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The Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders predominantly occurring in elderly, whereas in children and young adults are quite infrequent. Therefore, less is known about clinical presentation, genetic abnormalities, prognosis and best management strategies for this groups of patients. Currently, more cases of younger MPN patients are diagnosed. Nevertheless, diagnosis of MPNs, especially in childhood, may be difficult due to lower incidence of JAK2V617F and CALR mutations and differences in peripheral blood counts between adults and children. Challenges for younger MPN patients are longer life expectances, specific psychosocial need, fertility and pregnancy need and a long term therapy side effect (including second cancers). The most severe MPNs complication is transformation to secondary myelofibrosis (MF) or acute myeloid leukemia (AML). Optimal management of young MPNs remains a challenge as the classical risk scores fail in young MPNs. Moreover, the main objective of young MPNs therapy should be the disease outcome modification. Therefore, international collaborative work between pediatricians and "adult hematologists" is required to measure outcomes and generate protocol of management of young MPNs.
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The most important challenges in acute promyelocytic leukemia (APL) is preventing early death and reducing long-term events, such as second neoplasms (s-NPLs). We performed a retrospective analysis of 2670 unselected APL patients, treated with PETHEMA "chemotherapy based" and "chemotherapy free" protocols. Only de novo APL patients who achieved complete remission (CR) and completed the three consolidation cycles were enrolled into the analysis. Out of 2670 APL patients, there were 118 (4.4%) who developed s-NPLs with the median latency period (between first CR and diagnosis of s-NPL) of 48.0 months (range 2.8-231.1): 43.3 (range: 2.8-113.9) for s-MDS/AML and 61.7 (range: 7.1-231.1) for solid tumour. The 5-year CI of all s-NPLs was of 4.43% and 10 years of 7.92%. Among s-NPLs, there were 58 cases of s-MDS/AML, 3 cases of other hematological neoplasms, 57 solid tumours and 1 non-identified neoplasm. The most frequent solid tumour was colorectal, lung and breast cancer. Overall, the 2-year OS from diagnosis of s-NPLs was 40.6%, with a median OS of 11.1 months. Multivariate analysis identified age of 35 years (hazard ratio = 0.2584; p < 0.0001) as an independent prognostic factor for s-NPLs. There were no significant differences in CI of s-NPLs at 5 years between chemotherapy-based vs chemotherapy-free regimens (hazard ratio = 1.09; p = 0.932). Larger series with longer follow-up are required to confirm the potential impact of ATO+ATRA regimens to reduce the incidence of s-NPLs after front-line therapy for APL.
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Leucemia Promielocítica Aguda , Neoplasias Primarias Secundarias , Humanos , Adulto , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/epidemiología , Tretinoina , Neoplasias Primarias Secundarias/tratamiento farmacológico , Incidencia , Estudios Retrospectivos , Resultado del Tratamiento , Factores de Riesgo , Respuesta Patológica Completa , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Thrombosis and haemorrhage are frequent in patients with essential thrombocythaemia (ET). The 2016 revised International Prognostic Score for Thrombosis in Essential Thrombocythaemia-thrombosis (r-IPSET-t) score stratifies patients into very-low- (VLR), low- (LR), intermediate- (IR) and high-risk (HR) groups. We validated the r-IPSET-t in the biggest population of patients with ET (n = 1381) to date and found it to be a better fit than the earlier IPSET-t score. With an average follow-up of 87.7 months, there were 0.578 thrombotic events/person-year and 0.286 bleeding events/person-year after diagnosis. The 10-year thrombosis-free survival was 88% and 99% for the r-IPSET-t LR and VLR groups (p < 0.001). Cytoreduction was a thrombotic risk factor in younger patients (aged <60 years, hazard ratio 9.49, p = 0.026; aged ≥60 years, hazard ratio 1.04, p = 0.93). In multivariable Cox regression analysis, anti-aggregation after diagnosis was protective for thrombosis (hazard ratio 0.31, p = 0.005) but a risk factor for major bleeding (hazard ratio 10.56, p = 0.021). Of the IPSET-t HR and LR groups, 132/780 and 249/301 were re-classified as LR and VLR respectively (p < 0.001). The European LeukemiaNET (ELN) does not recommend aspirin for VLR patients but in this real-life analysis 83.1% of VLR patients received it. Our results validate the r-IPSET-t score as more predictive for thrombosis than the ELN-recommended IPSET-t and raise concerns about unnecessary cytoreductive and anti-aggregative therapy.
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Trombocitemia Esencial , Trombosis , Aspirina/uso terapéutico , Humanos , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Trombocitemia Esencial/diagnóstico , Trombosis/diagnóstico , Trombosis/epidemiología , Trombosis/etiologíaRESUMEN
OBJECTIVES: In patients with essential thrombocythemia (ET), after the JAK2V617F driver mutation, mutations in CALR are common (classified as type 1, 52-bp deletion or type 2, 5-bp insertion). CALR mutations have generally been associated with a lower risk of thrombosis. This study aimed to confirm the impact of CALR mutation type on thrombotic risk. METHODS: We retrospectively investigated 983 ET patients diagnosed in Spanish and Polish hospitals. RESULTS: With 7.5 years of median follow-up from diagnosis, 155 patients (15.8%) had one or more thrombotic event. The 5-year thrombosis-free survival (TFS) rate was 83.8%, 91.6% and 93.9% for the JAK2V617F, CALR-type 1 and CALR-type 2 groups, respectively (P = .002). Comparing CALR-type 1 and CALR-type 2 groups, TFS for venous thrombosis was lower in CALR-type 1 (P = .046), with no difference in TFS for arterial thrombosis observed. The cumulative incidence of thrombosis was significantly different comparing JAK2V617F vs CALR-type 2 groups but not JAK2V617F vs CALR-type 1 groups. Moreover, CALR-type 2 mutation was a statistically significant protective factor for thrombosis with respect to JAK2V617F in multivariate logistic regression (OR: 0.45, P = .04) adjusted by age. CONCLUSIONS: Our results suggest that CALR mutation type has prognostic value for the stratification of thrombotic risk in ET patients.
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Calreticulina/genética , Predisposición Genética a la Enfermedad , Mutación , Trombocitemia Esencial/complicaciones , Trombocitemia Esencial/genética , Trombosis/etiología , Estudios de Seguimiento , Estudios de Asociación Genética , Humanos , Incidencia , Janus Quinasa 2/genética , Oportunidad Relativa , Pronóstico , Estudios Retrospectivos , Trombocitemia Esencial/diagnóstico , Trombocitemia Esencial/mortalidad , Trombosis/diagnóstico , Trombosis/mortalidadRESUMEN
Introduction: Primary cutaneous indolent B-cell lymphomas (PCBCLs) are not well characterized due to their rarity and indolent character.Methods: We retrospectively reviewed the data from 52 patients with primary cutaneous follicular lymphoma (PCFL) (n = 26), marginal zone lymphoma (PCMZL) (n = 25) or undefined PCBCL (n = 1) treated in 10 hematology centers in 1999-2019.Results: Patients characteristics and diagnostic approach: In almost half of the patients, pruritus or pain were present at diagnosis. The lesions were predominantly located on the head and trunk. The disease was present in a form of solitary infiltration or disseminated lesions with a similar frequency.Treatment details and outcomes: Surgery, radiotherapy, rituximab alone or combined with chemotherapy were applied as first-line treatment in 33%, 25%, 21% and 21% of patients, with complete response (CR) achieved by 94%, 83%, 50% and 70% of patients, respectively (p = 0.28). The median duration of response (DoR) was 65 months (95%CI 35-155).Survival: After the median follow-up time of 46 months (range: 3-225), the estimated 5-year overall survival (OS) and progression-free survival (PFS) were 93% and 54%, respectively.Discussion: Clinical presentation was largely consistent with the literature data, however, we observed some differences, including higher predilection to affect upper extremities (25%) and more frequent multifocal appearance in PCFCL (64%) and unifocal in PCMZL (70%).A high proportion of patients with indolent PCBCL achieved CR after the first-line therapy (77%), regardless of treatment mode. We did not find any impact of clinical features on treatment outcomes.Conclusions: All treatment modalities resulted in a high overall response rate. Surgery and/or radiotherapy are the optimal therapeutic options for patients with localized disease. The decision to treat systemically should rather be limited to the generalized form of the disease. High response rate, long duration of remission and excellent long-term survival confirm the truly indolent character of PCFCL and PCMZL.
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Linfoma de Células B de la Zona Marginal , Linfoma Folicular , Neoplasias Cutáneas , Humanos , Linfoma de Células B de la Zona Marginal/terapia , Linfoma Folicular/terapia , Estudios Multicéntricos como Asunto , Estudios Retrospectivos , Rituximab , Neoplasias Cutáneas/terapiaRESUMEN
This article collects several published cases in which immune thrombocytopenic purpura (ITP) is followed by essential thrombocythemia (ET) and vice versa. This surprising clinical condition is possible, but very rare and difficult to diagnose and manage. We have made an attempt to analyse the possible causes of the sequential appearance of ITP and ET taking into consideration the following: alteration of the thrombopoietin (TPO) receptor, the role of autoimmunity and inflammation, and cytokine modulation. A better understanding of these interactions may provide opportunities to determine predisposing factors and aid in finding new treatment modalities both for ITP and ET patients.
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Púrpura Trombocitopénica Idiopática/metabolismo , Trombocitemia Esencial/metabolismo , Autoantígenos/metabolismo , Citocinas/metabolismo , Predisposición Genética a la Enfermedad , Humanos , Yoduro Peroxidasa/metabolismo , Proteínas de Unión a Hierro/metabolismo , Púrpura Trombocitopénica Idiopática/genética , Trombocitemia Esencial/genéticaRESUMEN
OBJECTIVE: The obesity/overweight may have an influence on APL outcomes. METHODS: This is the biggest multicentre analysis on 1320 APL patients treated with AIDA-induction and risk-adapted consolidation between 1996 and 2012. Patients body mass index (BMI) was classified as underweight (<18.5 kg/m2 ), normal (18.5-25 kg/m2 ), overweight (25-29.9 kg/m2 ), and obese (≥30 kg/m2 ) according to the World Health Organization (WHO) criteria. RESULTS AND CONCLUSIONS: Relationship between male gender, older age, and other known laboratory abnormalities in overweight/obese patients was significant. The induction mortality rate was significantly higher in APL with BMI ≥25 vs BMI <25 (10% vs 6%; P = .04). APL patients with BMI ≥25 had a trend to lower OS (74% vs 80%; P = .06). However, in the multivariate analysis, BMI did not retain the independent predictive value (P = .46). There was no higher incidence of differentiation syndrome with BMI ≥25, but there was a trend in obese. There was no difference in relapse rate according to the BMI. In summary, overweight/obesity does not represent an independent risk factor for APL outcomes. The influence of obesity in APL patients treated with chemotherapy-free regimens remains to be established.
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Leucemia Promielocítica Aguda/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Asparaginasa/efectos adversos , Asparaginasa/uso terapéutico , Índice de Masa Corporal , Femenino , Humanos , Leucemia Promielocítica Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/mortalidad , Masculino , Mercaptopurina/efectos adversos , Mercaptopurina/uso terapéutico , Metotrexato/efectos adversos , Metotrexato/uso terapéutico , Persona de Mediana Edad , Obesidad , Vigilancia de la Población , Prednisona/efectos adversos , Prednisona/uso terapéutico , Pronóstico , Recurrencia , Resultado del Tratamiento , Vincristina/efectos adversos , Vincristina/uso terapéutico , Adulto JovenRESUMEN
In our study, we describe the outcomes of the intercalation of different anthracycline antibiotics in double-stranded DNA at the nanoscale and single molecule level. Atomic force microscopy analysis revealed that intercalation results in significant elongation and thinning of dsDNA molecules. Additionally, using optical tweezers, we have shown that intercalation decreases the stiffness of DNA molecules, that results in greater susceptibility of dsDNA to break. Using DNA molecules with different GC/AT ratios, we checked whether anthracycline antibiotics show preference for GC-rich or AT-rich DNA fragments. We found that elongation, decrease in height and decrease in stiffness of dsDNA molecules was highest in GC-rich dsDNA, suggesting the preference of anthracycline antibiotics for GC pairs and GC-rich regions of DNA. This is important because such regions of genomes are enriched in DNA regulatory elements. By using three different anthracycline antibiotics, namely doxorubicin (DOX), epirubicin (EPI) and daunorubicin (DAU), we could compare their detrimental effects on DNA. Despite their analogical structure, anthracyclines differ in their effects on DNA molecules and GC-rich region preference. DOX had the strongest overall effect on the DNA topology, causing the largest elongation and decrease in height. On the other hand, EPI has the lowest preference for GC-rich dsDNA. Moreover, we demonstrated that the nanoscale perturbations in dsDNA topology are reflected by changes in the microscale properties of the cell, as even short exposition to doxorubicin resulted in an increase in nuclei stiffness, which can be due to aberration of the chromatin organization, upon intercalation of doxorubicin molecules.
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Antraciclinas/química , Antibióticos Antineoplásicos/química , ADN de Cadena Simple/química , Núcleo Celular/genética , Simulación por Computador , Daunorrubicina/química , Doxorrubicina/química , Epirrubicina/química , Humanos , Sustancias Intercalantes/química , Microscopía de Fuerza Atómica , Simulación de Dinámica Molecular , Conformación de Ácido Nucleico , Pinzas ÓpticasRESUMEN
Introduction: Mixed-phenotype acute leukemia (MPAL) is a rare disease with poor prognosis. So far, no standard approach has been established as the "know-how" of MPAL is based only on retrospective analyses performed on small groups of patients. Materials and methods: In this study, a retrospective analysis of the outcomes of adult MPAL patients included in the PALG registry between 2005 and 2024 who received the CLAG-M hybrid protocol as induction or salvage therapy was performed. Results: Sixteen of 98 MPAL patients received CLAG-M: eight as first-line and eight as salvage therapy. In the first line, two patients achieved partial response (PR), and six achieved complete remission (CR), of whom four successfully underwent allogeneic hematopoietic stem cell transplantation (alloHSCT). Two patients who did not undergo alloHSCT promptly relapsed. Within the whole group, the overall response rate (ORR) was 75% (n = 12/16). With the median follow-up of 13 months, six out of eight patients remain in CR, however, two of them died due to acute graft versus host disease. Out of eight patients who received CLAG-M in the second line, four patients (50%) obtained CR. AlloHSCT was conducted in seven cases, six of which were in CR. Only two patients remained in CR at the time of the last follow-up. Tolerance to treatment was good. The median times for severe neutropenia and thrombocytopenia were 22 days (range, 16-24) and 17 days (range, 12-24), respectively. Overall, grade 3-4 infections were observed in 12 cases, and all infections presented successful outcomes. Conclusions: CLAG-M is an effective first-line salvage regimen for MPAL with an acceptable safety profile. Early achievement of CR with prompt alloHSCT allows for satisfactory disease control.
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BACKGROUND: Polycythemia vera (PV) patients are classified as high or low thrombotic risk based on age and prior history of thrombosis. Despite adherence to treatment recommendations, vascular events remain frequent, leading us to question whether thrombotic risk stratification could be improved. We previously reported an association between thrombotic events and mutations in DTA genes (DNMT3A, TET2, and ASXL1). The objective of this study was to confirm this observation in a larger series of PV patients. METHODS: PV patients with a minimum follow-up of 3 years were recruited from 8 European centers. Medical history was searched for thrombotic event recorded at any time and next-generation sequencing carried out with a myeloid panel. Multivariable logistic regression evaluated the impact of variables on thrombotic risk. Kaplan-Meier thrombosis-free survival curves were compared by the log rank test. Associations in the total cohort were confirmed in a case-control study to exclude selection bias. RESULTS: Of the 136 patients recruited, 74 (56.1%) had a thrombotic event, with an incidence density of 2.83/100 person-years. In multivariable analysis, DTA mutation was a risk factor for thrombotic event, being predictive for shorter thrombosis-free survival in the whole cohort (p = 0.007), as well as in low-risk patients (p = 0.039) and older patients (p = 0.009), but not for patients with a prediagnostic event. A gender- and age-matched case-control study confirmed the increased risk of thrombotic event for PV patients with a DTA mutation. CONCLUSION: Our results support the use of molecular testing at diagnosis to help predict which PV patients are at higher risk of developing thrombosis.
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ADN (Citosina-5-)-Metiltransferasas , ADN Metiltransferasa 3A , Proteínas de Unión al ADN , Dioxigenasas , Mutación , Policitemia Vera , Proteínas Proto-Oncogénicas , Proteínas Represoras , Trombosis , Humanos , Masculino , Femenino , Persona de Mediana Edad , Trombosis/genética , Factores de Riesgo , Anciano , Policitemia Vera/genética , Policitemia Vera/complicaciones , Proteínas Represoras/genética , Factores de Edad , Proteínas Proto-Oncogénicas/genética , ADN (Citosina-5-)-Metiltransferasas/genética , Proteínas de Unión al ADN/genética , Estudios de Casos y Controles , Adulto , Europa (Continente)/epidemiología , Incidencia , Predisposición Genética a la Enfermedad , Medición de Riesgo , Estimación de Kaplan-Meier , Anciano de 80 o más AñosRESUMEN
Balanced rearrangements involving the KMT2A gene (KMT2Ar) are recurrent genetic abnormalities in acute myeloid leukemia (AML), but there is lack of consensus regarding the prognostic impact of different fusion partners. Moreover, prognostic implications of gene mutations co-occurring with KMT2Ar are not established. From the HARMONY AML database 205 KMT2Ar adult patients were selected, 185 of whom had mutational information by a panel-based next-generation sequencing analysis. Overall survival (OS) was similar across the different translocations, including t(9;11)(p21.3;q23.3)/KMT2A::MLLT3 (p = 0.756). However, independent prognostic factors for OS in intensively treated patients were age >60 years (HR 2.1, p = 0.001), secondary AML (HR 2.2, p = 0.043), DNMT3A-mut (HR 2.1, p = 0.047) and KRAS-mut (HR 2.0, p = 0.005). In the subset of patients with de novo AML < 60 years, KRAS and TP53 were the prognostically most relevant mutated genes, as patients with a mutation of any of those two genes had a lower complete remission rate (50% vs 86%, p < 0.001) and inferior OS (median 7 vs 30 months, p < 0.001). Allogeneic hematopoietic stem cell transplantation in first complete remission was able to improve OS (p = 0.003). Our study highlights the importance of the mutational patterns in adult KMT2Ar AML and provides new insights into more accurate prognostic stratification of these patients.
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Apart from the driver mutations, high molecular risk (HMR) variants and other factors have been reported to influence the prognosis of primary myelofibrosis (PMF). The aim of our study was to investigate the impact of laboratory and molecular characteristics at the time of diagnosis (TOD) on the PMF outcome. The study group consisted of 82 patients recruited from three Polish university centers. Among the driver mutations, only CALR type 1 positively influenced the overall survival (OS). The risk of progression to accelerated or blastic disease phase (AP/BP) did not depend on the driver mutation type, but was closely associated with the presence of HMR variants (p = 0.0062). The risk of death (ROD) was higher in patients with HMR variants (OR[95%CI] = 4.33[1.52;12.34], p = 0.0044) and in patients with a platelet count at the TOD between 50-100 G/L (HR[95%CI] = 2.66[1.11;6.35]) and < 50 G/L (HR[95%CI] = 8.44[2.50;28.44]). Median survival time was 7.8, 2.2 and 1.4 years in patients with large unstained cells (LUC) count of [0.0-0.2], (0.2-0.4] and > 0.4 G/L at the TOD, respectively. We found an unexpected, hitherto undescribed, association between LUC count at the TOD and PMF prognosis. Our analysis led to the following conclusions: in PMF patients at the TOD 1) the presence of HMR variants, especially combined, is associated with an increased risk of progression to the AP and BP, and shorter OS, 2) severe thrombocytopenia confers worse prognosis than the moderate one, 3) LUC count is closely related with the disease phase, and associated with the ROD and OS.
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Mielofibrosis Primaria , Trombocitopenia , Humanos , Mielofibrosis Primaria/diagnóstico , Mielofibrosis Primaria/genética , Mutación , Pronóstico , Trombocitopenia/genética , Janus Quinasa 2/genéticaRESUMEN
Essential thrombocythemia (ET) and prefibrotic primary myelofibrosis (prePMF) initially have a similar phenotypic presentation with thrombocytosis. The aim of our study was to determine significant clinical-laboratory parameters at presentation to differentiate prePMF from ET as well as to develop and validate a predictive diagnostic prePMF model. This retrospective study included 464 patients divided into ET (289 pts) and prePMF (175 pts) groups. The model was built using data from a development cohort (229 pts; 143 ET, 86 prePMF), which was then tested in an internal validation cohort (235 pts; 146 ET, 89 prePMF). The most important prePMF predictors in the multivariate logistic model were age ≥ 60 years (RR = 2.2), splenomegaly (RR = 13.2), and increased lactat-dehidrogenase (RR = 2.8). Risk scores were assigned according to derived relative risk (RR) for age ≥ 60 years (1 point), splenomegaly (2 points), and increased lactat-dehidrogenase (1 point). Positive predictive value (PPV) for pre-PMF diagnosis with a score of ≥points was 69.8%, while for a score of ≥3 it was 88.2%. Diagnostic performance had similar values in the validation cohort. In MPN patients with thrombocytosis at presentation, the application of the new model enables differentiation of pre-PMF from ET, which is clinically relevant considering that these diseases have different prognoses and treatments.
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The goal of therapy in essential thrombocythemia (ET) is reducing thrombotic risk. No algorithm to predict hemorrhage risk exists. The impact ofanti-platelet, cytoreductive and anticoagulation therapies on risk of major bleeding (MB) was evaluated. MB events were retrospectively analyzed in 1381 ET from 10 European centers. There were 0.286 MB events/person-year. Neither the International Thrombosis Prognostic Score for thrombosis in essential thrombocythemia (IPSET-t) nor the revised IPSET-t (r-IPSET-t) was predictive for hemorrhage-free survival at 10 years (p = 0.092 vs p = 0.1). Ageand leukocyte count were MB risk factors, while low hemoglobin was protective. For ET with extreme thrombocytosis (ExtT) and leukocytosis cytoreduction was not protective. MB were more frequent in ET with ExtT who received anticoagulation. Antiplatelet therapy was not, while anticoagulation was a risk factor for MB (HR 3.05, p = 0.016, CI 1.23-7.56), in particular vitamin K antagonists (22.6% of those treated had a MB event, HR 2.96, p = 0.004, CI 1.41-6.22). Survival at 10 years was associated with hemorrhage (OR 2.54, p < 0.001) but not thrombosis (HR 0.95, p = 0.829). Hemorrhage has a higher risk of mortality than thrombosis. Improved risk stratification for MB is necessary. The choice of anticoagulation, cytoreduction and antiplatelet therapies is an important area of research in ET.
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Trombocitemia Esencial , Trombocitosis , Trombosis , Humanos , Trombocitemia Esencial/complicaciones , Trombocitemia Esencial/tratamiento farmacológico , Estudios Retrospectivos , Pronóstico , Trombosis/etiología , Hemorragia/etiología , Factores de Riesgo , Anticoagulantes/efectos adversos , Trombocitosis/etiologíaRESUMEN
INTRODUCTION: Ruxolitinib is widely used in myelofibrosis (MF). However, some patients do not optimally respond and require more efficacious treatment. Our analysis aimed to establish predictors of ruxolitinib response. PATIENTS AND METHODS: We designed a multicenter, retrospective analysis of the efficacy of ruxolitinib treatment in patients with MF in 15 Polish hematology centers. As responses to ruxolitinib occur within the first 6 months, we used this point to evaluate the efficacy of treatment. Symptoms response was defined as ≥50% reduction of the MF constitutional symptoms assessed by Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS). Spleen response was defined as ≥50% reduction of the difference between the spleen's baseline length and the upper limit norm measured by ultrasonography. RESULTS: 320 MF patients were enrolled. At 6 months of therapy, the spleen response was detected in 140 (50%) patients, and symptoms response in 241 patients (76%). Multivariable analysis identified leukocytosis <25 G/L (OR 2.06, 95%CI: 1.12-3.88, P = .0200), and reticulin fibrosis MF 1 (OR 2.22, 95%CI: 1.11-4.46, P = .0249) contributed to better spleen response. The time interval between MF diagnosis and ruxolitinib administration shorter than 3 months, and platelets ≥150 G/L (OR 1.69, 95% CI 1.01-2.83, P = .0466) influenced symptoms response. CONCLUSION: Establishing predictive factors for ruxolitinib response is particularly important given the potential for new therapies in MF. In patients with a low likelihood of responding to ruxolitinib, using other JAK inhibitors or adding a drug with a different mechanism of action to ruxolitinib may be of clinical benefit.
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Leucemia , Mielofibrosis Primaria , Humanos , Adulto , Mielofibrosis Primaria/diagnóstico , Mielofibrosis Primaria/tratamiento farmacológico , Estudios Retrospectivos , Polonia , Sistema de RegistrosRESUMEN
The safety profile of the novel oral JAK2/IRAK1 inhibitor pacritinib in patients with cytopenic myelofibrosis was described in the Phase 2 PAC203 and Phase 3 PERSIST-2 studies. To account for longer treatment durations on the pacritinib arms compared to best available therapy (BAT), we present a risk-adjusted safety analysis of event rates accounting for different time on treatment. While the rate of overall events was higher on pacritinib compared to BAT, the rate of fatal events was lower, and there was no excess in bleeding, cardiac events, secondary malignancy, or thrombosis on pacritinib, including in patients with severe thrombocytopenia.
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Myeloproliferative neoplasms (MPNs) are uncommon in children/young adults. Here, we present data on unselected patients diagnosed before 25 years of age included from 38 centers in 15 countries. Sequential patients were included. We identified 444 patients, with median follow-up 9.7 years (0-47.8). Forty-nine (11.1%) had a history of thrombosis at diagnosis, 49 new thrombotic events were recorded (1.16% patient per year [pt/y]), perihepatic vein thromboses were most frequent (47.6% venous events), and logistic regression identified JAK2V617F mutation (P = .016) and hyperviscosity symptoms (visual disturbances, dizziness, vertigo, headache) as risk factors (P = .040). New hemorrhagic events occurred in 44 patients (9.9%, 1.04% pt/y). Disease transformation occurred in 48 patients (10.9%, 1.13% pt/y), usually to myelofibrosis (7.5%) with splenomegaly as a novel risk factor for transformation in essential thrombocythemia (ET) (P= .000) in logistical regression. Eight deaths (1.8%) were recorded, 3 after allogeneic stem cell transplantation. Concerning conventional risk scores: International Prognostic Score for Essential Thrombocythemia-Thrombosis and new International Prognostic Score for Essential Thrombocythemia-Thrombosis differentiated ET patients in terms of thrombotic risk. Both scores identified high-risk patients with the same median thrombosis-free survival of 28.5 years. No contemporary scores were able to predict survival for young ET or polycythemia vera patients. Our data represents the largest real-world study of MPN patients age < 25 years at diagnosis. Rates of thrombotic events and transformation were higher than expected compared with the previous literature. Our study provides new and reliable information as a basis for prospective studies, trials, and development of harmonized international guidelines for the specific management of young patients with MPN.
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Trastornos Mieloproliferativos , Policitemia Vera , Mielofibrosis Primaria , Trombocitemia Esencial , Trombosis , Adulto , Niño , Humanos , Trastornos Mieloproliferativos/complicaciones , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/epidemiología , Policitemia Vera/complicaciones , Mielofibrosis Primaria/genética , Estudios Prospectivos , Trombosis/etiología , Adulto JovenRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection produces higher morbidity and mortality in hematological malignancies, but evidence in acute myeloid leukemia (AML) is scarce. A multicenter observational study was conducted to determine the clinical outcomes and assess the impact of therapeutic approaches in adult AML patients with SARS-CoV-2 infection in the first wave (March-May 2020). Overall, 108 patients were included: 51.9% with active leukemia and 70.4% under therapeutic schedules for AML. Signs and symptoms of SARS-CoV-2 were present in 96.3% of patients and 82.4% received specific treatment for SARS-CoV-2. The mortality rate was 43.5% and was correlated with age, gender, active leukemia, dyspnea, severe SARS-CoV-2, intensive care measures, neutrophil count, and D-dimer levels. A protective effect was found with azithromycin, lopinavir/ritonavir, and normal liver enzyme levels. During the SARS-CoV-2 first wave, our findings suggested an increased mortality in AML in a short period. SARS-CoV-2 management could be guided by risk factors in AML patients.
Asunto(s)
COVID-19 , Leucemia Mieloide Aguda , Adulto , Humanos , Leucemia Mieloide Aguda/epidemiología , Leucemia Mieloide Aguda/terapia , Lopinavir , Factores de Riesgo , SARS-CoV-2RESUMEN
In a multicenter European retrospective study including 162 patients with COVID-19 occurring in essential thrombocythemia (ET, n = 48), polycythemia vera (PV, n = 42), myelofibrosis (MF, n = 56), and prefibrotic myelofibrosis (pre-PMF, n = 16), 15 major thromboses (3 arterial and 12 venous) were registered in 14 patients, of whom all, but one, were receiving LMW-heparin prophylaxis. After adjustment for the competing risk of death, the cumulative incidence of arterial and venous thromboembolic events (VTE) reached 8.5% after 60 days follow-up. Of note, 8 of 12 VTE were seen in ET. Interestingly, at COVID-19 diagnosis, MPN patients had significantly lower platelet count (p < 0.0001) than in the pre-COVID last follow-up.This decline was remarkably higher in ET (-23.3%, p < 0.0001) than in PV (-16.4%, p = 0.1730) and was associated with higher mortality rate (p = 0.0010) for pneumonia. The effects of possible predictors of thrombosis, selected from those clinically relevant and statistically significant in univariate analysis, were examined in a multivariate model. Independent risk factors were transfer to ICU (SHR = 3.73, p = 0.029), neutrophil/lymphocyte ratio (SHR = 1.1, p = 0.001) and ET phenotype (SHR = 4.37, p = 0.006). The enhanced susceptibility to ET-associated VTE and the associated higher mortality for pneumonia may recognize a common biological plausibility and deserve to be delved to tailor new antithrombotic regimens including antiplatelet drugs.