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Despite increased understanding of the genomic landscape of Myeloproliferative Neoplasms (MPNs), the pathological mechanisms underlying abnormal megakaryocyte (Mk)-stromal crosstalk and fibrotic progression in MPNs remain unclear. We conducted mass spectrometry-based proteomics on mice with Romiplostim-dependent myelofibrosis to reveal alterations in signaling pathways and protein changes in Mks, platelets, and bone marrow (BM) cells. The chemokine Platelet Factor 4 (PF4)/Cxcl4 was up-regulated in all proteomes and increased in plasma and BM fluids of fibrotic mice. High TPO concentrations sustained in vitro PF4 synthesis and secretion in cultured Mks, while Ruxolitinib restrains the abnormal PF4 expression in vivo. We discovered that PF4 is rapidly internalized by stromal cells through surface glycosaminoglycans (GAGs) to promote myofibroblast differentiation. Cxcl4 gene silencing in Mks mitigated the profibrotic phenotype of stromal cells in TPO-saturated co-culture conditions. Consistently, extensive stromal PF4 uptake and altered GAGs deposition were detected in Romiplostim-treated, JAK2V617F mice and BM biopsies of MPN patients. BM PF4 levels and Mk/platelet CXCL4 expression were elevated in patients, exclusively in overt fibrosis. Finally, pharmacological inhibition of GAGs ameliorated in vivo fibrosis in Romiplostim-treated mice. Thus, our findings highlight the critical role of PF4 in the fibrosis progression of MPNs and substantiate the potential therapeutic strategy of neutralizing PF4-GAGs interaction.
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Here, we reviewed clinical-morphological data and investigated mutational profiles by NGS in a single-center series of 28 consecutive patients admitted to our hospital between September 2011 and November 2021 for idiopathic hypereosinophilia (HE).Bone marrow (BM) morphology was evaluated in 22 patients: while in six subjects BM was unremarkable, in the remaining cases an increase in BM eosinophils was observed, together with a slight increase in BM fibrosis (MF-1) in 5/22 patients.A total of 4/28 patients had at least one genetic lesion by targeted NGS. In particular, the genes involved were: two each of TET2 and DNMT3A; and one each of JAK2V617F, ASXL1, PPM1D, and ZBTB33. Notably, JAK2V617F and TET2 mutations co-occurred, with the JAK2V617F-mutated sample also carrying TET2 lesions. Median VAF was 21%, with the exception of the oncodriver JAK2V617F, which showed a VAF > 50% in the reported case. Of note, of the four cases bearing lesions, 2/4 had multiple hits in different genes.While in recent years mutational analysis using NGS has proven to be able to differentiate clonal hematopoietic neoplasms from reactive processes in diagnostically difficult cases, we found somatic mutations in only 14.3% of patients who acceded to our hospital for idiopathic HE. More importantly, excluding the JAK2V617F-mutated case with an underlying MPN-Eo diagnosis, NGS was able to identify somatic mutations in only three cases, all older than 70 years. Consequently, the detection of these mutations in idiopathic HE patients should be interpreted with caution and only in the context of other supportive clinical-pathological findings.
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Sequenciamento de Nucleotídeos em Larga Escala , Mutação , Humanos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Masculino , Pessoa de Meia-Idade , Feminino , Adulto , Idoso , Dioxigenases/genética , Janus Quinase 2/genética , Medula Óssea/patologia , Proteínas Proto-Oncogênicas/genética , Proteínas de Ligação a DNA/genética , Síndrome Hipereosinofílica/genética , Síndrome Hipereosinofílica/diagnóstico , DNA Metiltransferase 3A , Idoso de 80 Anos ou mais , Análise Mutacional de DNA/métodos , Adulto Jovem , Proteínas RepressorasRESUMO
Patients with essential thrombocythemia (ET) are treated with once-daily low-dose aspirin to prevent thrombosis, but their accelerated platelet turnover shortens the antiplatelet effect. The short-term Aspirin Regimens in EsSential Thrombocythemia trial showed that twice-daily aspirin dosing restores persistent platelet thromboxane (TX) inhibition. However, the long-term pharmacodynamic efficacy, safety and tolerability of twice-daily aspirin remain untested. We performed a multicenter, randomized, open-label, blinded-endpoint, phase-2 trial in which 242 patients with ET were randomized to 100 mg aspirin twice- or once-daily and followed for 20 months. The primary endpoint was the persistence of low serum TXB2, a surrogate biomarker of antithrombotic efficacy. Secondary endpoints were major and clinically relevant non-major bleedings, serious vascular events, symptom burden assessed by validated questionnaires, and in vivo platelet activation. Serum TXB2 was consistently lower in the twice-daily versus once-daily regimen on 10 study visits over 20 months: median 3.9 ng/mL versus 19.2 ng/mL, respectively; p < .001; 80% median reduction; 95% CI, 74%-85%. No major bleeding occurred. Clinically relevant non-major bleedings were non-significantly higher (6.6% vs. 1.7%), and major thromboses lower (0.8% vs. 2.5%) in the twice-daily versus once-daily group. Patients on the twice-daily regimen had significantly lower frequencies of disease-specific symptoms and severe hand and foot microvascular pain. Upper gastrointestinal pain was comparable in the two arms. In vivo platelet activation was significantly reduced by the twice-daily regimen. In patients with ET, twice-daily was persistently superior to once-daily low-dose aspirin in suppressing thromboxane biosynthesis and reducing symptom burden, with no detectable excess of bleeding and gastrointestinal discomfort.
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Aspirina , Esquema de Medicação , Hemorragia , Inibidores da Agregação Plaquetária , Trombocitemia Essencial , Humanos , Aspirina/administração & dosagem , Aspirina/uso terapêutico , Trombocitemia Essencial/tratamento farmacológico , Trombocitemia Essencial/sangue , Masculino , Pessoa de Meia-Idade , Feminino , Idoso , Adulto , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/uso terapêutico , Inibidores da Agregação Plaquetária/efeitos adversos , Hemorragia/induzido quimicamente , Tromboxano B2/sangue , Ativação Plaquetária/efeitos dos fármacos , Idoso de 80 Anos ou mais , Resultado do TratamentoRESUMO
We evaluated RDW in a single-center series of 61 consecutive patients with primary and secondary MF at diagnosis and during treatment with ruxolitinib (RUX) and examined any possible prognostic impact. Elevated RDW values were present in all but 4 patients at diagnosis with a median RDW of 18.9%. RDW was higher in subjects with palpable splenomegaly (p = 0.02), higher ferritin, as well as among those cases who did not receive any cytoreduction before RUX (p = 0.04). Interestingly, higher RDW at diagnosis also correlated with a shorter time from MF diagnosis to RUX start (-4.1 months per one RDW unit; p = 0.03). We observed a modest increase (< 1%) in RDW during the first 6 months of RUX treatment. In a multivariable random-intercept model that considered all time points and contained the covariates time and RUX dose, we also observed a clear decrease in RDW with increasing hemoglobin (Hb) during RUX (slope: -0.4% per g/dL of Hb; p < 0.001). The median RDW at diagnosis of 18.9% was used as a cut-off to identify two subgroups of patients [Group 1: RDW 19.0-25.7%; Group 2: RDW 13.1-18.7%], showing a difference in mortality [Group 1 vs. 2: crude HR 2.88; p = 0.01]. Using continuous RDW at diagnosis, the crude HR was 1.21 per RDW unit (p = 0.002). In a Cox model adjusted for gender, age and Hb at diagnosis, the HR was 1.13 per RDW unit (p = 0.07). RDW may have prognostic significance at MF diagnosis and during RUX, helping in the rapid detection of patients with poor prognosis.
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Índices de Eritrócitos , Nitrilas , Mielofibrose Primária , Pirazóis , Pirimidinas , Humanos , Nitrilas/uso terapêutico , Pirazóis/uso terapêutico , Masculino , Feminino , Pirimidinas/uso terapêutico , Pessoa de Meia-Idade , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/sangue , Mielofibrose Primária/mortalidade , Idoso , Prognóstico , Idoso de 80 Anos ou mais , AdultoRESUMO
BACKGROUND: Intermittent treatment with tyrosine kinase inhibitors (TKIs) is an option for elderly chronic myeloid leukemia (CML) patients who are often candidates for life-long treatment. MATERIALS AND METHODS: The Italian phase III multicentric randomized Optimize TKIs Multiple Approaches (OPTkIMA) study aimed to evaluate if a progressive de-escalation of TKIs is able to maintain the molecular remission (MR)3.0 and to improve Health-Related Quality of Life (HRQoL) in CML elderly patients. RESULTS: A total of 215 patients in stable MR3.0/MR4.0 were randomized to receive an intermittent TKI schedule 1 month ON-1 month OFF for 3 years (FIXED arm; n = 111) vs. a progressive de-escalation TKI dose up to one-third of the starting dose at the 3rd year (PROGRESSIVE arm; n = 104). Two hundred three patients completed the 3rd year of OPTkIMA study. At the last follow-up, MR3.0 loss was 27% vs. 46% (P = .005) in the FIXED vs PROGRESSIVE arm, respectively. None of these patients experienced disease progression. The 3-year probability of maintaining the MR3.0 was 59% vs. 53%, respectively (P = .13). HRQoL globally improved from the baseline to the 3rd year, without any significant difference between the 2 arms. After the 3rd year, the proportion of patients who was address to TKI discontinuation in the 2 arms was 36% (FIXED) vs. 58% (PROGRESSIVE) (P = .03). CONCLUSIONS: The intensification of intermittent TKI therapy is associated with a higher incidence of MR3.0 loss, but those patients who maintain the MR3.0 molecular response at the end of the study have been frequently considered eligible for TFR. The HRQoL generally improved during the de-escalation therapy in both randomization arms.
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Leucemia Mielogênica Crônica BCR-ABL Positiva , Inibidores de Proteínas Quinases , Qualidade de Vida , Humanos , Idoso , Masculino , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Feminino , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Itália , Idoso de 80 Anos ou mais , Resultado do TratamentoRESUMO
BCR::ABL1-negative myeloproliferative neoplasms (MPNs) are classically represented by polycythemia vera, essential thrombocythemia, and primary myelofibrosis. BCR::ABL1-negative MPNs are significantly associated with morbidity and mortality related to an increased risk of thrombo-hemorrhagic events. They show a consistent association with splanchnic vein thrombosis (SVT), either represented by the portal, mesenteric or splenic vein thrombosis, or Budd-Chiari Syndrome. SVT is also a frequent presenting manifestation of MPN. MPNs associated with SVT show a predilection for younger women, high association with JAK2V617F mutation, low JAK2V617F variant allele frequency (generally <10 %), and low rates of CALR, MPL, or JAK2 exon 12 mutations. Next-Generation Sequencing techniques have contributed to deepening our knowledge of the molecular landscape of such cases, with potential diagnostic and prognostic implications. In this narrative review, we analyze the current perspective on the molecular background of MPN associated with SVT, pointing as well future directions in this field.
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Transtornos Mieloproliferativos , Policitemia Vera , Trombocitemia Essencial , Trombose Venosa , Humanos , Feminino , Transtornos Mieloproliferativos/complicações , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/diagnóstico , Trombose Venosa/genética , Policitemia Vera/complicações , Trombocitemia Essencial/genética , Mutação , Calreticulina/genética , Janus Quinase 2/genéticaRESUMO
In patients with low-risk polycythemia vera, exposure to low-dose Ropeginterferon alfa-2b (Ropeg) 100 µg every 2 weeks for 2 years was more effective than the standard treatment of therapeutic phlebotomy in maintaining target hematocrit (HCT) (< 45%) with a reduction in the need for phlebotomy without disease progression. In the present paper, we analyzed drug survival, defined as a surrogate measure of the efficacy, safety, adherence, and tolerability of Ropeg in patients followed up to 5 years. During the first 2 years, Ropeg and phlebotomy-only (Phl-O) were discontinued in 33% and 70% of patients, respectively, for lack of response (12 in the Ropeg arm vs. 34 in the Phl-O arm) or adverse events (6 vs. 0) and withdrawal of consent in (3 vs. 10). Thirty-six Ropeg responders continued the drug for up to 3 years, and the probability of drug survival after a median of 3.15 years was 59%. Notably, the primary composite endpoint was maintained in 97%, 94%, and 94% of patients still on drug at 3, 4, and 5 years, respectively, and 60% of cases were phlebotomy-free. Twenty-three of 63 Phl-O patients (37%) failed the primary endpoint and were crossed over to Ropeg; among the risk factors for this failure, the need for more than three bloodletting procedures in the first 6 months emerged as the most important determinant. In conclusion, to improve the effectiveness of Ropeg, we suggest increasing the dose and using it earlier driven by high phlebotomy need in the first 6 months post-diagnosis.
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Policitemia Vera , Humanos , Policitemia Vera/tratamento farmacológico , Policitemia Vera/diagnóstico , Hematócrito , Fatores de Risco , Flebotomia , SangriaRESUMO
OPINION STATEMENT: The introduction of TKIs into the therapeutic armamentarium of CML has changed the disease paradigm, increasing long-term survival from 20% to over 80%, with a life expectancy now approaching that of the general population. Although highly effective, TKIs also have a toxicity profile that is often mild to moderate, but sometimes severe, with multiple kinases involved in the development of adverse events (AEs). Among others, cardiovascular AEs observed in TKI-treated CML patients may represent a significant cause of morbidity and mortality, and their pathogenesis is still only partially understood. In view of the recent introduction into daily clinical practice of new TKIs, namely the STAMP inhibitor asciminib, with a distinct safety profile, hematologists now more than ever have the opportunity to select the most suitable TKI for each patient, an aspect that will be fundamental in terms of personalized preventive and therapeutic strategies. Furthermore, physicians should be aware of the feasibility of TKI dose modifications at all stages of the patients' treatment journey, both at diagnosis for frail or elderly subjects or with multiple comorbidities, and during follow-up for those patients who experience toxicity, as well as to prevent it, with the main objective of reducing side effects while maintaining the response. Consequently, preserving the cardiovascular health of CML patients will likely be a more urgent topic in the near future, with specific measures aimed at controlling cardiovascular risk factors through a multidisciplinary approach involving a panel of healthcare professionals together with the hematologist.
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Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Idoso , Antineoplásicos/efeitos adversos , Relevância Clínica , Inibidores de Proteínas Quinases/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológicoRESUMO
Disease progression to accelerated/blast phase (AP/BP) in patients with chronic phase chronic myeloid leukemia (CP-CML) after treatment discontinuation (TD) has never been systematically reported in clinical trials. However, recent reports of several such cases has raised concern. To estimate the risk of AP/BP among TD-eligible patients, we conducted TFR-PRO, a cohort retro-prospective study: 870 CP-CML patients eligible for TD formed a discontinuation cohort (505 patients) and a reference one (365 patients). The primary objective was the time adjusted rate (TAR) of progression in relation to TD. Secondary endpoints included the TAR of molecular relapse, that is, loss of major molecular response (MMR). With a median follow up of 5.5 years and 5188.2 person-years available, no events occurred in the TD cohort. One event of progression was registered 55 months after the end of TD, when the patient was contributing to the reference cohort. The TAR of progression was 0.019/100 person-years (95% CI [0.003-0.138]) in the overall group; 0.0 (95% CI [0-0.163]) in the discontinuation cohort; and 0.030 (95% CI [0.004-0.215]) in the reference cohort. These differences are not statistically significant. Molecular relapses occurred in 172/505 (34.1%) patients after TD, and in 64/365 (17.5%) patients in the reference cohort, p < .0001. Similar rates were observed in TD patients in first, second or third line of treatment. CML progression in patients eligible for TD is rare and not related to TD. Fears about the risk of disease progression among patients attempting TD should be dissipated.
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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.
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Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide de Fase Crônica , Humanos , Mesilato de Imatinib , Estudos Retrospectivos , Inibidores de Proteínas Quinases , Dasatinibe , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológicoRESUMO
Lymphomatoid papulosis (LyP) is a benign condition, listed among primary cutaneous CD30+ lymphoproliferative disorders. Its typical picture consists of relapsing-remitting papular lesions and it can be encountered in the course of a hematologic disease, at times representing its first manifestation. Hypereosinophilic syndromes are a heterogeneous group of disorders characterized by persistent peripheral blood hypereosinophilia that may lead to life-threatening organ damage. Among eosinophilic disorders, the subtype identified as myeloid/lymphoid neoplasm with eosinophilia and tyrosine kinase gene fusions has aroused particular interest due to its excellent response to tyrosine kinase inhibitors, including imatinib. Here, we described the case of two 33-year-old men presenting with LyP and myeloid neoplasm with eosinophilia and FIP1L1::PDGFRA rearrangement who achieved complete clinical and molecular remission of both conditions a few months after starting imatinib.
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Síndrome Hipereosinofílica , Papulose Linfomatoide , Masculino , Humanos , Mesilato de Imatinib/uso terapêutico , Papulose Linfomatoide/diagnóstico , Papulose Linfomatoide/tratamento farmacológico , Papulose Linfomatoide/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Síndrome Hipereosinofílica/diagnóstico , Síndrome Hipereosinofílica/tratamento farmacológico , Síndrome Hipereosinofílica/genética , Fatores de Transcrição , Proteínas de Fusão Oncogênica/genéticaRESUMO
OPINION STATEMENT: Current treatment of essential thrombocythemia (ET) should primarily prevent thrombo-hemorrhagic events, without increasing the rate of fibrotic progression or leukemic evolution, and secondarily control microvascular symptoms. Unlike other classic BCR::ABL1-negative myeloproliferative neoplasms, ET is frequently diagnosed in adolescents and young adults (AYA), defined as individuals aged 15 to 39 years, in up to 20% of patients. However, since the current risk stratification of this disease is based on models, including that of ELN, IPSET-Thrombosis and its revised version, mainly applied to an older patients' population, international guidelines are needed that specifically consider how to evaluate the prognosis of AYAs with ET. Furthermore, although ET is the most frequent MPN among AYA subjects, there is a lack of specific recommendations on how to treat it in this subgroup of patients, as management decisions are typically extrapolated from those for the elderly. Accordingly, since AYAs with ET represent a unique disease subset defined by attenuated genetic risk, more indolent phenotype, and longer survival than their older counterparts, treatment selection requires special attention to specific issues such as the risk of fibrotic/leukemic transformation, carcinogenicity, and fertility. This review article will provide a comprehensive overview of the diagnosis, prognostic stratification, and possible therapeutic approaches for AYA patients with ET, including antiplatelets/anticoagulants and cytoreductive agents, with a focus on pregnancy management in real-life clinical practice.
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Trombocitemia Essencial , Trombose , Humanos , Trombocitemia Essencial/diagnóstico , Trombocitemia Essencial/etiologia , Trombocitemia Essencial/terapia , Trombose/epidemiologia , Fatores de Risco , PrognósticoRESUMO
Here, we reviewed clinical-morphological data and investigated mutational profiles by NGS in a single-center series of 58 consecutive MPN-SVT patients admitted to our hospital between January 1979 and November 2021. We identified 15.5% of PV, 13.8% of ET, 34.5% of PMF, 8.6% of SMF and 27.6% of MPN-U. Most cases (84.5%) carried JAK2V617F mutation, while seven patients were characterized by other molecular markers, namely MPL in four and CALR mutations in three cases. NGS was performed in 54 (93.1%) cases: the most frequent additional mutations were found in TET2 (27.8%) and DNMT3A (16.7%) genes, whereas 25 (46.3%) patients had no additional mutation. Cases with JAK2V617F homozygosity had a higher median number of additional mutations than those with low allele burden. More importantly, all cases of leukemic evolution were characterized by a higher median number of co-mutations, and a co-mutational pattern of high-risk lesions, such as truncating mutations of ASXL1, bi-allelic TP53 loss, and CSMD1 mutations. Nevertheless, no difference was found between cases with and without additional somatic mutations regarding fibrotic progression, SVT recurrence, other thrombo-hemorrhagic complications, or death. After a median follow-up of 7.1 years, ten deaths were recorded; fibrotic progression/leukemic evolution was ascertained in one (1.7%) and six (10.3%) patients, respectively, while 22 (37.9%) patients suffered from recurrent thrombosis. In conclusion, our data underline the importance of using NGS analysis in the management of MPN-related SVT as it can support the MPN diagnosis, particularly in "triple-negative" cases, and provide additional information with potential consequences on prognosis and therapeutic strategies.
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Transtornos Mieloproliferativos , Neoplasias , Trombose Venosa , Humanos , Transtornos Mieloproliferativos/genética , Trombose Venosa/genética , Mutação , Genômica , Janus Quinase 2/genética , Calreticulina/genéticaRESUMO
We evaluated CD34+ cells in a single-centre series of 49 consecutive patients with myelofibrosis (MF) at baseline and during ruxolitinib therapy and examined any association with spleen response. The median (range) absolute number of circulating CD34+ cells was 0.0835 (0.001-1.528) × 109 /L at diagnosis, and 0.123 (0.002-1.528) × 109 /L at ruxolitinib start. With the exception of a transient increase after 3 months of ruxolitinib therapy, a progressive reduction in CD34+ cells count was documented, down to a minimum of 0.063 × 109 /L after 36 months. We then assessed the association between spleen diameter expressed as the distance from the left costal margin (outcome) and log(CD34+ ) cells count using random-intercept and random slope multivariable regression models to take into account within subject correlation: after adjusting for time and ruxolitinib dosage, we estimated a 0.7 cm increase (95% confidence interval 0.2-1.2, p = 0.003) in spleen length for each unit increase in log(CD34+ ) cells count (× 109 /L). Although our study has some limitations, mainly related to its retrospective design, our approach may introduce a reproducible and simple tool that could facilitate the assessment of spleen response more objectively in patients with MF treated with ruxolitinib.
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Mielofibrose Primária , Baço , Humanos , Nitrilas , Mielofibrose Primária/diagnóstico , Estudos Retrospectivos , Resultado do Tratamento , Antígenos CD34RESUMO
BACKGROUND: Whether phlebotomy alone can adequately maintain target hematocrit in patients with low-risk polycythemia vera (PV) remains elusive. METHODS: In a phase 2 open-label randomized trial, we compared ropeginterferon alfa-2b (ropeg; 100 µg every 2 weeks) with phlebotomy only regarding maintenance of a median hematocrit level (≤45%) over 12 months in the absence of progressive disease (primary end point). In follow-up, crossover to the alternative treatment group was allowed if the primary end point was not met. RESULTS: In total, 127 patients were enrolled (ropeg: n=64; standard group: n=63). The primary end point was met in 81% and 51% in the ropeg and standard groups, respectively. Responders continued the assigned treatment until month 24 and maintained response in 83% and 59%, respectively (P=0.02). Ropeg responders less frequently experienced moderate/severe symptoms (33% vs. 67% in the standard group) and palpable splenomegaly (14% vs. 37%) and showed normalization of ferritin levels and blood counts. Nonresponders at 12 months crossed over to the standard (n=9) or ropeg (n=23) group; in patients switched to ropeg only, 7 of 23 met the response criteria in 12 months, and phlebotomy need was high (4.7 per patient per year). Discontinuation because of adverse events occurred in seven patients treated with ropeg. CONCLUSIONS: In this 24-month trial, ropeg was superior to phlebotomy alone in maintaining hematocrit on target. No dose-limiting side effects or toxicities were noted; 9.2% of patients on ropeg and no patients on standard treatment developed neutropenia. (Funded by AOP Health and others; ClinicalTrials.gov number, NCT03003325.)
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Policitemia Vera , Policitemia , Trombocitose , Trombose , Humanos , LeucocitoseRESUMO
Purpose: Patients with chronic myeloid leukemia (CML) who present a sustained deep molecular response (DMR) for a stable period of time might benefit from discontinuing tyrosine kinase inhibitors (TKIs). A significant number of patients seem able to reach this stage due to the availability of TKIs. However, many patients remain reluctant about TKI discontinuation and may refuse treatment interruption. The purpose of this study was to explore the clinical and psycho-cognitive factors that may influence the decision to discontinue TKI therapy, thereby gaining a better understanding of patients' viewpoints on TKI discontinuation. Patients and Methods: One hundred and nineteen patients diagnosed with CML aged between 34 and 69 were enrolled (67 males and 52 females). Different clinical information and psycho-cognitive aspects such as attitude toward risk behaviours, risk preferences, need for cognitive closure, and tendency to resist to changes were assessed through the administration of a battery of questionnaires. Results: A higher tendency toward risk behaviours and the tendency to focus on possible gain in the short term rather than on losses might represent important predictors for the willingness to accept TKI discontinuation. Possible relapses following interruption of the therapy are the most common reason for concern. Furthermore, lower levels of resistance to change and having previously experienced the desire to interrupt the therapy might lead patients to accept a higher probability of relapse risk when facing such a decision. Conclusion: TKI discontinuation appears appealing and challenging at the same time for many CML patients, and different factors may influence this decision. Psychology plays a crucial role in assisting physician-patient communication and informed decision-making.
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The spectrum of TKI-related adverse events (AEs) is variable. Pleural effusion (PE) is a frequent AE attributable to dasatinib treatment, while it is only rarely associated with nilotinib. The pathogenetic mechanism leading to PE during nilotinib therapy is still unknown and its management has not yet been defined. To the best of our knowledge, only a limited number of similar case reports have already been reported in the literature so far. Here, we describe the case of a 41-year-old CML patient who developed PE during first-line nilotinib, successfully treated with steroids and nilotinib permanent discontinuation. We highlight the differences among our patient and the others, proposing therapeutic strategies to solve this rare but still possible AE, of which physicians should be aware.