EFFECT OF ANTI-SPIKE NEUTRALIZING MONOCLONAL ANTIBODIES ON COVID-19 PROGRESSION AND TIME TO VIRAL CLEARANCE IN PATIENTS WITH HEMATOLOGICAL MALIGNANCIES AND SARS-COV-2 INFECTION: THE GIMEMA EXPERIENCE

Background: Patients with hematological malignancies (HM) infected with SARS-CoV-2 hae a higher risk of deeloping seere coronairus disease (COVID-19) with consequent death, due to immune system impairment. Anti-spike Neutralizing Monoclonal Antibodies (nMoAbs) are indicated for the treatment of paucisymptomatic COVID-19 patients, but eidence of safety and efficacy among HM subjects is still lacking. Aims: To assess the efficacy of different nMoAbs approed by Agenzia Italiana del Farmaco (AIFA) on HM patients affected by paucisymptomatic SARS-COV-2. Methods: Multicenter retrospectie obserational study at ten sites in Italy, which enrolled consecutie patients with SARS-CoV-2 infection and treated with nMoAbs from February 2020 to December 2021. Only HM subjects on treatment or in disease remission within 6 months from treatment discontinuation with paucisymptomatic SARSCOV- 2 infection were included. nMoAbs approed by AIFA include Bamlaniimab, Bamlaniimab/Eteseimab, Casiriimab/Imdeimab, Sotroimab, and Regdanimab. The primary endpoint was to assess the time to SARS-CoV- 2 molecular swab negatiization. A comparison to an historical control not receiing nMoAbs was assessed. Secondary endpoints consisted in ealuation of Hospitalization rate due to COVID-19, including intensie care unit (ICU) admission rate due to respiratory failure, and safety assessment. Results: Oerall 51 HM patients (median age 62 years;35% women) were ealuated. Seenteen of them had non- Hodgkin lymphomas, 9 multiple myeloma, 6 chronic lymphocytic leukemia, 6 acute myeloid leukemia, 3 Hodgkin lymphoma, 2 acute lymphoblastic leukemia, 2 myeloproliferatie neoplasm, 1 Waldenstrom macroglobulinemia and 5 had other HM diagnosis. Thirty-six patients were on actie treatment, whereas 11 had completed their therapies within 6 months from nMoAbs administration, for 4 patients data were missing. In 7 subjects the last treatment was chemotherapy, in 19 immunotherapy with or without chemotherapy, in 9 target therapy, in 4 autologous stem cell transplantation, in 2 allogeneic stem cell transplantation, for 4 patients data were missing. Detailed description of patients' characteristics is reported in table 1. Twenty-six patients were treated with Bamlaniimab/Eteseimab, 17 with Casiriimab/Imdeimab, 3 with Bamlaniimab, and 2 with Sotroimab, for 3 patients data were missing. Median time to SARS-CoV-2 molecular swab negatiization was ealuable in 41 subjects and was 17 days (min 5, IQR 12-26, max 174). This result compared well with the preious finding of 28 days reported in an historical group of HM patients not treated with nMoAbs. We did not find any subpopulation, according to age, diagnosis, period of infection or type of nMoAbs who achieed a major benefit from nMoAbs treatment. The rate of Hospitalization due to COVID-19 progression was 19% (10/51), with an extremely low percentage of patients requiring ICU admission due to seer COVID-19 (2%,1/51). Most frequent side effects included chills (8%), diarrhea (6%), headache (2%), nausea (2%) and omiting (2%). Summary/Conclusion: Among paucisymptomatic SARS-CoV-2 positie HM patients on actie treatment or in disease remission within 6 months from treatment discontinuation, the administration of nMoAbs substantially reduced the time to swab negatiization compared to an historical control of HM subjects. This treatment was also able to reduce the rate of Hospitalization and death due to COVID-19 progression in this high risk group. (Table Presented).

Real-life experience of edoxaban treatment for venous thromboembolism (VTE)/pulmonary embolism (PE) in patients with isolated positive Lupus Anticoagulant (LAC) during the COVID-19 pandemic lockdown in Italy.

OBJECTIVE: Direct-acting oral anticoagulants (DOACs) have established indications, according to recent guidelines for the treatment and prevention of venous thromboembolism (VTE), including pulmonary embolism (PE), with a safer profile compared to vitamin K antagonist (VKA) in terms of a lower risk for major bleeding and no need of blood coagulation tests. However, DOACs are not indicated in the treatment of patients with triple-positive antiphospholipid syndrome (APS). This limitation is often extended in clinical practice to patients with isolated positivity. The COVID-19 pandemic has sometimes made it difficult to maintain a safe VKA treatment, due to the practical difficulties of performing INR. PATIENTS AND METHODS: We evaluated 39 patients with a previous unprovoked VTE/PE, who were no longer eligible for VKA treatment due to the difficulty of performing INR during the COVID-19 pandemic lockdown, in Italy. All patients had a positive LAC and refused a long-term anticoagulation with low molecular weight heparin. They were shifted to edoxaban. RESULTS: Any recurrence of VTE/PE occurred during the observation period (up to eight months of treatment), while only one minor bleeding event was recorded (Hazard ratio=0.06, 95% confidence interval 0.03-0.11, p=0.094). No arterial events occurred during the observation period. Hemoglobin, platelets, and creatinine were unchanged during the observation period. CONCLUSIONS: Edoxaban treatment may be safe and effective in preventing the recurrence of VTE/PE in patients with isolated LAC positivity, without the occurrence of arterial events.

COVID-19 Infection in chronic myeloid leukemia after 1 year of the pandemic in Italy. A campus CML analysis

Background: An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started in December 2019 in the province of Hubei in China. Italy was one of the most affected countries with many cases diagnosed already in February 2020 and a lockdown was declared on March 9th. Limited information has been reported with regard to the impact of the pandemic on chronic myeloid leukemia (CML) patients. Aims: To observe the temporal course of Covid-19 infection and the characteristics of positive patients. Methods: The Campus CML Italian group carried out a first survey on the management of CML patients during the lockdown. We launched a second survey during the pandemic phases 2 and 3, between May 2020 and January 2021. Results: We collected retrospective information on 8665 CML patients followed at 46 centers throughout the country. Within this cohort, we recorded 217 Covid-19-positive symptomatic patients (2.5%). Most patients (57%) were diagnosed as having Covid-19 infection between September 2020 and January 2021;30% were diagnosed in phase 1 (March-April 2020) and only 13% between May and August. Most of the positive patients were between 50 and 65 years (35%), while 26% had less than 50 years, 18.8% were between 65 and 75 years, and 11% had more than 75 years. A male prevalence was observed (73%). The median time from CML diagnosis to Covid-19 infection was 6 years (3 months-18 years). Fifty-six percent of patients presented concomitant comorbidities at the time of infection. When Covid-19 was diagnosed, 27% of patients were receiving imatinib, 26% nilotinib, 18% dasatinib, 8% ponatinib, 8% bosutinib, 2% asciminib, while 11% were not receive treatment. At the time of the infection, 74% of patients were in molecular remission, 6% in complete cytogenetic remission, 3% in partial cytogenetic remission, 6% in complete hematological response and 11% in treatment-free remission. At diagnosis, 28% of patients presented fever and respiratory symptoms, 13% cough, 10% isolated fever, 13% ageusia, 12% anosmia, 4% had more than 1 symptom, while 20% were completely asymptomatic. Twenty-one patients (9.6%) required hospitalization without the need of respiratory assistance, 18 (8.2%) were hospitalized for respiratory assistance, 8 (3.6%) were admitted to an ICU, while 150 patients (69%) were only quarantined. Twenty-three percent of patients discontinued TKI therapy during the infection. The source of contagion was familiar in 49% of patients, 18% due to work, 3% in healthcare professionals, whereas in 30% was not known. Twelve patients died due to Covid-19 infection with a mortality rate of 5.5% in the positive cohort and of 0.13% in the whole cohort. Five patients reported consequences post-infection: 1 patient reported a Guillan-Barrè syndrome, 1 patient a maculopapular rash, 1 patient a pulmonary fibrosis, 1 patient a bacterial endocarditis and 1 patient was diagnosed as having alterations of the microcirculation. Summary/Conclusion: This study reports the 1-year of data on the Covid- 19 infection in a specific hematological malignancy in the European country first hit by the pandemic. A longer follow-up is needed to further define the impact of Covid-19 infection sequelae in CML patients.

Second-Line Bosutinib in Elderly CML Patients: Final Results of Best Study

Introduction: The median age of CML patients failing a first-line TKI because of resistance or intolerance is higher than 60 years. Bosutinib (BOS), dasatinib (DAS) and nilotinib (NIL) have similar second-line efficacy, but in elderly patients DAS and NIL toxicity is more frequent and more clinically relevant. BOS safety profile may be an added value in this setting, but the approved initial dose of 500 mg OAD may be higher than necessary. Aims: All TKIs have been tested in CML patients at a fixed initial dose, with dose reductions in case of toxicity. On the contrary, the aim of our study was to evaluate the efficacy and the tolerability of low-dose second-line BOS in elderly CML patients, using the molecular response at given timepoints to increase the dose only in selected patients, thus finding the minimum effective dose. Methods: A prospective phase 2 single-arm multicenter study has been designed by the GIMEMA CML Working Party (NCT02810990). Study design: All patients started BOS 200 mg OAD for 2 weeks (ârun-inâ period), then the dose was increased to 300 mg OAD;after 3 months, patients with BCR-ABLIS transcript ≤ 1% continued 300 mg OAD, while in patients with transcript > 1% the dose is furtherly increased to 400 mg OAD, in absence of relevant toxicity. The primary endpoint was the rate of MR3 at 12 months. Key inclusion criteria: > 60 yrs old, chronic phase CML, intolerance or failure of any first-line TKI (2013 ELN criteria), absence of T315I or V299L mutation. Results: Sixty-three patients have been enrolled. Median age: 73 yrs (range 60-90). Reasons for switching to BOS: Intolerance 63%, resistance 37%. First-line TKI: Imatinib 83%, DAS 11%, NIL 6%. All patients reached at least 1-year observation. Due to the emergency situation caused by SARS CoV2 spread in Italy, few data are still missing, but final results will be presented onsite. Maximum BOS dose: 400 mg OAD, 19%;300 mg OAD, 76%;200 mg OAD, 5%. At baseline, 17% of patients were already in MR3;MR3 rates at 3, 6 and 12 months were 44%, 54% and 59%, respectively. The cumulative rate of patients achieving or maintaining a MR3 by 12 months was 67%;patients achieving MR4 or MR4.5 by 12 months were 44% and 24%, respectively. Overall, 30%, 29% and 8% of patients had 1 log, 2 logs or > 3 logs reduction from baseline BCR-ABLIS transcript level (67% of patients had a molecular improvement from baseline). Selected adverse events: Acute coronary syndromes, 4 patients;pericarditis, 2 patients;peripheral arterial thrombosis, 1 patient;no pleural effusions were observed. Events leading to permanent treatment discontinuation: 2 unrelated deaths, 7 adverse events, 4 unsatisfactory responses (without progressions), 1 second neoplasia. Fourty-nine patients are still on BOS at the last contact: 10% of them on 400 mg OAD, 61% on 300 mg OAD, 29% on 200 mg OAD. Conclusions: These results trial showed that in elderly patients intolerant to or failing a first-line TKI BOS may be highly effective and better tolerated at a dose lower than 500 mg OAD, namely at 300 mg OAD.