RESUMO
Despite the high probability of cure of patients with acute promyelocytic leukemia (APL), mechanisms of relapse are still largely unclear. Mutational profiling at diagnosis and/or relapse may help to identify APL patients needing frequent molecular monitoring and early treatment intervention. Using an NGS approach including a 31 myeloid gene-panel, we tested BM samples of 44 APLs at the time of diagnosis, and of 31 at relapse. Mutations in PML and RARA genes were studied using a customized-NGS-RNA panel. Patients relapsing after ATRA-chemotherapy rarely had additional mutations (P = .009). In patients relapsing after ATRA/ATO, the PML gene was a preferential mutation target. We then evaluated the predictive value of mutations at APL diagnosis. A median of two mutations was detectable in 9/11 patients who later relapsed, vs one mutation in 21/33 patients who remained in CCR (P = .0032). This corresponded to a significantly lower risk of relapse in patients with one or less mutations (HR 0.046; 95% CI 0.011-0.197; P < .0001). NGS-analysis at the time of APL diagnosis may inform treatment decisions, including alternative treatments for cases with an unfavorable mutation profile.
Assuntos
Leucemia Promielocítica Aguda/genética , Mutação , Proteínas de Fusão Oncogênica/genética , Proteína da Leucemia Promielocítica/genética , RNA Mensageiro/genética , RNA Neoplásico/genética , Receptor alfa de Ácido Retinoico/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Trióxido de Arsênio/administração & dosagem , Trióxido de Arsênio/farmacologia , Medula Óssea/patologia , Células Clonais , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas , Domínios Proteicos/genética , Recidiva , Indução de Remissão , Reprodutibilidade dos Testes , Tretinoína/administração & dosagemRESUMO
Once the diagnostic suspicion of acute promyelocytic leukemia (APL) has been raised, international guidelines recommend prompt initiation of tailored therapy and supportive care, while awaiting for genetic confirmation of the diagnosis, and the identification of the specific PML/RARA isoform by reverse transcriptase polymerase chain reaction (RT-PCR). Depending on the PML break point, usually located within intron 6, exon 6, or intron 3, different PML/RARA transcript isoforms may be generated, that is, long (bcr1), variant (bcr2), and short (bcr3), respectively. We report here the characterization of three APL cases harboring atypical PML/RARA transcripts, which were not clearly detectable after standard RT-PCR amplification. In all three cases, clinical, morphological, and immunophenotypic features were consistent with APL. Direct sequencing allowed the identification of atypical break points within the PML and RARA genes. Then, we designed a patient-specific quantitative real-time PCR for the atypical transcripts, which allowed for specific quantitative evaluation of minimal residual disease (MRD) during follow-up. Despite the rarity of APL cases with an atypical PML/RARA fusion, our study indicates that an integrated laboratory approach, employing several diagnostic techniques is crucial to timely diagnose APL. This approach allows prompt initiation of specific targeted treatment and reliable MRD monitoring in atypical APL cases.
Assuntos
Leucemia Promielocítica Aguda/genética , Neoplasia Residual/genética , Proteína da Leucemia Promielocítica/genética , Receptor alfa de Ácido Retinoico/genética , Adulto , Idoso , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 17 , Éxons/genética , Feminino , Humanos , Íntrons/genética , Cariotipagem , Leucemia Promielocítica Aguda/patologia , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/patologia , Proteínas de Fusão Oncogênica/genéticaRESUMO
Prolonged therapy with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) is highly effective in newly diagnosed acute promyelocytic leukemia (APL) but there is limited data on the efficacy of this regimen in the relapse setting. We report here on 22 APL patients treated with prolonged ATRA-ATO therapy at the time of disease relapse. Twenty patients obtained molecular complete remission (CRm) after 2 cycles (90%). Of these, two patients underwent hematopoietic stem cell transplant (HSCT) while the remaining proceeded to receive additional cycles (up to a total of 5) of ATRA-ATO. With a median follow-up of 58 months from the time of relapse (range: 21-128 months), the 4-year OS probability was 0.85 (95% CI 0.61-0.94), DFS was 0.74 (95% CI 0.49-0.88), and EFS 0.68 (95% CI 0.45-0.83). Two patients were resistant to ATRA-ATO salvage and five relapsed at a median of 19 months. Of these, four died due to progressive disease while three relapsed achieved a new CRm after further salvage therapy. This experience confirms the potentially curative effect of prolonged ATRA-ATO therapy in relapsed APL, especially in patients with long first complete remission.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Trióxido de Arsênio , Arsenicais/administração & dosagem , Terapia Combinada , Intervalo Livre de Doença , Esquema de Medicação , Avaliação de Medicamentos , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas , Humanos , Estimativa de Kaplan-Meier , Leucemia Promielocítica Aguda/terapia , Masculino , Pessoa de Meia-Idade , Óxidos/administração & dosagem , Modelos de Riscos Proporcionais , Recidiva , Indução de Remissão , Estudos Retrospectivos , Terapia de Salvação , Resultado do Tratamento , Tretinoína/administração & dosagem , Adulto JovemAssuntos
DNA (Citosina-5-)-Metiltransferases/genética , Leucemia Mieloide Aguda/genética , RNA Mensageiro/análise , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , DNA Metiltransferase 3A , Humanos , Pessoa de Meia-Idade , Neoplasia Residual/diagnóstico , Proteínas Nucleares/genética , Nucleofosmina , Adulto JovemAssuntos
Biomarcadores Tumorais/genética , Pontos de Quebra do Cromossomo , Leucemia Promielocítica Aguda/genética , Proteína da Leucemia Promielocítica/genética , Receptor alfa de Ácido Retinoico/genética , Tretinoína/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Feminino , Humanos , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Prognóstico , Adulto JovemRESUMO
Acute promyelocytic leukaemia (APL) is characterized by the PML/RARA fusion transcript. PML and RARA mutations have been shown to directly respond to arsenic trioxide (ATO) and all-trans retinoic (ATRA). We analysed the prevalence of PML mutations in 32 patients with de novo or therapy-related APL (t-APL; n = 5), treated with ATO. We identified one ATO-resistant t-APL patient, who presented a PML A216T mutation in both the rearranged and unrearranged PML alleles, and two mutations in the rearranged RARA gene. In this patient, subclones with different PML and RARA mutations acquired clonal dominance during the disease course, probably leading to treatment resistance.
