Clinical Outcomes in Patients With COVID-19 and Hematologic Disease.

BACKGROUND: Patients with hematologic diseases are at higher risk of the SARS-CoV-2 infection and more severe clinical outcomes of the coronavirus disease. CHRONOS19 is an observational prospective cohort study with the aim to determine the short and longer-term clinical outcomes, risk factors for disease severity and mortality, and rates of postinfectious immunity in patients with malignant and nonmalignant hematologic diseases and COVID-19. PATIENTS AND METHODS: Overall, 666 patients were enrolled in the study, of which 626 were included in the final data analysis. The primary endpoint was 30-days all-cause mortality. Secondary endpoints included COVID-19 complications, rates of ICU admission and mechanical ventilation, outcomes of a hematologic disease in SARS-CoV-2 infected patients, overall survival, and risk factors for disease severity and mortality. Data from 15 centers were collected at 30, 90, and 180 days after COVID-19 was diagnosed and were managed using a web-based e-data capture platform. All evaluations were performed in the pre-omicron period of COVID-19 pandemic. RESULTS: Thirty-days all-cause mortality was 18.9%. The predominant cause of death (in 80% of cases) were COVID-19 complications. At 180 days, the majority (70%) of additional deaths were due to hematologic disease progression. At a median follow-up of 5.7 [0.03-19.04] months, 6-months overall survival was 72% [95% CI: 0.69-0.76]. One-third of patients had severe SARS-CoV-2 disease. The rate of ICU admission was 22% with 77% of these patients requiring mechanical ventilation, with poor survival rate. A univariate analysis revealed that older age (≥ 60 years), male sex, malignant hematologic disease, myelotoxic agranulocytosis, transfusion dependence, refractory disease or relapse, diabetes among comorbidities, any complications, especially ARDS alone or in combination with CRS, admission to an ICU, and mechanical ventilation were associated with higher risks of mortality. Treatment of the hematologic disease was changed, postponed, or canceled in 63% of patients. At a longer follow-up (90 and 180 days), the status of the hematologic disease changed in 7.5% of patients. CONCLUSION: Patients with hematologic disease and COVID-19 have high mortality rates, predominantly due to COVID-19 complications. At a longer-term follow-up, no significant impact of COVID-19 on the course of a hematologic disease was revealed.

Long-term outcomes of third-line therapy with tyrosine kinase inhibitors in chronic phase chronic myeloid leukemia: A real-life experience.

Introduction: Tyrosine kinase inhibitor (TKI) therapy has greatly improved the prognosis of patients with chronic myeloid leukemia (CML), improving the survival expectancy of patients with chronic phase (CP) CML to that of the general population. However, despite these advances, nearly 50% of patients with CP CML experience failure to respond to frontline therapy, and most fail to respond to the subsequent second-line TKI. Treatment guidelines for patients failing second-line therapy are lacking. This study aimed to determine the efficacy of TKIs as third-line therapy in a "real-world" clinical practice setting and identify factors favorably influencing the long-term outcomes of therapy. Methods: We have retrospectively analyzed the medical records of 100 patients with CP CML. Results: The median age of the patients was 51 (range, 21-88) years, and 36% of the patients were men. The median duration of the third-line TKI therapy was 22 (range, 1- 147) months. Overall, the rate of achieving complete cytogenetic response (CCyR) was 35%. Among the four patient groups with different levels of responses at baseline, the best results were achieved in the groups with any CyR at the baseline of third-line therapy. Thus, СCyR was reached in all 15 and 8/ 16 (50%) patients with partial cytogenetic response (PCyR) or minimal or minor CyR (mmCyR), respectively, whereas CCyR was detected only in 12/69 (17%) patients without any CyR at baseline (p < 0.001). Univariate regression analysis revealed that the factors negatively associated with CCyR achievement in thirdline TKI therapy were the absence of any CyR on first- or second-line TKI therapy (p < 0.001), absence of CHR prior to third-line TKI (p = 0.003), and absence of any CyR prior to third-line TKI (p < 0.001). During the median observation time from treatment initiation to the last visit [56 (4-180) months], 27% of cases progressed into accelerated phase or blast phase CML, and 32% of patients died. Discussion: Progression-free survival (PFS) and overall survival (OS) were significantly higher in patients with CCyR on third-line than in the group without CCyR on third-line therapy. At the last visit, third-line TKI therapy was ongoing in 18% of patients, with a median time of treatment exposure of 58 (range, 6-140) months; 83% of these patients had stable and durable CCyR, suggesting that patients without CHR at baseline and without CCyR at least by 12 months on third-line TKI should be candidates for allogeneic stem cell transplantation, third-generation TKIs, or experimental therapies.

Treatment-Free Remission After Second-Line Nilotinib Treatment in Patients With Chronic Myeloid Leukemia in Chronic Phase: Results From a Single-Group, Phase 2, Open-Label Study.

Background: Treatment-free remission (TFR)-that is, stopping tyrosine kinase inhibitor (TKI) therapy without loss of response-is an emerging treatment goal in chronic myeloid leukemia (CML). Objective: To evaluate TFR after discontinuation of second-line nilotinib therapy. Design: Single-group, phase 2, open-label study. (ClinicalTrials.gov: NCT01698905). Setting: 63 centers in 18 countries. Patients: Adults with CML in chronic phase who received TKI therapy for at least 3 years (>4 weeks with imatinib, then ≥2 years with nilotinib) and achieved MR4.5 (BCR-ABL1 ≤0.0032% on the International Scale [BCR-ABL1IS]) while receiving nilotinib entered a 1-year consolidation phase. Those with sustained MR4.5 during consolidation were eligible to enter TFR. Interventions: Patients received nilotinib during consolidation; those who entered TFR stopped treatment. Patients with loss of major molecular response (MMR) (BCR-ABL1IS ≤0.1%) or confirmed loss of MR4 (BCR-ABL1IS ≤0.01%) during TFR reinitiated nilotinib treatment. Measurements: Proportion of patients without loss of MMR, confirmed loss of MR4, or treatment reinitiation within 48 weeks of stopping treatment (primary end point). Results: 163 patients who had switched from imatinib to nilotinib (for reasons including resistance, intolerance, and physician preference) enrolled in the study and entered the consolidation phase. Of these patients, 126 met the criteria for entering the TFR phase, and 73 (58% [95% CI, 49% to 67%]) and 67 (53% [CI, 44% to 62%]) maintained TFR at 48 weeks (primary end point) and 96 weeks, respectively. Of the 56 patients who reinitiated nilotinib therapy, 55 regained MMR or better and 52 regained MR4.5. None had CML progression to accelerated phase or blast crisis. Musculoskeletal pain was more frequent during the first 48 weeks after nilotinib discontinuation. Limitation: The study included a heterogeneous patient population and was not designed to compare outcomes between patients continuing and those stopping treatment. Conclusion: TFR seems achievable in patients with sustained MR4.5 after switching to nilotinib. Primary Funding Source: Novartis Pharmaceuticals Corporation.