RESUMEN
Lenalidomide (LEN) can induce red blood cell-transfusion independence (RBC-TI) in 60-70% of del(5q) myelodysplastic neoplasm (MDS) patients. Current recommendation is to continue LEN in responding patients until failure or progression, with likelihood of toxicity and a high cost for healthcare systems. This HARMONY Alliance study investigated the outcome of MDS del(5q) patients who discontinued LEN while RBC-transfusion independent. We enrolled 118 patients with IPSS-R low-intermediate risk. Seventy patients (59%) discontinued LEN for intolerance, 38 (32%) per their physician decision, nine (8%) per their own decision and one (1%) for unknown reasons. After a median follow-up of 49 months from discontinuation, 50/118 patients lost RBC-TI and 22/30 who underwent cytogenetic re-evaluation lost complete cytogenetic response. The median RBC-TI duration was 56 months. In multivariate analysis, RBC-TI duration after LEN discontinuation correlated with low transfusion burden before LEN therapy, treatment ≥ 12 LEN cycles, younger age and higher Hb level at LEN withdrawal. Forty-eight patients were re-treated with LEN for loss of response and 28 achieved again RBC-TI. These data show that stopping LEN therapy in MDS del(5q) patients who reached RBC-TI allows prolonged maintenance of TI in a large subset of patients.
RESUMEN
The management of chronic myeloid leukemia (CML) diagnosed during pregnancy is a rare and challenging situation. We report the treatment and outcome of 87 cases diagnosed in chronic phase from 2001-2022 derived from the largest international observational registry, supported by the European LeukemiaNet (ELN), of 400 pregnancies in 299 CML women. Normal childbirth occurred in 76% without an increased rate of birth abnormalities or life-threatening events, including in patients untreated or treated with interferon-α and/or imatinib in 2nd-3rd trimester. The low birth weight rate of 12% was comparable to that seen in the normal population. Elective and spontaneous abortions occurred in 21% and 3%, respectively. The complete hematologic response rate before labor was 95% with imatinib and 47% with interferon only. No disease progression during pregnancy was observed, 28% of the patients switched their therapy at varying times after delivery. Treatment options balance the efficacy and safety for mother and infant: interferon-α can commence in the 1st trimester and continued throughout in cases of good disease control and tolerability. Because of limited placental crossing, selected tyrosine kinase inhibitors (imatinib and nilotinib) seem to be safe and effective options in 2nd and 3rd trimester while hydroxycarbamide offers few benefits.
Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva , Leucemia Mieloide de Fase Crónica , Humanos , Femenino , Embarazo , Mesilato de Imatinib , Inhibidores de Proteínas Quinasas/efectos adversos , Placenta , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Resultado del TratamientoAsunto(s)
Janus Quinasa 2/genética , Mutación/genética , Mielofibrosis Primaria/genética , Mielofibrosis Primaria/patología , Trombocitemia Esencial/genética , Trombocitemia Esencial/patología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recuento de Plaquetas/métodosAsunto(s)
Inhibidores de las Cinasas Janus/efectos adversos , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias Primarias Secundarias/etiología , Mielofibrosis Primaria/complicaciones , Pirazoles/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores , Duración de la Terapia , Femenino , Humanos , Italia/epidemiología , Inhibidores de las Cinasas Janus/uso terapéutico , Masculino , Persona de Mediana Edad , Mutación , Tasa de Mutación , Neoplasias Primarias Secundarias/epidemiología , Nitrilos , Mielofibrosis Primaria/tratamiento farmacológico , Mielofibrosis Primaria/epidemiología , Mielofibrosis Primaria/etiología , Pirazoles/uso terapéutico , Pirimidinas , Adulto JovenRESUMEN
Myelofibrosis (MF) is a heterogeneous disorder characterized by splenomegaly, constitutional symptoms, ineffective hematopoiesis, and an increased risk of leukemic transformation. The ongoing research in understanding the pathophysiology of the disease has allowed for the development of targeted drugs optimizing patient management. Furthermore, disease prognostication has significantly improved. Current therapeutic interventions are only partially effective with only allogeneic stem cell transplant potentially curative. Ruxolitinib is the only approved therapy for MF by the US Food and Drug Administration. However, despite efficacy in reducing splenomegaly and controlling symptomatology, it is not associated with consistent molecular or pathologic responses. Drug discontinuation is associated with a dismal outcome. The therapeutic landscape in MF has significantly improved, and emerging drugs with different target pathways, alone or in combination with ruxolitinib, seem promising.
RESUMEN
Patients with myeloproliferative neoplasms (MPN) are known to have higher incidence of nonhematological second primary malignancies (SPM) compared to general population. In the MYSEC study on 781 secondary myelofibrosis (SMF) patients, the incidence of SPM after SMF diagnosis resulted 0.98/100 patient-years. When including non-melanoma skin cancers (NMSC), the incidence arose to 1.56/100 patient-years. In SMF, JAK inhibitor treatment was associated only with NMSC occurrence. Then, we merged the MYSEC cohort with a large dataset of PV and ET not evolving into SMF. In this subanalysis, we did not find any correlation between SPM and SMF occurrence. These findings highlight the need of studies aimed at identifying MPN patients at higher risk of SPM.
Asunto(s)
Neoplasias Primarias Secundarias/epidemiología , Policitemia Vera/epidemiología , Mielofibrosis Primaria/epidemiología , Neoplasias Cutáneas/epidemiología , Trombocitemia Esencial/epidemiología , Estudios de Cohortes , Femenino , Humanos , Incidencia , Inhibidores de las Cinasas Janus/uso terapéutico , Masculino , Neoplasias Primarias Secundarias/tratamiento farmacológico , Policitemia Vera/tratamiento farmacológico , Mielofibrosis Primaria/tratamiento farmacológico , Resultado del TratamientoAsunto(s)
Genotipo , Fenotipo , Policitemia Vera/diagnóstico , Policitemia Vera/genética , Mielofibrosis Primaria/diagnóstico , Mielofibrosis Primaria/genética , Trombocitemia Esencial/diagnóstico , Trombocitemia Esencial/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Policitemia Vera/mortalidad , Mielofibrosis Primaria/mortalidad , Pronóstico , Índice de Severidad de la Enfermedad , Factores Sexuales , Trombocitemia Esencial/mortalidadRESUMEN
PURPOSE OF REVIEW: The purpose of this review is to help doctors in the management of patients with post-polycythemia (PPV) and post-essential thrombocythemia (PET) myelofibrosis (MF) facing diagnostic criteria, prognostication, and treatment possibilities. RECENT FINDINGS: Diagnostic criteria of primary myelofibrosis (PMF) have been recently updated from the WHO classification. A clear-cut distinction between pre-fibrotic and overt PMF has been done. Concerning PPV and PET MF, the criteria come from 2008. Prognostication of PMF has been well established on clinical criteria, but recent molecular acquisitions will improve the strategy. For PPV and PET MF, the new MYSEC-PM is helpful for prediction of survival. JAK2-inhibitors and stem cell transplant are the two critical therapeutic approaches in myelofibrosis. Differences between PMF and SMF substantiate the efforts underway to adequately stratify SMF patients with ad hoc prognostic tools and to use such categorization to evaluate available treatment modalities.
Asunto(s)
Policitemia , Mielofibrosis Primaria , Trombocitemia Esencial , Humanos , Policitemia/sangre , Policitemia/complicaciones , Policitemia/diagnóstico , Policitemia/terapia , Mielofibrosis Primaria/sangre , Mielofibrosis Primaria/diagnóstico , Mielofibrosis Primaria/etiología , Mielofibrosis Primaria/terapia , Pronóstico , Trombocitemia Esencial/sangre , Trombocitemia Esencial/complicaciones , Trombocitemia Esencial/diagnóstico , Trombocitemia Esencial/terapiaAsunto(s)
Policitemia Vera/patología , Mielofibrosis Primaria/patología , Trombocitemia Esencial/patología , Progresión de la Enfermedad , Humanos , Fenotipo , Policitemia Vera/sangre , Policitemia Vera/complicaciones , Mielofibrosis Primaria/complicaciones , Estudios Retrospectivos , Trombocitemia Esencial/sangre , Trombocitemia Esencial/complicacionesAsunto(s)
Aberraciones Cromosómicas , Policitemia Vera/genética , Mielofibrosis Primaria/genética , Trombocitemia Esencial/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores , Biopsia , Médula Ósea/metabolismo , Médula Ósea/patología , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Policitemia Vera/mortalidad , Policitemia Vera/patología , Mielofibrosis Primaria/mortalidad , Mielofibrosis Primaria/patología , Pronóstico , Trombocitemia Esencial/mortalidad , Trombocitemia Esencial/patologíaRESUMEN
One-hundred Mayo Clinic patients with high/intermediate-risk myelofibrosis (MF) received momelotinib (MMB; JAK1/2 inhibitor) between 2009 and 2010, as part of a phase 1/2 trial (NCT00935987); 73% harbored JAK2 mutations, 16% CALR, 7% MPL, 44% ASXL1, and 18% SRSF2. As of July 2017, MMB was discontinued in 91% of the patients, after a median treatment duration of 1.4 years. Grade 3/4 toxicity included thrombocytopenia (34%) and liver/pancreatic test abnormalities (<10%); grade 1/2 peripheral neuropathy occurred in 47%. Clinical improvement (CI) occurred in 57% of patients, including 44% anemia and 43% spleen response. CI was more likely to occur in ASXL1-unmutated patients (66% vs 44%) and in those with <2% circulating blasts (66% vs 42%). Response was more durable in the presence of CALR type 1/like and absence of very high-risk karyotype. In multivariable analysis, absence of CALR type 1/like (HR 3.0; 95% CI 1.2-7.6) and presence of ASXL1 (HR 1.9; 95% CI 1.1-3.2) or SRSF2 (HR 2.4, 95% CI 1.3-4.5) mutations adversely affected survival. SRSF2 mutations (HR 4.7, 95% CI 1.3-16.9), very high-risk karyotype (HR 7.9, 95% CI 1.9-32.1), and circulating blasts ≥2% (HR 3.9, 95% CI 1.4-11.0) predicted leukemic transformation. Post-MMB survival (median 3.2 years) was not significantly different than that of a risk-matched MF cohort not receiving MMB.
Asunto(s)
Benzamidas/administración & dosificación , Mielofibrosis Primaria/tratamiento farmacológico , Mielofibrosis Primaria/mortalidad , Pirimidinas/administración & dosificación , Anciano , Benzamidas/efectos adversos , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Janus Quinasa 2/genética , Masculino , Persona de Mediana Edad , Mutación , Mielofibrosis Primaria/genética , Pirimidinas/efectos adversos , Tasa de SupervivenciaAsunto(s)
Mielofibrosis Primaria , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Humanos , Persona de Mediana Edad , Mielofibrosis Primaria/clasificación , Mielofibrosis Primaria/genética , Mielofibrosis Primaria/metabolismo , Mielofibrosis Primaria/mortalidad , Tasa de SupervivenciaAsunto(s)
Citogenética , Policitemia Vera/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Cariotipo , Masculino , Persona de Mediana Edad , Policitemia Vera/diagnóstico , Policitemia Vera/mortalidad , Pronóstico , Factores de Riesgo , Análisis de Supervivencia , Adulto JovenAsunto(s)
Leucocitosis/mortalidad , Monocitos/patología , Mielofibrosis Primaria/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mielofibrosis Primaria/patología , Mielofibrosis Primaria/terapia , Pronóstico , Trasplante de Células Madre/métodos , Trasplante de Células Madre/mortalidad , Trasplante Homólogo/métodos , Trasplante Homólogo/mortalidadRESUMEN
Based on suggestive information from recent epidemiologic data and earlier retrospective studies, we revisited the effect of gender on survival in 1,494 patients with essential thrombocythemia (ET). The primary study population included 904 patients from the Mayo Clinic (median age 58 years; 65% females); risk distribution, according to the international prognostic score for ET (IPSET), was 23% high, 42% intermediate and 35% low. Multivariable analysis that included IPSET-relevant risk factors identified male sex (HR 1.6, 95% CI 1.3-2.0), age ≥60 years (HR 4.3, 95% CI 3.4-5.4) and leukocyte count ≥11 × 10(9)/L (HR 1.5, 95% CI 1.3-1.9) as independent predictors of shortened survival. These findings were confirmed by analysis of a separate cohort of 590 ET patients (65% females) from the University of Florence, Italy, with corresponding HRs (95% CI) of 1.6 (1.1-2.5), 4.6 (2.2-9.5) and 1.8 (1.1-2.8). The independent prognostic effect of gender was further corroborated by a separate multivariable analysis against IPSET risk categories; HR (95% CI) for the Mayo Clinic/Florence cohorts were 1.5/1.6 (1.2/1.1-1.8/2.5) for male sex, 6.8/7.5 (5.0/3.1-9.3/18.3) for IPSET high risk and 2.8/4.1 (2.1/1.8-3.8/9.5) for IPSET intermediate risk. Furthermore, the survival disadvantage in men was most apparent in IPSET high risk category and in patients older than 60 years. In both patient cohorts, thrombosis history garnered significance in univariate, but not in multivariable analysis. The observations from the current study suggest that women with ET live longer than their male counterparts and that gender might supersede thrombosis history as a risk variable for overall survival.
Asunto(s)
Trombocitemia Esencial/mortalidad , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Vigilancia de la Población , Pronóstico , Factores de Riesgo , Factores Sexuales , Análisis de Supervivencia , Trombocitemia Esencial/diagnóstico , Trombocitemia Esencial/epidemiología , Trombocitemia Esencial/etiología , Adulto JovenRESUMEN
Monocytosis (absolute monocyte count, AMC ≥ 1 × 109 /L) might accompany a spectrum of myeloid neoplasms, other than chronic myelomonocytic leukemia (CMML). In the current study, we examined the prevalence, laboratory and molecular correlates, and prognostic relevance of monocytosis in polycythemia vera (PV). Among 267 consecutive patients with World Health Organization (WHO)-defined PV, 55 (21%) patients displayed an AMC of ≥1 × 109 /L and 18 (7%) an AMC of ≥1.5 × 109 /L. In general, PV patients with monocytosis were significantly older and displayed higher frequencies of leukocytosis (81% vs. 50% at AMC ≥1 × 109 /L) and TET2/SRSF2 mutations (57%/29% vs. 19%/1% at AMC ≥ 1.5 × 109 /L). In univariate analysis, AMC ≥1.5 × 109 /L adversely affected overall (OS; P = .004; HR 2.6, 95% CI 1.4-4.8) and myelofibrosis-free (MFFS; P = .02; HR 4.4, 95% CI 1.3-15.1) survival; during multivariable analysis, significance was borderline sustained for OS (P = .05) and MFFS (P = .06). Other independent risk factors for OS included unfavorable karyotype (P = .02, HR 3.39, 95% CI 1.17-9.79), older age (P < .0001, HR 3.34 95% CI 1.97-5.65), and leukocytosis ≥15 × 109 /L (P = .004, HR 2.04, 95% CI 1.26-3.29). In conclusion, in the current study, we encountered a higher than expected prevalence of monocytosis in patients with PV and the mutation profile and age distribution of PV patients with monocytosis is akin to those of patients with CMML and might partly contribute to their worse prognosis.
Asunto(s)
Leucocitosis/sangre , Monocitos/patología , Policitemia Vera/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Análisis Mutacional de ADN , Femenino , Humanos , Estimación de Kaplan-Meier , Cariotipificación , Recuento de Leucocitos , Leucocitosis/diagnóstico , Masculino , Persona de Mediana Edad , Mutación , Fenotipo , Policitemia Vera/diagnóstico , Policitemia Vera/genética , Policitemia Vera/mortalidad , Pronóstico , Adulto JovenRESUMEN
Atypical chronic myeloid leukemia (aCML) is an aggressive myeloid neoplasm with overlapping features of myelodysplastic syndromes (prominent granulocytic dysplasia) and myeloproliferative neoplasms (neutrophilic leukocytosis). We studied 25 molecularly-annotated and World Health Organization defined aCML patients; median age 70 years, 84% males. Cytogenetic abnormalities were seen in 36% and gene mutations in 100%. Mutational frequencies were, ASXL1 28%, TET2 16%, NRAS 16%, SETBP1 12%, RUNX1 12%, ETNK1 8%, and PTPN11 4%. Fifteen patients (60%) had >1 mutation, while 9 (36%) had ≥3. The median overall survival (OS) was 10.8 months and at last follow up (median 11 months), 17 (68%) deaths and 2 (8%) leukemic transformations were documented. On univariate analysis, survival was adversely impacted by advanced age (P = .02), low hemoglobin (P = .01), red blood cell transfusion dependence (P = .03), high white blood cell count (P = .02), TET2 (P = .03), NRAS (P = .04), PTPN11 (P = .02) mutations and the presence of ≥3 gene mutations (P = .006); ASXL1, SETBP1, and ETNK1 mutations did not impact OS. In multivariable analysis, advanced age (P = .003) [age >67: HR 10.1, 95% CI 1.3-119], low hemoglobin (P = .008) [HB< 10 gm/dL: HR 8.2, 95% CI 1.6-23.2] and TET2 mutations (P = .01) [HR 8.8, 95% CI 1.6-47.7] retained prognostic significance. We then used age >67 years, hemoglobin <10 gm/dL and the presence of TET2 mutations (each counted as one risk factor) to create a hazard ratio weighted prognostic model; effectively stratifying patients into two risk categories, low (0-1 risk factor) and high (≥2 risk factors), with median OS of 18 and 7 months, respectively.