The new Systematic Coronary Risk Evaluation (SCORE2 and SCORE2-OP) estimates the risk of arterial occlusive events in chronic myeloid leukemia patients treated with nilotinib or ponatinib.

Patients with chronic myeloid leukemia (CML) treated with nilotinib or ponatinib may experience arterial occlusive events (AOEs). It is currently recommended to thoroughly assess cardiovascular risk factors before treating CML. We identified 455 consecutive CML adult patients, 335 treated with nilotinib and 120 with ponatinib; 380 patients without previous cardiovascular diseases or diabetes were stratified according to the Systematic Coronary Risk Evaluation (SCORE2) and SCORE2-Older Persons (SCORE2-OP). This updated algorithm from the European Society of Cardiology (ESC) estimates a 10-year risk of fatal and non-fatal cardiovascular diseases. It is based on sex, age, smoking habits, systolic blood pressure, non-high-density lipoprotein cholesterol, and European geographical region of cardiovascular risk. The SCORE2/SCORE2-OP algorithm translated more patients (50.2%) to the high-very high cardiovascular risk category than the previous SCORE (25.3%). Patients with a high to very high SCORE2/SCORE2-OP risk showed a significantly higher incidence rate of AOEs (69.2% vs. 46.5%, p < 0.001). The older SCORE was less specific in estimating AOEs in patients classified as low-intermediate risk (69.8 vs. 54.2%). In multivariate analysis, no associations were found between AOEs and gender, age, and type or dose of tyrosine kinase inhibitor. Only the SCORE2/SCORE2-OP risk was confirmed as a significant predictive factor (p = 0.028; hazard ratio = 2.2; 95% confidence interval = 1.1-4.5). Patients with AOEs required, in most cases, imaging diagnostic tests, additional drugs, and sometimes invasive procedures, increasing access to visits and hospital management. This real-life study suggested that the SCORE2 and SCORE2-OP charts could help identify cardiovascular fragility in CML patients providing them with more attention and a proper TKI selection.

COVID-19 infection in chronic myeloid leukaemia after one year of the pandemic in Italy. A Campus CML report.

Limited information is available on the impact of the COVID-19 pandemic on the management of chronic myeloid leukaemia (CML). The Campus CML network collected retrospective information on 8 665 CML patients followed at 46 centres throughout Italy during the pandemic between February 2020 and January 2021. Within this cohort, we recorded 217 SARS-CoV-2-positive patients (2·5%). Most patients (57%) were diagnosed as having SARS-CoV-2 infection during the second peak of the pandemic (September 2020 to January 2021). The majority (35%) was aged between 50 and 65 years with a male prevalence (73%). Fifty-six percent of patients presented concomitant comorbidities. The median time from CML diagnosis to SARS-CoV-2 infection was six years (three months to 18 years). 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 intensive care unit, while 170 (78%) were only quarantined. Twenty-three percent of patients discontinued tyrosine kinase inhibitor (TKI) therapy during the infection. Twelve patients died due to COVID-19 with a mortality rate of 5·5% in the positive cohort and of 0·13% in the whole cohort. We could also document sequelae caused by the SARS-CoV-2 infection and an impact of the pandemic on the overall management of CML patients.

Bosutinib in the real-life treatment of chronic myeloid leukemia patients aged >65 years resistant/intolerant to previous tyrosine-kinase inhibitors.

To evaluate the role of bosutinib in elderly patients aged >65 years with chronic myeloid leukemia (CML), a real-life cohort of 101 chronic-phase CML patients followed up in 23 Italian centers and treated with bosutinib in second or a subsequent line was retrospectively evaluated. Starting dose of bosutinib was 500 mg/day in 25 patients (24.8%), 400 mg/day in 7 patients (6.9%), 300 mg/day in 33 patients (32.7%), 200 mg/day in 34 patients (33.6%), and 100 mg/day in 2 patients (2.0%). Grade 3/4 hematological toxicity occurred in 7/101 patients (6.9%) and grade 3/4 extra-hematological toxicity in 19/101 patients (18.8%). Permanent bosutinib discontinuation due to toxicity was needed in 12 patients (11.9%). Among the 96 patients evaluable for response, 74 (77.0%) achieved a complete cytogenetic response (CCyR), while 64 of these 74 patients in CCyR (66.6% of all 96 evaluable patients) also achieved a molecular response (MR) (major MR [MR 3.0] in 21 [21.8%], deep MR [MR 4.0/4.5] in 43 [44.8%]). The 3-year event-free survival and overall survival of the whole patients' cohort from bosutinib start were 60.9% (CI 95% 49.3-72.5) and 86.4% (CI 95% 77.2-95.6), respectively. Our real-life data show that bosutinib is effective, with a favorable safety profile, also in elderly patients with important comorbidities and resistance and/or intolerance to previous tyrosine-kinase inhibitor treatments. As a consequence, it could play a significant role in current clinical practice for frail patients.

Low-density lipoprotein (LDL) levels and risk of arterial occlusive events in chronic myeloid leukemia patients treated with nilotinib.

Recommendations for dyslipidemia management aimed at reducing arterial occlusive events (AOEs) have been recently published. So far, no data have been reported on the management of dyslipidemia in chronic myeloid leukemia (CML) patients treated with nilotinib. We investigated 369 CML adult patients, stratified according to the new Systematic Coronary Risk Evaluation (SCORE) scoring system. Plasma levels of cholesterol, HDL, LDL, and triglycerides were measured prior to the start of nilotinib and after 3, 6, and 12 months. The 5-year cumulative incidence of AOEs was 15.9%. Patients with cholesterol levels > 200 mg/dL and LDL > 70 mg/dL 3 months after treatment showed a significantly higher incidence of AOEs (21.9 ± 4.6% vs 6.2 ± 2.5, P = 0.003). Patients belonging to the high and very high SCORE risk group showed a significant increase of AOEs (34.4 ± 6% vs 10 ± 2.1%, P < 0.001). In multivariate analysis, both high cholesterol and LDL levels and a high and very high SCORE risk remained significantly associated with the risk of AOEs (P = 0.008; HR = 3.5; 95% CI = 1.4-8.7 and P < 0.001; HR = 4.4; 95% CI = 2-9.8, respectively). Overall, 78 patients (21.1%) presented dyslipidemia at the time of CML diagnosis and 88 (23.3%) after starting nilotinib, but only 26 of them (29.5%) were treated with statins.Low LDL and cholesterol plasma levels are associated with a significant lower risk of AOEs in CML patients treated with nilotinib in the real life.

Long term follow-up of frontline Dasatinib in older patients with chronic myeloid leukemia in chronic phase treated outside clinical trials: a real-life cohort observational study.

BACKGROUND: A limited amount of data has been published in chronic-phase chronic myeloid leukemia (CP-CML) patients aged >75 years treated frontline with second-generation tyrosine kinase inhibitors. AIMS: To address this issue in a clinical 'real-life' setting, we retrospectively analyzed 45 CP-CML patients (pts) followed in 20 Italian Centers and treated frontline with dasatinib (DAS). PATIENTS AND METHODS: Median age was 78.4 years (range 75-89.2 years). DAS starting dose was 100 mg QD in 35 pts (77.7%), 80 mg QD in 1 pts (2.2%) and 50 mg QD in 9 pts (20.1%), respectively. The median follow-up was 42.6 months (IQR 20.4 - 63.3). RESULTS: Grade 3 and 4 side effects, both hematological and non-hematological, were detected in 6 (13.3%) and 12 (26.6%) pts, respectively. Pleural effusions of all grades occurred in 13 pts (28.8%) after a median period of DAS exposure of 14.7 months (IQR 3.0 - 33.1). The rates of DAS dose reduction and permanent drug discontinuation were 53.3% and 20.0%, respectively. As the best response, 42/45 patients (93.3%) achieved a complete cytogenetic response (CCyR), 35/45 (77.7%) a major molecular response (MMR) and 24/45 (53.3%) a deep molecular response (both MR 4.0 and MR 4.5). Only 1 patient (2.2%) progressed to the blast phase after 13 months of therapy; 8 deaths were observed (1 CML-related and 7 CML-unrelated). Cumulative event-free survival and overall survival at 36 months were 64.7% (95%, CI 49.4 - 80.0) and 82.3% (95%, CI 70.3-94.3), respectively. CONCLUSION: These findings, although evaluated in a limited and selected cohort of patients, suggest that DAS might be effective in older patients (aged >75 years) affected by CP-CML with acceptable toxicity.

Renin angiotensin system inhibitors reduce the incidence of arterial thrombotic events in patients with hypertension and chronic myeloid leukemia treated with second- or third-generation tyrosine kinase inhibitors.

Hypertension is a commonly reported comorbidity in patients diagnosed with chronic myeloid leukemia (CML), and its management represents a challenge in patients treated with 2nd- or 3rd-generation tyrosine kinase inhibitors (TKIs), considering their additional cardiovascular (CV) toxicity. The renin angiotensin system (RAS) contributes to hypertension genesis and plays an important role in atherosclerosis development, proliferation, and differentiation of myeloid hematopoietic cells. We analyzed a cohort of 192 patients with hypertension at CML diagnosis, who were treated with 2nd- or 3rd-generation TKIs, and evaluated the efficacy of RAS inhibitors (angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-II receptor blockers (ARBs)) in the prevention of arterial occlusive events (AOEs), as compared with other drug classes. The 5-year cumulative incidence of AOEs was 32.7 ± 4.2%. Patients with SCORE ≥ 5% (high-very-high) showed a significantly higher incidence of AOEs (33.7 ± 7.6% vs 13.6 ± 4.8%, p = 0.006). The AOE incidence was significantly lower in patients treated with RAS inhibitors (14.8 ± 4.2% vs 44 ± 1%, p < 0.001, HR = 0.283). The difference in the low and intermediate Sokal risk group was confirmed but not in the high-risk group, where a lower RAS expression has been reported. Our data suggest that RAS inhibitors may represent an optimal treatment in patients with hypertension and CML, treated with 2nd or 3rdG TKIs.

Erythropoietin treatment in chronic phase chronic myeloid leukemia patients treated with frontline imatinib who developed late anemia.

BACKGROUND: Role of erythropoietin (EPO) in the treatment of late anemia in patients with Chronic Myeloid Leukemia (CML) is still undefined. METHODS: Fifty CML patients treated at 14 institutions with frontline imatinib for at least 12 months and in stable complete cytogenetic response who developed a late chronic anemia treated with EPO were retrospectively evaluated. RESULTS: Median time from imatinib start to EPO treatment was 42.2 months [interquartile range (IQR) 20.8-91.9]. Median Hb value at EPO starting time was 9.9 g/dL (IQR 8.9-10.3): Eleven patients (22.0%) were transfusion dependent. Alpha-EPO (40 000 UI weekly) was employed in 37 patients, beta-EPO (30 000 UI weekly) in 9 patients, zeta-EPO (40 000 UI weekly) in 2 patients, and darbepoetin (150 mcg/weekly) in the remaining 2 patients. On the whole, 41 patients (82.0%) achieved an erythroid response, defined as a stable (>3 months) improvement >1.5 g/dL of Hb level, and 9 patients (18.0%) indeed resulted resistant. Among responding patients, 10 relapsed after a median time from EPO start of 20.7 months (IQR 10.8-63.7). No EPO-related toxicity was observed. CONCLUSIONS: Results of EPO treatment for late chronic anemia during long-lasting imatinib therapy are encouraging, with a high rate of response.

Arterial occlusive events in chronic myeloid leukemia patients treated with ponatinib in the real-life practice are predicted by the Systematic Coronary Risk Evaluation (SCORE) chart.

Arterial occlusive events (AOEs) represent emerging complications in chronic myeloid leukemia (CML) patients treated with ponatinib. We identified 85 consecutive CML adult patients who were treated with ponatinib in 17 Italian centers. Patients were stratified according to the Systematic Coronary Risk Evaluation (SCORE) assessment, based on sex, age, smoking habits, systolic blood pressure, and total cholesterol levels. The 60-month cumulative incidence rate of AOEs excluding hypertension was 25.7%. Hypertension was reported in 14.1% of patients. The median time of exposure to ponatinib was 28 months (range, 3-69 months). Patients with a high to very high SCORE risk showed a significantly higher incidence rate of AOEs (74.3% vs 15.2%, P < 0.001). Patients aged ≥60 years showed a significantly higher incidence rate of AOEs (51.5% vs 16.9%, P = 0.008). In multivariate analysis, no association was found between AOEs and positive history of CV disease, age, dose of ponatinib, previous exposure to nilotinib, and comorbidities. Only the SCORE risk was confirmed as a significant predictive factor (P = 0.01; HR = 10.9; 95% C.I. = 1.7-67.8). Patients aged ≥60 years who were treated with aspirin had a lower incidence rate of AOEs (33.3% vs 61.8%). Among the 14 reported AOEs, 78.6% of them showed grade 3 to 4 toxicity. This real-life study confirmed the increased incidence of AOEs in CML patients treated with ponatinib, with high to very high SCORE risk. We suggest that patients aged ≥60 years who were treated with ponatinib should undergo prophylaxis with 100 mg/day of aspirin. Our findings emphasize personalized prevention strategies based on CV risk factors.

Efficacy and safety of ruxolitinib and hydroxyurea combination in patients with hyperproliferative myelofibrosis.

Ruxolitinib is the only commercially available JAK1/2 inhibitor approved for the treatment of myelofibrosis-related splenomegaly and symptoms. During treatment, as rare conditions, leukocytosis and/or thrombocytosis could develop and the management of these situations is not well established. We report here 53 myelofibrosis patients that received a combination of hydroxyurea and ruxolitinib because of uncontrolled myeloproliferation. Both drugs were administered outside clinical trials. At 48 weeks, a significant reduction in leucocyte and platelet counts was observed (p = 0.02 and p = 0.04, respectively). Additionally, the spleen volume decreased from a median value of 10 cm below the left costal margin (range, 0-10) to 6 cm (range, 0-15). The rate of spleen response increased from 14% at the start of the combination to 45% after 48 weeks. The safety profile of the combination was consistent with that observed with ruxolitinib single agent. These data require further confirmation in large cohorts of patients prospectively assessed.

Outcome of very elderly chronic myeloid leukaemia patients treated with imatinib frontline.

Very elderly (> 75 years) chronic myeloid leukaemia (CML) patients at diagnosis are sometimes treated with different doses of imatinib (IM) based on concomitant diseases and physicians' judgement. However, data on long-term follow-up of these patients are still lacking. To investigate treatment response and outcome, we retrospectively revised an Italian database of 263 very elderly CML patients receiving IM from the time of diagnosis. Median age at diagnosis was 78.5 years and 56% of patients had 2 or 3 comorbidities. A complete haematological and cytogenetic response were achieved in 244 (92.8%) and 184 (69.9%) patients, respectively. In 148 cases (56.2%), a major molecular response was observed, which was deep in 63 cases (24%). A blastic phase occurred in 11 patients (4.2%). After a median follow-up of 45.0 months, 93 patients have died (9 from disease progression) and 104 (39.5%) are still in treatment with IM. Incidence of grades 3-4 haematological and non-haematological toxicity was similar to those reported in younger patients. Five-year event-free survival was 54.5% and 45.2% in patients ≤ 80 years and > 80 years, respectively (p = 0.098). Five years OS was 75.7% and 61.6% in patients ≤80 years and > 80 years, respectively (p = 0.003). These findings show that IM plays an important role in frontline treatment of very elderly CML patients without increased toxicity and any effort to treat these patients with standard doses should be made in order to achieve responses as in younger subjects.

Identification and assessment of frailty in older patients with chronic myeloid leukemia and myelofibrosis, and indications for tyrosine kinase inhibitor treatment.

The incidence of cancer, including myeloproliferative neoplasms (MPNs), is projected to increase significantly due to the growing proportion of people aged > 65 years. These older individuals are a heterogeneous population in terms of fitness, comorbidity, and psychological reserve. Therefore, age per se does not always provide an accurate indication of condition in patients with cancer. Frailty has been proposed as an alternative measure of vulnerability that might better indicate which patients can tolerate standard cancer treatment and those who may benefit from treatment adjustment. A number of methods can be used to assess frailty in older patients with hematological malignancies, including the Cardiovascular Health Study Frailty Screening Measure, the FRAIL (Fatigue, Resistance, Ambulation, Illnesses, and Loss of weight) questionnaire, the Clinical Frailty Scale (CFS), and the Gérontopôle Frailty Screening Tool. In addition to physical frailty, comorbidity and quality of life should also be included in the assessment. Prior to the introduction of tyrosine kinase inhibitors (TKIs), age was considered a marker of poor prognosis in patients with MPNs. In contrast, data show that age is not necessarily a contraindication for TKI use. In CML, the efficacy of TKIs has been shown to be independent of age. The JAK1/2 inhibitor ruxolitinib also seems to be effective across a range of patient ages. Available data suggest that chronological age itself should not necessarily be a contraindication for many new therapies in patients with MPNs, and that frailty does provide a better measure of vulnerability. There is a need for specific methods to assess frailty in patients with MPNs, particularly the context of effective new treatment options, such as TKIs and ruxolitinib.

Ponatinib as second-line treatment in chronic phase chronic myeloid leukemia patients in real-life practice.

Scarce information is available on the use of ponatinib as second-line treatment in chronic phase chronic myeloid leukemia (CP-CML) patients resistant and/or intolerant to prior tyrosine kinase inhibitor (TKI) therapy. We collected data from 29 CML patients, with a median age of 54 years (range 32-72). Eleven patients had received dasatinib, 15 patients received nilotinib, and 3 patients received imatinib as first-line treatment. Forty-five percent of patients started ponatinib for secondary resistance, 38% for primary resistance, 7% for severe intolerance associated to a molecular warning, 7% due to the presence of a T315I mutation, and 3% for severe intolerance. Ponatinib was started at a dose of 45 mg in 60% of patients, 30 mg in 38%, and 15 mg in 2% of patients. Overall, at a median follow-up of 12 months, 85% of treated patients improved the level of response as compared to baseline, with 10 patients achieving a deep molecular response (MR4-4.5). No thrombotic events were recorded. The dose was reduced during treatment in 2 patients due to intolerance and in 8 patients in order to reduce the cardiovascular risk. Ponatinib seems a valid second-line treatment option for chronic phase CML, in particular for patients who failed a front-line second-generation TKI due to BCR-ABL-independent mechanisms of resistance.

Pleural effusion and molecular response in dasatinib-treated chronic myeloid leukemia patients in a real-life Italian multicenter series.

Pleural effusion (PE) represents the leading cause of dasatinib (DAS) discontinuation. However, the pathogenic mechanism of this adverse event (AE) is unknown and its management unclear. We investigated if a DAS dose reduction after the first PE would prevent the recurrence of this AE. We retrospectively collected data on all the cases of PE in CML-chronic phase (CP) DAS-treated patients from November 2005 to February 2017 in 21 Italian hematological centers. We identified 196 cases of PE in a series of 853 CML-CP DAS-treated patients (incidence 23.0%). DAS starting dose was 100 mg/day in 70.4% of patients, less than 100 mg/day in 14.3%, and more than 100 mg/day in the remaining cases. Median time from DAS start to PE was 16.6 months. At first PE development, 28.6% of patients were in MMR, and 37.8% in deep molecular response (DMR). DAS was temporary interrupted in 71.9% of cases, with a dose reduction in 59.2%. Recurrence was observed in 59.4% of the cases. Treatment was definitively discontinued due to PE in 29.1% of the cases. Interestingly, among patients whose DAS dosage was reduced, 59.5% experienced PE recurrence. DAS dose reduction after the first episode of PE did not prevent recurrence of this AE. Therefore, once a MMR or a DMR is achieved, different strategies of DAS dose management can be proposed prior to the development of PE, such as daily dose reduction or, as an alternative option, an on/off treatment with a weekend drug holiday.

Outcome of 82 chronic myeloid leukemia patients treated with nilotinib or dasatinib after failure of two prior tyrosine kinase inhibitors.

There have been few reports of a response to dasatinib or nilotinib after failure of two prior sequential tyrosine kinase inhibitors. We report the outcome of 82 chronic phase patients who received nilotinib or dasatinib as third-line alternative tyrosine kinase inhibitor therapy. Thirty-four patients failed to respond to nilotinib and were started on dasatinib as third-line tyrosine kinase inhibitor therapy while 48 patients were switched to nilotinib after dasatinib failure. Overall, we obtained a cytogenetic response in 32 of 82 patients and major molecular response in 13 patients; disease progression occurred in 12 patients. At last follow up, 70 patients (85.4%) were alive with a median overall survival of 46 months. Our results show that third-line tyrosine kinase inhibitor therapy in chronic myeloid leukemia patients after failure of two prior sequential tyrosine kinase inhibitors may induce a response that, in some instances, could prolong overall survival and affect event-free survival.

Incidence, risk factors and management of pleural effusions during dasatinib treatment in unselected elderly patients with chronic myelogenous leukaemia.

To assess the most important features and clinical impact of pleural effusions, which are a common toxicity during dasatinib treatment and often impair its high efficacy, 172 unselected consecutive patients with chronic myelogenous leukaemia in chronic phase treated in 27 Italian centres, with dasatinib when aged >60 years for resistance/intolerance to imatinib, were examined. During treatment, 52/172 patients (30.2%) presented pleural effusion, which was grades 1-2 in 38 patients and grades 3-4 in 14 patients (8.1% of the entire cohort of patients), according to the WHO scale; in 14/52 patients (26.9%), there was a concomitant pericardial effusion. Pleural effusion was recurrent in 25/52 patients (48.0%). Median time from dasatinib to first pleural effusion was 11.0 months (interquartile range 3.6-18.6). Eleven patients (6.4%) required permanent dasatinib discontinuation. Only presence of concomitant pulmonary disease ( p = 0.035) and initial daily dose of dasatinib (140 mg vs 100 mg, p = 0.014) were significantly associated with pleural effusions. There were no differences among patients with or without pleural effusions as concerns response rates and overall survival. Pleural effusions were common in our unselected 'real-life' population of elderly patients but were clinically manageable and did not seem to affect treatment results.

Impact of BCR-ABL mutations on response to dasatinib after imatinib failure in elderly patients with chronic-phase chronic myeloid leukemia.

To assess the impact of BCR-ABL kinase domain mutations on dasatinib response in elderly chronic myeloid leukemia (CML) patients, we analyzed the outcome of 76 individuals aged >60 affected by imatinib-resistant chronic-phase CML. We found that 36 cases (47 %) displayed mutations before dasatinib. Compared to non-mutated patients, subjects with point mutations had a worse response to dasatinib, with significantly lower rates of complete cytogenetic response (57 vs 32 %), higher percentage of primary resistance (16/36 vs 6/40) and a trend towards a shorter median event-free survival. Our data suggest that, in elderly patients, detection of BCR-ABL mutations negatively affects response to dasatinib.