Determinants of frontline tyrosine kinase inhibitor choice for patients with chronic-phase chronic myeloid leukemia: A study from the Registro Italiano LMC and Campus CML.

BACKGROUND: Imatinib, dasatinib, and nilotinib are tyrosine kinase inhibitors (TKIs) approved in Italy for frontline treatment of chronic-phase chronic myeloid leukemia (CP-CML). The choice of TKI is based on a combined evaluation of the patient's and the disease characteristics. The aim of this study was to analyze the use of frontline TKI therapy in an unselected cohort of Italian patients with CP-CML to correlate the choice with the patient's features. METHODS: A total of 1967 patients with CP-CML diagnosed between 2012 and 2019 at 36 centers throughout Italy were retrospectively evaluated; 1089 patients (55.4%) received imatinib and 878 patients (44.6%) received a second-generation (2G) TKI. RESULTS: Second-generation TKIs were chosen for most patients aged <45 years (69.2%), whereas imatinib was used in 76.7% of patients aged >65 years (p < .001). There was a predominant use of imatinib in intermediate/high European long-term survival risk patients (60.0%/66.0% vs. 49.7% in low-risk patients) and a limited use of 2G-TKIs in patients with comorbidities such as hypertension, diabetes, chronic obstructive pulmonary disease, previous neoplasms, ischemic heart disease, or stroke and in those with >3 concomitant drugs. We observed a greater use of imatinib (61.1%) in patients diagnosed in 2018-2019 compared to 2012-2017 (53.2%; p = .002). In multivariable analysis, factors correlated with imatinib use were age > 65 years, spleen size, the presence of comorbidities, and ≥3 concomitant medications. CONCLUSIONS: This observational study of almost 2000 cases of CML shows that imatinib is the frontline drug of choice in 55% of Italian patients with CP-CML, with 2G-TKIs prevalently used in younger patients and in those with no concomitant clinical conditions. Introduction of the generic formulation in 2018 seems to have fostered imatinib use.

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.

Delayed cytogenetic and major molecular responses associated to increased BMI at baseline in chronic myeloid leukemia patients treated with imatinib.

Obesity, measured as body mass index (BMI), has been identified as a possible risk factor for several solid tumors as well as for chronic myeloid leukemia (CML). To date, no correlations have been reported in this latter disease between BMI at baseline and response to targeted therapies. We refer here on the impact of BMI on clinical response in 339 chronic phase (CP) CML patients treated with imatinib and 35 CP-CML patients treated frontline with nilotinib. If compared to patients with low BMI (<18.5-25), patients with increased BMI (>25-40) at diagnosis who received imatinib showed a significantly longer median time to achieve complete cytogenetic response (6.8 months vs 3.3 months, p=0.001), a reduced rate of major molecular response (77% vs 58%, p=0.01) which was also achieved in a longer median time (29 months compared to 14 months, p=0.01). Conversely, no differences were revealed with respect to BMI in patients treated frontline with nilotinib and also patients with increased BMI obtained rapidly CCyR and MMR with an incidence similar to that of underweight/normal weight patients. These results suggest that CML patients with increased weight at baseline should be followed and carefully monitored if treated with standard dose imatinib frontline for a possible early switch.

Influence of time to complete remission and duration of all-trans retinoic acid therapy on the relapse risk in patients with acute promyelocytic leukemia receiving AIDA protocols.

Despite the impressive results obtained with standard chemotherapy, approximately 20% of acute promyelocytic leukemia (APL) patients undergo disease relapse thereby requiring salvage therapy. Few data is available on long-term prognosis in relation to time to complete remission (CR): we reviewed 142 patients treated with AIDA protocols and we found that 42 out of 142 (29.6%) patients achieved CR after 35 days (median time, 42 days). No significant differences in presenting features, including FAB subtype, type of PML/RARA transcript and relapse risk at presentation between the two patient groups achieving CR > or <35 days were revealed, except for male sex and older age that were significantly associated with delayed CR. Rate of relapse was 31% in patients with delayed CR compared to 17% in the group of patients who achieved CR<35 days (p=0.001), with a 5-year CIR of 29.6% compared to 12% (p=0.03). APL patients with delayed CR should be more closely monitored during follow-up for early identification of relapse and prompt administration of pre-emptive salvage therapy.

Complete clearance of Ph+ metaphases after 3 months is a very early indicator of good response to imatinib as front-line treatment in chronic myelogenous leukemia.

AIM: To address the incidence and the prognostic role of a very early standard complete cytogenetic response (CCyR) or all Ph- metaphases (MET-, when <20 cells were evaluable). METHODS: We revised 182 chronic phase chronic myelogenous leukemia patients treated with frontline imatinib (IM) at two institutions from June 2002 to June 2011. RESULTS: After 3 months of treatment, 138 patients (75.8%) achieved CCyR/MET- while 44 patients (24.2%) still presented Ph+ metaphases (MET+) (<33%, 24 patients; ≥33%, 20 patients). On univariate analysis, palpable spleen enlargement (p < 0.001), WBC count >100.0 × 10(9)/l at onset (p < 0.001), and male gender (p = 0.019) had a negative impact on achievement of CCyR/MET- at 3 months. Among patients with CCyR/MET- after 3 months, there were 15 failures (10.8%) compared to 21 (47.7%) among patients with MET+ (p < 0.001). The 5-year overall survival was 97.0% in patients CCyR/MET- at 3 months and 91.8% in patients MET+ at 3 months (p = 0.277); the 5-year progression-free survival was 88.2% in patients CCyR/MET- at 3 months and 48.4% in patients MET+ at 3 months (p < 0.001). CONCLUSIONS: The achievement of CCyR/MET- at 3 months seems to have prognostic relevance and could be a very early and useful indicator of an excellent response to IM beyond European LeukemiaNet guidelines.

Prognostic features of patients with myelodysplastic syndromes aged < 50 years: update of a single-institution experience.

Fewer than 10% of patients with myelodysplastic syndromes (MDS) are younger than 50 years. A series of 91 younger patients (median age 44 years with female prevalence) are reported and compared with elderly patients. Frequent karyotypic changes were trisomy 8 (9.8%) and monosomy 7 (5%). Twenty-three patients had occupational exposure to potential mutagens (benzene and solvents), with a male predominance, higher frequency of refractory cytopenia with multilineage dysplasia (RCMD) (52%) and higher frequency of monosomy 7 (21.7%). At a median follow-up of 72 months, 22 patients (24%) evolved to acute leukemia, with higher frequency being observed among the exposed cohort (39% vs. 19% non-exposed). Unfavorable factors for overall survival were: age > 40 years, > 5% of blasts, trilinear bone marrow involvement and intermediate-high World Health Organization Prognostic Scoring System (WPSS) risk. The present results suggest that younger MDS could be identified as a distinct subset. For patients belonging to the low/intermediate-I risk group, due to a low transformation rate, aggressive approaches should rarely be recommended.

Deferasirox treatment for myelodysplastic syndromes: "real-life" efficacy and safety in a single-institution patient population.

We here describe a single-institution experience on 40 patients with myelodysplastic syndromes (MDS) consecutively treated with deferasirox at the dose of 10-30 mg/kg/day according to Consensus Guidelines on Iron Chelation Therapy, outside of clinical trials. Serum ferritin (SF) was measured monthly, and safety assessment included monitoring of adverse events during treatment and of liver and renal parameters. Median SF at baseline of the 40 patients was 2,878 ng/ml. Median dose of deferasirox was 1,125 mg/day. At a median follow-up of 12 months of treatment, there was a significant reduction in SF from baseline, the median value being 1,400 ng/ml (p = 0.001). Interruptions due to toxicity were recorded in 40 % of patients: most common adverse events were diarrhoea (five patients, 12.5 %) and skin rash (four patients, 10 %). Seven patients had increased serum creatinine values >33 % above baseline, but there were no progressive increases. Four patients (three refractory anaemia and one refractory anaemia with excess blasts type 1) had a reduction of transfusion requirement (from a median of 5 to 1 unit/month) according to International Working Group 2006 criteria, with mean Hb value increasing from 8.5 to 10.5 g/dl, and mean Hb improvement being 2 g/dl (p = 0.02). No increased toxicity was noted when deferasirox was used concomitantly with azacitidine (eight patients who were intermediate 2 International Prognostic Scoring System risk) or lenalidomide (two patients with del(5q)). In conclusion, the oral iron chelator deferasirox is effective and safe when used in MDS patients with transfusion requirement, also if administered concomitantly with other drugs.

5-azacitidine efficacy and safety in patients aged >65 years with myelodysplastic syndromes outside clinical trials.

The efficacy and safety of azacitidine in elderly patients (aged >65 years) with myelodysplastic syndromes (MDS) treated outside clinical trials are reported. Thirty-eight patients with MDS received azacitidine (75 mg/m(2), schedule 5+2 +2): seven patients were classified as having refractory cytopenia with multilineage dysplasia (RCMD), nine patients with refractory anemia with excess of blasts (RAEB) type 1, 18 patients with RAEB type 2 and four patients with chronic myelomonocytic leukemia type 2 (CMML-2). According to International Working Group (IWG) 2006 criteria, after the first four cycles we detected complete remission in seven patients (CR, 18%), improvement of bone marrow dysplasia and reduction of blast percentage in seven patients (partial response, 18%), stable disease in 20 patients (53%) and progression to acute leukemia in four patients (10%). Median overall survival for all patients treated was 16.4 months. Only mild non-hematologic toxicity was detected (grade 1-2 nausea and pruritus), whereas 55% of patients experienced hematologic side effects (25% grade 3-4 thrombocytopenia and 30% grade 3-4 neutropenia). Our results suggest that advanced age should not preclude effective treatment with azacitidine in non-selected elderly patients wih MDS.