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Ponatinib may be effective in chronic myeloid leukemia (CML) patients after failure of first/second line therapies. Although its efficacy for minimum plasma concentrations (Cmin) is >21.3 ng/mL (equal to 40 nM), ponatinib may cause adverse events (AE) that require dose optimization. The present study was aimed at investigating any possible correlations among ponatinib dose, plasma concentration, molecular response (MR), and tolerability in a real-world setting. Clinical and laboratory records (including MR and drug plasma concentrations) of 32 CML patients treated with ponatinib were harvested and analyzed. Twenty-seven patients (71%) had ponatinib Cmin values > 21.3 ng/mL, but Cmin values > 10.7 ng/mL (considered efficacious in BCR-Abl unmutated patients) were achieved by 80% of the patients receiving ≥30 mg/day and 45% of the subjects treated with 15 mg/day. No significant correlations were identified among clinical efficacy, tolerability, daily dose, and plasma concentration. Notably, patients who underwent dose tapering for tolerability or safety reasons did not experience treatment failure. In a real-world setting, adjustment of ponatinib daily doses lower than those registered may maintain therapeutic efficacy while reducing the risk of vascular events and improving tolerability. Further studies are warranted to confirm the present results in a larger cohort of patients.
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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.
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Doenças Cardiovasculares , Leucemia Mielogênica Crônica BCR-ABL Positiva , Piridazinas , Adulto , Humanos , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/epidemiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/induzido quimicamente , Imidazóis/efeitos adversos , Pirimidinas/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversosRESUMO
A panel of chronic lymphocytic leukemia (CLL) experts from Tuscany propose a real-life diagnostic and therapeutic approach CLL that considers the role of genomic and somatic prognostic factors in risk stratification and treatment decisions. Safety and efficacy of new agents has been demonstrated now not only in clinical trials but also in many real-world series. The BTK inhibitors, ibrutinib and acalabrutinib, and BH3 mimetic venetoclax are now indicated as first-line therapy and chemoimmunotherapy can be spared to the majority of CLL patients, thus preventing unnecessary hematological and non-hematological toxicity and second primary tumors. For treatment, FISH for 17 p and P53 mutational status are essential. IGHV mutation can be done at diagnosis or before treatment. Echography is the gold standard radiological investigation in CLL, at both diagnosis and response evaluation. Chemotherapy is virtually abandoned. Age, genetic risk, and patient comorbidities have to be carefully evaluated for treatment decision. With the availability of different drugs, there is a need for a uniform and shared approach in daily therapeutic choice. The proposed approach is based on current evidence and guidelines as well as results from clinical trials and daily clinical experience.
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Leucemia Linfocítica Crônica de Células B , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imunoterapia , Fatores de RiscoRESUMO
Clinical or biological parameters useful to predict progression during treatment in real-life setting with ibrutinib, idelalisib and venetoclax in relapsed/refractory chronic lymphocytic leukemia (CLL) are still debated. We conducted a multi-center retrospective study on CLL patients treated with ibrutinib and/or idelalisib who were switched to venetoclax for progression or due to adverse events to identify any clinical and/or biological parameters useful to predict progression during treatment with venetoclax. Of all the 128 evaluable patients, 81 had received ibrutinib prior to switching to venetoclax, 35 had received idelalisib and 12 both. When comparing the three subgroups, we did not notice any statistical difference in terms of clinical or biological features. No variable at baseline and at different time points during the follow-up (at 6, 12, 18 and 24 months) was found to predict progression nor to have significance for Progression Free Survival (PFS) in the ibrutinib group and in the idelalisib group and in subgroups according to the line of treatment. Analyzing the data of the venetoclax treatment, after a median follow up of 14.3 months, median PFS was not reached and estimated 3-year PFS was 54%. Of the 128 patients treated with venetoclax, 28 (22%) experienced progressive disease. At multivariate analysis for predictive factors for progression, lymph node diameter >56.5 mm before starting treatment emerged as an independent risk factor for progression. The lymph node predictive role for progression during venetoclax treatment could be a new parameter that deserves to be investigate in future studies.
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Leucemia Linfocítica Crônica de Células B , Linfadenopatia , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Estudos Retrospectivos , Linfadenopatia/induzido quimicamente , Linfadenopatia/tratamento farmacológico , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Recidiva , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
BACKGROUND AND OBJECTIVES: Neuropathy with antibodies to myelin-associated glycoprotein (MAG) is the most common paraproteinemic IgM neuropathy. Recently, the mutational profile of the MYD88 and CXCR4 genes has been included in the diagnostic workup of IgM monoclonal gammopathies. The objective of our study was to assess the prevalence of MYD88 L265P and CXCR4 S338X gene variants in patients with anti-MAG antibody neuropathy. Secondary aims were to evaluate possible correlations between the mutational profile and neuropathy severity, antibody titers, and treatment response. METHODS: Seventy-five patients (47 men, mean age at molecular analysis 70.8 ± 10.2 years; mean disease duration 5.1 ± 4.9 years) with anti-MAG antibody neuropathy were recruited. Among them, 38 (50.7%) had IgM monoclonal gammopathy of undetermined significance, 29 (38.7%) Waldenstrom macroglobulinemia (WM), and 8 (10.6%) chronic lymphocytic leukemia/marginal zone lymphoma/hairy cell leukemia variant. Molecular analysis was performed on DNA from the bone marrow mononuclear cells in 55 of 75 patients and from peripheral mononuclear cells in 18 of 75 patients. Forty-five patients were treated with rituximab, 6 with ibrutinib, 2 with obinutuzumab-chlorambucil, and 3 with venetoclax-based therapy. All the patients were assessed with the Inflammatory Neuropathy Cause and Treatment (INCAT) Disability Scale, INCAT Sensory Sum Score, and MRC Sum Score at baseline and follow-up. We considered as responders, patients who improved by at least 1 point in 2 clinical scales. RESULTS: Fifty patients (66.7%) carried the MYD88L265P variant, with a higher frequency in WM and naive patients (77.2% vs 33.3%, p = 0.0012). No patients harbored the CXCR4S338X variant. There were no significant differences in hematologic data (IgM levels, M protein, and anti-MAG antibody titers), neuropathy severity, or response to rituximab in MYD88-altered and MYD88 wild-type patients. Nine of 11 (81.8%) patients treated with novel targeted drug, according to the MYD88 status, responded to treatments. DISCUSSION: MYD88L265P variant has a high prevalence (66.7%) in anti-MAG antibody neuropathy representing a potential effective mutational target for Bruton tyrosine kinase inhibitors. MYD88L265P variant, however, does not seem to be a prognostic factor of neuropathy severity or response to rituximab. In patients not responding or becoming refractory to rituximab, a tailored therapy with new effective target therapies should be considered.
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Doenças do Sistema Nervoso Periférico , Macroglobulinemia de Waldenstrom , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Autoanticorpos , Glicoproteínas , Imunoglobulina M , Fator 88 de Diferenciação Mieloide/genética , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/genética , Rituximab/uso terapêutico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , FemininoRESUMO
A fixed duration of venetoclax-rituximab (VenR) resulted in a significant benefit of both PFS and in the attainment of an undetectable minimal residual disease (uMRD) compared with bendamustine-rituximab in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) patients. The 2018 International Workshop on CLL guidelines, outside the context of clinical trials, suggested ultrasonography (US) as a possible imaging technique to evaluate visceral involvement, and palpation to evaluate superficial lymph nodes (SupLNs). In this real-life study we prospectively enrolled N = 22 patients. Patients were assessed by US, to determine nodal and splenic response in R/R CLL patients treated with a fixed duration VenR. We found an overall response rate, complete remission, partial remission, and stable disease, of 95.4%, 68%, 27.3%, and 4.5%, respectively. Responses were also correlated with risk categories. The time to response, and the time to clearance of the disease in the spleen, in abdominal LN (AbdLNs), and in SupLNs were discussed. Responses were independent from LN size. The correlation between response rate with MRD were also investigated. US allowed to detect a substantial CR rate correlated with uMRD.
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Vaccination represents the best strategy to fight COVID-19 pandemics, especially in immune compromised subjects. In chronic lymphatic leukemia patients, a marked impairment of the immune response to mRNA SARS-CoV-2 vaccine was observed. In this report, we analyzed anti-RBD and neutralizing antibodies in CLL patients after two doses of mRNA SARS CoV 2 vaccine and evaluated the impact of Bruton kinase inhibitory agents. Twenty-seven CLL patients vaccinated with mRNA vaccines against SARS CoV-2 were recruited. Serum IgG, IgM and IgA anti-RBD antibodies and neutralizing antibodies were detected, and antibody avidity was measured. Peripheral blood leukocytes subsets were evaluated by flow cytometry. After two vaccine doses anti-RBD IgG were produced in 11/27 (40.5%) of patients and levels of IgG and IgA anti RBD in CLL patients were sensibly lower than in controls. Neutralizing antibodies were detectable in 12/27 (44.5%) of the patients and their level was lower than that observed in controls. Disease burden and treatment with Bruton kinases inhibitors markedly impaired vaccine induced antibody response. However, in responder patients, antibody avidity was comparable to normal subjects, indicating that the process of clonal selection and affinity maturation takes place as expected. Taken together, these data confirm the impact of disease burden and therapy on production of anti-RBD and neutralizing antibodies and support the current policy of vaccinating CLL patients.
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COVID-19 , Leucemia Linfocítica Crônica de Células B , Humanos , Anticorpos Neutralizantes , Vacinas contra COVID-19 , SARS-CoV-2 , COVID-19/prevenção & controle , Vacinação , Imunoglobulina A , Imunoglobulina GRESUMO
OBJECTIVES: Polycythemia vera (PV) is an acquired clonal hematopoietic stem cell disorder characterized by the overproduction of red blood cells. It has long been underlined that there are differences in treatment patterns in routine practice. Therapeutic strategies have also expanded, and in recent years the JAK1/JAK2 inhibitor ruxolitinib has emerged as a second-line therapeutic option in patients who are intolerant to or resistant to hydroxyurea. Determining the impact of changes on practice patterns is of interest, especially for aspects that lack detailed guidance for management. METHODS: To gain insights into treatment patterns by clinicians treating patients with PV in Italy, we carried out a survey of 60 hematologists and transfusion specialists. The questions covered: treatment of low-risk patients, definition of significant leukocytosis, splenomegaly and excessive phlebotomies, resistance/intolerance to hydroxyurea, use of ruxolitinib, cytoreductive therapy, and vaccines. RESULTS: In general, the results of the survey indicate that there is a large heterogeneity in management of patients with PV across these areas. CONCLUSIONS: While helping to provide greater understanding of treatment patterns for patients with PV in Italy, our survey highlights the need for additional clinical studies to obtain more precise guidance for the routine care of patients with PV.
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Inibidores de Janus Quinases , Policitemia Vera , Humanos , Policitemia Vera/diagnóstico , Policitemia Vera/epidemiologia , Policitemia Vera/terapia , Hidroxiureia/uso terapêutico , Pirazóis/uso terapêutico , Janus Quinase 2 , Inibidores de Janus Quinases/uso terapêutico , Itália/epidemiologiaRESUMO
Background: The question of which parameters may be informative on venetoclax outcome in chronic lymphocytic leukemia (CLL) is still unclear. Furthermore, the choice to treat with venetoclax can be challenging in patients with baseline characteristics or comorbidities that may potentially favor some specific adverse events. Objectives: This study was aimed to evaluate whether age, fitness status, patients'/disease characteristics, or concomitant medications may predict outcomes in CLL patients receiving venetoclax. Design: Retrospective observational study. Methods: Impact of age, presence of Cumulative Illness Rating Scale (CIRS) >6 or severe organ impairment (CIRS3+), Eastern Cooperative Oncology Group-Performance Status (ECOG-PS), renal function, and concomitant medications were retrospectively analyzed on treatment management (definitive discontinuation due to toxicity, discontinuation due to toxicity, Tox-DTD; permanent dose reduction, PDR) and survival [progression free survival (PFS), event free survival (EFS), overall survival (OS)] in unselected patients receiving venetoclax monotherapy in common practice. Results: A total of 221 relapsed/refractory patients were included. Tox-DTD and PDR were reported in 5.9% and 21.7%, respectively, and were not influenced by any fitness parameter, age, number or type of concomitant medication, baseline neutropenia, or impaired renal function. None of these factors were associated with tumor lysis syndrome (TLS) development. Age and coexisting conditions had no influence on PFS and EFS. At univariate analysis, OS was significantly shorter only in patients with ECOG-PS >1 (p < 0.0001) and elderly (⩾65 years) with CIRS >6 (p = 0.014) or CIRS3+ (p = 0.031). ECOG-PS >1 retained an independent role only for EFS and OS. While Tox-DTD affected all survival outcomes, no differences in PFS were reported among patients permanently reducing dose or interrupting venetoclax for > 7 days. Conclusion: Clinical outcome with venetoclax is not influenced by comorbidities, patients' clinical characteristics, or concomitant medications. Differently from other targeted therapies, this demonstrates that, except ECOG-PS, none of the parameters generally considered for treatment choice, including baseline neutropenia or impaired renal function, should rule the decision process with this agent. Anyway, if clinically needed, a correct drug management does not compromise treatment efficacy and may avoid toxicity-driven discontinuations. Plain Language Summary: Chapter 1: Why was this study done? Chapter 2: Which are the main findings of the study? Chapter 3: How these findings may impact on clinical practice? Coexisting conditions and concomitant medications do not affect venetoclax management and survival in chronic lymphocytic leukemia ⢠The question of which parameters may be informative on venetoclax outcome in chronic lymphocytic leukemia is still unclear. Furthermore, the choice to treat with venetoclax can be challenging in patients with baseline characteristics or comorbidities that may potentially favor some specific adverse events (e.g. compromised renal function or baseline neutropenia).⢠In our large series of patients treated outside of clinical trials, we demonstrated that neither age, fitness, comorbidities nor concomitant medications impact on venetoclax management and survival. Importantly, patients presenting with baseline neutropenia or impaired renal function did not have a higher rate of dose reductions or toxicity-driven discontinuations, thus further underlining that venetoclax may be safely administered even in those categories with no preclusions.⢠Differently from other targeted agents, our data demonstrate that none of the baseline factors commonly considered in treatment decision process retains a role with venetoclax. Finally, permanent dose reductions and temporary interruptions did not adversely impact PFS suggesting that, if clinically needed, a correct drug management should be adopted with no risk of compromising venetoclax efficacy.
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Vaccination against SARS-CoV-2 using mRNA-based vaccines has been highly recommended for fragile subjects, including myelofibrosis patients (MF). Available data on the immune responsiveness of MF patients to mRNA SARS-CoV-2 vaccination, and the impact of the therapy with the JAK inhibitor ruxolitinib, are still fragmented. Here, we profile the spike-specific IgG and memory B-cell response in MF patients, treated or not with ruxolitinib, after the second and the third dose of SARS-CoV-2 BNT162b2 (BioNTech) and mRNA-1273 (Moderna) vaccines. Plasma and peripheral blood mononuclear cells samples were collected before vaccination, post the second and the third doses and tested for spike-specific antibodies, ACE2/RBD antibody inhibition binding activity and spike-specific B cells. The third vaccine dose significantly increased the spike-specific IgG titers in both ruxolitinib-treated and untreated patients, and strongly enhanced the percentage of subjects with antibodies capable of in vitro blocking ACE2/RBD interaction, from 50% up to 80%. While a very low frequency of spike-specific B cells was measured in blood 7 days after the second vaccination dose, a strong and significant increase was elicited by the third dose administration, generating a B cell response similar to the one detected in healthy controls. Despite the overall positive impact of the third dose in MF patients, two patients that were under active concomitant immunosuppressive treatment at the time of vaccination, and a patient that received lymphodepleting therapies in the past, remained low responders. The third mRNA vaccine dose strongly increases the SARS-CoV-2 specific humoral and B cell responses in MF patients, promoting a reactivation of the immune response similar to the one observed in healthy controls.
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COVID-19 , Inibidores de Janus Quinases , Mielofibrose Primária , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinas Virais , Enzima de Conversão de Angiotensina 2 , Anticorpos Antivirais , Vacina BNT162 , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Humanos , Imunoglobulina G , Leucócitos Mononucleares , Células B de Memória , Nitrilas , Pirazóis , Pirimidinas , RNA Mensageiro , SARS-CoV-2 , Vacinas Sintéticas , Vacinas de mRNARESUMO
Background. In IWCLL guidelines, progressive splenomegaly and lymphadenopathy are signs of active disease. In this study, we have tested the hypotheses if US could be a reliable tool for both superficial lymphnodes (SupLNs) and splenic assessment in chronic lymphocytic leukemia (CLL) patients. Methods. We enrolled N = 75 patients. SupLN and the spleen were assessed by two independent physicians (M1 and M2) by palpation and by a third physician (M3) with ultrasound sonography (US) using two different sonographers (US1 and US2). The results of M1 vs. M2 assessment, US1 vs. US2, palpation vs. US were compared. The echostructure of N = 1037 SupLN and of the spleen was also investigated. Results. The dimensions of SupLNs assessed by MD1 vs. MD2 were statistically discordant. Splenic size was concordant. There was concordance between US1 and US2 SupLN and splenic assessment. US found a higher number of pathological SupLN (Cohen's Kappa < 0.1) than palpation, which misses remarkable-sized SupLNs. LN echostructure and splenic involvement patterns were described. Conclusions. US is a reliable, radiation-free tool useful in clinical practice to assess SupLN and splenic involvement in CLL.
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OBJECTIVES: To investigate the prognostic significance of concomitant autoimmune diseases (ADs) in myeloproliferative neoplasms (MPNs). METHODS: 435 subjects with a diagnosis of MPNs were included in this observational single institution longitudinal study. Of them, 34 patients presented an overt AD at diagnosis of MPN. Clinical presenting features, progression-free and overall survival were compared between MPN subgroups in relation to co-existence of AD at diagnosis of MPN. RESULTS: Compared to cases without ADs, the subjects with ADs were significantly younger, had lower haemoglobin and haematocrit levels and more frequently presented with splenomegaly. The clinical and biological features associated to progression-free and overall survival were: age, presence of splenomegaly, histotype (MF vs. PV vs. ET), anaemia, high platelet count and presence of any AD at diagnosis of MPN. The age-adjusted hazard ratio (HR) of progression for the presence of AD at diagnosis of MPN was 2.76. Overall survival was not significantly associated to AD at diagnosis, but the HR of progression for the presence of AD at diagnosis of MPN was 2.18. CONCLUSIONS: A possible common genetic predisposition, the inflammatory bone marrow microenvironment and the activation of theJAK/STAT pathway could be considered as responsible for the observed association between MPNs and ADs.
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Doenças Autoimunes , Transtornos Mieloproliferativos , Neoplasias , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/epidemiologia , Humanos , Estudos Longitudinais , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/epidemiologia , Modelos de Riscos Proporcionais , Microambiente TumoralRESUMO
Immunization with mRNA SARS-CoV-2 vaccines has been highly recommended and prioritized in fragile subjects, including patients with myelofibrosis (MF). Available data on the vaccine immune response developed by MF patients and the impact of ruxolitinib treatment are still too fragmented to support an informed decision on a third dose for this category of subjects. Here, we show that 76% of MF patients develop spike-specific IgG after the second mRNA SARS-CoV-2 vaccine dose, but the response has a slower kinetics compared to healthy subjects, suggesting a reduced capability of their immune system to promptly react to vaccination. A reduced ACE2/RBD binding inhibition activity of spike-specific antibodies was also observed, especially in ruxolitinib-treated patients. Our results, showing slow kinetics of antibody responses in MF patients following vaccination with mRNA SARS-CoV-2 vaccines, support the need for a third vaccine dose.
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INTRODUCTION: In patients with primary immune thrombocytopenia (ITP), a short course of steroids is routinely given as first-line therapy. However, the response is often transient and additional therapy is usually needed. Thrombopoietin receptor agonists (TPO-RAs) are frequently used as second-line therapy, although there is little clinical guidance on the timing of their administration and on tapering/discontinuation of the drug. To provide clinical recommendations, we used the Delphi technique to obtain consensus for statements regarding administration and on tapering/discontinuation of second-line TPO-RAs among a group of Italian clinicians with expertise in management of ITP. METHODS: The Delphi process was used to obtain agreement on five statements regarding initiation and on tapering/discontinuation of second-line TPO-RAs. Agreement was considered when 75% of participants approved the statement. Eleven experts participated in the voting. RESULTS: Full consensus was reached for three of the five statements. The experts held that an early switch from corticosteroids to a TPO-RA has the dual advantage of sparing patients from corticosteroid abuse and improve long-term clinical outcomes. All felt that dose reduction of TPO-RAs can be considered in patients with a stable response and platelet count >100 × 109/L that is maintained for at least 6 months in the absence of concomitant treatments, although there was less agreement in patients with a platelet count >50 × 109/L. Near consensus was reached regarding the statement that early treatment with a TPO-RA is associated with an increase in clinically significant partial or complete response. The experts also agreed that optimization of tapering and discontinuation of TPO-RA therapy in selected patients can improve the quality of life. CONCLUSION: The present consensus can help to provide guidance on use of TPO-RAs in daily practice in patients with ITP. PLAIN LANGUAGE SUMMARY: Second-line administration of thrombopoietin receptor agonists in immune thrombocytopenia There is little guidance on the timing of administration and tapering/discontinuation of thrombopoietin receptor agonists (TPO-RAs) in patients with primary immune thrombocytopenia (ITP).The Delphi technique was used to obtain consensus for five statements.The present consensus among Italian clinicians aims to provide guidance on second-line use of TPO-RAs for patients with ITP in daily practice.
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Functional reserve of organs and systems is known to be relevant in predicting immunochemotherapy tolerance. Age and comorbidities, assessed by the cumulative illness rating scale (CIRS), have been used to address chemotherapy intensity. In the ibrutinib era, it is still unclear whether age, CIRS, and Eastern Cooperative Oncology Group performance status (ECOG-PS) retain their predictive role on treatment vulnerability. In this series of 712 patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib outside clinical trials, baseline ECOG-PS and neutropenia resulted as the most accurate predictors of treatment feasibility and outcomes. Age did not independently influence survival and ibrutinib tolerance, indicating that not age per se, but age-related conditions, may affect drug management. We confirmed the role of CIRS > 6 as a predictor of a poorer progression- and event-free survival (PFS, EFS). The presence of a severe comorbidity was significantly associated with permanent dose reductions (PDRs), not translating into worse outcomes. As expected, del(17p) and/or TP53mut and previous therapies affected PFS, EFS, and overall survival. No study so far has analyzed the influence of concomitant medications and CYP3A inhibitors with ibrutinib. In our series, these factors had no impact, although CYP3A4 inhibitors use correlated with Cox regression analysis, with an increased risk of PDR. Despite the limitation of its retrospective nature, this large study confirmed the role of ECOG-PS as the most accurate predictor of ibrutinib feasibility and outcomes, and importantly, neutropenia emerged as a relevant tool influencing patients' vulnerability. Although CIRS > 6 retained a significant impact on PFS and EFS, its value should be confirmed by prospective studies.
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Leucemia Linfocítica Crônica de Células B , Preparações Farmacêuticas , Adenina/análogos & derivados , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Piperidinas , Estudos Prospectivos , Estudos RetrospectivosAssuntos
COVID-19/complicações , Leucemia Linfocítica Crônica de Células B/terapia , SARS-CoV-2/imunologia , Vacinação/métodos , Idoso , COVID-19/prevenção & controle , COVID-19/transmissão , COVID-19/virologia , Gerenciamento Clínico , Feminino , Humanos , Itália/epidemiologia , Leucemia Linfocítica Crônica de Células B/epidemiologia , Leucemia Linfocítica Crônica de Células B/virologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de TempoRESUMO
We prospectively evaluated changes in cardiac and hepatic iron overload (IO) and in morpho-functional cardiac parameters and myocardial fibrosis by magnetic resonance imaging (MRI) in patients with low-risk and intermediate-1-risk myelodysplastic syndromes (MDS). Fifty patients enrolled in the Myocardial Iron Overload in MyElodysplastic Diseases (MIOMED) study were followed for 12 months. IO was quantified by the T2* technique and biventricular function parameters by cine images. Macroscopic myocardial fibrosis was detected by late gadolinium enhancement technique. Twenty-eight patients (71.89±8.46 years; 8 females) performed baseline and follow-up MRIs. Thirteen patients had baseline hepatic IO, with a higher frequency among transfusion-dependent patients. Out of the 15 patients with a baseline MRI liver iron concentration <3 mg/g/dw, two (non-chelated) developed hepatic IO. Thirteen (46.4%) patients had an abnormal T2* value in at least one myocardial segment. One patient without hepatic IO and non-transfused had baseline global T2* <20 ms. Among the 15 patients with no baseline myocardial IO (MIO), 2 worsened. There was a significant increase in both left and right ventricular end-diastolic volume indexes. Thirty-six percent of patients showed myocardial fibrosis correlating with aging. Two new occurrences were detected at the follow-up. In conclusion, by a more sensitive segmental approach, MIO is quite frequent in MDS patients and it can be present also in non-transfused patients and in absence of detectable hepatic iron. The incidence of cardiac and hepatic IO and of myocardial fibrosis and the increase in biventricular volumes after a 12-month interval suggest performing periodic MRI scans to better manage MDS patients.
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Coração/diagnóstico por imagem , Imageamento por Ressonância Magnética , Síndromes Mielodisplásicas/diagnóstico por imagem , Idoso , Feminino , Fibrose , Humanos , Sobrecarga de Ferro/complicações , Sobrecarga de Ferro/diagnóstico por imagem , Itália/epidemiologia , Fígado/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/epidemiologia , Miocárdio/patologia , Estudos ProspectivosRESUMO
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.
Assuntos
Compostos de Anilina/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Nitrilas/administração & dosagem , Quinolinas/administração & dosagem , Idoso , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/administração & dosagem , Taxa de SobrevidaRESUMO
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.