RESUMO
We sought to appraise the value of overall response and salvage chemotherapy, inclusive of allogeneic hematopoietic stem cell transplant (AHSCT), in primary refractory acute myeloid leukemia (prAML). For establishing consistency in clinical practice, the 2017 European LeukemiaNet (ELN) defines prAML as failure to attain CR after at least 2 courses of intensive induction chemotherapy. Among 60 consecutive patients (median age 63 years) correspondent with ELN-criteria for prAML, salvage was documented in 48 cases, 30/48 (63%) being administered intensive chemotherapy regimens and 2/48 consolidated with AHSCT as first line salvage. 13/48 (27%) attained response: CR, 7/13 (54%), CRi, 2/13 (15%), MLFS, 4/13 (31%). The CR/CRi rate was 9/48 (19%), with CR rate of 7/48 (15%). On univariate analysis, intermediate-risk karyotype was the only predictor of response (44% vs 17% in unfavorable karyotype; P = 0.04). Administration of any higher-dose (>1 g/m2) cytarabine intensive induction (P = 0.50), intensive salvage chemotherapy (P = 0.72), targeted salvage (FLT3 or IDH inhibitors) (P = 0.42), greater than 1 salvage regimen (P = 0.89), age < 60 years (P = 0.30), and de novo AML (P = 0.10) did not enhance response achievement, nor a survival advantage. AHSCT was performed in 12 patients with (n = 8) or without (n = 4) CR/CRi/MLFS. 1/2/5-year overall survival (OS) rates were 63%/38%/33% in patients who received AHSCT (n = 12) vs 27%/0%/0% in those who achieved CR/CRi/MLFS but were not transplanted (n = 5), vs 14%/0%/0% who were neither transplanted nor achieved CR/CRi/MLFS (n = 43; P < 0.001); the median OS was 18.6, 12.6 and 5.6 months, respectively. Although CR/CRi/MLFS bridged to AHSCT (n = 8), appeared to manifest a longer median OS (20 months), vs (13.4 months) for those with no response consolidated with AHSCT (n = 4), the difference was not significant P = 0.47. We conclude AHSCT as indispensable for securing long-term survival in prAML (p = 0.03 on multivariate analysis), irrespective of response achievement.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Quimioterapia de Indução , Leucemia Mieloide Aguda/epidemiologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Terapia de Salvação , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
Current prognostic models for myelodysplastic syndromes (MDS), including the Revised International Prognostic Scoring System (IPSS-R), do not account for host immunity. We retrospectively examined the prognostic relevance of monocytopenia, lymphocytopenia and lymphocyte-to-monocyte ratio (LMR) in a cohort of 889 patients with primary MDS. After a median follow-up of 27 months, 712 (80%) deaths and 116 (13%) leukemic transformation were documented. In univariate analysis, subnormal absolute lymphocyte count (ALC) <0.9 × 109/l; P=0.001), ALC<1.2 × 109/l (P=0.0002), subnormal absolute monocyte count (AMC) <0.3 × 109/l (P=0.0003), LMR (P⩽0.0001) and LMR⩾5 (P=0.03) were all associated with inferior overall survival. In multivariable analysis that included other risk factors, significance was retained for LMR (P=0.02) and became borderline for ALC <1.2 × 109/l (P=0.06). Analysis in the context of IPSS-R resulted in P-values of 0.06 for ALC<1.2 × 109/l, 0.7 for monocytopenia and 0.2 for LMR. Leukemia-free survival was not affected by ALC, AMC or LMR. The observations from the current study suggest a possible detrimental role for altered host immunity in primary MDS, which might partly explain the therapeutic benefit of immune-directed therapy, including the use of immune modulators; however, IPSS-R-independent prognostic value for either ALC or AMC was limited.
Assuntos
Contagem de Leucócitos , Linfócitos , Linfopenia/sangue , Monócitos , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/metabolismo , Medula Óssea/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/epidemiologia , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Adulto JovemAssuntos
Antineoplásicos Alquilantes/uso terapêutico , Bussulfano/uso terapêutico , Transtornos Mieloproliferativos/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/patologia , Policitemia Vera/tratamento farmacológico , Policitemia Vera/patologia , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/patologia , Estudos Retrospectivos , Trombocitemia Essencial/tratamento farmacológico , Trombocitemia Essencial/patologia , Resultado do TratamentoAssuntos
Anemia/etiologia , Estudos de Associação Genética , Mutação , Proteínas Nucleares/genética , Mielofibrose Primária/complicações , Mielofibrose Primária/genética , Ribonucleoproteínas/genética , Anemia/diagnóstico , Humanos , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/mortalidade , Prognóstico , Fator de Processamento U2AFAssuntos
Anemia Refratária/complicações , Anemia Refratária/tratamento farmacológico , Anemia Sideroblástica/complicações , Anemia Sideroblástica/tratamento farmacológico , Indóis/uso terapêutico , Niacinamida/análogos & derivados , Trombocitose/complicações , Anemia Refratária/diagnóstico , Anemia Refratária/genética , Anemia Sideroblástica/diagnóstico , Anemia Sideroblástica/genética , Terapia Combinada , Humanos , Niacinamida/uso terapêutico , Oligonucleotídeos , Trombocitose/diagnósticoAssuntos
Benzamidas/uso terapêutico , Calreticulina/genética , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/genética , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Proteínas Repressoras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Esquema de Medicação , Feminino , Expressão Gênica , Marcadores Genéticos , Humanos , Janus Quinase 1/genética , Janus Quinase 2/genética , Masculino , Pessoa de Meia-Idade , Mutação , Mielofibrose Primária/mortalidade , Mielofibrose Primária/patologia , Prognóstico , Receptores de Trombopoetina/genética , Análise de SobrevidaAssuntos
Benzamidas/uso terapêutico , Mielofibrose Primária/terapia , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Feminino , Seguimentos , Humanos , Janus Quinase 2/imunologia , Masculino , Pessoa de Meia-Idade , Nitrilas , Mielofibrose Primária/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Indução de Remissão , Resultado do TratamentoRESUMO
JAK-STAT is a rational drug target in myelofibrosis (MF) given its association with JAK2/MPL mutations and aberrant inflammatory cytokine expression. We conducted a Phase 1/2 trial of CYT387, a potent JAK1/2 inhibitor, in patients with high- or intermediate-risk primary or post-polycythemia vera/essential thrombocythemia MF. Pre-planned safety and efficacy analysis has been completed for the initial 60 patients. In the dose-escalation phase (n=21), the maximum-tolerated dose was 300 mg/day based on reversible grade 3 headache and asymptomatic hyperlipasemia. Twenty-one and 18 additional patients were accrued at two biologically effective doses, 300 mg/day and 150 mg/day, respectively. Anemia and spleen responses, per International Working Group criteria, were 59% and 48%, respectively. Among 33 patients who were red cell-transfused in the month prior to study entry, 70% achieved a minimum 12-week period without transfusions (range 4.7->18.3 months). Most patients experienced constitutional symptoms improvement. Grade 3/4 adverse reactions included thrombocytopenia (32%), hyperlipasemia (5%), elevated liver transaminases (3%) and headache (3%). New-onset treatment-related peripheral neuropathy was observed in 22% of patients (sensory symptoms, grade 1). CYT387 is well tolerated and produces significant anemia, spleen and symptom responses in MF patients. Plasma cytokine and gene expression studies suggested a broad anticytokine drug effect.
Assuntos
Benzamidas/uso terapêutico , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Mielofibrose Primária/tratamento farmacológico , Pirimidinas/uso terapêutico , Idoso , Benzamidas/efeitos adversos , Benzamidas/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pirimidinas/efeitos adversos , Pirimidinas/farmacologiaAssuntos
Leucemia/etiologia , Leucemia/mortalidade , Modelos Estatísticos , Mielofibrose Primária/complicações , Mielofibrose Primária/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Seguimentos , Humanos , Agências Internacionais , Cariotipagem , Leucemia/terapia , Masculino , Pessoa de Meia-Idade , Mielofibrose Primária/terapia , Curva ROC , Fatores de Risco , Taxa de Sobrevida , Adulto JovemRESUMO
Recent studies suggest a powerful prognostic value for plasma cytokine levels in primary myelofibrosis (interleukin (IL)-2R, IL-8, IL-12, IL-15 and C-X-C motif chemokine 10 (CXCL10)) and large-cell lymphoma (IL-2R, IL-8, IL-10, IL-12, CXCL9 and CXCL10). To examine the possibility of a similar phenomenon in myelodysplastic syndromes (MDS), we used multiplex enzyme-linked immunosorbent assay to measure 30 plasma cytokines in 78 patients with primary MDS. Compared with normal controls (n = 35), the levels of 19 cytokines were significantly altered. Multivariable analysis identified increased levels of CXCL10 (P<0.01), IL-7 (P = 0.02) and IL-6 (P = 0.07) as predictors of shortened survival; the survival association remained significant when the Cox model was adjusted for the International Prognostic Scoring System, age, transfusion-need or thrombocytopenia. MDS patients with normal plasma levels of CXCL10, IL-7 and IL-6 lived significantly longer (median survival 76 months) than those with elevated levels of at least one of the three cytokines (median survival 25 months) (P<0.01). Increased levels of IL-6 were associated with inferior leukemia-free survival, independent of other prognostic factors (P = 0.01). Comparison of plasma cytokines between MDS (n = 78) and primary myelofibrosis (n = 127) revealed a significantly different pattern of abnormalities. These observations reinforce the concept of distinct and prognostically relevant plasma cytokine signatures in hematological malignancies.
Assuntos
Quimiocina CXCL10/sangue , Interleucina-6/sangue , Interleucina-7/sangue , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/sangue , Prognóstico , Modelos de Riscos ProporcionaisRESUMO
In a previous study, we reported on the safety and efficacy of low-dose (0.5 mg) pomalidomide and prednisone and pomalidomide alone (2 mg/day), for the treatment of anemia associated with myelofibrosis (MF). The current study examined the value of low-dose pomalidomide alone. The main eligibility criterion was transfusion-dependency or hemoglobin <10 gm per 100 ml. Anemia response was assessed by International Working Group criteria. Pomalidomide (0.5 mg/day) was given to 58 patients (median age 68 years); 46 (79%) were transfusion-dependent and 42 were JAK2V617F positive. Anemia response was documented only in the presence of JAK2V617F (24 vs 0%; P=0.03) but was not further affected by mutant allele burden (P=0.39); 9 of the 10 anemia responders became transfusion independent. Anemia response in JAK2V617F-positive patients was predicted by the presence of pomalidomide-induced basophilia in the first month of therapy (38 vs 6%; P=0.02) or absence of marked splenomegaly (38 vs 11%; P=0.05). A total of 14 (58%) of 24 patients with a platelet count of ≤ 100 × 10(9) cells/l experienced a >50% increment in platelet count. There were no spleen responses. Grade 3 or 4 thrombocytopenia/neutropenia occurred in 2%/0% of patients. Low-dose pomalidomide is effective in the treatment of anemia associated with JAK2V617F-positive MF; response is predicted by early drug-induced basophilia.
Assuntos
Anemia/tratamento farmacológico , Mielofibrose Primária/tratamento farmacológico , Talidomida/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Anemia/patologia , Anemia/terapia , Basófilos/patologia , Transfusão de Eritrócitos , Feminino , Humanos , Janus Quinase 2/genética , Masculino , Pessoa de Meia-Idade , Mutação , Mielofibrose Primária/patologia , Mielofibrose Primária/terapia , Talidomida/administração & dosagemRESUMO
We have previously identified sole +9, 13q- or 20q-, as 'favorable' and sole +8 or complex karyotype as 'unfavorable' cytogenetic abnormalities in primary myelofibrosis (PMF). In this study of 433 PMF patients, we describe additional sole abnormalities with favorable (chromosome 1 translocations/duplications) or unfavorable (-7/7q-) prognosis and also show that other sole or two abnormalities that do not include i(17q), -5/5q-, 12p-, inv(3) or 11q23 rearrangement are prognostically aligned with normal karyotype, which is prognostically favorable. These findings were incorporated into a refined two-tired cytogenetic-risk stratification: unfavorable and favorable karyotype. The respective 5-year survival rates were 8 and 51% (hazard ratio (HR): 3.1, 95% confidence interval (CI): 2.2-4.3; P<0.0001). Multivariable analysis confirmed the International Prognostic Scoring System (IPSS)-independent prognostic value of cytogenetic-risk categorization and also identified thrombocytopenia (platelets <100 × 10(9)/l) as another independent predictor of inferior survival (P<0.0001). A similar multivariable analysis showed that karyotype (P=0.001) and platelet count (P=0.04), but not IPSS (P=0.27), predicted leukemia-free survival; the 5-year leukemic transformation rates for unfavorable versus favorable karyotype were 46 and 7% (HR: 5.5, 95% CI: 2.5-12.0; P<0.0001). This study provides the rationale and necessary details for incorporating cytogenetic findings and platelet count in future prognostic models for PMF.