Management of cardiovascular complications of BTKis: Are we complying with the good practice guidelines?

Bruton tyrosine kinase inhibitors (BTKis) were approved for use at the end of 2013 and have since been used for indications including chronic lymphocytic leukaemia (CLL), Waldenstrom's macroglobulinaemia and mantle cell lymphoma. The use of BTKis has increased significantly in the UK since they achieved NICE (National Institute for Health and Care Excellence) approval for frontline treatment of CLL in 2021. However, they are associated with significant adverse cardiovascular events. In September 2021 the British Journal of Haematology published good practice guidelines for the management of cardiovascular complications of BTKis. Our aim was to see whether these guidelines had been adhered to for patients taking BTKis. Method(s): Data was collected for all patients being prescribed BTKis (ibrutinib and acalabrutinib) in the South Tees NHS Trust in July 2022. Patients' medical records were used to assess whether their management adhered to the good practice guidelines. Data was collated for 67 patients in total. Result(s): The data showed that although all patients were consented for the risk of atrial fibrillation only 6% were consented for hypertension and only 1.5% for ventricular arrhythmias and sudden cardiac death. The guidelines recommend a baseline ECG (electrocardiogram) on commencement of treatment;however, only 7% had this completed and 0% had the minimum monitoring recommendation of 6-monthly ECGs. Thirty patients (45%) had an indication for a baseline echocardiogram;however, only one had this completed. For patients reporting symptoms of syncope, dizziness or palpitations only 50% had an ECG completed. Three patients developed worsening heart failure. The recommendations suggest referral to a cardio-oncologist;however, due to lack of availability of this service the referrals were instead made to the usual cardiologist. Conclusion(s): Although there was a lack of compliance with guideline recommendations, it should be considered that most usual checks were affected by COVID-19 outbreaks and a drop in face-to- face clinics, which were replaced by phone clinics and home delivery of medications. However, the premade consent forms for BTKis need to be updated to include consent for ventricular arrhythmias and sudden cardiac death. There also needs to be routine procedures in place to ensure that regular blood pressure testing and ECG monitoring occurs and that there is prompt recognition of cardiovascular complications. Action and implementation: To ensure improved compliance with these guidelines we plan to update our consent forms and create a proforma for clinic use to ensure that clinicians are aware of the various monitoring criteria required.

Case Report of Succesful Multidisiplinary Treatment for Patient with Metastatic Lung Cancer and Relapsed/Refractory Chronic Lymphatic Leukemia/Small Lymphocytic Lymphoma

Introduction: Croatian National Cancer Registry of Croatian Institute for Public Health reported that in year 2020 lung cancer was the second most common cancer site diagnosed in men with 16% and the third most common in women with 10% incidence among all cancer sites. Unfortunatelly lung cancer has the highest mortality in both men and women. Haematological malignancies had 7% share in all malignancies in both male and female cances cases. In 2020 190 newly diagnosed cases of lymphatic leukemia in men and 128 cases in women were reporeted, meaning 1.5 and 1.2% of all malignancies, respectively. Chronic lymphatic leukemia (CLL) is an advanced age disease and incidence increases with age. Impaired immunity, T and B cell dysfunction in CLL, chromosomal aberations, long-term immunosuppressive therapy and genetic factors can all cause secondary malignancies. Co- occurence of solid tumors and CLL is very rare. Although patiens with CLL have an increased risk of developing second primary malignancies including lung carcinoma, the data about their clinical outcomes are lacking. Parekh et al. retrospectively analyzed patients with simultaneous CLL and lung carcinoma over a 20-year period, and they found that ~2% of patients with CLL actually developed lung carcinoma. The authors claimed that up to 38% of patients will also develop a third neoplasm more likely of the skin (melanoma and basal cell carcinoma), larynx (laryngeal carcinoma) or colon. Currently there are no specific guidelines for concurrent CLL and non-small cell lung carcinoma (NSCLC) treatment. Usually, when the tumors are diagnosed simultaneously, treatment is based to target the most aggressive malignancy, as the clinical outcomes depend on the response of the tumor with the poorest prognosis. For this reason, a multidisciplinary approach is mandatory. Case report: A patient with history of coronary heart disease, myocardial infarction and paroxysmal atrial fibrillation was diagnosed in 2019 (at the age of 71) with B chronic lymphocytic leukemia with bulky tumor (inguinal lymph nodes 8x5 cm), stage B according to Binet, intermediate risk. He was treated with 6 cycles of chemoimmunotherapy (rituximab/cyclofosfamid/fludarabine). In 10/2019 remission was confirmed, but MSCT described tumor in the posterior segment of upper right lung lobe measuring 20x17 mm and bilateral metastases up to 11 mm. Bronchoscopy and biopsy were performed, and EGFR neg, ALK neg, ROS 1 neg, PD-L1>50% adenocarcinoma was confirmed. He was referred to Clinical Hospital Center Osijek where monotherapy with pembrolizumab in a standard dose of 200 mg intravenously was started in 01/2020. Partial remission was confirmed in October 2020. Immunotherapy was discontinued due to development of pneumonitis, dysphagia and severe weight loss (20kg), but without radiologically confirmed disease progression. At that time he was referred to our hospital for further treatment. Gastroscopy has shown erosive gastritis with active duodenal ulcus, Forrest III. Supportive therapy and proton pump inhibitor were introduced. After complete regression of pneumonitis, improvement of general condition and resolution of dysphagia, no signs of lung cancer progression were found and pembrolizumab was reintroduced in 12/2021. Hypothyroidism was diagnosed in 01/2021 and levothyroxine replacement ther apy was started. In 03/2021 he underwent surgical removal of basal cell carcinoma of skin on the right temporal region with lobe reconstruction. From 02/2021, when pembrolizumab was reintroduced, regression in tumor size was continously confirmed with complete recovery of general condition. He was hospitalized for COVID 19 infection in 09/2021, and due to complications pembrolizumab was discontinued till 11/2021. Lung cancer immunotherapy proceeded till 11/2022, when Multidisciplinary team decided to finish pembrolizumab because of CLL relapse. CLL was in remission till August 2022 when due to B symptoms, lymphcytosis, anemia and generalized lymphadenopathy, hematological workup including biopsy of cervical lymph node was performed and CLL/SLL relapse was confirmed. Initially chlorambucil was introduced, but disease was refractory. Based on cytogenetic test results (IGHV unmutated, negative TP53) and due to cardiovascular comorbidity (contraindication for BTK inhibitors) venetoclax and rituximab were started in 01/2023. After just 1 cycle of treatment normal blood count as well as regression of B symptoms and peripheral lymphadenopathy occured, indicating the probability of complete disease remission. In our patient with metastatic lung adenocarcinoma excellent disease control is achieved during 41 month of treatment in first line setting. Furthermore, relapsed/refractory CLL/SLL is currently in confirmed remission. Conclusion(s): Successful treatment of patients with multiple primary malignancies is based on multidisciplinarity, early recognition and management of side effects, treatment of comorbidities with the aim of prolonging life, controlling symptoms of disease and preserving quality of life.

Long-Term Efficacy and Safety of Zanubrutinib in Patients with Relapsed/Refractory (R/R) Marginal Zone Lymphoma (MZL): Final Analysis of the Magnolia (BGB-3111-214) Trial

Introduction: Advanced MZL is generally incurable, with periods of remission and relapse. Zanubrutinib (BGB-3111), a potent and highly specific next-generation Bruton tyrosine kinase (BTK) inhibitor, was approved in the US and Canada for R/R MZL based on the MAGNOLIA primary analysis (BGB- 3111-214;NCT03846427);here, the final MAGNOLIA analysis is presented. Method(s): This was a phase 2, multicenter, single-arm study of adult patients (pts) with R/R MZL (>=1 prior CD20-directed therapy). Zanubrutinib (160 mg twice daily) was given until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR) by independent review committee (IRC) per Lugano classification. Secondary endpoints were investigator-assessed ORR, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Efficacy was assessed by positron emission tomography (PET)-based Lugano criteria for IRC-confirmed fluorodeoxyglucose (FDG)-avid disease at baseline;non-avid disease was assessed by computed tomography (CT)-based criteria. Result(s): As of May 4, 2022, 68 pts were treated (median age=70 y [range 37-95];>=75 y=27.9%). MZL subtypes included extranodal (38.2%), nodal (38.2%), splenic (17.6%), and unknown (5.9%). The median number of prior therapies was 2 (range 1-6);32.4% of pts had disease refractory to last therapy, most (89.7%) had prior chemoimmunotherapy, and 7 (10.3%) had rituximab monotherapy as their only prior treatment. Sixty-one pts (89.7%) had FDG-avid disease. After a median follow-up of 28.0 mos (range 1.6-32.9) and a median treatment duration of 24.2 mos (range 0.9-32.9), 66 pts were efficacy- evaluable. IRC-assessed ORR (complete response [CR]+partial response [PR]) was 68.2% (CR=25.8%). By subtype, (Figure Presented)(Figure Presented)ORR/CR rates were 64.0%/40.0% (extranodal), 76.0%/20.0% (nodal), 66.7%/8.3% (splenic), and 50.0%/25.0% (unknown). Median DOR, PFS, and OS were not reached. Over 70.0% of pts were alive or progression-free after 2 years (Figure). Sensitivity analysis using only CT-based criteria (n=66) showed an ORR of 66.7% and CR of 24.2%. The most common treatment-emergent AEs were bruising (23.5%), diarrhea (22.1%), and constipation (17.6%). Neutropenia (8.8%) and COVID-19 pneumonia (5.9%) were the most common Grade >=3 AEs. Five pts (7.4%) died due to unrelated AEs: COVID-19 pneumonia=2, acute myeloid leukemia=1, myocardial infarction=1, septic encephalopathy=1. Hypertension occurred in 3 pts (4.4%), atrial fibrillation and atrial flutter in 1 pt (1.5%) each;none led to treatment withdrawal. One pt (1.5%) had a Grade 3 gastrointestinal hemorrhage while receiving rivaroxaban. None of the pts required dose reduction. Conclusion(s): In this final analysis with over 2 years of median follow-up, zanubrutinib continues to demonstrate durable disease control and was generally well tolerated, with no new safety signals observedCopyright © 2023 American Society for Transplantation and Cellular Therapy

Current and Future Trends in MS Management: Near East Perspective

Objective(s): The objectives were to provide an overview of the current practices of Near East (NE) healthcare practitioners (HCPs) by probing their prescribing decisions, to report the COVID-19 impacts on neurologists' prescribing habits, and to explore the future relevance of current medication used in MS management among other newcomers Material(s) and Method(s): A cross-sectional study was carried out using an online survey from April 27, 2022, to July 5, 2022. The questionnaire was designed with the input of five neurologists representing five NE countries (Iran, Iraq, Lebanon, Jordan & Palestine). They identified several factors that play a crucial role in the optimal care of MS patients. The link was shared among neurologists using snowball sampling Result(s): The survey included 98 neurologists from the included NE countries, the majority of whom had more than 15 years of experience in the field, and 39% were seeing more than 40 MS patients a month. Effectiveness and safety balance was the most important factor considered when selecting the MS treatment. In the treatment of mild to moderate RRMS in men, Interferon beta 1a SC, Fingolimod, and Glatiramer acetate were the most commonly recommended treatments. Dimethyl fumarate substituted fingolimod in female patients. According to 80.7% of participants, interferon beta 1a SC was the safest treatment for mild to moderate RRMS. Interferon beta 1a SC was preferred over other treatments for patients with mild to moderate MS and planning for pregnancy (56.6%) or breastfeeding (60.2%). Fingolimod was not a choice for these patients. Neurologists seemed to discuss the top three treatments of Natalizumab, Ocrelizumab, and Cladribine with patients with highly active MS. Conclusion(s): Most neurologists in the NE region followed MENACTRIMS recommendations for prescribing treatment. The treatment choice also depended on the availability of DMTs in the region. Regarding the use of upcoming DMTs such as Ofatumumab, Siponimod, Ozanimod, and BTK inhibitors, there is a clear need for real-world data, long-term extension studies, and comparative studies to support their efficacy and safety profiles in treating patients with MSCopyright © 2022

Features of COVID-19 in patients with congenital antibody deficiency

Background: Congenital/primary immunodeficiency (PID) affects about 6 million people worldwide, about 50% of whom are antibody deficient. During the COVID-19 pandemic, these people are at special risk because they have inborn errors of immunity and immune defense against infections. A number of immune mediators, in particular serum levels of interleukin 6 (IL-6), are closely correlated with severity and mortality from COVID-19. Method(s): The clinical course of COVID-19 and IL-6 levels in 14 patients with PID were studied. The age of patients ranged from 18 to 46 years. Among 14 patients with PID, 5 were diagnosed with common variable immunodeficiency (CVID), 4 with IgG4 deficiency, 4 with X-linked agammaglobulinemia (XLA), and 1 with WHIM syndrome. All patients with PID received replacement immunoglobulin therapy. The control group was randomly selected from 25 patients with COVID-19 without immune deficiency disease. The level of IL-6 was determined by ELISA. Result(s): Among 14 patients with PID, 10 patients (71.4%) had mild COVID-19 and 4 patients (28.57%) had moderate COVID-19. Importantly, all 4 patients with IgG4 deficiency, 1 patient with WHIM syndrome, 3 out of 5 patients with CVID, and 2 out of 4 patients with XLA had mild COVID-19. It should be noted that the clinical course and level of IL-6 in all patients with PID and control group did not differ statistically. Conclusion(s): More than 70% of patients with congenital antibody deficiencies had a mild form of COVID-19. The predominantly mild course of COVID-19 confirms the important role of cellular immunity in protecting against SARS Cov-2. Interestingly, all patients with XLA experienced mild or moderate COVID-19 without elevated IL-6 levels likely due to decreased activity of Bruton tyrosine kinase, which mediates development of a cytokine storm through activation of NF-kappabeta. Mild forms of COVID-19 in XLA may reflect a decrease in cytokine storm, in particular IL-6 production.

Patients with B-cell malignancies experience reduced antibody responses with class switching defect following BNT162b2 SARS-CoV-2 vaccination

Vaccines having aided in escaping the majority of the population from immunological naïvety, our strategies are now shifting towards an increased focus on identifying and protecting the extremely vulnerable. We here describe the results of testing 12 patients, those with lymphoid malignancies having been targeted their B-cells for therapy with rituximab-containing regimens or a Bruton tyrosine kinase inhibitor, for anti-SARS-CoV-2 spike antibodies after receiving the BNT162b2 mRNA vaccine doses. The interval from last dosing of B-cell depletion therapy to SARS-CoV-2 vaccination was at median 5.3 (range 3.1–6.6) months. Using the ‘seroprotection' threshold of 775 [BAU/mL] for the anti-spike antibody titer, our finding points out the crucial unresponsiveness of the targeted population with 0/12 (0%) achieving ‘seroprotection'. Although IgG seroconversion was observed in 4/12 (33%), supporting the overall benefit of vaccination, the figures still point out a potential need for optimization of practice. IgA was further less responsive (unsuccessful ‘seroconversion' in 11/12 (92%)), implicating an underlying class switch defect. Those with depletion on B-cells are caught at a dilemma between, being too early and too late on receiving SARS-CoV-2 vaccines. They wish to get over their immunological naïvety at the earliest, while, in order to assure quality immune memory, are also required to hold the patience for their B-cells to repopulate. Although it remains an issue whether intensified vaccine schedules and/or regimens will lead to stronger immunogenicity or more effective boosters for non-responders, we shall take advantage of every increasing evidence in order to optimize current options. © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases

A Case of a Malignant Lymphoma Patient Persistently Infected with SARS-CoV-2 for More than 6 Months.

Coronavirus disease 2019 (COVID-19) is an emerging infectious disease caused by severe acute respiratory syndrome 2 (SARS-CoV-2). There are many unknowns regarding the handling of long-term SARS-CoV-2 infections in immunocompromised patients. Here, we describe the lethal disease course in a SARS-CoV-2-infected patient during Bruton's tyrosine kinase inhibitor therapy. We performed whole-genome analysis using samples obtained during the course of the disease in a 63-year-old woman who was diagnosed with intraocular malignant lymphoma of the right eye in 2012. She had received treatment since the diagnosis. An autologous transplant was performed in 2020, but she experienced a worsening of the primary disease 26 days before she was diagnosed with a positive SARS-CoV-2 RT-PCR. Tirabrutinib was administered for the primary disease. A cluster of COVID-19 infections occurred in the hematological ward while the patient was hospitalized, and she became infected on day 0. During the course of the disease, she experienced repeated remission exacerbations of COVID-19 pneumonia and eventually died on day 204. SARS-CoV-2 whole-viral sequencing revealed that the patient shed the virus long-term. Viral infectivity studies confirmed infectious virus on day 189, suggesting that the patient might be still infectious. This case report describes the duration and viral genetic evaluation of a patient with malignant lymphoma who developed SARS-CoV-2 infection during Bruton's tyrosine kinase inhibitor therapy and in whom the infection persisted for over 6 months.

Platelet caspase-1 and Bruton tyrosine kinase activation in patients with COVID-19 is associated with disease severity and reversed in vitro by ibrutinib.

Background: Severity of coronavirus disease 2019 (COVID-19) is often associated with thrombotic complications and cytokine storm leading to intensive are unit (ICU) admission. Platelets are known to be responsible for abnormal hemostasis parameters (thrombocytopenia, raised D-dimers, and prolonged prothrombin time) in other viral infections through the activation of the nucleotide-binding domain leucine repeat rich containing protein 3 inflammasome induced by signaling pathways driven by Bruton tyrosine kinase (BTK) and leading to caspase-1 activation. Objectives: We hypothesized that caspase-1 activation and the phosphorylation of BTK could be associated with the severity of the disease and that ibrutinib, a BTK inhibitor, could inhibit platelet activation. Methods and Results: We studied caspase-1 activation by flow cytometry and the phosphorylation of BTK by Western blot in a cohort of 51 Afro-Carribean patients with COVID-19 disease (19 not treated in ICU and 32 treated in ICU). Patients with a platelet count of 286.7 × 109/L (69-642 × 109/L) were treated by steroids and heparin preventive anticoagulation. Caspase-1 and BTK activation were associated with the severity of the disease and with the procoagulant state of the patients. Furthermore, we showed in vitro that the plasma of ICU patients with COVID-19 was able to increase CD62P expression and caspase-1 activity of healthy platelets and that ibrutinib could prevent it. Conclusions: Our results show that caspase-1 and BTK activation are related to disease severity and suggest the therapeutic hope raised by ibrutinib in the treatment of COVID-19 by reducing the procoagulant state of the patients.

HEMORRHAGIC PLEURAL EFFUSION IN A PATIENT WITH CHRONIC LYMPHOCYTIC LEUKEMIA ON IBRUTINIB THERAPY

SESSION TITLE: Problems in the Pleura Case Posters 1 SESSION TYPE: Case Report Posters PRESENTED ON: 10/17/2022 12:15 pm - 01:15 pm INTRODUCTION: Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (Btk), approved for treatment of a variety of B-cell malignancies, including chronic lymphocytic leukemia (CLL). There is an association of increased risk of bleeding with ibrutinib due to platelet dysfunction caused by the medication. Bleeding is usually non-life threating such as subcutaneous or mucosal bleeding, epistaxis, and ecchymosis. But major bleeding has been reported such as intracranial hemorrhage and gastrointestinal hemorrhage. Thoracic complications from ibrutinib are rare. Below is a case report discussing a hemorrhagic pleural effusion thought to be caused by Ibrutinib. CASE PRESENTATION: Patient is a 78-year-old male initially diagnosed with CLL on flow cytometry showing a low-grade B cell lymphoproliferative process. Patient was monitored by Hematology and when kappa light chain numbers began to rise, a bone marrow biopsy was performed showing 90% infiltration of the marrow with lymphoid cells. Patient was started on Ibrutinib therapy and responded well to treatment. A year after starting therapy, patient presented to the emergency room with increased shortness of breath and fatigue. Patient was found to be COVID-19 positive and chest x-ray showed a large right sided pleural effusion. Thoracentesis was performed draining 1650cc of bloody fluid. Fluid studies revealed a lymphocytic effusion with RBC count 1,185375, WBC of 1751. Cultures and cytology were negative. On further history, patient was without recent trauma or surgery, CTA chest was negative for pulmonary embolism. QuantiFERON Gold test was negative, indicating low likelihood of tuberculosis. Patient was not on any antiplatelet or systemic anticoagulation medications. Ibrutinib therapy was held during hospitalization and pleural effusion did not reaccumulate. Patient passed away during hospital stay secondary to respiratory failure due to COVID-19. DISCUSSION: Ibrutinib is an orally bioavailable bruton tyrosine kinase inhibitor (BTKi) and forms an irreversible covalent bound to BTK at the Cysteine-481 residue. Ibrutinib predisposes to bleeding by inhibiting BTK and Tec, which play a role in the inhibitory signaling pathway of platelet collagen receptors such as glycoprotein VI (GP VI) and C-type lectin-like receptor 2 (CLEC-2). Our patient had no other risk factors for developing a hemorrhagic effusion. CLL itself can cause malignant effusions, one study found the incidence of malignant effusions among patients with CLL to be 9%, but the effusion was noted to be serous or serosanguinous and there was pleural involvement in all patients which was not the case in our patient. CONCLUSIONS: There is currently a minimal amount of data to guide clinicians regarding the use of ibrutinib in patients at high risk of bleeding or on anticoagulant or antiplatelet therapy. It is important to realize bleeding complications related to ibrutinib therapy can occur. Reference #1: Shatzel JJ, Olson SR, Tao DL, McCarty OJT, Danilov AV, DeLoughery TG. Ibrutinib-associated bleeding: pathogenesis, management and risk reduction strategies. J Thromb Haemost. 2017;15(5):835-847. doi:10.1111/jth.13651 Reference #2: Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N Engl J Med. 2015;373(25):2425-2437. doi:10.1056/NEJMoa1509388 Reference #3: Paydas S. Management of adverse effects/toxicity of ibrutinib. Crit Rev Oncol Hematol. 2019;136:56-63. doi:10.1016/j.critrevonc.2019.02.001 DISCLOSURES: No relevant relationships by fatima ali No relevant relationships by Joan Wiley

B-CELL MALIGNANCIES TREATED WITH TARGETED DRUGS AND SARS-COV-2 INFECTION. A EUROPEAN HEMATOLOGY ASSOCIATION SURVEY (EPICOVIDEHA)

Background: Patients with lymphoproliferatie diseases (LPD) appear particularly ulnerable to SARS-CoV-2 infection, partly because of the effects of the anti-neoplastic regimens (chemotherapy, signaling pathway inhibitors, and monoclonal antibodies) on the immune system. The real impact of COVID-19 on the life expectancy of patients with different subtypes of lymphoma and targeted treatment is still unknown. Aims: The aim of this study is to describe and analyse the outcome of COVID-19 patients with underlying LPD treated with targeted drugs such as monoclonal antibodies (obinutuzumab, ofatumumab, brentuximab, niolumab or pembrolizumab), BTK inhibitors (ibrutinib, acalabrutinib), PI3K inhibitors (idelalisib), BCL2 inhibitors (enetoclax) and IMIDs, (lenalidomide). Methods: The surey was supported by EPICOVIDEHA registry. Adult patients with baseline CLL or non-Hodgkin Lymphoma (NHL) treated with targeted drugs and laboratory-confirmed COVID-19 diagnosed between January 2020 and January 2022 were selected. Results: The study included 368 patients (CLL n=205, 55.7%;NHL n=163, 44.3%) treated with targeted drugs (Table 1). Median follow-up was 70.5 days (range 19-159). Most used targeted drugs were ITKs (51.1%), anti-CD20 other than rituximab (16%), BCL2 inhibitors (7.3%) and lenalidomide (7.9%). Of note, only 16.0% of the patients were accinated with 2 or more doses of accine at the onset of COVID-19. Pulmonary symptoms were present at diagnosis in 244 patients (66.2%). Seere COVID-19 was obsered in 47.8 % patients while 21.7% were admitted to to intensie care unit (ICU), being 55 (26.8%) CLL patients and 25 (15.3%) NHL patients. More comorbidities were reported in patients with seere-critical COVID-19 compared to those with mild- asymptomatic infection (p=0.002). This difference was releant in patients with chronic heart diseases (p=0.005). Oerall, 134 patients (36.4%) died. Primary cause of death was COVID-19 in 92 patients (68.7%), LPD in 14 patients (10.4%), and a combination of both in 28 patients (20.9%).Mortality was 24.2% (89/368) at day 30 and 34.5%(127/368) at day 200. After a Cox multiariable regression age >75 years (p<0.001, HR 1.030), actie malignancy (p=0.011, HR 1.574) and admission to ICU (p<0.00, HR 4.624) were obsered as risk factors. Surial in patients admitted to ICU was 33.7% (LLC 38.1%, NHL 24%). Mortality rate decreased depending on accination status, being 34.2% in not accinated patients, 15.9-18% with one or two doses, decreasing to 9.7% in patients with booster dose (p<0.001). There was no difference in OS in NLH s CLL patients (p=0.344), nor in ITKs s no ITKs treated patients (p=0.987). Additionally, mortality rate dropped from the first semester 2020 (41.3%) to last semester 2021 (25%). Summary/Conclusion: - Our results confirm that patients with B--mallignancies treatted with targeted drugs hae a high risk off seere infection (47.8%) and mortality (36.4%) from COVID-19. - Pressence of comorbidities,, especially heart disease,, is a risk factor for seere COVIID--19 infection in ourr series. - Age >75 years,, actie mallignancy att COVIID--19 onset and ICU admission were mortality risk factors. - COVIID--19 acination was a protectie factor for mortality,, een iin this popullation wiitth humorall immunity impairment. - The learning cure in the management of the infection throughout the pandemiic and the deelopmentt off COVIID--19 treatments showed benefit in this partticullarlly ullnerablle popullation? (Table Presented).

RISK FACTORS FOR UNFAVORABLE OUTCOME OF HOSPITALIZED PANTIENTS WITH CONCURENT CHRONIC LYMPHOCYTIC LEUKEMIA AND COVID-19 - EXPERIENCE OF THREE SERBIAN UNIVERSITY CENTERS

Background: Vulnerability of patients (pts) with chronic lymphocytic leukemia (CLL) and their susceptibility to Covid-19 infection is documented in several studies with reported case fatality rates (CFRs) up to 40%, but there is still paucity of data on identifying risk factors of their adverse outcome. Aims: To evaluate demographic, patient-related, CLL-related and Covid-19 related risk factors in hospitalized pts with concurrent CLL and Covid-19. Methods: Total of 81 CLL pts were identified in medical records of three University centers in Belgrade: Clinical Hospital Center (CHC) Zemun, CHC Bezanijska kosa and CHC Zvezdara dedicated to treatment of Covid-19 pts during pandemic (from 15 March 2020 to 31 December 2021). Results: For all 81 pts CFR was 32.1%. Age (median age 68 yrs;range 45-90 yrs) and sex (apparent male prevalence: 61 male and 20 female;M:F=3.05) had no influence on outcome. Pts with Charlson comorbidity index >4 (29/81;35.8%) had significantly higher CFR (38% vs 9.5%, p=0,025). Concerning CLL-directed treatment: 26/81(32.1%) pts were on active treatment (5 pts were on Bruton tyrosine kinase inhibitor, 21pts receiving imunochemotherapy), 11/81(13.6%) pts were in remission on previous lines of therapy, while 44/81(54.3%) pts were treatment naive. CLL treatment history had no impact on CFR, as well as anemia (Hb<100g/l) that was present in 29/81(35.8%)pts, hipogammaglobulinemia (21/81;26%pts) and hiperferritinemia>450ng/mL (50/81;61.7%pts). Of evaluated laboratory parameters, high levels of lactate-dehydrogenase (LDH>2xUNL:6/81;7.4%pts), D-dimer (>1000ng/mL:36/81;44.4%pts), and C-reactive protein (CRP>100mg/L: 31/81;38.3%pts) proved to be associated with adverse outcome;p-values 0.002, 0.039 and <0.001, respectively. According to Covid-19 clinical course, the severe Covid-19 score had 35(43,2%)pts, and critical 19(23.5%)pts. Covid-19 infection was treated according to current National guidelines. Corticosteroids were administrated to 81.5% of pts, antiviral agents to 38.3%, IL-6 receptor inhibitor to 11.1%, antiviral monoclonal antibodies to 7.4% and intravenous immunoglobulin to 19.8% of pts. None of listed therapeutic approaches had impact on CFRs. Antibiotics were administrated to 43/81 (53.1%) of pts with documented or highly suspected concomitant bacterial infection (procaltitonin level>0.5ng/mL and/or chest X-Ray image corresponding to bacterial pneumonia), and the bacterial coinfection had adverse impact on CFR (51.2% vs.10.2%;p<0.001). Significantly higher mortality was documented in pts who needed supplemental oxygen (58/81;71%) (CFR 43.1 vs.4.3%;p<0.001), and intensive care unit (ICU) admission (25/81-30.9%;19/25 needed mechanical ventilation) (CFR 88% vs.7.1%;p<0.001). In multivariate analysis, bacterial coinfection and ICU admission proved to be the most significant adverse parameters influencing outcome (p=0.012). Summary/Conclusion: Our study proved the dismal outcome of CLL pts with concurrent Covid-19. That could be mainly attributed to the high proportion of bacterial coinfections reflecting their frailty and sucessibility to both viral and bacterial infections.

Impact of cancer diagnosis, stage, and systemic therapies on immunogenicity after COVID-19 vaccination in patients with cancer: A systematic review and metaanalysis

Background: Patients (pts) with cancer are at increased risk of severe COVID-19. Both underlying malignancy and anti-cancer treatments influence the immune system, potentially impacting the level of vaccine protection achieved. Methods: A systematic literature search of PubMed, Embase, CENTRAL and conference proceedings (ASCO annual meetings and ESMO congress) up to 28/09/21, was conducted to identify studies reporting anti-SARS-CoV-2 spike protein immunoglobulin G seroconversion rates (SR) at any time point after complete COVID-19 immunization (mRNA- or adenoviral-based vaccines) in cancer pts. Complete immunization was defined as 1 dose of JNJ-78436735 vaccine or 2 doses of BNT162b2, mRNA-1273 or ChAdOx1 nCoV-19 vaccines. Subgroup analyses were performed to examine the impact of cancer diagnosis, disease stage, and anticancer therapies on the SR. Overall effects were pooled using random-effects models and reported as pooled SR with 95% confidence intervals (CI). Results: Of 1,548 identified records, 64 studies were included in this analysis reporting data from 10,511 subjects. The Table shows the SR in the overall population and specific subgroups. In pts with solid malignancies (SM), disease stage and primary site did not significantly impact the SR. In pts with hematologic malignancies (HM), SR were significantly lower in pts with chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) compared to acute lymphoblastic leukemia (ALL), Hodgkin lymphoma (HL), and multiple myeloma (MM). Concerning the impact of cancer therapies on SR, pts with SM undergoing chemotherapy had numerically lower SR (N = 1,234, SR 87%, CI 81-92) compared to those treated with immune checkpoint inhibitors (N = 574, SR 94%, CI 88-97) or endocrine therapy (N = 326, SR 94%, CI 86-97) with or without another targeted therapy. Pts with HM treated with anti-CD20 therapy (within the last 12 months: N = 360, SR 7%, CI 2-20;or more than 12m: N = 175, SR 59%, CI 35-80), immune-modulating agents (BTK or BCL2 inhibitors) (N = 462, SR 47%, CI 32-64%) or other immunotherapies (anti-CD19/CART or anti-CD38) (N = 293, SR 37%, CI 23-53) had lower SR compared to pts treated with autologous (N = 353, SR 77%, CI 67- 85) or allogenic stem cell transplantation (N = 509, SR 77%, CI 68-84). Conclusions: SR varies between cancer types and anticancer therapies with some cancer pts having low protection against COVID- 19 even after complete vaccination.

Safety/efficacy of evobrutinib, a Bruton's tyrosine kinase inhibitor, 2.5 years into Phase II MS open-label extension

Background and aims: Evobrutinib, a Bruton's tyrosine kinase inhibitor, was well tolerated and effective in a double-blind, randomised Phase II trial in patients with relapsing multiple sclerosis (pwRMS;NCT02975349). Objective: report evobrutinib safety and efficacy data 2.5 years into an open-label extension (OLE). Methods: In the 48-week (W) double-blind period (DBP), pwRMS (n=267) received placebo (switched to evobrutinib 25mg once-daily, W24), evobrutinib 25mg once-daily, 75mg once-daily, or 75mg twice-daily, or open-label dimethyl fumarate (DMF;240mg twice-daily). At W48 patients could enter the OLE (DMF: 4-8W washout);evobrutinib 75mg once-daily (median ∼48W) then 75mg twice-daily. We report the latest available OLE data. Results: Of 267 DBP patients, 213 (80%) entered the OLE;164 (61%) completed ≥132W OLE treatment. Treatmentemergent adverse events (TEAEs) were reported by 165/213 patients (77.5%);59 (27.7%) had a treatment-related TEAE (six were serious;Table). Severe/opportunistic infections (≥Grade 3) were reported by 9/213 patients (4.2%);three (not treatment related;Covid pneumonia [n=2]) were fatal. Most patients had normal IgG (91%), IgA (88%) and IgM (82%) levels (OLE W120). Mean CD19+ B cells levels were 0.218x106cells/mL (OLE baseline) and 0.122x106cells/ mL (OLE W96). ALT/AST elevations only occurred in patients previously receiving DMF/evobrutinib 25mg, and within 12W of OLE initiation. Amylase/lipase increases occurred in 6 (2.8%)/24 (11.3%) patients, without clinical signs and symptoms. ARR, for patients receiving 75mg twice-daily in the DBP, was 0.12 (95%CI 0.07-0.20 [all available OLE data]). Conclusion: Evobrutinib safety and efficacy data over 2.5 years shows acceptable tolerability, no new safety signals and maintained efficacy in pwRMS.

The Use of Bruton Tyrosine Kinase Inhibitors in Severe Covid-19 Patients

RATIONALE: SARS-CoV-2, a novel coronavirus, is the third coronavirus with an associated severe acute respiratory syndrome since SARS-CoV [1]. Patients with severe COVID-19 suffer from immune hyperactivity, also referred to as a cytokine storm, which causes increased vascular permeability and multiorgan dysfunction and is a significant source of morbidity and mortality.1 Because Bruton's Tyrosine Kinase (BTK) activity is thought to play a role in the cytokine storm, with elevated activity found in monocytes, it has been explored as a target for intervention for COVID- 19.2 METHODS : This observational, case-control study included 49 hospitalized patients with severe COVID-19. Of the 49 patients, 11 patients received off-label Acalabrutinib between May 2020 through June 2020. The purpose of the study is the assess the use of Acalabrutinib as a potential strategy for management of COVID-19 patients. Bivariate and Multivariate logistic regression models were used to analyze the data. The response variable was patient outcome (remission discharge or death). The main predictor of interest was the administration of Acalabrutinib on patients (Yes/No). For the multivariate analysis the covariates included were age, gender, change in CRP levels (Discharge CRP - Admission CRP), hypertension, COPD, and comorbidities status (Yes/No). Stata Version 17.0 (Stata Corp, College Station, Texas USA) was used in all analyses. RESULTS : The median age of patients was 58 with a majority being male (51%). The average length of hospitalization was 17 days with 23 (46.9%) patients receiving mechanical ventilation. Bivariate analysis revealed that acalabrutinib was protective against death from COVID-19. However, these results were nonsignificant (OR 0.36, 95 CI [0.04, 2.87], P=0.31). The multivariate analysis supported the results of the bivariate analysis. However, we did not observe a significant association between outcome and acalabrutinib when adjusted for the study covariates (OR 0.32, 95% CI [0.03, 3.79], P=0.37). CONCLUSION: Acalabrutinib did not significantly reduce morbidity or mortality on severe COVID-19 patients. Further studies are warranted to assess the efficacy of BTK inhibitors for COVID-19 in a larger clinical trial. (Table Presented).

Safety and Clinical Efficacy Outcomes From the Long-term Extension Study of Tolebrutinib in Patients With Relapsing Multiple Sclerosis:18-Month Results

Objective: To describe safety and efficacy of tolebrutinib in patients with relapsing multiple sclerosis at Week 72 (Month 18) in the long-term safety (LTS) extension of the phase 2b trial. Background: In the phase 2b trial (NCT03889639), tolebrutinib, a CNS-penetrant Bruton's tyrosine kinase inhibitor, was well tolerated over 12 weeks with dose-dependent reduction in new gadolinium-enhancing T1 and new/enlarging T2 lesions. Design/Methods: The LTS extension (NCT03996291) consists of 2 parts: patients continued their core study tolebrutinib dose (5, 15, 30, or 60 mg/day) double-blind until the phase 3 study dose was selected (Part A), and currently receive tolebrutinib 60 mg/day open-label (Part B). Long-term safety and tolerability is the primary objective. Secondary endpoints include annualized relapse rate (ARR) and change from baseline in Expanded Disability Status Scale (EDSS) score. Results: 124 of 125 patients treated in the extension completed Part A and transitioned to Part B. One patient (on 5 mg/day) discontinued Part A due to progressive disease and 6 discontinued Part B due to a variety of reasons, including adverse event (AE;n=2), lack of efficacy (n=1), progressive disease (n=1), and emigration (n=2). To date, no new safety signals have been observed. The most common treatment-emergent AEs (TEAEs) were headache (12.8% [16/125]), COVID-19 (12.8% [16/125]), nasopharyngitis (10.4% [13/125]), upper respiratory tract infection (8.0% [10/125]), and arthralgia (5.6% [7/125]). There was no suggestion of a dose effect for TEAE or serious AE in Part A and no emergence of new safety signals for patients switching to 60 mg in Part B. ARR on tolebrutinib 60 mg was 0.17 (95% CI: 0.11, 0.27);84.7% of patients were relapse-free at the LTS Week 72 cut-off. Mean EDSS scores remained stable to LTS Week 72. Conclusions: Through LTS Week 72, tolebrutinib 60 mg continues to show favorable safety and tolerability, and low ARR.

Safety and Efficacy of Evobrutinib, a Bruton's Tyrosine Kinase Inhibitorin Relapsing Multiple Sclerosis Over 2.5 Years of The Open-Label Extension to a Phase II Trial

Objective: Report the safety and efficacy of evobrutinib over 2.5 years in an open-label extension (OLE). Background: Evobrutinib, a covalent, blood-brain barrier-penetrating Bruton's tyrosine kinase inhibitor, was well tolerated and effective at reducing gadolinium-enhancing lesions in a double-blind, randomized phase II trial in patients with relapsing multiple sclerosis (pwRMS;NCT02975349). Design/Methods: In the 48-week (W) double-blind period (DBP), pwRMS (n=267) received placebo (switched to evobrutinib 25mg once-daily at W24), evobrutinib 25mg once-daily, 75mg once-daily, or 75mg twice-daily, or open-label dimethyl fumarate (DMF;240mg twice-daily). At W48 patients could enter the OLE (DMF: 4-8W washout);evobrutinib 75mg once-daily (median ~48W) then 75mg twice-daily. The latest available OLE data are now reported. Results: Of 267 DBP patients, 213 (80%) entered the OLE;164 (61%) completed ≥132W of OLE treatment. Treatment-emergent adverse events (TEAEs) were reported by 165/213 patients (77.5%);59 (27.7%) had a treatment-related TEAE. Six serious TEAEs were deemed treatment-related. Severe/opportunistic infections (≥Grade 3) were reported by 9/213 patients (4.2%);3 were fatal (Covid-19 pneumonia [n=2] and E. coli sepsis [n=1];not considered treatment-related). At OLE W120, most patients had IgG (91%), IgA (88%) and IgM (82%) within normal ranges. Overall mean CD19+ B cells levels were 0.218×10 cells/mL (OLE baseline) and 0.122×10 cells/mL (OLE W96). ALT/AST elevations were observed only in patients previously receiving DMF/evobrutinib 25mg and occurred within 12W of OLE initiation. Amylase/lipase increases occurred in 6 (2.8%)/24 (11.3%) patients, but without clinical signs and symptoms. Based on all available OLE data, ARR was 0.12 (95%CI 0.07-0.20) for patients receiving 75mg twice-daily in the DBP. 6 6 Conclusions: Evobrutinib safety and efficacy data over 2.5 years in pwRMS continue to show acceptable tolerability, with no new safety signals, and maintained efficacy.

The Role of BTK Inhibition in the Treatment of Chronic Lymphocytic Leukemia: A Clinical View.

The B cell receptor (BCR) signaling pathway is functional and has critical cell survival implications in B cell malignancies, such as chronic lymphocytic leukemia (CLL). Orally administered small molecule tyrosine kinase inhibitors of members of the BCR signaling pathway have proven to be transformational in treatment of CLL. The first-generation inhibitor, ibrutinib, covalently binds to the C481 amino acid of Bruton's tyrosine kinase (BTK), thereby irreversibly inhibiting its kinase activity, and interferes with the biology of the cells, ultimately resulting in CLL cell death and therapeutic response. Remissions are not deep to the point of considering discontinuation for most patients, but BTK-inhibitor-based therapy provides exceptional long-term disease control with continuous treatment. There are in-class toxicities and more selective second- and subsequent-generation agents and reversible inhibitors have been developed with the intent of reducing toxicities. Also, strategies to subvert resistance have included tighter or alternative, non-covalent, inhibitor binding. Furthermore, other strategies to deplete BTK protein, such as degraders, are in development and being tested in the clinic. Ultimately, the development and approval of these agents targeting BTK have ushered in a new era of chemotherapy-free treatments with remarkably improved survival outcomes for patients with CLL.