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Introduction: Ibrutinib, an oral Bruton Kinase inhibitor, is a highly effective treatment for patients with chronic lymphocytic leukemia (CLL). Previous studies reported an increased risk of bleeding due to impaired platelet function. Patients with CLL experience significant thrombocytopenia, which increases their risk for bleeding. This population was excluded from major trials and data is lacking to inform management in this setting. Methods: This is a single center retrospective study of all adult patients with CLL who received single agent ibrutinib in London, Ontario, Canada between January 2014 to December 2020. The primary objective was to investigate the risk of major bleeding associated with thrombocytopenia. Secondary objective was to investigate potential predictors of bleeding. Bleeding events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grading system. A major bleed was defined as CTCAE grade 3 or higher as well as bleeding in the central nervous system. To assess the effect of independent variables on the outcome of bleeding, univariate analysis using chi square and t-tests was performed. Multivariate analysis was then preformed with the variables that were significant (p Results: A total of 170 patients were included in this study. There were 54 bleeding events documented in 42 patients (24.7 %) of which 19(35 %) were major bleeding occurring in 17 patients. Median time to major bleeding was 2.4 months. Of the patients with major bleeding, 4(21%) were on anticoagulation, 2(10%) were on antiplatelet and 2(10%) were on combined anticoagulation and antiplatelet. There were 8 central nervous system (CNS) bleeding and 2 of them died. The mean platelet (PLT) nadir, defined as lowest PLT count at any point during ibrutinib treatment, was 73 x 10 9/Lin patients with major bleeding compared to 116 x 10 9/L in patients with minor and 91 x 10 9/L in patients with no bleeding events. On the univariate analysis, when compared patients with major bleeding to patients with no bleeding, potential predictors of major bleeding included PLT nadir (p=0.09), haemoglobin (Hb) < 100 g/L at ibrutinib initiation (p=0.027) and anticoagulation (p=0.009). When compared patients with major bleeding to patients with minor or no bleeding, potential predictors of major bleeding included PLT nadir (p=0.045), Hb To confirm the significance of these variables, multivariate analysis was performed. When compared patients with major bleeding to patients with no bleeding, PLT nadir (OR= 0.9, p=0.008) and anticoagulation (OR=4.02, p=0.001) were confirmed to be the potential predictors of major bleeding. When compared patients with major bleeding to patients with minor or no bleeding, PLT nadir (OR=0.9 p=0.005) and Hb Conclusions: Although not common, Ibrutinib is associated with increased risk of bleeding and identifying high risk patients is essential to prevent major bleeding events. This retrospective Canadian study was done with the primary objective to assess the association between PLT count and major bleeding in patients on ibrutinib for treatment of CLL. In this analysis patients with major bleeding tend to have lower PLT counts compared to patients with minor or no bleeding, with mean PLT nadir of 73x 10 9/L. However, grade 3 thrombocytopenia (PLT nadir Figure 1 Figure 1. Disclosures Louzada: Amgen: Honoraria; Pfizer: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Lam: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hoffmann-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; SeaGen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Phua: Amgen: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria.

Warfarin remains the most commonly used oral anticoagulant. Its efficacy is closely correlated with the time in therapeutic range (TTR) of the international normalized ratio (INR). Excellent anticoagulant management systems can achieve TTRs in excess of 80%: however, in day-to-day clinical practice TTR values in the range of 50 to 60% are more commonly seen. Strategies to increase TTR are widely sought; one such intervention is the daily administration of low dose vitamin K (VK) administered to reduce variations in VK intake and thus reduce fluctuations in the INR due to such variability. In this multicentre, blinded, randomized controlled trial we allocated patients on chronic warfarin therapy to receive either 0.150 mg of daily oral VK, or matching placebo. After a one month “run in period” to allow adjustment of the warfarin dose, patients were followed for a maximum of 9 months (mean 6 months), their INR was determined, their TTR calculated and their mean warfarin dose calculated. A total of 253 patients were enrolled at 4 clinical centres between Aug 19, 2010 and Aug 30, 2013; 18 (9 in each group) were excluded from this analysis due to inadequate follow-up data, mostly as a result of withdrawal from the study during the run in period. Of the 117 analyzable patients allocated to VK, 66 were male (average age 66.9 yrs). Of the 118 analyzable patients allocated to placebo 59 were male (average age 65.7 yrs). Indications for warfarin were similar between the two groups, as was the frequency of renal insufficiency and the presence of cancer. Patients allocated to placebo were more likely to report a history of bleeding (7% vs 3%). Mean TTR over the 6 months prior to enrollment to the study was 54.6% in the placebo group, and 51.8% in the VK group. Mean TTR over an average follow-up of 6 months after completion of the 1 month run-in period was 66% in the placebo group, and 65.1% in the VK group. We conclude that inclusion in this study resulted in a statistically (and likely clinically) significant improvement in the TTR. The improvement in the TTR we observed appeared to be predominately as a result of attentive clinical management, rather than administration of VK. Our findings do not support the use of daily, low dose oral vitamin K administered in an effort to improve TTR. Disclosures Crowther: Portola: Consultancy; Leo: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy; AKP America: Consultancy; Heart and Stroke Foundation: Career Investigator award Other; Celgene: Honoraria; Shire: Honoraria; CSL Behring: Honoraria. Lazo Langer:Pfizer: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; Leo Pharma: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria; Alexion: Research Funding; Daichii Sankyo: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Yeo:Bayer: Honoraria. Schulman:Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Bayer HealthCare: Consultancy, Honoraria, Research Funding.

Background: An error at the drug compounder source resulted in accidental over-dilution of the chemotherapy drugs cyclophosphamide and gemcitabine utilized by several cancer centers in Ontario and New Brunswick in Canada between March 2012 and March 2013. The exact degree of unintentional dose reduction for each patient is unknown, but the estimate is between 3-20% given the type of dilution error. One thousand two-hundred and two cancer patients were affected overall, including 177 hematology patients at London Regional Cancer Center (LRCP). We evaluated the effect of cyclophosphamide under-dosing on patients with diffuse large B cell lymphoma (DLBCL) treated with chemotherapy containing cyclophosphamide (mostly R-CHOP), the largest subset of patients affected. Methods: We conducted a retrospective cohort study of all DLBCL patients at LRCP who received at least one cycle of chemotherapy containing diluted cyclophosphamide between March 2012 and March 2013. The affected cohort was compared to a historical group of DLBCL patients matched by stage (early versus advanced) and age (±5 years) who were treated prior to the dilution error from January 2008 to December 2010. The main study outcome was event-free survival defined as a composite of disease progression or death. Groups were compared using unpaired Student’s t-test, Chi-squared or Fisher’s exact tests, as appropriate. Survival analysis was done using the Kaplan-Meier method. Results: Seventy-seven patients received diluted cyclophosphamide and were matched to 74 historical controls. There were no differences in the baseline characteristics between groups ( Table 1 ). Complete remission was achieved in 41 (53.2%) cases and 43 (58.1%) controls (p= 0.55). Overall response rate was 71.2% in cases and 67.6% in controls. At a median follow up of 490 days, progression or death occurred in 21 (27.3%) cases and 24 (32%) controls (P= 0.49). Survival analysis of the main outcomes showed no difference between the two study groups (log rank 0.999). Conclusion: There is no difference in the rate of response or in event-free survival among DLBCL patients receiving one or more doses of accidentally diluted cyclophosphamide, compared to a matched historical control group. This suggests that a minor dose reduction in 1 drug in multi-agent chemotherapy may be inconsequential in terms of disease response and risk of relapse. | Variable | Cases N=77 | Control N= 74 | P value | | ----------------------------------------------- | -------------------------- | -------------------------- | ------- | | Male [N (%)] | 39 (52) | 36 (48) | 0.87 | | Age (Mean) Interquartile range | 77 (SD ± 16) 55-79 | 66 (SD±14) 56 - 77 | 0.665 | | Age > 60 [N (%)] | 29 (37.7) | 24 (32.4) | 0.5 | | LDH [Mean (SD)] | 408 (375) | 394 (50) | 0.819 | | WBC [Mean (SD)] | 8.2 (4) | 7.5 (3) | 0.193 | | Hemoglobin[Mean (SD)] | 117 (22) | 120 (21) | 0.348 | | Platelets [Mean (SD)] | 259 (175) | 253 (128) | 0.82 | | Extra-nodal > 1 [N (%)] | 18 (23.4) | 18 (24.3) | 0.89 | | Stage III/IV [N (%)] | 53 (68.9) | 51 (68.8) | 0.99 | | B-symptoms [N (%)] | 44 (57.1) | 43 (49.4) | 0.83 | | ECOG ≥ 2 [N (%)] | 33 (42.9) | 36 (49.3) | 0.4 | | High LDH [N (%)] | 52 (67.5) | 43 (58.1) | 0.23 | | High risk (R-IPI of score ≥3) [N (%)] | 27 (35.1) | 28 (37.8) | 0.5 | | Prescribed (intentional) dose reduction [N (%)] | 23 (30) | 25 (34.7) | 0.52 | | Radiation therapy [N (%)] | 33 (42.9) | 34 (46.6) | 0.53 | | Febrile neutropenia [N (%)] | 21 (27.3) | 15 (20.3) | 0.31 | | GCSF use [N (%)] | 48 (62.3) | 38 (53.5) | 0.28 | Table 1 Baseline Characteristics ![Figure 1][1] Figure 1 Disclosures No relevant conflicts of interest to declare. [1]: pending:yes