RESUMO
NPM 1-mutated acute myeloid leukemia (AML) shows unique features. However, the characteristics of "therapy-related" NPM1-mutated AML (t-NPM1 AML) are poorly understood. We compared the genetics, transcriptional profile, and clinical outcomes of t-NPM1 AML, de novo NPM1-mutated AML (dn-NPM1 AML), and therapy-related AML (t-AML) with wild-type NPM1 (t-AML). Normal karyotype was more frequent in t-NPM1 AML (n = 78/96, 88%) and dn-NPM1 (n = 1986/2394, 88%) than in t-AML (n = 103/390, 28%; P < .001). DNMT3A and TET2 were mutated in 43% and 40% of t-NPM1 AML (n = 107), similar to dn-NPM1 (n = 88, 48% and 30%; P > 0.1), but more frequently than t-AML (n = 162; 14% and 10%; P < 0.001). Often mutated in t-AML, TP53 and PPM1D were wild-type in 97% and 96% of t-NPM1 AML, respectively. t-NPM1 and dn-NPM1 AML were transcriptionally similar, (including HOX genes upregulation). At 62 months of median follow-up, the 3-year overall survival (OS) for t-NPM1 AML (n = 96), dn-NPM1 AML (n = 2394), and t-AML (n = 390) were 54%, 60%, and 31%, respectively. In multivariable analysis, OS was similar for the NPM1-mutated groups (hazard ratio [HR] 0.9; 95% confidence interval [CI], 0.65-1.25; P = .45), but better in t-NPM1 AML than in t-AML (HR, 1.86; 95% CI, 1.30-2.68; P < .001). Relapse-free survival was similar between t-NPM1 and dn-NPM1 AML (HR, 1.02; 95% CI, 0.72-1.467; P = .90), but significantly higher in t-NPM1 AML versus t-AML (HR, 1.77; 95% CI, 1.19-2.64; P = .0045). t-NPM1 and dn-NPM1 AML have overlapping features, suggesting that they should be classified as a single disease entity.
Assuntos
Leucemia Mieloide Aguda , Proteínas Nucleares , Humanos , Proteínas Nucleares/genética , Nucleofosmina , Mutação , Prognóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapiaRESUMO
Very few data are available about hypomethylating agent (HMA) efficiency in core binding factor acute myeloid leukemias (CBF-AML). Our main objective was to evaluate the efficacy and safety of HMA in the specific subset of CBF-AML. Here, we report the results of a multicenter retrospective French study about efficacy of HMA monotherapy, used frontline or for R/R CBF-AML. Forty-nine patients were included, and received a median of 5 courses of azacitidine (n = 46) or decitabine (n = 3). ORR was 49% for the whole cohort with a median time to response of 112 days. After a median follow-up of 72.3 months, median OS for the total cohort was 10.6 months. In multivariate analysis, hematological relapse of CBF-AML at HMA initiation was significantly associated with a poorer OS (HR: 2.13; 95%CI: 1.04-4.36; p = 0.038). Responders had a significantly improved OS (1-year OS: 75%) compared to non-responders (1-year OS: 15.3%; p < 0.0001). Hematological improvement occurred for respectively 28%, 33% and 48% for patients who were red blood cell or platelet transfusion-dependent, or who experienced grade 3/4 neutropenia at HMA initiation. Adverse events were consistent with the known safety profile of HMA. Our study highlights that HMA is a well-tolerated therapeutic option with moderate clinical activity for R/R CBF-AML and for patients who cannot handle intensive chemotherapy.
Assuntos
Azacitidina , Leucemia Mieloide Aguda , Humanos , Estudos Retrospectivos , Decitabina/uso terapêutico , Azacitidina/efeitos adversos , Leucemia Mieloide Aguda/tratamento farmacológico , Fatores de Ligação ao Core , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resultado do TratamentoRESUMO
Venetoclax-azacitidine is the standard of treatment for unfit acute myeloid leukemia patients. In the VIALE-A study, treatment was given until progression but there are no data on its optimal duration for responding patients who do not tolerate indefinite therapy. We retrospectively analyzed the outcome of patients who discontinued venetoclax or venetoclax-azacitidine due to poor tolerance. Sixty-two newly diagnosed (ND) AML patients and 22 patients with morphological relapse or refractory AML were included. In the ND cohort (n = 62), 28 patients stopped venetoclax and azacitidine and 34 patients continued azacitidine monotherapy. With a median follow-up of 23 months (IQR, 20-32), median overall survival and treatment-free survival were 44 (IQR, 16-NR) and 16 (IQR, 8-27) months, respectively. Patients who stopped both treatments and those who continued azacitidine monotherapy had the same outcomes. Negative minimal residual disease was associated with a 2-year treatment-free survival of 80%. In the RR cohort (n = 22), median overall survival and treatment-free survival were 19 (IQR, 17-31) and 10 (IQR, 5-NR) months, respectively. Prior number of venetoclax-azacitidine cycles and IDH mutations were associated with increased overall survival. The only factor significantly impacting treatment-free survival was the number of prior cycles. This study suggests that patients who discontinued treatment in remission have favorable outcomes supporting the rationale for prospective controlled trials.
RESUMO
Harnessing or monitoring immune cells is actually a major topic in pre-clinical and clinical studies in acute myeloid leukemia (AML). Mucosal-Associated Invariant T cells (MAIT) constitute one of the largest subset of innate-like, cytotoxic T cell subsets in humans. Despite some papers suggesting a role for MAIT cells in cancer, their specific involvement remains unclear, especially in myeloid malignancies. This prospective monocentric study included 216 patients with a newly diagnosed AML. Circulating MAIT cells were quantified by flow cytometry at diagnosis and during intensive chemotherapy. We observed that circulating MAIT cells show a specific decline in AML patients at diagnosis compared to healthy donors. Post-induction monitored patients presented with a drastic drop in MAIT cell numbers, with recovery after one month. We also found correlation between decrease in MAIT cells number and adverse cytogenetic profile. FLT3-ITD and IDH ½ mutations were associated with higher MAIT cell numbers. Patients with high level of activated MAIT cells are under-represented within patients with a favorable cytogenetic profile, and over-represented among patients with IDH1 mutations or bi-allelic CEBPA mutations. We show for the first time that circulating MAIT cells are affected in newly diagnosed AML patients, suggesting a link between MAIT cells and AML progression. Our work fosters new studies to deepen our knowledge about the role of MAIT cells in cancer.
Assuntos
Leucemia Mieloide Aguda , Células T Invariantes Associadas à Mucosa , Análise Citogenética , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Mutação , Estudos ProspectivosRESUMO
OBJECTIVES: Complete responses have been observed in NPM1-mutated AML patients with dactinomycin, a nucleolar stress-inducing drug. Here, we report a single-center experience of compassionate use of dactinomycin in untreated or relapsed/ refractory NPM1-mutated AML. METHODS: From September 2015 to February 2019, 26 adult patients with NPM1-mutated AML received dactinomycin in different situations: front-line treatment in 4 unfit patients (16%); morphologic (n = 16, 62%), molecular relapses (n = 4, 16%), refractory disease (n = 1, 13%), or postremission therapy in second complete response (n = 1, 13%). RESULTS: Median age was 62.5 years. Median number of dactinomycin cycle was 1 (1-8), and 7 patients (27%) received more than 3 cycles. Three out of 17 patients (18%) in morphologic relapse or refractory to chemotherapy achieved complete remission after the first cycle of dactinomycin. None of the 4 patients unfit for intensive chemotherapy responded to dactinomycin as front-line therapy. Grade 3-4 adverse events were thrombocytopenia (n = 11, 42%), neutropenia (n = 11, 42%), GI toxicity (n = 6, 23%), mucositis (n = 5, 19%), lung infection (n = 5, 19%), and skin rash (n = 2, 7.6%). CONCLUSIONS: Dactinomycin is an inexpensive and easily available drug that may induce significant responses in few AML patients with NPM1 mutations with an acceptable safety profile.
Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Dactinomicina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação , Proteínas Nucleares/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/farmacologia , Biomarcadores Tumorais , Dactinomicina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Nucleofosmina , Prognóstico , Recidiva , Indução de Remissão , Retratamento , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Evidences support social inequalities in cancer survival. Studies on hematological malignancies, and more specifically Acute Myeloid Leukemia (AML), are sparser. Our study assessed: 1/ the influence of patients' socioeconomic position on survival, 2/ the role of treatment in this relationship, and 3/ the influence of patients' socioeconomic position on treatment utilization. METHODS: This prospective multicenter study includes all patients aged 60 and older, newly diagnosed with AML, excluding promyelocytic subtypes, between 1st January 2009 to 31st December 2014 in the South-West of France. Data came from medical files. Patients' socioeconomic position was measured by an ecological deprivation index, the European Deprivation Index. We studied first, patients' socioeconomic position influence on overall survival (n = 592), second, on the use of intensive chemotherapy (n = 592), and third, on the use of low intensive treatment versus best supportive care among patients judged unfit for intensive chemotherapy (n = 405). RESULTS: We found an influence of patients' socioeconomic position on survival (highest versus lowest position HRQ5: 1.39 [1.05;1.87] that was downsized to become no more significant after adjustment for AML ontogeny (HRQ5: 1.31[0.97;1.76] and cytogenetic prognosis HRQ5: 1.30[0.97;1.75]). The treatment was strongly associated with survival. A lower proportion of intensive chemotherapy was observed among patients with lowest socioeconomic position (ORQ5: 0.41[0.19;0.90]) which did not persist after adjustment for AML ontogeny (ORQ5: 0.59[0.25;1.40]). No such influence of patients' socioeconomic position was found on the treatment allocation among patients judged unfit for intensive chemotherapy. CONCLUSIONS: Finally, these results suggest an indirect influence of patients' socioeconomic position on survival through AML initial presentation.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sobreviventes de Câncer , Disparidades em Assistência à Saúde , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Aceitação pelo Paciente de Cuidados de Saúde , Fatores Socioeconômicos , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , França , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
OBJECTIVES: We previously reported the prognostic value of serum ferritin in younger patients with intermediate-risk acute myeloid leukemia (AML). The aims of this study were to confirm this finding in a larger cohort regardless of age and prognostic subgroups, to explore the expression and functional role of ferritin in AML cells as well as the regulation of serum ferritin levels in AML patients. PATIENTS/MATERIALS/METHODS: Serum ferritin levels at diagnosis were collected in a cohort of 525 patients treated by intensive chemotherapy. In silico, in vitro, and in vivo analyses were conducted to assess the pattern of expression and functional role of FTH1 and FTL in AML. RESULTS: We confirmed the independent prognostic value of serum ferritin. In transcriptomic databases, FTH1 and FTL were overexpressed in AML and leukemic stem cells compared to normal hematopoietic stem cells. The gene signature designed from AML patients overexpressing FTH1 revealed a significant enrichment in genes of the immune and inflammatory response including Nf-KB pathway, oxidative stress, or iron pathways. This gene signature was enriched in cytarabine-resistant AML cells in a patient-derived xenograft model. FTH1 protein was also overexpressed in patient's samples and correlated with the in vitro cytotoxic activity of cytarabine. Lastly, we demonstrated that chemotherapy induced an inflammatory response including a significant increase in serum ferritin levels between day 1 and 8 of induction chemotherapy that was blocked by dexamethasone. CONCLUSION: Ferritin is deregulated in most AML patients likely through inflammation, associated with chemoresistance, and could represent a new therapeutic target.
Assuntos
Apoferritinas/genética , Ferritinas/sangue , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/genética , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoferritinas/sangue , Biomarcadores , Terapia Combinada , Resistencia a Medicamentos Antineoplásicos , Feminino , Ferritinas/genética , Perfilação da Expressão Gênica , Humanos , Mediadores da Inflamação , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Oxirredutases , Prognóstico , Modelos de Riscos Proporcionais , Resultado do TratamentoRESUMO
Elderly patients with acute myeloid leukemia can be treated with intensive chemotherapy, low-intensity therapy such as low-dose aracytine or hypomethylating agents, or best supportive care. The choice between these treatments is a function of many patient-related and disease-related factors. We investigated how physicians' behavioral characteristics affect medical decision-making between intensive and non-intensive therapy in this setting. A nationwide cross-sectional online survey of hematologists collected data on medical decision-making for 6 clinical vignettes involving older acute myeloid leukemia patients that were representative of routine practice. Questionnaires elicited physicians' demographic and occupational characteristics along with their individual behavioral characteristics according to a decision theory framework. From the pattern of responses to the vignettes, a K-means clustering algorithm was used to distinguish those who were likely to prescribe more intensive therapy and those who were likely to prescribe less intensive or no therapy. Multivariate analyses were used to identify physician's characteristics predictive of medical decision-making. We obtained 230 assessable answers, which represented an adjusted response rate of 45.4%. A multivariate model (n=210) revealed that physicians averse to uncertainty recommend significantly more intensive chemotherapy: Odds Ratio (OR) [95% Confidence Interval (CI)]: 1.15 [1.01;1.30]; P=0.039. Male physicians who do not conform to the expected utility model (assumed as economically irrational) recommend more intensive chemotherapy [OR (95% CI) = 3.45 (1.34; 8.85); P=0.01]. Patient volume per physician also correlated with therapy intensity [OR (95% CI)=0.98 (0.96; 0.99); P=0.032]. The physicians' medical decision-making was not affected by their age, years of experience, or hospital facility. The significant association between medical decision and individual behavioral characteristics of the physician identifies a novel non-biological factor that may affect acute myeloid leukemia patients' outcomes and explain variations in clinical practice. It should also encourage the use of validated predictive models and the description of novel bio-markers to best select patients for intensive chemotherapy or low-intensity therapy.
Assuntos
Tomada de Decisão Clínica , Leucemia Mieloide/terapia , Médicos/estatística & dados numéricos , Inquéritos e Questionários , Incerteza , Doença Aguda , Idoso , Estudos Transversais , Feminino , Humanos , Leucemia Mieloide/diagnóstico , Masculino , Pessoa de Meia-Idade , Médicos/psicologiaRESUMO
Patients with acute myeloid leukemia and a high white blood cell count are at increased risk of early death and relapse. Because mediators of inflammation contribute to leukostasis and chemoresistance, dexamethasone added to chemotherapy could improve outcomes. This retrospective study evaluated the impact of adding or not adding dexamethasone to chemotherapy in a cohort of 160 patients with at least 50×109 white blood cells. In silico studies, primary samples, leukemic cell lines, and xenograft mouse models were used to explore the antileukemic activity of dexamethasone. There was no difference with respect to induction death rate, response, and infections between the 60 patients in the dexamethasone group and the 100 patients in the no dexamethasone group. Multivariate analysis showed that dexamethasone was significantly associated with improved relapse incidence (adjusted sub-HR: 0.30; 95% CI: 0.14-0.62; P=0.001), disease-free survival (adjusted HR: 0.50; 95% CI: 0.29-0.84; P=0.010), event-free survival (adjusted HR: 0.35; 95% CI: 0.21-0.58; P<0.001), and overall survival (adjusted HR: 0.41; 95% CI: 0.22-0.79; P=0.007). In a co-culture system, dexamethasone reduced the frequency of leukemic long-term culture initiating cells by 38% and enhanced the cytotoxicity of doxorubicin and cytarabine. In a patient-derived xenograft model treated with cytarabine, chemoresistant cells were enriched in genes of the inflammatory response modulated by dexamethasone. Dexamethasone also demonstrated antileukemic activity in NPM1-mutated samples. Dexamethasone may improve the outcome of acute myeloid leukemia patients receiving intensive chemotherapy. This effect could be due to the modulation of inflammatory chemoresistance pathways and to a specific activity in acute myeloid leukemia with NPM1 mutation.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Dexametasona/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Leucocitose/tratamento farmacológico , Leucocitose/patologia , Adolescente , Adulto , Idoso , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Resistencia a Medicamentos Antineoplásicos , Feminino , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucocitose/genética , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Nucleares/genética , Nucleofosmina , Prognóstico , Recidiva , Indução de Remissão , Resultado do Tratamento , Adulto JovemRESUMO
Although core-binding factor-acute myeloid leukemia (CBF-AML) (t[8;21] or inv[16]/t[16;16]) represents a favorable cytogenetic AML subgroup, 30% to 40% of these patients relapse after standard intensive chemotherapy. The encouraging results of gemtuzumab ozogamicin (GO) in newly diagnosed AML, and particularly in CBF-AML, incited us to retrospectively investigate the impact of GO-based salvage in these patients. We retrospectively analyzed the outcome of 145 patients with CBF-AML (59 t[8;21], 86 inv[16]/t[16;16]) in first relapse. As salvage, 48 patients received GO-based chemotherapy and 97 patients received conventional chemotherapy. Median age was 43 years (range, 16-76). Median first complete remission duration was 12.1 months (range, 2.1-93.6). Overall, second complete remission (CR2) rate was 88%. With a median follow-up from relapse of 3.5 years, the estimated 5-year disease-free survival (DFS) was 50% and 5-year overall survival (OS) was 51%. Older age and shorter first complete remission duration was associated with a shorter OS. Patients treated with GO had similar CR2 rate but significantly higher 5-year DFS (68% vs 42%; P = .05) and OS (65% vs 44%; P = .02). In multivariate analysis, GO salvage was still associated with a significant benefit in DFS and OS. In the 78 patients who received allogeneic hematopoietic stem cell transplantation in CR2, GO before transplant significantly improved posttransplant DFS and OS without excess of treatment-related mortality.
Assuntos
Inversão Cromossômica , Cromossomos Humanos/genética , Fatores de Ligação ao Core , Fatores de Crescimento de Células Hematopoéticas , Leucemia Mieloide Aguda , Adolescente , Adulto , Idoso , Aloenxertos , Intervalo Livre de Doença , Feminino , Seguimentos , França , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
We assessed the influence of obesity on the characteristics and prognosis of acute myeloid leukemia (AML). Indeed, safety of intensive chemotherapy and outcome of obese AML patients in a real-life setting are poorly described, and chemotherapy dosing remains challenging. We included 619 consecutive genetically-defined cases of AML treated with intensive chemotherapy between 2004 and 2012. In this cohort, 93 patients (15%) were classified in the obese category according to WHO classification; 59% of them received capped doses of chemotherapy because of a body surface area above 2 m(2) . Obese patients were older and presented more often with cardiovascular comorbidities. Although obese patients had more frequently de novo AML, main characteristics of AML including white blood cell count, karyotype and mutations were well-balanced between obese and non-obese patients. After induction chemotherapy, early death and complete remission rates were similar. Overall (OS), event-free (EFS) and disease-free (DFS) survival were not significantly different compared to non-obese patients. However, in the European LeukemiaNet (ELN) favorable subgroup, obese patients had lower median OS, EFS and DFS than non-obese patients (18.4, 16.8 and 17.2 vs. 43.6, 31.8 and 29.7 months, respectively) and obesity showed a significant impact on OS (OR 2.54; P = 0.02) in multivariate models. Although we did not find any significant impact of obesity on outcome in the whole series, this study suggests that special efforts for chemotherapy dose optimization are needed in the ELN favorable subgroup since dose capping may be deleterious.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Obesidade/complicações , Idoso , Índice de Massa Corporal , Superfície Corporal , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Quimioterapia de Indução , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Obesidade/mortalidade , Estudos Retrospectivos , Risco , Resultado do TratamentoAssuntos
Benzotiazóis/administração & dosagem , Leucemia Mieloide Aguda , Linfócitos , Linfocitose , Compostos de Fenilureia/administração & dosagem , Idoso , Humanos , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Linfócitos/metabolismo , Linfócitos/patologia , Linfocitose/sangue , Linfocitose/induzido quimicamente , Linfocitose/genética , Linfocitose/patologia , Masculino , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismoRESUMO
In acute myeloid leukemia (AML), new strategies assess the potential benefit of genetically targeted therapy at diagnosis. This implies waiting for laboratory tests and therefore a delay in initiation of chemotherapy. We studied the impact of time from diagnosis to treatment (TDT) on overall survival, early death, and response rate in a retrospective series of 599 newly diagnosed AML patients treated by induction chemotherapy between 2000 and 2009. The effect of TDT was assessed using multivariate analysis. TDT was analyzed as a continuous variable using a specific polynomial function to model the shape and form of the relationship. The median TDT was 8 days (interquartile range, 4-16) and was significantly longer in patients with a white blood cell count (WBC) <50 Giga per liter (G/L) (P < .0001) and in older patients (P = .0004). In multivariate analysis, TDT had no impact on overall survival (P = .4095) compared with age >60 years, secondary AML, WBC >50 G/L, European LeukemiaNet risk groups, and Eastern Cooperative Oncology Group performance status. Furthermore, TDT was not associated with response rate and early death. Thus, waiting a short period of time for laboratory tests to characterize leukemias better and design adapted therapeutic strategies at diagnosis seems possible.
Assuntos
Citarabina/uso terapêutico , Daunorrubicina/uso terapêutico , Idarubicina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Tempo para o Tratamento/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/uso terapêutico , Antimetabólitos Antineoplásicos/uso terapêutico , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Adulto JovemRESUMO
Hemophagocytic lymphohistiocytosis is a condition of immune dysregulation characterized by severe organ damage induced by a hyperinflammatory response and uncontrolled T-cell and macrophage activation. Secondary hemophagocytic lymphohistiocytosis typically occurs in association with severe infections or malignancies. Patients with acute myeloid leukemia may be prone to develop hemophagocytic lymphohistiocytosis because of an impaired immune response and a high susceptibility to severe infections. In a series of 343 patients treated by intensive chemotherapy over a 5-year period in our center, we identified 32 patients (9.3%) with fever, very high ferritin levels, and marrow hemophagocytosis (i.e. patients with hemophagocytic lymphohistiocytosis). Compared to patients without hemophagocytic lymphohistiocytosis, these 32 patients had hepatomegaly, pulmonary or neurological symptoms, liver abnormalities, lower platelet count and higher levels of C-reactive protein as well as prolonged pancytopenia. A microbial etiology for the hemophagocytosis was documented in 24 patients: 14 bacterial infections, 9 Herpesviridae infections and 11 fungal infections. The treatment of hemophagocytic lymphohistiocytosis consisted of corticosteroids and/or intravenous immunoglobulins along with adapted antimicrobial therapy. Patients with hemophagocytic lymphohistiocytosis had a median overall survival of 14.9 months, which was significantly shorter than that of patients without hemophagocytic lymphohistiocytosis (22.1 months) (P=0.0016). Hemophagocytic lymphohistiocytosis was significantly associated with a higher rate of induction failure, mainly due to deaths in aplasia. Hemophagocytic lymphohistiocytosis can be diagnosed in up to 10% of patients with acute myeloid leukemia undergoing intensive chemotherapy and is associated with early mortality. Fever, very high ferritin levels and marrow hemophagocytosis represent the cornerstone of the diagnosis. Further biological studies are needed to better characterize and recognize this syndrome in patients with acute myeloid leukemia.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/etiologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Medula Óssea/metabolismo , Medula Óssea/patologia , Feminino , Ferritinas/metabolismo , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Imunossupressores/uso terapêutico , Leucemia Mieloide Aguda/diagnóstico , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Early response to chemotherapy has a major prognostic impact in acute myeloid leukemia patients treated with a double induction strategy. Less is known about patients treated with standard-dose cytarabine and anthracycline. We designed a risk-adapted remission induction regimen in which a second course of intermediate-dose cytarabine was delivered after standard "7+3" only if patients had 5% or more bone marrow blasts 15 days after chemotherapy initiation (d15-blasts). Of 823 included patients, 795 (96.6%) were evaluable. Five hundred and forty-five patients (68.6%) had less than 5% d15-blasts. Predictive factors for high d15-blasts were white blood cell count (P<0.0001) and cytogenetic risk (P<0.0001). Patients with fewer than 5% d15-blasts had a higher complete response rate (91.7% vs. 69.2%; P<0.0001) and a lower induction death rate (1.8% vs. 6.8%; P=0.001). Five-year event-free (48.4% vs. 25%; P<0.0001), relapse-free (52.7% vs. 36.9%; P=0.0016) and overall survival (55.3% vs. 36.5%; P<0.0001) were significantly higher in patients with d15-blasts lower than 5%. Multivariate analyses identified d15-blasts and cytogenetic risk as independent prognostic factors for the three end points. Failure to achieve early blast clearance remains a poor prognostic factor even after early salvage. By contrast, early responding patients have a favorable outcome without any additional induction course. (ClinicalTrials.gov identifier NCT01015196).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea/patologia , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Adolescente , Adulto , Fatores Etários , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Aberrações Cromossômicas , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Indução de Remissão , Fatores de Tempo , Transplante Autólogo , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
We assessed in a French regional healthcare network the distribution of treatments, prognostic factors, and outcome of 334 newly diagnosed acute myeloid leukemia patients aged 60 years or older over a 4-year period of time (2007-2010). Patients were selected in daily practice for intensive chemotherapy (n = 115), azacitidine (n = 95), or best supportive care (n = 124). In these three groups, median overall survival was 18.9, 11.3, and 1.8 months, respectively. In the azacitidine group, multivariate analysis showed that overall survival was negatively impacted by higher age (P = 0.010 for one unit increase), unfavorable cytogenetics (P = 0.001), lymphocyte count <0.5 G/L (P = 0.015), and higher lactate dehydrogenase level (P = 0.005 for one unit increase). We compared the survival of patients treated by azacitidine versus intensive chemotherapy and best supportive care using time-dependent analysis and propensity score matching. Patients treated by intensive chemotherapy had a better overall survival compared with those treated by azacitidine from 6 months after diagnosis, whereas patients treated by azacitidine had a better overall survival compared with those treated by best supportive care from 1 day after diagnosis. This study of "real life" practice shows that there is a room for low intensive therapies such as azacitidine in selected elderly acute myeloid leukemia patients.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Azacitidina/uso terapêutico , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Cuidados Paliativos , Idoso , Idoso de 80 Anos ou mais , Feminino , França , Humanos , L-Lactato Desidrogenase , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Estudos Prospectivos , Programas Médicos Regionais , Análise de SobrevidaRESUMO
Adult T-cell acute lymphoblastic leukemia has a poor outcome after relapse. Because the subtype of early T-cell precursor displays characteristics close of those of acute myeloid leukemia, such as epigenetic dysregulation, hypomethylating agents might prove of interest. We describe the case of a patient relapsing 3 months only after allogeneic stem cell transplantation who achieved complete remission on azacitidine, and is still on therapy 9 years later. We discuss the biological background of this very long-term response, underlining the immunological effects of hypomethylating agents, and the perspectives opened by combination of hypomethylating agents with other drugs such as venetoclax.
RESUMO
We designed artificial intelligence-based prediction models (AIPM) using 52 diagnostic variables from 3687 patients included in the DATAML registry treated with intensive chemotherapy (IC, N = 3030) or azacitidine (AZA, N = 657) for an acute myeloid leukemia (AML). A neural network called multilayer perceptron (MLP) achieved a prediction accuracy for overall survival (OS) of 68.5% and 62.1% in the IC and AZA cohorts, respectively. The Boruta algorithm could select the most important variables for prediction without decreasing accuracy. Thirteen features were retained with this algorithm in the IC cohort: age, cytogenetic risk, white blood cells count, LDH, platelet count, albumin, MPO expression, mean corpuscular volume, CD117 expression, NPM1 mutation, AML status (de novo or secondary), multilineage dysplasia and ASXL1 mutation; and 7 variables in the AZA cohort: blood blasts, serum ferritin, CD56, LDH, hemoglobin, CD13 and disseminated intravascular coagulation (DIC). We believe that AIPM could help hematologists to deal with the huge amount of data available at diagnosis, enabling them to have an OS estimation and guide their treatment choice. Our registry-based AIPM could offer a large real-life dataset with original and exhaustive features and select a low number of diagnostic features with an equivalent accuracy of prediction, more appropriate to routine practice.