Although infectious complications represent a relevant cause of morbidity and mortality in patients with myelofibrosis (MF), little is known about their incidence, outcome and risk factors. We retrospectively evaluated a cohort of 507 MF patients, diagnosed between 1980 and 2014 in five Italian hematology centers, to define the epidemiology of infections and describe the impact of ruxolitinib (RUX) treatment. Overall, 112 patients (22%) experienced 160 infectious events (grade 3-4, 45%) for an incidence rate of 3.9% per patientyear. Infections were mainly bacterial (78%) and involving the respiratory tract (52% of cases). Also, viral (11%) and fungal infections (2%) were recorded. Overall, infections were fatal in 9% of the cases. Among baseline features, high/intermediate-2 IPSS category (HR 1.8, 95%CI:1.2-2.7; P 5 0.02) and spleen length 10 cm below left costal margin (HR 1.6, 95%CI:1.1-2.5; P 5 0.04) were associated with higher infectious risk in multivariate analysis. Overall, the rate of infections was higher in the cohort of 128 RUX-treated patients (44% vs. 20%, P < 0.001). In conclusion, IPSS-category and splenomegaly, emerged as the main risk factors for infections in MF. RUX-treated patients experienced significantly more infection episodes; however, future prospective studies are needed to isolate the confounding contribution of other risk factors such as disease stage.
Deep molecular response in chronic myeloid leukemia (CML) patients treated with imatinib is a prerequisite for possible discontinuation. We identify clinico-biologic features linked with the probability of reaching MR4.5 (BCR-ABL/ABL ≤ 0.0032% IS) as a stable response (confirmed on two or more consecutive determinations). In a series of 208 patients treated with imatinib first-line outside clinical trials, after a median follow-up of 7 years the incidence of stable MR4.5 was 34.6%, obtained in median time of 5.4 years. In univariate analysis, female gender (p = 0.02), lower median age (56.4 vs 58.6, p = 0.03), Sokal risk stratification (p = 0.01) and e14a2 type of transcript (43% vs 31%, p = 0.02) are associated to achievement of a stable MR4.5. In multivariate regression analysis, female gender (HR 1.6, 95% CI: 1.1–2.6; P = 0.022), Sokal risk (HR 1.4, 95% CI: 1.1–2.3; p = 0.03), type of transcript (e14a2 vs e13a2 type, HR 1.6, 95% CI: 1.3–2.9; P = 0.03) and achievement of an early molecular response (EMR) at 3 months (HR 1.5, 95% CI: 1.2–2.8; P = 0.01), retained statistical significance. These clinical and biologic features associated with the achievement of a stable deep molecular response should be taken into account at a time when treatment-free remission strategies are being actively pursued in the management of CML.
There are five tyrosine kinase inhibitors (TKIs) that are currently approved (in the European Union and the United States) for the treatment of chronic myeloid leukaemia (CML) in the chronic phase (CP) and each of them has its own efficacy and toxicity profile. Oral ponatinib (Iclusig ® ) is a third-generation TKI structurally designed to inhibit native BCR-ABL1 tyrosine kinase and several BCR-ABL1 mutants, including T315I. Ponatinib is now approved for patients with CML who are resistant or intolerant to prior TKI therapy (European Union) or for whom no other TKI therapy is indicated (United States). Despite achieving results in heavily treated patients, which led to its approval, the drug may induce cardiovascular events, requiring a careful baseline assessment of predisposing risk factors and specific management during treatment. Pharmacokinetic analysis has indicated the possibility of reducing the starting dose of ponatinib to 15 mg/day and preliminary data showed advantages in terms of safety while maintained its efficacy. This review summarizes the results achieved and drug-related side effects reported in all clinical trials and real-life experiences, testing ponatinib in patients with CP-CML. In addition, we focus on the appropriate use of ponatinib in clinical practice suggesting some useful recommendations on the proper management of this drug.
Ruxolitinib, a JAK1 and JAK2 inhibitor, has been tested and approved for the treatment of primary and secondary myelofibrosis (MF). Aim of our study is to report safety and efficacy of ruxolitinib in 98 patients affected by MF treated outside clinical trials and collected and treated consecutively by the Lazio Cooperative Group for Ph negative myeloproliferative diseases.There were 45 males and 53 females; median age was 61.8 years (range 35.3-88). Forty-five patients were diagnosed as primary MF and 53 as secondary MF. Seventy-seven patients (78.5%) experienced constitutional symptoms at baseline, and out of 94 patients tested, 66 (70%) were JAK2 mutated. Overall, 40 patients received hydroxyurea as firstline treatment, 30 patients received other chemotherapeutic approaches, whereas 28 were treated with ruxolitinib frontline. Median time from diagnosis to start of ruxolitinib in the whole cohort was 34.6 months. Fifty-eight patients (59%) required a dose reduction during the first 3 months due to hematological toxicity in the majority of cases. At 48 weeks, 52% of patients obtained a clinical benefit: of them 7 patients (7%) had a CR, 10 (10%) a PR, 6 patients (6%) a CI, and 28 patients (28.5%) a spleen response. Overall, 66% of patients had disappearance of baseline symptoms burden. After 1 year, of 72 evaluable patients, 52% achieved and maintained a clinical benefit. Adverse events of special interest at any grade included anemia (39.7%), thrombocytopenia (25.5%), infections (16.3%, of which 10 were bronchopneumonia), fluid retention (3%), diarrhea (2%) and abdominal pain (2%). After a median follow-up of 16 months from start of ruxolitinib, median daily dose decreased to 10 mg BID and 21 patients (21%) discontinued the drug. The results of this retrospective multicentric analysis confirmed the efficacy of ruxolitinib outside clinical trials with more than half of treated patients achieving and maintaining a clinical benefit and most of them reporting relief from symptoms.
We investigated the median estimated glomerular filtration rate (eGFR) changes in chronic myeloid leukemia (CML) patients treated front line with tyrosine kinase inhibitors (TKIs). A large cohort of 397 patients-320 treated front line with imatinib, 25 with dasatinib, and 53 with nilotinib-was retrospectively analyzed at a single institution. The eGFR was calculated according to the Chronic Kidney Disease Epidemiology Collaboration equation for all patients at baseline and then at 6 and 12 months, and at the last follow-up. Taking into account eGFR changes during the first year of treatment and excluding other possible cardiovascular risk factors, we considered also the percentage of cardiovascular events in patients with modifications of this single parameter. Imatinib induced a decrease in median eGFR (p = 0.01): 42 patients treated with imatinib had a cardiovascular event, related to modification of eGFR, in the absence of other cardiovascular risk factors. In patients treated with nilotinib, the median eGFR did not decline from baseline: only 1 patient experienced an ischemic event, but the eGFR remained unchanged. In patients treated with dasatinib, the mean eGFR did not change significantly: 3 patients experienced a cardiac ischemic event, but in all patients the eGFR remained unchanged over time, while advanced age and metabolic alterations contributed to the ischemic events. This long-term follow-up has documented that imatinib may induce changes in the eGFR, which may contribute to the onset of ischemic events. Further analyses on larger series of CML patients are required to conclusively define the potential renal toxicity of second generation TKIs and the consequent risk of developing ischemic events.
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.