RESUMO
Myelodysplastic syndromes (MDS) are hematological malignancies classically defined by the presence of cytopenia(s) and dysmorphic myeloid cells. It is now known that MDS can be preceded by a pre-malignant condition called clonal cytopenia of unknown significance (CCUS), which associates a clonality marker with cytopenia in the absence of criteria of dysplasia. However, to date, it is not clear whether chromosomal abnormalities should be considered in the definition of CCUS or if they carry a prognostic impact in CCUS patients. In this study, we analyzed the clinico-biological features and outcomes of 34 patients who presented with one or more cytopenias, an absence of significant dysplasia, and a presence of a chromosomal abnormality (CA). We named this entity chromosomal abnormality with cytopenia of undetermined significance (CACtUS). We show that these patients are slightly older than MDS patients and that they more frequently presented with normocytic anemia. Most CACtUS patients exhibited only one unbalanced CA. The number and type of mutations were comparable between CACtUS patients and MDS patients. Regardless of the cytogenetic abnormality, the clinicobiological characteristics, overall survival, and risk of progression to high-risk (HR) MDS were similar between CACtUS patients and low-risk MDS patients. Thus, we suggest that CACtUS patients can be considered as HR-CCUS and should receive the follow-up regimen recommended for MDS patients.
Assuntos
Anemia , Transtornos Cromossômicos , Neoplasias Hematológicas , Síndromes Mielodisplásicas , Humanos , Aberrações Cromossômicas , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , MutaçãoRESUMO
Germline GATA2 mutations predispose to myeloid malignancies resulting from the progressive acquisition of additional somatic mutations. Here we describe clinical and biological features of 78 GATA2-deficient patients. Hematopoietic stem and progenitor cell phenotypic characterization revealed an exhaustion of myeloid progenitors. Somatic mutations in STAG2, ASXL1 and SETBP1 genes along with cytogenetic abnormalities (monosomy 7, trisomy 8, der(1;7)) occurred frequently in patients with GATA2 germline mutations. Patients were classified into three hematopoietic spectra based on bone marrow cytomorphology. No somatic additional mutations were detected in patients with normal bone marrow (spectrum 0), whereas clonal hematopoiesis mediated by STAG2 mutations was frequent in those with a hypocellular and/or myelodysplastic bone marrow without excess blasts (spectrum 1). Finally, SETBP1, RAS pathway and RUNX1 mutations were predominantly associated with leukemic transformation stage (spectrum 2), highlighting their implications in the transformation process. Specific somatic alterations, potentially providing distinct selective advantages to affected cells, are therefore associated with the clinical/hematological evolution of GATA2 syndrome. Our study not only suggests that somatic genetic profiling will help clinicians in their management of patients, but will also clarify the mechanism of leukemogenesis in the context of germline GATA2 mutations.
Assuntos
Deficiência de GATA2 , Transtornos Mieloproliferativos , Humanos , Deficiência de GATA2/diagnóstico , Deficiência de GATA2/genética , Transtornos Mieloproliferativos/genética , Mutação , Medula Óssea , Mutação em Linhagem Germinativa , Fator de Transcrição GATA2/genéticaRESUMO
Acute lymphoblastic leukemias (ALL) are characterized by a large number of cytogenetic abnormalities of clinical interest that require the use of several complementary techniques. Optical genome mapping (OGM) is based on analysis of ultra-high molecular weight DNA molecules that provides a high-resolution genome-wide analysis highlighting copy number and structural anomalies, including balanced translocations. We compared OGM to standard techniques (karyotyping, fluorescent in situ hybridization, single nucleotide polymorphism-array and reverse transcription multiplex ligation-dependent probe amplification) in 10 selected B or T-ALL. Eighty abnormalities were found using standard techniques of which 72 (90%) were correctly detected using OGM. Eight discrepancies were identified, while 12 additional anomalies were found by OGM. Among the discrepancies, four were detected in raw data but not retained because of filtering issues. However, four were truly missed, either because of a low variant allele frequency or because of a low coverage of some regions. Of the additional anomalies revealed by OGM, seven were confirmed by another technique, some of which are recurrent in ALL such as LMO2-TRA and MYC-TRB fusions. Despite false positive anomalies due to background noise and a case of inter-sample contamination secondarily identified, the OGM technology was relatively simple to use with little practice. Thus, OGM represents a promising alternative to cytogenetic techniques currently performed for ALL characterization. It enables a time and cost effective analysis allowing identification of complex cytogenetic events, including those currently inaccessible to standard techniques.
Assuntos
Biomarcadores Tumorais/metabolismo , Variações do Número de Cópias de DNA , Regulação Neoplásica da Expressão Gênica , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocação Genética , Adolescente , Adulto , Biomarcadores Tumorais/genética , Criança , Pré-Escolar , Mapeamento Cromossômico , Análise Citogenética , Feminino , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Adulto JovemRESUMO
A translocation involving the cyclin-dependent kinase 6 (CDK6) gene [t(CDK6)] is a rare but recurrent abnormality in B-cell neoplasms. To further characterise this aberration, we studied 57 cases; the largest series reported to date. Fluorescence in situ hybridisation analysis confirmed the involvement of CDK6 in all cases, including t(2;7)(p11;q21) immunoglobulin kappa locus (IGK)/CDK6 (n = 51), t(7;14)(q21;q32) CDK6/immunoglobulin heavy locus (IGH) (n = 2) and the previously undescribed t(7;14)(q21;q11) CDK6/T-cell receptor alpha locus (TRA)/T-cell receptor delta locus (TRD) (n = 4). In total, 10 patients were diagnosed with chronic lymphocytic leukaemia, monoclonal B-cell lymphocytosis or small lymphocytic lymphoma, and 47 had small B-cell lymphoma (SmBL) including 36 cases of marginal zone lymphoma (MZL; 34 splenic MZLs, one nodal MZL and one bronchus-associated lymphoid tissue lymphoma). In all, 18 of the 26 cytologically reviewed cases of MZL (69%) had an atypical aspect with prolymphocytic cells. Among the 47 patients with MZL/SmBL, CD5 expression was found in 26 (55%) and the tumour protein p53 (TP53) deletion in 22 (47%). The TP53 gene was mutated in 10/30 (33%); the 7q deletion was detected in only one case, and no Notch receptor 2 (NOTCH2) mutations were found. Immunoglobulin heavy-chain variable-region (IGHV) locus sequencing revealed that none harboured an IGHV1-02*04 gene. Overall survival was 82% at 10 years and not influenced by TP53 aberration. Our present findings suggest that most t(CDK6)+ neoplasms correspond to a particular subgroup of indolent marginal zone B-cell lymphomas with distinctive features.
Assuntos
Antígenos CD5/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Leucemia Linfocítica Crônica de Células B/metabolismo , Linfoma de Zona Marginal Tipo Células B/metabolismo , Neoplasias Esplênicas/patologia , Proteína Supressora de Tumor p53/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Brônquicas/diagnóstico , Neoplasias Brônquicas/metabolismo , Diferenciação Celular , Aberrações Cromossômicas , Feminino , Genes p53/genética , Humanos , Cadeias Pesadas de Imunoglobulinas/metabolismo , Hibridização in Situ Fluorescente/métodos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Análise de Sobrevida , Estruturas Linfoides Terciárias/patologia , Translocação Genética/genética , Trissomia/genéticaRESUMO
In this randomized phase 3 study, the FILO group tested whether the addition of 6 mg/m2 of gemtuzumab ozogamycin (GO) to standard chemotherapy could improve outcome of younger patients with de novo acute myeloid leukemia (AML) and intermediate-risk cytogenetics. GO arm was prematurely closed after 254 inclusions because of toxicity. A similar complete remission rate was observed in both arms. Neither event-free survival nor overall survival were improved by GO in younger AML patients (<60 years) ineligible for allogeneic stem-cell transplantation. (P = .086; P = .149, respectively). Using unsupervised hierarchical clustering based on mutational analysis of seven genes (NPM1, FLT3-ITD, CEBPA, DNMT3A, IDH1, IDH2, and ASXL1), six clusters of patients with significant different outcome were identified. Five clusters were based on FLT3-ITD, NPM1, and CEBPA mutations as well as epigenetic modifiers (DNMT3A, IDH1/2, ASXL1), whereas the last cluster, representing 25% of patients, had no mutation and intermediate risk. One cluster isolated FLT3-ITD mutations with higher allelic ratio and a very poor outcome. The addition of GO had no impact in these molecular clusters. Although not conclusive for GO impact in AML patients <60 years, this study provides a molecular classification that distinguishes six AML clusters influencing prognosis in younger AML patients with intermediate-risk cytogenetic.
Assuntos
Gemtuzumab/farmacologia , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Adolescente , Adulto , Análise por Conglomerados , Análise Citogenética , Citogenética , Análise Mutacional de DNA , Intervalo Livre de Doença , Feminino , Perfilação da Expressão Gênica , Transplante de Células-Tronco Hematopoéticas , Humanos , Cariotipagem , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Indução de Remissão , Risco , Adulto JovemRESUMO
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
Clonal chromosome abnormalities in Philadelphia-negative cells could concern chronic myeloid leukemia patients treated by tyrosine kinase inhibitors. The European LeukemiaNet distinguishes -7/del(7q) abnormalities as a "warning". However, the impact of clonal chromosome abnormalities, and specifically those of -7/del(7q), in Philadelphia-negative cells on clinical outcomes is unclear and based on case-reports showing morphological dysplasia and increased risk of acute myeloid leukemia, suggesting the coexistence of chronic myeloid leukemia and high-risk myelodysplastic syndrome. The aim of this study was to determine whether the impact of -7/del(7q) clonal chromosome abnormalities in Philadelphia-negative cells on the clinical outcome is different from that of other types of abnormalities, and we argue for an underlying associated high-risk myelodysplastic syndrome. Among 102 chronic myeloid leukemia patients with clonal chromosome abnormalities in Philadelphia-negative cells with more than a median of 6 years of follow up, patients with -7/del(7q) more frequently had signs of dysplasia, a lower cumulative incidence of deep molecular response and often needed further treatment lines, with the consequent impact on event-free and progression-free survival. Morphological features of dysplasia are associated with myelodysplastic syndrome/acute myeloid leukemia mutations and compromise the optimal response to tyrosine kinase inhibitors, irrespectively of the type of clonal chromosome abnormalities in Philadelphia-negative cells. However, mutation patterns determined by next-generation sequencing could not clearly explain the underlying high-risk disease. We hereby confirm the pejorative prognostic value of -7/del(7q) clonal chromosome abnormalities in Philadelphia-negative cells and suggest that myelodysplastic features constitute a warning signal that response to tyrosine kinase inhibitors may be less than optimal.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 7 , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/etiologia , Metáfase/genética , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Alelos , Deleção Cromossômica , Progressão da Doença , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hibridização in Situ Fluorescente , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Mutação , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/terapia , Prognóstico , Análise de SobrevidaRESUMO
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive leukemia for which knowledge on disease mechanisms and effective therapies are currently lacking. Only a handful of recurring genetic mutations have been identified and none is specific to BPDCN. In this study, through molecular cloning in an index case that presented a balanced t(3;5)(q21;q31) and molecular cytogenetic analyses in a further 46 cases, we identify monoallelic deletion of NR3C1 (5q31), encoding the glucocorticoid receptor (GCR), in 13 of 47 (28%) BPDCN patients. Targeted deep sequencing in 36 BPDCN cases, including 10 with NR3C1 deletion, did not reveal NR3C1 point mutations or indels. Haploinsufficiency for NR3C1 defined a subset of BPDCN with lowered GCR expression and extremely poor overall survival (P = .0006). Consistent with a role for GCR in tumor suppression, functional analyses coupled with gene expression profiling identified corticoresistance and loss-of-EZH2 function as major downstream consequences of NR3C1 deletion in BPDCN. Subsequently, more detailed analyses of the t(3;5)(q21;q31) revealed fusion of NR3C1 to a long noncoding RNA (lncRNA) gene (lincRNA-3q) that encodes a novel, nuclear, noncoding RNA involved in the regulation of leukemia stem cell programs and G1/S transition, via E2F. Overexpression of lincRNA-3q was a consistent feature of malignant cells and could be abrogated by bromodomain and extraterminal domain (BET) protein inhibition. Taken together, this work points to NR3C1 as a haploinsufficient tumor suppressor in a subset of BPDCN and identifies BET inhibition, acting at least partially via lncRNA blockade, as a novel treatment option in BPDCN.
Assuntos
Células Dendríticas/patologia , Haploinsuficiência , Leucemia/genética , Receptores de Glucocorticoides/genética , Neoplasias Cutâneas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Células Dendríticas/metabolismo , Regulação Leucêmica da Expressão Gênica , Humanos , Leucemia/patologia , Pessoa de Meia-Idade , Invasividade Neoplásica , RNA Longo não Codificante/genética , Receptores de Glucocorticoides/química , Neoplasias Cutâneas/patologia , Células Tumorais Cultivadas , Adulto JovemRESUMO
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
Optimal treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare entity of dismal prognosis previously described as CD4+/CD56+ hematodermic malignancies, is not defined. We report five cases of relapsed BPDCN treated with bendamustine hydrochloride, a well-tolerated bifunctional drug acting as an alkylating and antimetabolite agent. All patients were above the age of 50 years and in advanced disease (early first relapse in two, subsequent relapse in three; multi-organ involvement in four; previous intensive chemotherapy in five; and stem cell transplantation in four). Four patients were evaluable for response. Two failed therapy, one died from tumor lysis syndrome after rapid blast clearance from blood, and one reached and maintained complete remission for 7 months. Bendamustine should be further evaluated in BPDCN. Copyright © 2015 John Wiley & Sons, Ltd.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Cloridrato de Bendamustina/uso terapêutico , Células Dendríticas/patologia , Neoplasias Hematológicas/tratamento farmacológico , Idoso , Crise Blástica , Neoplasias Hematológicas/patologia , Humanos , Masculino , Pessoa de Meia-Idade , RecidivaRESUMO
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 TratamentoRESUMO
Not all patients with core binding factor acute myeloid leukemia (CBF-AML) display a good outcome. Modern risk factors include KIT and/or FLT3 gene mutations and minimal residual disease (MRD) levels, but their respective values have never been prospectively assessed. A total of 198 CBF-AML patients were randomized between a reinforced and a standard induction course, followed by 3 high-dose cytarabine consolidation courses. MRD levels were monitored prospectively. Gene mutations were screened at diagnosis. Despite a more rapid MRD decrease after reinforced induction, induction arm did not influence relapse-free survival (RFS) (64% in both arms; P = .91). Higher WBC, KIT, and/or FLT3-ITD/TKD gene mutations, and a less than 3-log MRD reduction after first consolidation, were associated with a higher specific hazard of relapse, but MRD remained the sole prognostic factor in multivariate analysis. At 36 months, cumulative incidence of relapse and RFS were 22% vs 54% (P < .001) and 73% vs 44% (P < .001) in patients who achieved 3-log MRD reduction vs the others. These results suggest that MRD, rather than gene mutations, should be used for future treatment stratifications in CBF-AML patients. This trial was registered at EudraCT as #2006-005163-26 and at www.clinicaltrials.gov as #NCT 00428558.
Assuntos
Fatores de Ligação ao Core/genética , Genes Neoplásicos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Mutação , Adolescente , Adulto , Antimetabólitos Antineoplásicos/administração & dosagem , Citarabina/administração & dosagem , Análise Mutacional de DNA , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Genes Neoplásicos/genética , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Mutação/fisiologia , Neoplasia Residual , Prognóstico , Estudos Prospectivos , Resultado do Tratamento , Adulto JovemRESUMO
The aim of our study was to analyze the factors contributing to heterogeneity of prognosis in patients with hyperdiploidy>50 chromosomes (HD>50), a group of B-cell precursor acute lymphoblastic leukemia with favorable outcome. The 541 HD>50 patients registered prospectively in the 58951 European Organisation for Research and Treatment of Cancer (EORTC) Children's Leukemia Group (CLG) trial, identified by karyotype (446 patients) and by DNA index (DI) (490 patients), had a 6-year event-free survival (EFS) of 89.0% (standard error [SE] = 1.5%) and a 6-year overall survival (OS) of 95.9% (SE = 0.9%). The strongest prognostic factor was the modal number of chromosomes (MNC): the 6-year EFS of 51-53, 54-57, and 58-66 MNC groups were 80%, 89%, and 99%, respectively (P < .0001). Ploidy assessed by DI was also a favorable factor: the higher the DI, the better the outcome. The 6-year EFS of the 3 subgroups of DI < 1.16/≥1.16-<1.24/≥1.24 were 83%, 90%, and 95%, respectively (P = .009). All usual combinations of trisomies (chromosomes 4, 10, 17, 18) were significant favorable factors but had lower EFS when MNC was lower than 58. In multivariate analysis, MNC remained the strongest factor. Consequently, the best indicator for excellent outcome was ploidy assessed by karyotype because patients with 58-66 chromosomes stood every chance of being cured (OS of 100% at 6-year follow-up) with less-intensive therapy. This trial was registered at www.clinicaltrials.gov as #NCT00003728. Registered: http://www.eortc.org/, http://clinicaltrials.gov/show/NCT00003728.
Assuntos
Ensaios Clínicos como Assunto , Diploide , Poliploidia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Adolescente , Idade de Início , Criança , Pré-Escolar , Aberrações Cromossômicas/estatística & dados numéricos , Cromossomos/genética , Ensaios Clínicos como Assunto/métodos , Feminino , Seguimentos , Heterogeneidade Genética , Humanos , Lactente , Recém-Nascido , Cariotipagem , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Indução de RemissãoRESUMO
Deletions of the long arm of chromosome 14 [del(14q)] are rare but recurrently observed in mature B-cell neoplasms, particularly in chronic lymphocytic leukemia (CLL). To further characterize this aberration, we studied 81 cases with del(14q): 54 of CLL and 27 of small lymphocytic lymphoma (SLL), the largest reported series to date. Using karyotype and fluorescence in situ hybridization (FISH), the most frequent additional abnormality was trisomy 12 (tri12), observed in 28/79 (35%) cases, followed by del13q14 (12/79, 15%), delTP53 (11/80, 14%) delATM (5/79, 6%), and del6q21 (3/76, 4%). IGHV genes were unmutated in 41/53 (77%) patients, with a high frequency of IGHV1-69 (21/52, 40%). NOTCH1 gene was mutated in 14/45 (31%) patients. There was no significant difference in cytogenetic and molecular abnormalities between CLL and SLL. Investigations using FISH and SNP-array demonstrated the heterogeneous size of the 14q deletions. However, a group with the same del(14)(q24.1q32.33) was identified in 48% of cases. In this group, tri12 (P = 0.004) and NOTCH1 mutations (P = 0.02) were significantly more frequent than in the other patients. In CLL patients with del(14q), median treatment-free survival (TFS) was 27 months. In conclusion, del(14q) is associated with tri12 and with pejorative prognostic factors: unmutated IGHV genes (with over-representation of the IGHV1-69 repertoire), NOTCH1 mutations, and a short TFS.
Assuntos
Cromossomos Humanos Par 14/genética , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Leucemia Linfocítica Crônica de Células B/genética , Receptor Notch1/genética , Trissomia/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 12/genética , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , MutaçãoRESUMO
The LAM2001 phase 3 trial, involving 832 patients with acute myeloid leukemia (AML; median: 46 years) proposed HLA-identical sibling allograft HSCT for all patients with an identified donor. The trial compared reduced-intensity conditioning (RIC) for patients older than 50 years of age (N = 47) and myeloablative conditioning for younger patients (N = 117). BM HSCT was performed in the younger patients, while the older ones received a consolidation course, followed by peripheral blood allo-HSCT using RIC. The incidence of grade II-IV acute GVHD, was 51.9% (95% confidence interval [CI]: 42.1-61.8) and 11.3% (1.6-21.2) after myeloablative or RIC, respectively (P < .0001) and that of chronic GVHD 45.8% (95% CI: 34.8-56.7) and 41.7% (24.7-58.6; NS). Cumulative incidence of nonrelapse mortality at 108 months was 15.8% (95% CI: 9.8-23.2) for myeloablative, and 6.5% (0.2-16.2) for RIC (NS). CI of relapse at 108 months was 21.7% (95% CI: 13.9-28.6) and 28.6% (16.5-43.4; NS). Overall survival at 108 months was 63.4% (95% CI: 54.6-72.2) and 65.8% (52.2-72.2), respectively, after myeloablative or RIC (NS). RIC peripheral blood stem cell allo-HSCT is prospectively feasible for patients between the ages of 51 and 60 years without excess of relapse or nonrelapse mortality, and compares favorably with myeloablative marrow allo-HSCT proposed to younger patients.
Assuntos
Doença Enxerto-Hospedeiro/epidemiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/cirurgia , Condicionamento Pré-Transplante/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Medula Óssea/efeitos adversos , Transplante de Medula Óssea/métodos , Transplante de Medula Óssea/mortalidade , Feminino , Doença Enxerto-Hospedeiro/mortalidade , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Incidência , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Transplante de Células-Tronco de Sangue Periférico/métodos , Transplante de Células-Tronco de Sangue Periférico/mortalidade , Modelos de Riscos Proporcionais , Indução de Remissão , Irmãos , Condicionamento Pré-Transplante/mortalidadeRESUMO
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
Acute myeloid leukemia (AML) with t(9;22) (q34.1; q11.2)/BCR::ABL1, a distinct entity within the group of AML with defining genetic abnormalities, belong to the adverse-risk group of the 2022 ELN classification. However, there is little data on outcome since the era of tyrosine kinase inhibitors. Among 5819 AML cases included in the DATAML registry, 20 patients with de novo BCR::ABL1+AML (0.3%) were identified. Eighteen patients treated with standard induction chemotherapy were analyzed in this study. Imatinib was added to chemotherapy in 16 patients. The female-to-male ratio was 1.25 and median age was 54 years. The t(9;22) translocation was the sole chromosomal abnormality in 12 patients. Main gene mutations detected by NGS were ASXL1, RUNX1 and NPM1. Compared with patients with myeloid blast phase of chronic myeloid leukemia (CML-BP), de novo BCR::ABL1+AML had higher WBC, fewer additional chromosomal abnormalities, lower CD36 or CD7 expression and no ABL1 mutations. Seventeen patients (94.4%) achieved complete remission (CR) or CR with incomplete hematologic recovery. Twelve patients were allografted in first remission. With a median follow-up of 6.3 years, the median OS was not reached and 2-year OS was 77% (95% CI: 50-91). Four out of five patients who were not transplanted did not relapse. Comparison of BCR::ABL1+AML, CML-BP, 2017 ELN intermediate (n = 643) and adverse-risk patients (n = 863) showed that patients with BCR::ABL1+AML had a significant better outcome than intermediate and adverse-risk patients. BCR::ABL1+AML patients treated with imatinib and intensive chemotherapy should not be included in the adverse-risk group of current AML classifications.
Assuntos
Mesilato de Imatinib , Leucemia Mieloide Aguda , Sistema de Registros , Translocação Genética , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Mesilato de Imatinib/uso terapêutico , Mesilato de Imatinib/administração & dosagem , Idoso , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Cromossomos Humanos Par 22/genética , Proteínas de Fusão bcr-abl/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cromossomos Humanos Par 9/genética , Adulto Jovem , NucleofosminaRESUMO
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.
Assuntos
Antimetabólitos Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Antimetabólitos Antineoplásicos/uso terapêutico , Inteligência Artificial , Resultado do Tratamento , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Azacitidina/uso terapêutico , Sistema de RegistrosRESUMO
BACKGROUND: Acute myeloid leukemia (AML) with myelodysplasia-related characteristics is a heterogeneous subset of AML that has been challenged throughout the history of myeloid malignancies classifications, considered to have similar outcomes as intermediate- or adverse-risk AML depending on the subgroup. However, little is known about the fate of these patients in refractory or relapsed situation (R/R) after first line therapy. METHODS: A large series of R/R AML patients, recorded in the French DATAML registry, have received either intensive chemotherapy (ICT), azacitidine (AZA) as single agent, or best supportive care (BSC). A cohort of 183 patients (median age 63-year-old) with what was called at the time AML-MRC has been explored, and data are reported here. RESULTS: Patient status was refractory for 93, while 90 had relapsed. Respectively, 88, 34, and 61 were included in the three treatment arms. The median OS of the whole cohort was 4.2 months (95%CI: 3.1-5.6) with a mean 1-year overall survival of 24% ± 3.2%. There was no significant survival difference between refractory and relapsed patients. The BSC group had overall a significantly worse outcome (p = 0.0001), and this remained true in both refractory (p = 0.01) and relapsed (p = 0.002) patients. Similar survivals were observed in both groups comparing ICT and AZA. CONCLUSIONS: These data, reporting about an ill-explored population, indicate the poor prognosis of this condition where both ICT and AZA can be proposed. The latter, which was demonstrated here to be a feasible option, should be added to new targeted therapies.
Assuntos
Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/tratamento farmacológico , Azacitidina/uso terapêutico , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/tratamento farmacológico , RecidivaRESUMO
B cell acute lymphoblastic leukemia (B-ALL) is a multistep disease characterized by the hierarchical acquisition of genetic alterations. However, the question of how a primary oncogene reprograms stem cell-like properties in committed B cells and leads to a preneoplastic population remains unclear. Here, we used the PAX5::ELN oncogenic model to demonstrate a causal link between the differentiation blockade, the self-renewal, and the emergence of preleukemic stem cells (pre-LSCs). We show that PAX5::ELN disrupts the differentiation of preleukemic cells by enforcing the IL7r/JAK-STAT pathway. This disruption is associated with the induction of rare and quiescent pre-LSCs that sustain the leukemia-initiating activity, as assessed using the H2B-GFP model. Integration of transcriptomic and chromatin accessibility data reveals that those quiescent pre-LSCs lose B cell identity and reactivate an immature molecular program, reminiscent of human B-ALL chemo-resistant cells. Finally, our transcriptional regulatory network reveals the transcription factor EGR1 as a strong candidate to control quiescence/resistance of PAX5::ELN pre-LSCs as well as of blasts from human B-ALL.