Search

Introduction: Proteasome inhibitors-based regimens are the mainstay of initial therapy for most patients with multiple myeloma. Daratumumab is a human IgGκ monoclonal antibody that targets CD38 with direct antitumor effects and has an immunomodulatory component. Recent studies have demonstrated that addition of daratumumab to standard regimens enhance direct cytotoxicity on myeloma cells and have shown survival benefits. Yet, there are notable safety concerns. We performed a combined analysis of randomized controlled trials (RCT) to determine the risk of second primary malignancies (SPM) and peripheral sensory neuropathy (PSN) with newer daratumumab combination regimens. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase III RCTs utilizing daratumumab in patients with multiple myeloma that mention SPM and PSN as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results: A total of 3,547 patients with multiple myeloma from 5 phase III RCTs were eligible. Studies compared daratumumab (D) + bortezomib (V) + melphan (M) + prednisone (P) vs VMP, D + lenalidomide (R) + dexamethasone (d) vs Rd, DVd vs Vd and DVd + thalidomide (T) vs VTd. The randomization ratio was 1:1 in all studies. Daratumumab was utilized in relapsed and refractory multiple myeloma in the POLLUX study (n= 564) and the CASTOR study (n= 480) and as first-line treatment for patients with multiple myeloma in the ALCYONE study (n= 700), the CASSIOPEIA study (n= 1085) and the MAIA study (n= 737). The I2 statistic for heterogeneity was 25, suggesting some heterogeneity among RCT. The SPM incidence was 76 (4.29%) in study group vs 77 (4.34%) in control group. The RR for SPM was 1.12 (95% CI: 0.74 - 1.69; P = 0.58) and RD was 0.01 (95% CI: -0.01 to 0.02; P = 0.34). The RR for SPM was noted at 2.56 (95% CI: 0.26 - 25.46; P = 0.42) in a subset of relapsed and refractory multiple myeloma. Any-grade PSN was reported in 527 (46.84%) in daratumumab arm vs 550 (48.72%) in control arm with the RR of 0.98 (95% CI: 0.80 -1.21; P = 0.88). High-grade PSN was noted in 63 (5.6%) vs 76 (6.73%) in control group with the RR of 0.73 (95% CI: 0.42 -1.27; P = 0.27). Conclusions: Our meta-analysis depicted that there was no significant increase in the risk of second primary malignancies and peripheral sensory neuropathy in patients on daratumumab combination regimen, in newly diagnosed and relapsed refractory multiple myeloma, compared to control arm. However, long-term follow-up of these patients is required to determine the actual relation with second primary malignancies. Disclosures No relevant conflicts of interest to declare.

Introduction: Chronic lymphocytic leukemia is the most prevalent adult leukemia in western countries. Phosphatidylinositol 3-kinase (PI3K) is a kinase protein involved in downstream signaling for the B-cell receptor signaling pathway and has been shown to involve in the pathogenesis of chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/ SLL) by promoting B-cell survival, proliferation and metabolism. Two prominent PI3K inhibitors, idelalisib (PI3Kδ-selective inhibitor) and duvelisib (PI3Kδ/γ-combinatorial inhibitor), have recently shown to improve survival in patients with relapsed and refractory CLL/ SLL. We undertook a systematic review and meta-analysis of phase 3 randomized controlled trials to determine the risk of hematological toxicities associated with PI3K inhibitors. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase 3 RCTs utilizing PI3K inhibitors in patients with relapsed and refractory CLL/SLL that mention hematological toxicities as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results: Four phase 3 RCTs with a total of 1,216 patients with relapsed and refractory CLL/SLL were included. Studies compared ofatumumab vs idelalisib+ofatumumab, rituximab vs idelalisib+rituximab, bendamustine+ rituximab vs idelalisib+bendamustine+rituximab and ofatumumab vs duvelisib. The randomization ratio was 2:1 in Jones et al. study and 1:1 in other studies. The I2 statistic for heterogeneity was 49, suggesting some heterogeneity among RCTs. The RR of all-grade side effects were as follows: anemia, 1.39 (95% CI: 0.89 - 2.17; p = 0.15); neutropenia, 1.33 (95% CI: 1.06 - 1.67; p = 0.02); and thrombocytopenia, 1.23 (95% CI: 0.69 - 2.18; p = 0.48). The RR of high-grade adverse effects were as follows: anemia, 1.29 (95% CI: 0.62 - 2.67, p = 0.50); neutropenia, 1.51 (95% CI: 1.22 - 1.88; p = 0.0001); and thrombocytopenia, 1.21 (95% CI: 0.66 - 2.22; p = 0.53). The incidence of febrile neutropenia was 76 (11.69%) in study group vs 22 (3.92%) in control group with RR of 2.62 (95% CI: 1.27 -5.41, P = 0.009). Conclusions: PI3K inhibitors, idelalisib (PI3Kδ-selective inhibitor) and duvelisib (PI3Kδ/γ-combinatorial inhibitor), increased the risk of all grades of neutropenia and febrile neutropenia, with RR of 2.62 for febrile neutropenia, in patients with relapsed and refractory CLL/SLL. Vigilant monitoring is warranted, and proper supportive care and dose modifications should be followed. Disclosures No relevant conflicts of interest to declare.

Background Multiple risk factors have been linked to venous thromboembolism (VTE). It is well established that elevated level of homocysteine correlated with increased risk of VTE. Some studies showed that vitamin B12 deficiency may be the cause for homocysteinemia. Therefore, it is recommended by some groups that vitamin B12 should be supplemented in the patient with high homocysteine to prevent VTE. However, more recent study has shown that there is correlation between the high serum Vitamin B12 level and risk of VTE in cancer patients.[1] provoked VTE after orthopedic surgery was also shown to be associated with elevated vitamin B12 serum levels in elderly patients. The role of vitamin B12 in VTE patients is not fully understood. Our study is to see whether there is correlation between serum Vitamin B12 level and risk of VTE in general population. Methods 177 Patients admitted to Kingsbrook Jewish Medical Center between January 1st, 2015 to December 31st, 2018 with the diagnosis of VTE were identified. 95 cases had measured serum Vitamin B12 results within 3 months. 97 patients without any history of VTE who were seen in the hematology clinic during the same period time were used as control in this study. Demographic information and Vitamin B12 level were collected. T test and chi-square were used for statistical analysis. Results VTE patients had a median age of 70, which is significantly higher than the median age of 57 in the control group. The mean level of vitamin B12 in control group was 620 pg/mL, which was lower than the average vitamin B12 level (770 pg/mL, p=0.0344) in the VTE group. When we divided the patients into 3 groups based on Vitamin B12 level: Low B12 (800 pg/mL). We observed 41% of VTE patients have B12 level more than 800 pg/mL while only 20% of control patients have high B12 level (chi-square, p=0.006). Discussion Our study showed that vitamin B12 level is significantly elevated in patients diagnosed with VTE and more than 40% of those patients actually have vitamin b12 level more than 800 pg/mL. It is known that elevated vitamin B12 level is associated with inflammation and increased mortality.[2] An association between elevated B12 levels and cancer has been reported in several studies [3]. It is unclear elevated vitamin B12 levels predict undiagnosed cancer which is a known risk factor for VTE or vitamin B12 directly contribute hypercoagulation. Nevertheless, we should be cautious when supplementing vitamin B12 and the dosage may need to be titrated closely. More clinical studies are definitely warranted. References 1. Arendt JFH, el al. Elevated plasma vitamin B12 levels and risk of venous thromboembolism among cancer patients: A population-based cohort study. PubMed ID: 26724465 2. Grossfeld A1, et al. Symptomatic venous thromboembolism in elderly patients following major orthopedic surgery of the lower limb is associated with elevated vitamin B12 serum levels. PubMed ID:23000313 3. Johan F.H. Arendt, Henrik T. Sørensen, Laura J. Horsfall and Irene Petersen. Elevated Vitamin B12 Levels and Cancer Risk in UK Primary Care: A THIN Database Cohort Study. EPI-17-1136 Published April 2019 Disclosures No relevant conflicts of interest to declare.

Background Rivaroxaban and apixaban are two direct oral anticoagulants (DOACs) targeting Factor Xa. Each DOAC was separately proven effective and safe when compared to standard treatment (heparin followed by warfarin) in patients diagnosed with venous thromboembolism (VTE). Several retrospective cohort analyses suggest apixaban may be superior to rivaroxaban due to less bleeding rates. One recent study showed the safety of apixaban and rivaroxaban for acute VTE were comparable. Also, long-term anticoagulation with low molecular weight heparin (LMWH), has never been directly compared with Factor Xa inhibitors. Given the patient population at our facility includes a significant percentage of elderly from nursing homes with multiple comorbidities and significantly higher bleeding risks than the general population, we aimed to evaluate the local real-world DOACs and heparin use with particular focus on safety. Methods A retrospective study was conducted at Kingsbrook Jewish Medical Center. Demographics, relevant laboratory/ imaging studies for patients admitted from 1/2016 to 12/2018 with the diagnosis of VTE based on the ICD 9/10 codes were collected from the IT dept. VTE patients who had bleeding events during the same admission for VTE or were admitted for relevant bleeding events based on ICD 9/10 codes within 6 months from the diagnosis of VTE were identified. Major bleeding events were defined as requiring hospitalization, blood transfusion or a significant drop in hemoglobin (more than 2 g/dl). The rest of the bleeding events were classified as minor. Demographics and clinical characteristics were summarized with means/median for continuous variables and with proportions for categorical variables. The differences in covaries were assessed with chi-square, Fisher exact test or t-tests. Results A total of 177 acute VTE patients were identified in the study. 37.9% (n=67) and 32.8% (n=58) patients were started on rivaroxaban and apixaban, respectively, as monotherapy. 29.3% (n=52) patients were given unfractionated heparin (23%, n=12) or LMWH (77%, n=40) based on the renal function. The bleeding rate in the apixaban group (4/58, 6.9%) was slightly higher than that in the rivaroxaban group (3/67, 4.5%), however, there was no statistical significance. Compared to patients received heparin (11/52, 21.2%), patients started on rivaroxaban (p=0.008) or apixaban (p=0.049) had a significantly lower rate of bleeding. Of note, majority of the bleeding event (16/18) was captured during the same admission when VTE was diagnosed. VTE patients in the apixaban group were older (p = 0.007) and had a longer length of stay (LOS, p= 0.024) compared to the ones in the rivaroxaban group. We then combined rivaroxaban and apixaban into DOAC group. Compared to Heparin group (n=11, 21.1%), the bleeding events in DOAC group (n=7, 5.6%) were significantly less (P=0.0045). Heparin group (n=21, 40.4%) included more patients with cancer than the DOAC group (n=9, 7.2%, p We then looked at the bleeding risk in non-cancer patients. Similarly, we didn't observe any superiority between rivaroxaban (n=2, 3.1%) and apixaban (n=3, 5.8%) regarding bleeding events in non-cancer patients with acute VTE. The average LOS in the apixaban group was significantly longer than that in the rivaroxaban group with non-cancer patients. It may be associated with relatively older age in the apixaban group compared to that in the rivaroxaban group. Most importantly, in patients without active malignancy, we found that the bleeding rate in the DOAC group was only 4.3% while the heparin group had a much high bleeding rate of 16.1% (p=0.035). Discussion Our study suggested that the safety of apixaban and rivaroxaban are comparable in VTE patients. In contrast, heparin including LMWH had much higher bleeding risk compared to either DOAC, especially in the beginning. For patients who are hospitalized for acute VTE, heparin intravenously or subcutaneously are usually initiated while the decision for oral anticoagulants are still pending. However, the benefits of such "bridging with heparin" strategy are not warranted, given the high bleeding risk associated with heparin treatment as shown in our study. Except for hemodynamically instability, excessive burden or clots, or impeding procedures, we recommend that DOACs should be used as monotherapy in VTE patients. Disclosures No relevant conflicts of interest to declare.