Michal Ariela Raz

Bio: Michal Ariela Raz is an academic researcher from Tel Aviv University. The author has contributed to research in topics: Antigen & T cell. The author has an hindex of 1, co-authored 2 publications receiving 3 citations.

The risk of bleeding in patients receiving ibrutinib combined with novel direct oral anticoagulants.

Abstract: Ibrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase, is an established therapeutic agent in a variety of Bcell lymphoproliferative disorders. Ibrutinib induces platelet dysfunction, and concurrent treatment with ibrutinib and warfarin has been shown to significantly increase the risk of bleeding. The current study was designed to investigate the safety of direct oral anticoagulants (DOACs) in patients receiving ibrutinib, taking into consideration their expanding employment together with the lack of data regarding their safety. Between January 2010 and October 2018, we conducted a retrospective cohort study in five participating centres to evaluate risks of major bleeding in patients with B-cell lymphoproliferative disorders that were treated with ibrutinib and DOACs but without concurrent antiplatelet therapy. Patient medical charts were reviewed for demographic parameters, comorbidities, ibrutinib dosage, DOACs dosage, blood count and chemistry tests, bleeding site and grade. The study included 30 patients (Table I, patient characteristics) with a median age of 71 6 years (range 50 9–88 2). Most patients were treated for chronic lymphocytic leukaemia (CLL) (n = 18, 60%) and mantle cell lymphoma (MCL) (n = 8, 26%). The most common daily doses of ibrutinib were 420 mg and 560 mg in 63 3% and 30%, respectively. Twenty-three patients were treated with apixaban (76 7%), four with rivaroxaban (13 3%) and three (10%) with dabigatran. The main indications for DOACs were atrial fibrillation and VTE (venous thromboembolism). Median follow-up after initiation of ibrutinib-DOAC combination was 13 4 months (range 1 8–47 9 months). Bleeding was reported in 22 patients (73 3%), mostly mucocutaneous (n = 12, 40%) and gastrointestinal tract (n = 7, 23 3%), followed by central nervous system (CNS) bleeding (n = 4, 13 3%). Mucocutaneous bleedings were all grade 1–2, and gastrointestinal tract and CNS bleeding events were grade 1– 4. Major bleeding events, defined as grade 3 or 4, occurred in five patients (16 6%) and did not result in the death of any of the patients. Major bleeding sites involved the gastrointestinal tract (n = 1), CNS (n = 2), intraocular (n = 1) and postoperative hip fracture repair (n = 1). Serious bleeding sequelae occurred in two patients, as well as urgent craniotomy due to grade 4 CNS bleeding and right eye blindness due to grade 4 intraocular bleeding. None of the patients died of bleeding. The median time for bleeding following ibrutinib-DOAC initiation was 5 6 months. Over a follow-up period of 21 months of combined treatment, the incidence of bleeding events (of all grades) increased to 75% and was similar between all DOAC subtypes (73 9% with apixaban, 75% with rivaroxaban and 66 7% with dabigatran). No statistically significant predictors for increased risk of bleeding in patients receiving ibrutinib combined with DOACs were detected. Ibrutinib was stopped in eight patients (26 7%) due to grade 1–4 bleeding events and was re-initiated in six patients, resulting in recurrent grade 3 and 4 bleeding events in two patients. Despite the insufficient data regarding the safety of DOACs in combination with ibrutinib, the employment of this combination in patients with CLL and NHL is rapidly expanding. Most of the patients included in our study experienced bleeding events. However, the majority were grade 1– 2 mucocutaneous bleeding only, and their incidence and severity were not higher than previously reported with ‘old’ anticoagulation agents (Boriani et al., 2018) (Table II). Major bleeding events occurred in five patients (16 6%); one of them was a life-threatening bleeding event and the other eventuated in right eye blindness. In previous CLL trials among ibrutinib-treated patients who received any type of anticoagulant (including four cases only treated with DOACs), major bleeding events were reported in 9% in the PCYC-1102 study and 2% in the PCYC-1112 study (Resonate) (Brown, 2018) during a median follow-up 22 and 10 months, respectively. In these studies, the most frequent anticoagulant treatment being used was LMWH (low molecular weight heparin), which was usually given in a prophylactic dose and for a limited duration of less than 3 months, whereas few patients only received DOACs (Brown et al., 2019). Similar to our results, most of these bleeding events occurred early, during the first 3–6 months of therapy. Patients with MCL had a significantly higher risk for major hemorrhage than patients with CLL, a finding which is probably dose-related (560 mg per day vs. 420 mg per day in patients with CLL) (Byrd et al., 2014). According to our study, risk of bleeding in patients treated with DOACs is higher than reported in previous trials studying bleeding in patients treated with ibrutinib and anticoagulants. However, DOACs are much easier to handle compared with warfarin and LMWH, being administered orally and not requiring any surveillance blood tests to monitor their activity. There is no consensus regarding the preferable DOAC in patients concomitantly treated with ibrutinib. Some studies correspondence

PD-1-inhibitor-induced PCA-2 (MAP1B) Autoimmunity in a Patient with Renal Cell Carcinoma.

Abstract: Immune check point inhibitors (ICIs) are a group of anti-cancer pharmacological agents which modify T cell activity in order to potentiate an effective immune response against tumor cells. While these drugs prove extremely potent against several types of malignancies, they may be associated with significant autoimmune adverse events. We report a patient who developed a subacute cerebellar syndrome shortly after starting treatment with nivolumab, a PD-1 inhibitor, for renal clear cell carcinoma, with detectable paraneoplastic PCA-2 antibodies. The tumor specimen stained positively for MAP1B, the antigen of PCA-2. The patient responded well to treatment with glucocorticosteroids. This is the first case to our knowledge of PCA-2 paraneoplastic cerebellar degeneration associated with ICI use, which presents in a patient with a malignancy not typically associated with neurological paraneoplastic phenomena. Treatment with immune checkpoint inhibitors (ICIs) is extremely effective in potentiating an immune response against tumor cells, but bears a substantial risk for the development of autoimmune phenomena, including paraneoplastic neurological syndromes. Increasing use of ICIs is leading to increasing numbers of patients with new-onset neurological symptoms. Awareness of these novel entities will aid in early diagnosis and proper treatment.

Risk of Bleeding Associated With Ibrutinib in Patients With B-Cell Malignancies: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Abstract: Background: Ibrutinib is an oral covalent Bruton's tyrosine kinase inhibitor that has been approved for chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia and some other B-cell malignancies Some studies have found an increased risk of bleeding with ibrutinib Some studies, however, found no significant differences in the risk of major bleeding between patients treated with ibrutinib and those with other regimens So, a systematic review and meta-analysis of randomized controlled trials (RCTs) were performed to estimate the risk of bleeding associated with ibrutinib in patients with B-cell malignancies Methods: A systematic search of PUBMED, EMBASE, Central Register of Controlled Trials, and ClinicalTrialsgov was conducted from January 2000 to February 2020 to identify RCTs by comparing ibrutinib with other agents or placebo in B-cell malignancies The RevMan software (version 53) was used to carry out this analysis, and the analyzed data were represented by risk ratios (RR) and 95% confidence intervals (CI) Results: There were 11 eligible RCTs (4,288 patients) All studies reported major bleeding, and seven studies reported overall bleeding (any-grade bleeding) Ibrutinib was associated with a significantly increased risk of bleeding (overall bleeding and major bleeding) in patients with B-cell malignancies [RR = 256, 95% CI 168-390, p < 00001 and RR = 208, 95% CI 136-316, p = 00006, respectively] The bleeding (overall bleeding and major bleeding) risk in patients with CLL was more obvious [RR = 308, 95% CI 207-458, p < 000001 and RR = 246, 95% CI 137-441, p = 0003, respectively] There were no statistically significant differences for risk of bleeding between the subgroups based on dose and treatment setting Conclusion: Ibrutinib was associated with a significantly higher risk of bleeding (both overall bleeding and major bleeding) in patients with B-cell malignancies, especially in CLL

Paraneoplastic and Other Autoimmune Encephalitides: Antineuronal Antibodies, T Lymphocytes, and Questions of Pathogenesis

Abstract: Autoimmune and paraneoplastic encephalitides represent an increasingly recognized cause of devastating human illness as well as an emerging area of neurological injury associated with immune checkpoint inhibitors. Two groups of antibodies have been detected in affected patients. Antibodies in the first group are directed against neuronal cell surface membrane proteins and are exemplified by antibodies directed against the N-methyl-D-aspartate receptor (anti-NMDAR), found in patients with autoimmune encephalitis, and antibodies directed against the leucine-rich glioma-inactivated 1 protein (anti-LGI1), associated with faciobrachial dystonic seizures and limbic encephalitis. Antibodies in this group produce non-lethal neuronal dysfunction, and their associated conditions often respond to treatment. Antibodies in the second group, as exemplified by anti-Yo antibody, found in patients with rapidly progressive cerebellar syndrome, and anti-Hu antibody, associated with encephalomyelitis, react with intracellular neuronal antigens. These antibodies are characteristically found in patients with underlying malignancy, and neurological impairment is the result of neuronal death. Within the last few years, major advances have been made in understanding the pathogenesis of neurological disorders associated with antibodies against neuronal cell surface antigens. In contrast, the events that lead to neuronal death in conditions associated with antibodies directed against intracellular antigens, such as anti-Yo and anti-Hu, remain poorly understood, and the respective roles of antibodies and T lymphocytes in causing neuronal injury have not been defined in an animal model. In this review, we discuss current knowledge of these two groups of antibodies in terms of their discovery, how they arise, the interaction of both types of antibodies with their molecular targets, and the attempts that have been made to reproduce human neuronal injury in tissue culture models and experimental animals. We then discuss the emerging area of autoimmune neuronal injury associated with immune checkpoint inhibitors and the implications of current research for the treatment of affected patients.