ABSTRACT
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.
ABSTRACT
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.