key: cord-0744344-qhjl9ztt authors: Molica, Stefano; Sportoletti, Paolo; Di Renzo, Nicola; Musto, Pellegrino; Pane, Fabrizio; Di Raimondo, Francesco title: Venetoclax-Rituximab Treatment of Relapsed/Refractory CLL During the COVID-19 Pandemic: A Real-Life Experience in Selected Central-Southern Italian Regions date: 2021-07-01 journal: Mediterr J Hematol Infect Dis DOI: 10.4084/mjhid.2021.042 sha: 296d311f01defd1c998f793ca4eb8e5a8c645ad4 doc_id: 744344 cord_uid: qhjl9ztt nan However, how these recommendations affect CLL patients' care in the real world has not been assessed. An exploratory survey was undertaken in selected regions of central-southern Italy (i.e., Umbria, Campania, Puglia, Calabria, and Sicilia) to ascertain the adherence to the recommendations mentioned above. That study also aimed to assess the prevalence and severity of COVID19 infection among CLL patients homogeneously treated in an area with an estimated population of about 18 million inhabitants. The target population consisted of patients with relapsed/refractory (R/R) CLL treated from February 1 th to Dec 31 th 2020 with time-limited venetoclax/rituximab (VR) combination as employed in the MURANO trial (i.e., venetoclax for up to 2 years plus rituximab for the first 6 months). The data collecting form focused on whether a test for detection of COVID-19 infection was performed only in patients with CLL who reported symptoms or universally; detailed information of the cases who contracted COVID-19 infection, its severity and outcome; and treatment modifications once the infection was detected. The questionnaire was sent to 30 CLL hematologists, of which 26 responded. Finally, we considered suitable for the present analysis the 24 questionnaires compiled by hematologists who declared to have treated at least one patient with VR combination in the observation period. Of those, 20.8% worked in academic hospitals. Overall, the survey allowed data collection on 124 patients who had begun treatment with VR combination for R/R CLL no earlier than February 1 st , 2020. The median number of patients treated in each center was 5 (range, 1-15). COVID-19 surveillance tests consisted of viral RNA reverse transcriptase PCR (RT-PCR) on nasopharyngeal swabs. Most patients (83/124, 66.9%) were tested before beginning the ramp-up with venetoclax; moreover, 66/124 (53.2%) were regularly tested before each rituximab infusion. The treatment adherence was relatively high (70.8%). Only 20.8% of physicians modified the therapeutic program, mainly because of WHO grade 3 neutropenia. Changes consisted of transient interruption of venetoclax (22%), reduction of doses (48%), and delay of rituximab infusion (30%). Only 2 (8.3%) physicians declared to have skipped or delayed rituximab infusions due to the concern about the potential higher risk of infection associated with anti-CD20 monoclonal antibodies combined to targeted agents. Overall, 2/124 patients (1.6%; 95% confidence interval [CI], 1.2-9.5%) had symptomatic RT-PCR proven diagnosis of COVID-19 infection and required hospitalization. Both patients needed oxygen therapy and admission into an intensive care unit. Of those, one patient who was receiving VR combination at the time of COVID infection eventually died. The second patient developed COVID-19 infection while receiving venetoclax monotherapy (after the VR combination period). He recovered from a COVID-19 infection, and after 21 days of treatment interruption, he was able to restart venetoclax. Despite the relatively close surveillance policy (i.e., approximately 70% of patients had a molecular nasopharyngeal swab at the start of venetoclax ramp-up and 53.2% before each rituximab infusion), no case of asymptomatic or paucisymptomatic COVID-19 infection was observed. The current study assessing the frequency and severity of COVID19 infection in a homogeneous cohort of patients with R/R CLL treated with VR is worth being compared with other reports. Compared to the Italian CLL Campus data, which includes a patient population heterogeneous for treatment, our findings indicate only an apparent higher incidence of COVID19 infections (i.e., 0.5% versus 1.6%). It is worth noting that our study examined the entire COVID19 outbreak period, whereas the CLL Campus analysis only looked at the first two months, resulting in a likely underestimation of the COVID19 infection rate. The current study also provides information on the strategy used to monitor CLL patients who were suitable for a therapeutic approach that requires, at least initially, regular clinic visits, which may theoretically conflict with a primary prevention policy. For example, in a survey conducted in the USA at the beginning of the outbreak, only 23% of clinicians recommended universal testing for all patients. 5 In our survey, 66.9% and 53.2% of patients were tested with molecular swabs, respectively, at the beginning of venetoclax and later before each rituximab infusion. Following these measures, physicians were confident in the use of the VR combination and provided patients unconditional continuation of CLL therapy unless a treatment-related adverse effect occurred (i.e., mainly WHO grade 3 neutropenia). To summarize, the findings of this study provide previously unknown details about the use of VR combination therapy in CLL patients in real-world clinical practice during the COVID19 pandemic. Our understanding of the COVID-19 pandemic is constantly evolving, and so are recommendations and practices. While waiting for results of ongoing observational and interventional studies to inform evidence-based recommendations, our survey suggests that VR timelimited combination therapy can be used safely in the era of the COVID19 outbreak. Moreover, recent access to vaccines against SARS-CoV-2 offers a unique chance to answer important practical questions. 17 Since the quality of a serologic response is scarce in CLL, the clinical impact of vaccination on the risk reduction for SARS-CoV-2 infection is a matter of study. 18 We also need to know whether differences in seroconversion in patients receiving small molecules (BTKi, BCL2i) vs. venetoclax exist. Clinical characteristics and risk factors associated with COVID-19 severity in patients with haematological malignancies in Italy: a retrospective, multicentre, cohort study Perturbation of the normal immune system in patients with CLL Immune Dysfunction in Patients with Chronic Lymphocytic Leukemia and Challenges during COVID-19 Online ahead of print Management of CLL patients early in the COVID-19 pandemic: An international survey of CLL experts CLL and COVID-19 at the Hospital Clinic of Barcelona: an interim report Protective role of Bruton tyrosine kinase inhibitors in patients with chronic lymphocytic leukaemia and COVID-19 Chronic lymphocytic leukemia management in Italy during the COVID-19 pandemic: a Campus CLL report Management of chronic lymphocytic leukemia in Canada during the coronavirus pandemic Reply to "CLL and COVID-19 at the Hospital Clinic of Barcelona: an interim report" analysis of six hematological centers in Lombardy : On behalf of CLL commission of Lombardy Hematology Network How We Manage Patients With Chronic Lymphocytic Leukemia During the SARS-CoV-2 Pandemic. Hemasphere When CLL meets COVID-19. Blood COVID-19 severity and mortality in patients with chronic lymphocytic leukemia: a joint study by ERIC, the European Research Initiative on CLL, and CLL Campus Outcomes of COVID-19 in patients with CLL: a multicenter international experience COVID-19 and CLL: Frequently Asked Questions recommendations-for-specific-hematologicmalignancies. COVID-19 and CLL: Frequently Asked Questions (Produced by the EHA SWG on CLL (ERIC) and endorsed by EHA) Vaccinations in CLL: implications for COVID-19 Anti-SARS-CoV-2 antibody response in patients with chronic lymphocytic leukemia