Dasatinib Related Pleural Effusions: Real-World Experience in a District General Hospital

Dasatinib, a second-generation BCRABL1 tyrosine kinase inhibitor (TKI), is an approved treatment for chronic myeloid leukaemia, both as first-line therapy and following imatinib intolerance or resistance. It is generally well tolerated, however, dasatinib has been associated with a higher risk for pleural effusions. Frequency, risk factors and outcomes of this significant side effect were analysed in the phase 3 DASISION and 034/Dose-optimization trials. Annual risk of 5%-15% was reported. Drug-related pleural effusion occurred in 28%-33% of patients in a minimum of 5-year follow-up period. One major risk factor was advanced age. We therefore reviewed a cohort of 34 patients treated with dasatinib between 2016 and 2021, to determine 'real-world' data of this toxicity. Case notes, pathology results and radiological reports were analysed. We identified 12 (35%) cases of pleural effusions. Eight (66%) cases were male. The median average age of patients with and without drug-related pleural effusion were 59.5 years (range: 31-91 years) and 54.5 years (range: 20-88 years) respectively. Cardiovascular and respiratory comorbidities were noted in eight patients (66.6%) with pleural effusion (ischaemic heart disease, hypertension, lung cancer, COVID, peripheral vascular disease and hyperlipidaemia) and nine patients (41%) without pleural effusion (prior non-TKI pleural effusion, hypertension, asthma, congenital heart defect, COPD and atrial fibrillation). Nine cases (75%) of those with pleural effusion were non-smokers. Lymphocytosis was not noted in any of those 12 cases of drug-related pleural effusion. Ten cases (83%) were on dasatinib 100 mg daily when pleural effusion was diagnosed, one was on 50 mg daily and the other was on 20 mg daily. Pleural effusion occurred after a median of 36 months (range: 6-108 months). Nine cases (75%) were mild to moderate in severity-Common Terminology Criteria for Adverse Events (CTCAE ) grade 1-2, two were grade 3 and one was grade 4. Two required no intervention, three required only medical intervention (steroid+/-antibiotics), three required pleural tap and three required pleural drain. One required VATS procedure with talc pleurodesis. The patient with grade 1 pleural effusion required no treatment change. One required dose reduction of dasatinib without interruption. One required temporary interruption but restarted on the same dose. Six required temporary interruption of dasatinib followed by dose reduction to 50 mg daily. Two of these subsequently recurred on lower dose dasatinib and were then switched to an alternative TKI (bosutinib and imatinib). Two required temporary TKI interruption and were restarted on a different TKI (nilotinib). One case of pleural effusion persisted and the patient was kept off TKI treatment. Although the numbers are too small for statistically robust analysis, we have observed several trends which may help to guide patient counselling and selection. Pleural effusion has an incidence of 35% in our local population. Risk factors were cardiovascular and respiratory comorbidities, advanced age and male sex. Smoking status and lymphocytosis did not appear to be risk factors in our cohort, where they have been in other reports. Most effusions were mild to moderate in severity and could usually be managed by steroid+/-pleural tap+/-drain. Most patients required temporary interruption of their dasatinib but were successfully able to restart at a lower dose without recurrence..

COVID-19 IN CHRONIC MYELOID LEUKEMIA PATIENTS – BRAZILIAN EXPERIENCE

Aims: To collect data about COVID-19 in CML patients from Brazilian centers and their outcomes. Methods: Observational, multicentric, ongoing register study. Hematologists from private and public CML reference centers from different regions of Brazil were invited to report their cases of COVID-19 in CML patients. Those centers are responsible for the care of approximately 3030 CML patients. Results: Between March 2020 and July 2021, 16 institutions contributed to this analysis, and reported 73 COVID-19 cases in CML patients (pts). Eight-five % were from the South and Southeast regions, 11% from Northeast. The median age was 50 years (22-79), with 33% of the pts older than 60. Male patients were predominant (60%). The median time of CML diagnosis was 9 years (0-29). Most of the pts were in first line therapy (57.5%), 27% in second line and 11% in third line. Current CML treatment at COVID-19 was: imatinib (46,5%), nilotinib (22%), dasatinib (16%), post-transplant (4%), asciminib (1%), ponatinib (1%), treatment-free remission (2%), no treatment (7%). COVID-19 grade: asymptomatic (4%), mild (66%), moderate (12%), severe/critical (16%). CML status at COVID: AP/BC (3%), CP (12,4%), hematologic response (11%), complete cytogenetic response (4%), MMR (34%), MR4.0 (8%), MR4.5 (27%). Eleven patients interrupted treatment temporarily during COVID. COVID-19 was confirmed by RT-PCR of oral and nasal swab collection (68%) or rapid/serologic test (32%). Comorbidities were present in 34 pts, most common were: hypertension (33%), diabetes (14%), chronic renal failure (4%), chronic obstructive pulmonary disease/emphysema (5.5%), pulmonary hypertension (1). Hospitalization occurred in 30% of the cases, 18% in an intensive care unit, 8% with mechanical ventilation. Treatment received for COVID-19: antibiotics (31%), steroids (16%), chloroquine (5.5%), oseltamivir (4%);ivermectin (8%): heparin (3%). Sixty-nine patients recovered, 4 died from COVID-19 (5,4%): one 42 year old newly diagnosed male patient with high leukocytes counts and with a simultaneous bacterial infection, two 70-year old patients treated with imatinib, both in MR4.5, and one 31-year old male patient treated with nilotinib, after imatinib and dasatinib failure, with hematologic response. A fifth patient in the accelerated phase died 2 months after discharge, from disease progression and pulmonary infection. All cases occurred before vaccination. There was one case of re-infection, in a patient treated with imatinib. Discussion: Conclusions: the majority of COVID-19 cases in the CML population was mild, but there were 2 deaths of young patients with active disease and two deaths in elderly patients, one of them with comorbidities. The mortality in CML was lower than observed in other hematologic cancers.

The new HFA/ICOS risk assessment tool to identify patients with chronic myeloid leukaemia at high risk of cardiotoxicity.

AIMS: Tyrosine kinase inhibitors (TKIs) used to treat chronic myeloid leukaemia (CML) can cause cardiovascular adverse events. So far, the Systematic Coronary Risk Evaluation (SCORE) charts of the European Society of Cardiology (ESC) have been used to identify cancer patients at increased cardiovascular risk. The primary aim of our study was to evaluate the usefulness of the new cardiovascular risk assessment model proposed by the Cardio-Oncology Study Group of the Heart Failure Association (HFA) of the ESC in collaboration with the International Cardio-Oncology Society (ICOS) to stratify the cardiovascular risk in CML patients, compared with SCORE risk charts. The secondary aim was to establish the incidence of adverse arterial events (AEs) in patients with CML treated with TKIs and the influence of preventive treatment with aspirin. METHODS AND RESULTS: A retrospective single-centre observational study was carried out on 58 patients (32 men and 26 women; mean age ± SD: 59 ± 15 years) with CML treated with TKIs for a median period of 43 ± 31 months. Cardiological evaluation was performed and cardiovascular risk was estimated with SCORE risk charts and with the new risk assessment tool proposed by HFA/ICOS. AEs were recorded. According to SCORE charts and the new HFA/ICOS risk stratification tool, respectively, 46% (Group A1) and 60% (Group A2) of patients were at high-very high risk, and 54% (Group B1) and 40% (Group B2) at low-moderate risk. AEs were significantly more frequent in Group A1 than Group B1 (P value < 0.01) when considered overall; they were significantly more frequent in Group A2 than Group B2 either overall or considered individually. HFA/ICOS risk stratification tool was significantly more sensitive than SCORE (P < 0.01) in identifying patients at higher risk of cardiovascular toxicity. In addition, we did not find AEs in patients pretreated with aspirin. CONCLUSIONS: The new HFA/ICOS risk stratification model allows a more tailored cardiovascular risk stratification in patients with CML and it is more sensitive than SCORE charts.

Covid-19 in patients with chronic myeloid leukemia: Poor outcomes for patients with comorbidities, older age, advanced phase disease, and those from low-income countries: An update of the candid study

Background The iCMLf CANDID study represents the largest global cohort study to date characterizing COVID-19 in CML. This real world data collection, from 157 institutions in 49 countries, is essential to differentiate impact of patient, disease, and therapy specific factors on risk and outcomes, as the pandemic continues. Objective The primary aim of the CANDID study is to collect and analyze information on COVID-19 cases among CML patients (pts) to define risk factors, clinical evolution and outcome. Patients and methods Since March 2020, the iCMLf has collected data, with contributions from physicians treating CML pts and partner organizations. Country income was determined according to the World Bank Data. COVID-19 severity was classified according to the World Health Organization criteria. Univariate analysis was performed using log-rank test or logistic regression. Multivariate analysis was performed using Cox proportional hazards model or multivariate logistic regression. All the statistical analysis was performed using R statistical software (version 4.0.2). Results By April 2021, 642 cases of COVID-19 were reported from 50 countries. COVID-19 was diagnosed by PCR and/or serology in 601 pts (94%) and clinically suspected in 41 pts (6%). These 642 pts were reported by 186 physicians managing an estimated 37,449 CML pts (approximate incidence 0.7%). Most cases reported were from Europe (52%), followed by Asia (18%) and South America (16%). North America reported 10% of the cases and Africa 2.8%. The median age at the time of COVID-19 diagnosis was 53 years (18-94) and 59% of pts were males. Median time from CML diagnosis to COVID-19 was 8.34 years (range: 0-34). CML treatment at the time of COVID-19 diagnosis: hydroxyurea in 4 pts (6%), 38 (6%) bosutinib, 96 (15%) dasatinib, 275 (43%) imatinib, 92 (14%) nilotinib, 18 (3%) ponatinib, 3 (0.5%) other 4th generation TKIs;one alpha interferon. Ninety-nine (15%) pts were not receiving any treatment: 53 (8%) were in treatment free-remission (TFR) and 46 were without treatment (7%) for other reasons: treatment side effects (7), stem cell transplantation (12), pregnancy (3), lack of efficacy (2), unknown (1) and newly diagnosed CML (21). Significant comorbidities were present in 281 pts (44%), most common were: heart conditions, including hypertension (162), diabetes (76), lung diseases (47) obesity (42) and others (84). COVID-19 was asymptomatic in 53 cases (8%), mild in 363 cases (56%), moderate in 119 cases (18%), severe/critical in 86 cases (13%) and of unknown severity in 21 cases (3%). At the data cut-off, from the 606 pts with known outcome, 48 pts died (8%) and 558 (92%) recovered. Age >75y (Fig 1A, p<0.001), comorbidities (Fig 1B, p=0.039), low income country (Fig 1C, p<0.001), advanced phase CML at time of COVID-19 (Fig 1D, p<0.001) had statistically significant association with overall survival (OS) in CML pts with COVID-19. OS was 71% in low or lower middle income countries, 93% in upper middle and 95% in high-income countries (Fig 1C, p<0.001). The mortality rate for pts with cardiovascular disease;heart failure, coronary artery disease, cardiomyopathies, hypertension, stroke or cerebrovascular disease (12%), and chronic lung disease (13%) were higher than those pts with other comorbidities (6%), or without comorbidities (4%;p=0.003;Fig 1E). By multivariate analysis, all these risk factors remained significantly associated with OS. For pts who were hospitalized with severe disease, age >75y (p=0.037), comorbidities (p=0.001), male gender (p=0.01), CML status (AP/BC vs CP in MMR;p=0.049), CML treatment (pre-TKI vs TFR;p=0.02) and length of time with CML (p<0.05) were significant risk factors for mortality. By multivariate analysis, all the risk factors except age remained significant. The risk factors for mortality for pts with moderate, severe, or critical disease were age >75y (p=0.003) and low and lower middle income countries (p<0.001), both confirmed by multivariate analysis. Conclusions We confirmed a higher mortality for CML pts with COVID-19 n older pts (>75y), pts with cardiovascular or pulmonary comorbidities and from low and low-middle income countries, the latter probably related to limitations in supportive care. Additionally, more deaths occurred in pts in advanced phases and in pts not in MMR.

First Interim Analysis of the Italian Dante Study: De-Escalation before Treatment-Free Remission in Patients with Chronic Myeloid Leukemia Treated with First-Line Nilotinib

Introduction: Treatment-free remission (TFR) in chronic myeloid leukemia (CML) is demonstrated to be achievable and recommended for patients (pts) in sustained deep molecular response (sDMR) who can discontinue tyrosine kinase inhibitor (TKI) treatment and maintain responses in ~50% of cases. While the feasibility and safety of TKI cessation have been largely demonstrated, the strategies of TFR optimization are yet to be clarified. Studies (eg. DESTINY) investigating de-escalation, mainly after imatinib, suggested that a stepwise approach may favor TFR outcome. We present the interim results of the phase 2, prospective, multicenter DANTE study (NCT03874858) evaluating de-escalation and TFR in Italian pts with CML in chronic phase (CML-CP) treated with nilotinib (NIL). Methods: Adults with CML-CP treated with NIL 300 mg twice daily (bid) in first-line for ≥3 years who achieved sDMR for ≥1 year (≥MR 4.0;BCR-ABL level ≤0.01% IS) were enrolled in 27 centers. The study consisted of 4 phases: screening (week [wk] −4-0), consolidation (wk 0-48), TFR (wk 48-144), and follow-up (until wk 144). Ongoing treatment with ≥400 mg/day dose was allowed at study entry. During consolidation, pts were treated with NIL 300 mg once daily (qd). At the end of consolidation phase, pts with sDMR entered TFR phase and discontinued NIL;indeed, pts with at least major molecular response (MMR;BCR-ABL ≤0.1% IS), but without sDMR, continued NIL 300 mg qd. At any time, pts with loss of MMR returned to NIL 300 mg bid. During TFR phase, BCR-ABL levels were monitored monthly from wk 52-96, and then every 3 months. Pts on half-dose or full-dose NIL were monitored every 3 months. The primary endpoint is the percentage of pts in full treatment-free remission (FTFR) 96 wks after the start of consolidation phase. FTFR is defined as pts with MMR or better, including those who remained in discontinuation during TFR phase and those who are treated with half the standard dose. Key secondary endpoints include percentage of pts with sDMR at wk 48;TFR rate at wk 96 and 144;BCR-ABL kinetics and safety. The predictive role of digital droplet PCR is also evaluated as an exploratory objective. Results: Overall, 113 pts were screened and 107 entered consolidation phase. This interim analysis included 52 pts who reached the end of consolidation phase by data cut-off period (February 8, 2021). Of these 52 pts, 49 (94.2%) were ongoing by data cut-off and 3 (5.8%) discontinued the study (1 patient due to adverse event (AE) and 2 per patient's decision). Median age at study entry was 49.5 years. Median time from diagnosis was 5.6 years and median dose of prior NIL treatment was 600 mg/day for all pts except one who was on NIL 450 mg/day at baseline. Median duration of last sustained MR4 and MR4.5 were 30 and 16.5 months, respectively. Further details are listed in Table 1. At screening, molecular response categories were MR4.0 in 13.7%, MR4.5 in 23.1% and undetectable MR4.5 in 63.5% of pts. During consolidation phase, 5 (9.6%) pts discontinued prematurely: 2 pts restarted NIL full dose (3.8%) for MMR loss, 2 (3.8%) discontinued for AEs and 1 (1.9%) for pt decision. Overall, 47 pts completed consolidation: of them 40 (76.9%) sustained DMR and 7 (13.5%) maintained MMR but not sDMR. Of the 7 pts not sustaining DMR during consolidation, 6 regained DMR after a median of 4.4 months, while 1 pt was still in MMR by data cutoff. The 2 pts who lost MMR after 5 and 8 months regained MMR and 1 regained DMR by data cutoff after increasing NIL to 300 mg bid. Median time spent in consolidation phase was 11.7 months, and the evolution of response categories over time is shown in Figure 1. During consolidation phase, AEs were observed in 16 pts (30.8%), of them 2 (3.8%) pts had serious AEs: 1 patient had skin ulcers and COVID-19 related pneumonia, while 1 patient had unstable angina. No deaths and disease progressions were observed. Conclusions: DANTE is the first study that showed the safety and feasibility of NIL de-escalation before TFR in CML-CP pts with sDMR. Inter m results suggest that loss of MMR during de-escalation is rare. De-escalation strategy may lead to further improvement of TFR outcome and tolerability and may also preemptively support the identification of pts who may not be ready for discontinuation, with a tailored approach. To date, accuracy in predicting TFR outcome is still low, and the de-escalation setting may sharpen biological and clinical predictive factors, including the potential role of digital PCR. [Formula presented] Disclosures: Breccia: Abbvie: Honoraria;Pfizer: Honoraria;Novartis: Honoraria;Incyte: Honoraria;Bristol Myers Squibb/Celgene: Honoraria. Abruzzese: Incyte: Consultancy, Honoraria;Novartis: Consultancy, Honoraria;Pfizer: Consultancy, Honoraria;Bristol Myers Squibb: Consultancy, Honoraria. Stagno: InCyte: Consultancy, Honoraria;Pfizer: Consultancy, Honoraria, Other: Support for attending meetings and/or travel;Novartis: Consultancy, Honoraria, Other: Support for attending meetings and/or travel, Research Funding. Iurlo: Incyte: Speakers Bureau;Novartis: Speakers Bureau;Pfizer: Speakers Bureau;Bristol Myers Squibb: Speakers Bureau. Sportoletti: AstraZeneca: Consultancy, Honoraria;Janssen: Consultancy, Honoraria;AbbVie: Consultancy, Honoraria. Lemoli: Jazz, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;AbbVie, Daiichi Sankyo, Servier: Honoraria, Speakers Bureau;Celgene: Other: Support for attending meetings and/or travel. Siragusa: Novartis, CSL, Behring, Amgen, Novonoridsk, SOBI, Bayer: Consultancy, Honoraria, Speakers Bureau. Chiodi: Novartis: Current Employment.

Half: A Prospective Multi-Centre Phase II Clinical Trial Evaluating the Efficacy and Safety of Tyrosine Kinase Inhibitors' Discontinuation after Two-Step Dose Reduction in Patients with Chronic Myeloid Leukemia in Deep Molecular Remission

Background. Treatment-free remission (TFR) has become a new treatment goal for chronic myeloid leukemia (CML) patients. However, usually abrupt tyrosine kinase inhibitors (TKIs) therapy discontinuation has been successful only in about half of eligible patients and it can cause burdening TKI withdrawal syndrome (TWS) in about 30% of them. Moreover, any robust clinical or biological factor predictive for successful TFR has not been identified yet. On top of that, sustainable deep molecular response (DMR) as the main prerequisite for TKI discontinuation attempt is achieved only in 20-40% of patients. The majority of CML patients, therefore, need to be treated with the effective and well-tolerated drug for a long time or even life-long. Study design and methods. With the recognition of all these aspects, we designed a nationwide prospective investigator-initiated phase II clinical trial HALF (ClinicalTrials.gov NCT04147533) in order to evaluate efficacy and safety of TKI discontinuation after previous two-step dose reduction in patients with CML in DMR (Fig. 1). Step-wise TKI dose reduction, i.e. half of the standard during the first 6 months after study entry, and the same dose given alternatively (every other day) during the next 6 months, was derived from pharmacokinetics and experimental data as well as from clinical trials' results. We assume that the step-wise and eventually meaningful TKI dose reduction enables a higher rate of patients achieving successful TFR with less pronounce TWS, or even would represent a more reasonable and safer alternative to the complete and sudden TKI interruption. This unique nationwide academic project has been facilitated by hematological patients care centralization in the Czech Republic. A primary study objective is to evaluate the proportion of patients in major molecular response (MMR) at 6 and 12 months and in TFR at 18, 24, and 36 months after the study enrollment, respectively, and molecular recurrence-free survival at all mentioned time points as well. Main secondary and exploratory objectives are: to evaluate the proportion of patients loosing MMR and in whom MMR and MR4.0 would be re-achieved after TKI re-introduction, time to MMR and MR4.0 re-achievement, FFS, PFS, OS, TWS, and QoL assessment, predictive factors for successful TFR identification, quantification of BCR-ABL1 using digital droplet PCR at both the DNA and mRNA levels, immunological profiling, BCR-ABL1 kinetics mathematical modeling, assessment of TKI pharmacokinetics, clonal hematopoiesis and pharmaco-economics. Results. The study was launched in December 2019;however, due to the COVID-19 outbreak, patients' recruitment started on June 16, 2020. Here, characteristics of the first 74 patients included in the study until April 2021 are presented. There were 37 males and 37 females, with median age at the time of diagnosis of 53 years (range, 23-74) and at the time of the study entry of 67 years (range, 35-86). A median time of CML disease, TKI treatment, and DMR duration before the study initiation was as follows: 9.9 years (range, 4.4-22.5), 9.8 years (range, 4.2-20.2), and 7.3 years (range, 3.2-18.3), respectively. The ELTS score was low, intermediate, high and unknown in 62.2%, 21.6%, 13.5%, and 2.7% of patients, respectively. At the time of study entry, 58 patients (79.5%) were treated with imatinib, 10 (13.7%) with nilotinib, and 5 (6.8%) with dasatinib, respectively, whereas in 63 patients (86.3%) it was in the first line of therapy. With almost half of patients (48.6%), the TKI dose was already reduced at the time of study entry. With 10 (13.5%) patients, interferon-α treatment preceded TKI administration. At the time of this preparation, on July 26, 2021, altogether 102 patients (from planned 150) have been enrolled in the study;48 of them (47.1%) have already moved to the second de-escalation phase and 9 (8.8%) patients to the TFR phase. There were 2 cases of confirmed MMR loss (both in month 8 after the study entry) and no patient experienced symptoms resembling TWS. Conclusions. Despite the COVID-19 pandemic, the HALF study was successfully launched and initiated in the majority of centers, with 102 already included patients and continuing intensive enrolment. Based on our very preliminary results, the step-wise dose reduction seems to be an effective and safe approach. More included patients, longer follow-up and further analyses are needed in order to reach all set up objectives. [Formula presented] Disclosures: Žácková: Angelini: Consultancy, Speakers Bureau;Novartis: Speakers Bureau. Faber: Angelini: Consultancy, Other: conference fees, Research Funding, Speakers Bureau;Bristol-Myers Squibb: Consultancy, Other: conference fees, Research Funding, Speakers Bureau;Novartis: Consultancy, Other: conference fees, Research Funding, Speakers Bureau;Pfizer: Other: conference fees;TERUMO: Other: conference fees. Bělohlávková: Novartis: Consultancy;BMS/Celgene: Consultancy. Horňák: Angelini: Honoraria. Svobodník: Roche: Speakers Bureau;Janssen-Cilag: Speakers Bureau. Machová Poláková: Incyte: Consultancy;Angelini: Consultancy;Novartis: Research Funding. Mayer: Principia: Research Funding.

A Survey Conducted during COVID-19 Pandemic Among Brazilian Chronic Myeloid Leukemia and Philadelphia-Negative Myeloproliferative Neoplasms Patients

Introduction: COVID-19 has severely affected the Brazilian population. By July 2021, the incidence was 19,9 million cases and 556.000 deaths. Recent studies suggest that patients with MPN have higher infection and death rates than the general population. Older age and comorbidities are risk factors for severe COVID-19 in CML and MPN. Objectives This study aimed to evaluate the incidence and clinical evolution of COVID-19 in a cohort of CML and MPN Brazilian patients. Methods This is a prospective, observational, ongoing study. All patients signed informed consent and answered two structured questionnaires within a six months interval. The questionnaire included questions about patient's behavior during pandemic, symptoms, contacts, COVID-19 infection, and vaccination data in the last six months. In addition, demographic data, CML and NMP treatment, comorbidities, laboratory tests, COVID severity, and outcome were collected from the medical records. Results From September 2020 to July 2021, 370 patients answered the first questionnaire, and 153 answered the second: 225 with CML and 145 with MPN (45% essential thrombocythemia, 27.6%, polycythemia vera, 23% myelofibrosis, and 4.8% not classified). In the CML population, the median age was 56 (19-90). Most were receiving tyrosine kinase inhibitors (88,5%) and 26 (11,5%) no treatment, in treatment-free remission (TFR). 80% of the patients were practicing social distancing, and 30% had at least one family member or close contact diagnosed with COVID-19. Comorbidities: hypertension (35%), diabetes (14%), pulmonary disease (6%), cardiac disease (16%), renal disease (7%), other (18%). A total of 28/225 (12.4%) patients had confirmed COVID-19 diagnosis (by serology or PCR), while 10 were suspect. The median age was 47 years, 68% were male, and 41% were not respecting social distancing. Thirty-five percent had comorbidities: 25% hypertension;68% had a history of close contact with an infected person. One patient was in the accelerated phase, and 27 were in the chronic phase;4 had a complete cytogenetic response, 13 major molecular response (MMR), 3 MR4.0, and 7 MR4.5. COVID-19 was mild/moderate in 27 and in severe in one case, resulting in death. This patient was a male, 71-year-old, with hypertension, in MMR with nilotinib. At COVID-19 onset, 16 pts were receiving imatinib, five dasatinib;five nilotinib e 2 were in TFR. There was one reinfection, in a 54 years old male patient, with no comorbidities. To date, 84 (37%) patients (pts) have received vaccines against COVID-19: 32 CORONAVAC (Sinovac/Butantan), 51 ChAdOx1nCov-19-Covishield (Astrazeneca/Oxford), and one BNT162 (Pfizer). All COVID-19 cases occurred before vaccination. Among the 145 MPN pts, the median age was 67 years (29-90), and 86% had comorbidities (52% hypertension, 17.5% diabetes, and 13% cardiac diseases). Social distancing was 83%. Nine out of 145 (6.2%) had confirmed COVID-19 diagnosis, and 3% suspect. The median age of these pts was 43 years (28-80). Seven patients had ET and 2 PV. Seven were female. Four pts received Hydroxyurea (HU) and aspirin, four aspirin, one HU, and one no treatment. There were seven mild and two moderate cases requiring hospitalization, none requiring oxygen or mechanical ventilation, none with thrombosis. Two COVID cases occurred after the first dose of vaccines (CORONAVAC and Covishield). In the whole MPN group, 11% have received two doses (57% CORONAVAC, 40% Covishield, and 3.6% BNT 162). Conclusions COVID-19 cases occurred more frequently in younger patients. COVID-19 incidence was higher in the CML than in the MPN population, probably because MPN patients were less exposed, and the older pts were the first to receive vaccines. The impact of the vaccination on the prevention of new cases will be evaluated during the follow-up. Disclosures: Bortolini: Novartis: Speakers Bureau. Pagnano: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;intpharma: Other: Lecture;EMS: Other: Lecture;Jansenn: Other: Lecture.

Proposition of a new allosteric binding site for potential SARS-CoV-2 3CL protease inhibitors by utilizing molecular dynamics simulations and ensemble docking.

The SARS-CoV-2 3CL protease (3CLpro) shows a high similarity with 3CL proteases of other beta-coronaviruses, such as SARS and MERS. It is the main enzyme involved in generating various non-structural proteins that are important for viral replication and is one of the most important proteins responsible for SARS-CoV-2 virulence. In this study, we have conducted an ensemble docking of molecules from the DrugBank database using both the crystallographic structure of the SARS-CoV-2 3CLpro, as well as five conformations obtained after performing a cluster analysis of a 300 ns molecular dynamics (MD) simulation. This procedure elucidated the inappropriateness of the active site for non-covalent inhibitors, but it has also shown that there exists an additional, more favorable, allosteric binding site, which could be a better target for non-covalent inhibitors, as it could prevent dimerization and activation of SARS-CoV-2 3CLpro. Two such examples are radotinib and nilotinib, tyrosine kinase inhibitors already in use for treatment of leukemia and which binding to the newly found allosteric binding site was also confirmed using MD simulations. Communicated by Ramaswamy H. Sarma.

The tyrosine kinase inhibitor nilotinib inhibits SARS-CoV-2 in vitro.

Since the emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the end of 2019, no vaccine has been approved to counter this infection and the available treatments are mainly directed against the immune pathology caused by the infection. The coronavirus disease 2019 (COVID-19) is currently causing a worldwide pandemic, pointing the urgent need for effective treatment. In such emergency, drug repurposing presents the best option for a rapid antiviral response. We assess here the in vitro activity of nilotinib, imatinib and dasatinib, three Abl tyrosine kinase inhibitors, against SARS-CoV-2. Although the last two compounds do not show antiviral efficacy, we observe inhibition with nilotinib in Vero-E6 cells and Calu-3 cells with EC50s of 1.44 µM and 3.06 µM, respectively. These values are close to the mean peak concentration of nilotinib observed at steady state in serum, making this compound a potential candidate for treatment of COVID-19 in vivo.

Tyrosine Kinase Inhibitors Play an Antiviral Action in Patients Affected by Chronic Myeloid Leukemia: A Possible Model Supporting Their Use in the Fight Against SARS-CoV-2.

SARS-CoV-2 is the viral agent responsible for the pandemic that in the first months of 2020 caused about 400,000 deaths. Among compounds proposed to fight the SARS-CoV-2-related disease (COVID-19), tyrosine kinase inhibitors (TKIs), already effective in Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myeloid leukemia (CML), have been proposed on the basis of their antiviral action already demonstrated against SARS-CoV-1. Very few cases of COVID-19 have been reported in Ph+ ALL and in CML Italian cohorts; authors suggested that this low rate of infections might depend on the use of TKIs, but the biological causes of this phenomenon remain unknown. In this study, the CML model was used to test if TKIs would sustain or not the viral replication and if they could damage patient immunity. Firstly, the infection and replication rate of torquetenovirus (TTV), whose load is inversely proportional to the host immunological control, have been measured in CML patients receiving nilotinib. A very low percentage of subjects were infected at baseline, and TTV did not replicate or at least showed a low replication rate during the follow-up, with a mean load comparable to the measured one in healthy subjects. Then, after gene expression profiling experiments, we found that several "antiviral" genes, such as CD28 and IFN gamma, were upregulated, while genes with "proviral" action, such as ARG-1, CEACAM1, and FUT4, were less expressed during treatment with imatinib, thus demonstrating that TKIs are not detrimental from the immunological point of view. To sum up, our data could offer some biological explanations to the low COVID-19 occurrence in Ph+ ALL and CML patients and sustain the use of TKIs in COVID-19, as already proposed by several international ongoing studies.