). Seventy percent of CAD patients were over 65 years of age, 62% were women and 84% were Caucasian. Forty-four percent of CAD patients reside in the midwest, 13% in the northeast, 29% in the south, 12% in the west, with 2% unknown. Thirty-one percent of CAD patients had a medical claim for any form of TE compared to 20% in the matched comparisons (p < 0.0001). Eighteen percent of CAD patients had 1 TE compared to 14% of the matched comparisons (p < 0.001). Thirteen percent of CAD patients had 2 or more types of TEs compared to 6% of matched comparisons (p < 0.001). Nearly 10% of all CAD patients had a venous TE compared to 3% of matched comparisons (p < 0.0001). Twenty five percent of all CAD patients had a cerebral TE compared to 16% of matched comparisons (p < 0.0001). Eight percent of all CAD patients had an arterial TE compared to 5% of matched comparisons (p < 0.0001). Of the 94 CAD patients that had available Hgb within a month prior to a medical claim for a TE, 47% had mild anemia (Hgb > 10 g/dL), 29% had moderate anemia (Hgb 8.1-10 g/dL) and 24% had severe anemia (Hgb < 8 g/dL). Forty-one of the 94 patients had LDH and bilirubin values documented within one month of a medical claim for TE. Ninety percent of these CAD patients had evidence of ongoing hemolysis, represented by an abnormal bilirubin or LDH. Seventy-nine percent of CAD patients treated with a rituximab-containing regimen had an abnormal bilirubin or LDH within 12 months of completion of therapy. Conclusion: Thromboembolic events have been an under-appreciated complication of CAD. Patients with CAD had a significantly higher overall incidence of TEs compared to matched comparisons including venous, arterial, and cerebral events. Furthermore, patients with CAD also had a higher incidence of more than one type of TE. The severity of anemia does not appear to predict TE risk, whereas markers of hemolysis (LDH/bilirubin) do. Standard therapy with rituximab did not result in sustained control of hemolysis, as demonstrated by abnormal bilirubin and LDH values in a majority of patients within 12 months of last dose. Therapeutic modalities that can quickly and completely inhibit complement activity in CAD may offer clinical benefits beyond correcting hemolysis and anemia, such as decreasing TE risk. Disclosures: This study was funded by True North Therapeutics, Inc., a Bioverativ Inc. company Disclosures Broome: TrueNorth Therapuetics: Honoraria; Alexion Pharmaceuticals: Honoraria. Cunningham: TrueNorth therapeutics: Honoraria. Rosenthal: Bioverativ Inc: Employment.
546 Background: Front-line chemotherapy for metastatic colorectal cancer (mCRC) consists of a fluoropyrimidine backbone plus either oxaliplatin (FOLFOX or XELOX) or irinotecan (FOLFIRI or XELIRI). Large, prospective trials enrolling chemotherapy-naïve patients (pts) show FOLFOX and FOLFIRI treatment to be equivalent with similar response rates. Methods: Irinotecan inhibits TOPO1, which is now a candidate marker for irinotecan treatment benefit. Thus, we retrospectively analyzed TOPO1 expression level in 49 pts with mCRC who were treated with irinotecan-containing regimens at the Lombardi Comprehensive Cancer Center between 2009 and 2014. Patient characteristics and outcomes were compiled through chart review and the effect of TOPO1 expression on clinical outcomes was assessed. TOPO1 expression in tumor tissue from each pt was analyzed using a commercially available molecular profiling (MP) service (Caris Life Sciences). Results: The median overall survival (OS) for all pts was 33.9 months (mo), defined as the time from metastasis to death or censorship. When grouped by “high” or “low” TOPO1 expression, as defined by Caris at the time of the testing, 29 pts were high-expressers and 20 were low-expressers. High TOPO1 expressers receiving irinotecan (n = 22) had a median OS of 27.2 mo, compared with median 41.5 mo for low-expressers (n = 14) (p = 0.27). Irinotecan is conventionally given as second-line therapy. The median OS of pts receiving second-line irinotecan was 38.2 mo for high-expressers [n = 11] vs. 68.5 mo for low-expressers [n = 5]) (p = 0.32). Conclusions: Our limited data do not support the use of TOPO1 expression levels as a predictive marker for irinotecan therapy in mCRC. However, our conclusions are limited by small sample size, lack of a control group to distinguish prognostic from predictive markers, and timing of TOPO1 measurement, which in many cases was after irinotecan therapy. Physicians currently lack an evidence-based way to choose between potentially efficacious regimens for mCRC. More rigorous studies are needed to assess the benefit of MP in mCRC care. We are currently planning a prospective study with the hope of validating the use of TOPO1 expression as a predictive marker for treatment of this disease.
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