RESUMEN
With emerging new drugs in myelofibrosis (MF), a robust and harmonized framework for defining the severity of anemia and response to treatment will enhance clinical investigation and facilitate inter-study comparisons. Accordingly, the lead authors on the 2013 edition of the International Working Group-European LeukemiaNet (IWG-ELN) response criteria in MF were summoned to revise their document with the intent to i) account for gender-specific differences in determining hemoglobin levels for eligibility criteria, ii) revise definition of transfusion-dependent anemia (TDA) based on current restrictive transfusion practices, and iii) provide a structurally simple and easy to apply response criteria that are sensitive enough to detect efficacy signals (minor response) and also account for major responses. The initial draft of the 2024 IWG-ELN proposed criteria was subsequently circulated around a wider group of international experts and their feedback incorporated. The proposed articles include new definitions for TDA (≥3 units in the 12 weeks prior to study enrollment) and hemoglobin thresholds for eligibility criteria (<10 g/dL for women and <11 g/dL for men). The revised document also provides separate (TDA vs. non-TDA) and graded (major vs. minor response) response criteria while preserving the requirement for a 12-week period of screening and observation on treatment.
RESUMEN
Mastocytosis constitutes the neoplastic proliferation of mast cells and is broadly classified into systemic mastocytosis (SM), cutaneous mastocytosis and mast cell sarcoma. SM is further partitioned into advanced (AdvSM) and non-advanced (SM-non-Adv) subcategories. AdvSM includes aggressive SM (ASM), SM with an associated haematological neoplasm (SM-AHN) and mast cell leukaemia (MCL). In 2022, two separate expert committees representing the 5th edition of the World Health Organization (WHO5) and the International Consensus (ICC) classification systems submitted revised classification criteria for SM, highlighted by the ICC-proposed incorporation of mast cell cytomorphology in the diagnostic criteria for MCL and myeloid-lineage restriction for the AHN component in SM-AHN. Recent developments in SM also include the introduction of KIT-targeting tyrosine kinase inhibitors (KITi), including midostaurin and avapritinib, both drugs have shown potent activity in reducing mast cell and mutant KIT burden and alleviating mast cell-associated organopathy and mediator symptoms; however, their overall impact on survival or superiority over pre-KITi era treatment options (e.g. cladribine) has not been studied in a controlled setting. In the current review, we provide a summary of recent changes in disease classification and an analysis of recent clinical trials and their impact on our current treatment approach in AdvSM.
Asunto(s)
Leucemia de Mastocitos , Mastocitosis Sistémica , Mastocitosis , Humanos , Mastocitosis Sistémica/diagnóstico , Mastocitos/metabolismo , Leucemia de Mastocitos/tratamiento farmacológico , Cladribina/uso terapéutico , Mastocitosis/metabolismo , Proteínas Proto-Oncogénicas c-kit/metabolismoRESUMEN
Venetoclax (VEN) is an FDA-approved selective inhibitor of B-cell leukaemia/lymphoma-2 (BCL-2), used for treating elderly or unfit acute myeloid leukaemia (AML) patients unable to undergo intensive chemotherapy. Combining VEN with hypomethylating agents (HMAs) has shown impressive response rates in high-risk myelodysplastic syndromes (MDS) and relapsed/refractory AML. However, the efficacy of VEN and HMAs in treating DDX41-mutated (mDDX41) MDS/AML patients remains uncertain. Despite the favourable prognostic nature of mDDX41 MDS/AML patients, there is a lack of clinical experience regarding their response to different treatment regimens, leading to an unknown optimal therapeutic approach.
Asunto(s)
Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Humanos , Anciano , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/inducido químicamente , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/inducido químicamente , Compuestos Bicíclicos Heterocíclicos con Puentes , Sulfonamidas , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , ARN Helicasas DEAD-boxRESUMEN
Among 210 patients with myelodysplastic syndromes (MDSs) with del(5q), molecular information was available at diagnosis or at least 3 months before leukaemic transformation in 146 cases. Multivariate analysis identified therapy-related setting (p = 0.02; HR 2.3) and TP53 variant allele frequency (VAF) ≥22% (p < 0.01; HR 2.8), but not SF3B1 mutation (p = 0.65), as independent risk factors for survival. Median survival was 11.7 versus 4 years (5/10-year survival 73%/52% vs. 42%/14%) in the absence (N = 112) versus presence (N = 34) of ≥1 risk factors; leukaemia-free survival was affected by TP53 VAF ≥22% (p < 0.01). Such information might inform treatment decision-making in MDS-del(5q) regarding allogeneic stem cell transplant.
Asunto(s)
Síndromes Mielodisplásicos , Humanos , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/terapia , Síndromes Mielodisplásicos/diagnóstico , Frecuencia de los Genes , Mutación , Pronóstico , Deleción Cromosómica , Cromosomas Humanos Par 5/genética , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Among 301 newly diagnosed patients with acute myeloid leukaemia receiving venetoclax and a hypomethylating agent, 23 (7.6%) experienced major cardiac complications: 15 cardiomyopathy, 5 non-ST elevation myocardial infarction and/or 7 pericarditis/effusions. Four patients had more than one cardiac complication. Baseline characteristics included median age ± interquartile range; 73 ± 5 years; 87% males; 96% with cardiovascular risk factors; and 90% with preserved baseline ejection fraction. In multivariate analysis, males were more likely (p = 0.02) and DNMT3A-mutated cases less likely (p < 0.01) to be affected. Treatment-emergent cardiac events were associated with a trend towards lower composite remission rates (43% vs. 62%; p = 0.09) and shorter survival (median 7.7 vs. 13.2 months; p < 0.01). These observations were retrospectively retrieved and warrant further prospective examination.
Asunto(s)
Cardiomiopatías , Leucemia Mieloide Aguda , Sulfonamidas , Masculino , Humanos , Femenino , Estudios Retrospectivos , Resultado del Tratamiento , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Cardiomiopatías/etiología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
The revised 4th edition of the World Health Organization (WHO4R) classification lists myelodysplastic syndromes with ring sideroblasts (MDS-RS) as a separate entity with single lineage (MDS-RS-SLD) or multilineage (MDS-RS-MLD) dysplasia. The more recent International Consensus Classification (ICC) distinguishes between MDS with SF3B1 mutation (MDS-SF3B1) and MDS-RS without SF3B1 mutation; the latter is instead included under the category of MDS not otherwise specified. The current study includes 170 Mayo Clinic patients with WHO4R-defined MDS-RS, including MDS-RS-SLD (N=83) and MDS-RSMLD (N=87); a subset of 145 patients were also evaluable for the presence of SF3B1 and other mutations, including 126 with (87%) and 19 (13%) without SF3B1 mutation. Median overall survival for all 170 patients was 6.6 years with 5- and 10-year survival rates of 59% and 25%, respectively. A significant difference in overall survival was apparent between MDS-RS-MLD and MDS-RS-SLD (P<0.01) but not between MDS-RS with and without SF3B1 mutation (P=0.36). Multivariable analysis confirmed the independent prognostic contribution of MLD (hazard ratio=1.8, 95% confidence interval: 1.1-2.8; P=0.01) and also identified age (P<0.01), transfusion need at diagnosis (P<0.01), and abnormal karyotype (P<0.01), as additional risk factors; the impact from SF3B1 or other mutations was not significant. Leukemia-free survival was independently affected by abnormal karyotype (P<0.01), RUNX1 (P=0.02) and IDH1 (P=0.01) mutations, but not by MLD or SF3B1 mutation. Exclusion of patients not meeting ICC-criteria for MDS-SF3B1 did not change the observations on overall survival. MLD-based, as opposed to SF3B1 mutation-based, disease classification for MDS-RS might be prognostically more relevant.
Asunto(s)
Anemia Sideroblástica , Mutación , Síndromes Mielodisplásicos , Fosfoproteínas , Factores de Empalme de ARN , Humanos , Factores de Empalme de ARN/genética , Masculino , Femenino , Anciano , Persona de Mediana Edad , Pronóstico , Anciano de 80 o más Años , Adulto , Fosfoproteínas/genética , Anemia Sideroblástica/genética , Anemia Sideroblástica/diagnóstico , Anemia Sideroblástica/mortalidad , Anemia Sideroblástica/patología , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/patología , Ribonucleoproteína Nuclear Pequeña U2/genética , Linaje de la Célula , Adulto JovenRESUMEN
The primary objective of treatment in myelofibrosis (MF) is prolongation of life, which is currently accomplished only by allogeneic hematopoietic stem cell transplantation (AHSCT). Determination of optimal timing for AHSCT is facilitated by molecular risk stratification. Non-transplant treatment options in MF are palliative in scope and include Janus kinase 2 (JAK2) inhibitors (JAKi): momelotinib (FDA approved on September 15, 2023), ruxolitinib (November 16, 2011), fedratinib (August 16, 2019), and pacritinib (February 28, 2022); all four JAKi are effective in reducing spleen size and alleviating symptoms, considered a drug class effect and attributed to their canonical JAK-STAT inhibitory mechanism of action. In addition, momelotinib exhibits erythropoietic effect, attributed to alleviation of ineffective erythropoiesis through inhibition of activin A receptor type-I (ACVR1). In transplant-ineligible or deferred patients, the order of treatment preference is based on specific symptoms and individual assessment of risk tolerance. Because of drug-induced immunosuppression and other toxicities attributed to JAKi, we prefer non-JAKi drugs as initial treatment for MF-associated anemia that is not accompanied by treatment-requiring splenomegaly or constitutional symptoms. Otherwise, it is reasonable to consider momelotinib as the first-line JAKi treatment of choice, in order to target the triad of quality-of-life offenders in MF: anemia, splenomegaly, and constitutional symptoms/cachexia. For second-line therapy, we favor ruxolitinib, over fedratinib, based on toxicity profile. Pacritinib and fedratinib provide alternative options in the presence of severe thrombocytopenia or ruxolitinib-resistance/intolerance, respectively. Splenectomy remains a viable option for drug-resistant symptomatic splenomegaly and cytopenia.
Asunto(s)
Anemia , Benzamidas , Hidrocarburos Aromáticos con Puentes , Mielofibrosis Primaria , Pirazoles , Pirimidinas , Humanos , Mielofibrosis Primaria/diagnóstico , Esplenomegalia/tratamiento farmacológico , Esplenomegalia/etiología , Nitrilos/uso terapéutico , Anemia/complicaciones , Janus Quinasa 2 , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
Mastocytoma in a colon polyp positive for tryptase, CD117/KIT, S100, weakly positive for CD25.
Asunto(s)
Mastocitoma , Trastornos Mieloproliferativos , Humanos , Hallazgos Incidentales , Proteínas Proto-Oncogénicas c-kit/genética , ColonRESUMEN
Two-hundred pregnancies involving 100 women with essential thrombocythemia (ET) were accessed from Mayo Clinic databases (1990-2023). Median platelet count displayed a decline during pregnancy, nadiring at 48% of baseline, in the third trimester: 704-369 × 109/L. Live birth rate was 72%. Of 53 (27%) unintentional pregnancy losses, 48 (24%) occurred in the first trimester. Other fetal complications included preterm birth 3%, intrauterine growth retardation 3%, and stillbirth 1%. Maternal complications included major hemorrhage (7%), preeclampsia (6%), thrombosis (1%), and placental abruption (0.5%). Antepartum management included no specific therapy in 52 (26%), aspirin alone in 112 (56%), aspirin combined with cytoreductive drugs or systemic anticoagulants in 23 (12%), and other permutations in the remaining. Postpartum systemic anticoagulation was documented in 29 (15%) pregnancies. Unintentional first-trimester loss was predicted by prior fetal loss (43% vs. 18%; p < .01), diabetes mellitus (DM; 67% vs. 23%; p = .02), and absence of aspirin therapy (45% vs. 14%; p < .01); the salutary effect of aspirin therapy was independent of the other two risk factors and apparent in both high (presence of ≥1 risk factor; 33% vs. 61%; p = .07) and low (absence of both risk factors; 10% vs. 34%; p < .01) risk scenarios. The benefit of aspirin therapy, in preventing first-trimester loss, was significant in both JAK2-mutated (18% vs. 50%; p < .01) and CALR-mutated (8% vs. 43%; p < .01) cases. Aspirin use was also associated with a lower risk of venous thrombosis (0% vs. 3%; p = .03). By contrast, the use of systemic anticoagulation, antepartum or postpartum, did not influence fetal or maternal complication rates. CALR mutation and DM predicted maternal hemorrhage (13% vs. 4%; p = .05) and preeclampsia (33% vs. 5%; p = .03), respectively. The current study demonstrates the protective role of aspirin in preventing first-trimester loss in ET, independent of driver mutation status or other risk factors.
RESUMEN
The World Health Organization (WHO) classification system categorizes advanced systemic mastocytosis (SM-Adv) into aggressive SM (ASM), mast cell leukemia (MCL), and SM with associated hematological neoplasm (SM-AHN). By contrast, the International Consensus Classification (ICC) requires "immature" MC cytomorphology for the diagnosis of MCL and limits SM-AHN to myeloid neoplasms (SM-AMN). The current study includes 329 patients with SM-Adv (median age 65 years, range 18-88; males 58%): WHO subcategories SM-AHN (N = 212; 64%), ASM (N = 99; 30%), and MCL (N = 18; 6%); ICC subcategories SM-AMN (N = 190; 64%), ASM (N = 99; 33%), and MCL (N = 9; 3%); WHO-defined MCL with "mature" MC cytomorphology and SM-AHN associated with lymphoid neoplasms were operationally labeled as "MCL-mature" (N = 9) and SM-ALN (N = 22), respectively, and distinguished from ICC-defined MCL and SM-AMN. Multivariable analysis that included the Mayo alliance risk factors for survival in SM (age >60 years, anemia, thrombocytopenia, increased alkaline phosphatase) revealed more accurate survival prediction with the ICC versus WHO classification order: (i) survival was significantly worse with MCL-immature versus MCL-mature (hazard ratio [HR] 15; p < .01), (ii) prognostic distinction between MCL and SM-AHN/AMN was confirmed in the context of ICC (HR 9.3; p < .01) but not WHO classification order (p = .99), (iii) survival was similar between MCL-mature and SM-AMN (p = .18), and (iv) SM-AMN (HR 1.7; p < .01) but not SM-ALN (p = .37) was prognostically distinct from ASM. The current study provides evidence for the independent prognostic contribution of both the ICC system for SM-Adv and the Mayo alliance risk factors for survival in SM.
Asunto(s)
Neoplasias Hematológicas , Leucemia de Mastocitos , Mastocitosis Sistémica , Mastocitosis , Masculino , Humanos , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Mastocitosis Sistémica/diagnóstico , Pronóstico , Factores de Riesgo , Neoplasias Hematológicas/diagnóstico , Mastocitos , Mastocitosis/diagnósticoRESUMEN
Cytologic abnormalities of atypical mast cells in mastocytosis. The mature mast cells have oval-shaped nuclei, cytoplasmic hypogranulation and spindle-shaped cytology. or well-differentiated displaying a round nucleus with condensed chromatin, and abundant dense cytoplasmic granulations. Immature mast cells include promastocytes and metachromatic blast-like forms.
Asunto(s)
Leucemia de Mastocitos , Mastocitosis , Humanos , MastocitosRESUMEN
Venetoclax + hypomethylating agent (Ven-HMA) is currently the standard frontline therapy for older/unfit patients with newly diagnosed acute myeloid leukemia (ND-AML). Our objective in the current retrospective study of 301 adult patients (median age 73 years; 62% de novo) with ND-AML was to identify molecular predictors of treatment response to Ven-HMA and survival; European LeukemiaNet (ELN) genetic risk assignment was favorable 15%, intermediate 16%, and adverse 69%. Complete remission, with (CR) or without (CRi), count recovery, was documented in 182 (60%) patients. In multivariable analysis, inclusive of mutations only, "favorable" predictors of CR/CRi were NPM1 (86% vs. 56%), IDH2 (80% vs. 58%), and DDX41 (100% vs. 58%) and "unfavorable" TP53 (40% vs. 67%), FLT3-ITD (36% vs. 63%), and RUNX1 (44% vs. 64%) mutations; significance was sustained for each mutation after adjustment for age, karyotype, and therapy-related qualification. CR/CRi rates ranged from 36%, in the presence of unfavorable and absence of favorable mutation, to 91%, in the presence of favorable and absence of unfavorable mutation. At median follow-up of 8.5 months, 174 deaths and 41 allogeneic stem cell transplants (ASCT) were recorded. In multivariable analysis, risk factors for inferior survival included failure to achieve CR/CRi (HR 3.4, 95% CI 2.5-4.8), adverse karyotype (1.6, 1.1-2.6), TP53 mutation (1.6, 1.0-2.4), and absence of IDH2 mutation (2.2, 1.0-4.7); these risk factors were subsequently applied to construct an HR-weighted risk model that performed better than the ELN genetic risk model (AIC 1661 vs. 1750): low (n = 130; median survival 28.9 months), intermediate (n = 105; median 9.6 months), and high (n = 66; median 3.1 months; p < .001); survival in each risk category was significantly upgraded by ASCT. The current study identifies genotype signatures for predicting response and proposes a 3-tiered, CR/CRi-based, and genetics-enhanced survival model for AML patients receiving upfront therapy with Ven-HMA.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes , Leucemia Mieloide Aguda , Sulfonamidas , Adulto , Humanos , Anciano , Supervivencia sin Enfermedad , Estudios Retrospectivos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Genotipo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Overall survival and response rates of 270 patients with newly diagnosed acute myeloid leukemia receiving venetoclax (Ven) plus hypomethylating agent, stratified by Ven dosing schedule (Cycle 1 Ven 14 vs. 21 vs. 28 days).
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes , Leucemia Mieloide Aguda , Humanos , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Sulfonamidas/efectos adversos , Leucemia Mieloide Aguda/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Janus kinase (JAK) 2 inhibitors are now part of the therapeutic armamentarium for primary and secondary myelofibrosis (MF). Patients with MF endure shortened survival and poor quality of life. Allogeneic stem cell transplantation (ASCT) is currently the only treatment modality in MF with the potential to cure the disease or prolong survival. By contrast, current drug therapy in MF targets quality of life and does not modify the natural history of the disease. The discovery of JAK2 and other JAK-STAT activating mutations (i.e., CALR and MPL) in myeloproliferative neoplasms, including MF, has facilitated the development of several JAK inhibitors that are not necessarily specific to the oncogenic mutations themselves but have proven effective in countering JAK-STAT signaling, resulting in suppression of inflammatory cytokines and myeloproliferation. This non-specific activity resulted in clinically favorable effects on constitutional symptoms and splenomegaly and, consequently, approval by the Food and Drug Administration (FDA) of three small molecule JAK inhibitors: ruxolitinib, fedratinib, and pacritinib. A fourth JAK inhibitor, momelotinib, is poised for FDA approval soon and has been shown to provide additional benefit in alleviating transfusion-dependent anemia in MF. The salutary effect of momelotinib on anemia has been attributed to inhibition of activin A receptor, type 1 (ACVR1) and recent information suggests a similar effect from pacritinib. ACRV1 mediates SMAD2/3 signaling which contributes to upregulation of hepcidin production and iron-restricted erythropoiesis. Targeting ACRV1 raises therapeutic prospects in other myeloid neoplasms associated with ineffective erythropoiesis, such as myelodysplastic syndromes with ring sideroblasts or SF3B1 mutation, especially those with co-expression of a JAK2 mutation and thrombocytosis.
Asunto(s)
Anemia , Inhibidores de las Cinasas Janus , Trastornos Mieloproliferativos , Neoplasias , Mielofibrosis Primaria , Humanos , Mielofibrosis Primaria/tratamiento farmacológico , Mielofibrosis Primaria/genética , Mielofibrosis Primaria/diagnóstico , Inhibidores de las Cinasas Janus/uso terapéutico , Calidad de Vida , Janus Quinasa 2/metabolismo , Trastornos Mieloproliferativos/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Nitrilos/uso terapéutico , Anemia/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Receptores de Activinas Tipo I/uso terapéuticoRESUMEN
OVERVIEW: Systemic mastocytosis (SM) results from clonal proliferation of mast cells (MC) in extracutaneous organs. DIAGNOSIS: The major criterion is presence of multifocal MC clusters in the bone marrow and/or extracutaneous organs. Minor diagnostic criteria include elevated serum tryptase level, MC CD25/CD2/CD30 expression, and presence of activating KIT mutations. RISK STRATIFICATION: Establishing SM subtype as per the International Consensus Classification/World Health Organization classification systems is an important first step. Patients either have indolent/smoldering SM (ISM/SSM) or advanced SM, including aggressive SM (ASM), SM with associated myeloid neoplasm (SM-AMN), and mast cell leukemia. Identification of poor-risk mutations (i.e., ASXL1, RUNX1, SRSF2, NRAS) further refines the risk stratification. Several risk models are available to help assign prognosis in SM patients. MANAGEMENT: Treatment goals for ISM patients are primarily directed toward anaphylaxis prevention/symptom control/osteoporosis treatment. Patients with advanced SM frequently need MC cytoreductive therapy to reverse disease-related organ dysfunction. Tyrosine kinase inhibitors (TKI) (midostaurin, avapritinib) have changed the treatment landscape in SM. While deep biochemical, histological and molecular responses have been documented with avapritinib treatment, its efficacy as monotherapy against a multimutated AMN disease component in SM-AMN patients remains unclear. Cladribine continues to have a role for MC debulking, whereas interferon-α has a diminishing role in the TKI era. Treatment of SM-AMN primarily targets the AMN component, particularly if an aggressive disease such as acute leukemia is present. Allogeneic stem cell transplant has a role in such patients. Imatinib has a therapeutic role only in the rare patient with an imatinib-sensitive KIT mutation.
Asunto(s)
Leucemia de Mastocitos , Mastocitosis Sistémica , Humanos , Adulto , Mesilato de Imatinib , Mastocitos , Medición de RiesgoRESUMEN
We retrospectively reviewed 72 anemic patients with myelofibrosis (MF; median age 68 years), who were JAK2 inhibitor-naïve at the time of study entry to a phase-1/2 momelotinib clinical trial. Driver mutation profile included JAK2 69%, CALR 17%, MPL 8%, and triple-negative 6%; other mutations included ASXL1 39% and SRSF2 17%. Momelotinib was administered at a median dose of 300 mg daily. Anemia response was assessed by formal criteria and documented in 44% of all patients with hemoglobin levels below the sex-adjusted reference range (n = 72), 48% of those with hemoglobin <10 g/dl (n = 54), and 46% of those who were transfusion-dependent at the time of study entry (n = 28). Anemia response was more likely with post-essential thrombocythemia MF (83% vs 37%; p = .001), lower serum ferritin (p = .003), and shorter time from diagnosis to momelotinib therapy (p = .001); the first two variables were also predictive in transfusion-dependent patients. Post-momelotinib median survival was 3.2 years; in univariate analysis, survival was superior in anemia responders (median 3.8 vs. 2.8 years; p = .14) and in the presence of type 1/like CALR mutation and inferior in the presence of age > 65 years, ASXL1/SRSF2 mutation, unfavorable karyotype, DIPSS-plus high risk, red cell transfusion need and higher serum ferritin. Multivariable analysis confirmed the favorable impact of anemia response on survival (p = .02; HR 0.5, 3/5/10-year survival; 69%/38%/25%). This survival advantage was also noted in transfusion-dependent patients (3.7 vs. 1.9 years; p = .01; HR 0.3) and appeared to be restricted to patients with an unfavorable genetic profile. The current study suggests a short-term survival benefit associated with anemia response in momelotinib-treated patients with MF.
Asunto(s)
Anemia , Mielofibrosis Primaria , Humanos , Anciano , Mielofibrosis Primaria/tratamiento farmacológico , Mielofibrosis Primaria/genética , Mielofibrosis Primaria/diagnóstico , Estudios Retrospectivos , Mutación , Janus Quinasa 2/genética , Anemia/tratamiento farmacológico , Anemia/etiología , Ferritinas/genética , Calreticulina/genéticaRESUMEN
We examined the individual prognostic contribution of absolute neutrophil (ANC), lymphocyte (ALC), and monocyte (AMC) counts, on overall (OS), leukemia-free (LFS), and myelofibrosis-free (MFFS) survival in essential thrombocythemia (ET). Informative cases (N = 598; median age 59 years; females 62%) were retrospectively accrued from a Mayo Clinic database: JAK2 59%, CALR 27%, triple-negative 11%, and MPL 3%; international prognostic scoring system for ET (IPSET) risk high 21%, intermediate 42%, and low 37%; 7% (37/515) had abnormal karyotype and 10% (21/205) adverse mutations (SF3B1/SRSF2/U2AF1/TP53). At median 8.4 years, 163 (27%) deaths, 71 (12%) fibrotic, and 20 (3%) leukemic transformations were recorded. Multivariable analysis resulted in HR (95% CI) of 16.5 (9.9-27.4) for age > 70 years, 3.7 (2.3-6.0) for age 50-70 years, 2.4 (1.7-3.3) for ANC ≥8 × 109 /L, and 1.9 (1.4-2.6) for ALC <1.7 × 109 /L. The corresponding HR-based scores were 4, 2, 1, and 1, resulting in an new 4-tiered AgeAncAlc (AAA; triple A) risk model: high (5-6 points; median survival 8 years; HR 30.1, 95% CI 17.6-54), intermediate-2 (4 points; median 13.5 years; HR 12.7, 95% CI 7.1-23.0), intermediate-1 (2-3 points; median 20.7 years; HR 3.8, 95% CI 2.3-6.4) and low (0-1 points; median 47 years). The AAA model (Akaike Information Criterion [AIC] 621) performed better than IPSET (AIC 647) and was subsequently validated by an external University of Florence ET cohort (N = 485). None of the AAA variables predicted LFS while ALC <1.7 × 109 /L was associated with inferior MFFS (p = .01). Adverse mutations (p < .01) and karyotype (p < .01) displayed additional prognostic value without disqualifying the prognostic integrity of the AAA model. This study proposes a simple and globally applicable survival model for ET, which can be used as a platform for further molecular refinement. This study also suggests a potential role for immune-related biomarkers, as a prognostic tool in myeloproliferative neoplasms.
Asunto(s)
Trombocitemia Esencial , Femenino , Humanos , Persona de Mediana Edad , Anciano , Trombocitemia Esencial/genética , Neutrófilos , Estudios Retrospectivos , Recuento de Leucocitos , Pronóstico , Recuento de Linfocitos , Biomarcadores , MutaciónRESUMEN
We describe our single institution experience with cladribine therapy in 42 patients with systemic mastocytosis (SM): 22 advanced (adv-SM; median age 65 years, 68% males) and 20 indolent/smouldering SM (ISM/SSM; median age 56 years, 45% males); subcategories included eight aggressive, 13 associated with another haematological neoplasm, one mast cell leukaemia, 17 ISM and three SSM. Overall/major response rates were 77%/45% for adv-SM and 70%/60% for ISM/SSM, and median (range) duration of response 10 (4-75) and 46 (4-140) months respectively. A >50% reduction in bone marrow mast cell burden and serum tryptase level was documented in 63% and 67% of patients with adv-SM and 50% and 46% with ISM/SSM respectively. The presence of KIT proto-oncogene, receptor tyrosine kinase (KIT)D816V predicted response in adv-SM: 17 (90%) of 19 with and none of three without the mutation responded (P < 0·01). Treatment-emergent adverse events were mostly limited to transient cytopenias: Grade 3/4 neutropenia, thrombocytopenia, or lymphopenia occurred in 27%, 27% and 27% of patients with adv-SM, and 5%, 5% and 30% with ISM/SSM respectively. The present study provides practical information that might be considered when making treatment choices between cladribine and newer KIT-targeted therapies and identifies the absence of KITD816V as a potential marker of cladribine resistance in advanced SM; the latter observation needs confirmation in a larger study.
Asunto(s)
Antineoplásicos/uso terapéutico , Cladribina/uso terapéutico , Mastocitosis Sistémica/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacología , Niño , Cladribina/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estados Unidos , Adulto JovenRESUMEN
The classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) consist of myelofibrosis, polycythemia vera, and essential thrombocythemia and are a heterogeneous group of clonal blood disorders characterized by an overproduction of blood cells. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for MPN were developed as a result of meetings convened by a multidisciplinary panel with expertise in MPN, with the goal of providing recommendations for the management of MPN in adults. The Guidelines include recommendations for the diagnostic workup, risk stratification, treatment, and supportive care strategies for the management of myelofibrosis, polycythemia vera, and essential thrombocythemia. Assessment of symptoms at baseline and monitoring of symptom status during the course of treatment is recommended for all patients. This article focuses on the recommendations as outlined in the NCCN Guidelines for the diagnosis of MPN and the risk stratification, management, and supportive care relevant to MF.