RESUMO
Recent studies on pediatric acute myeloid leukemia (pAML) have revealed pediatric-specific driver alterations, many of which are underrepresented in the current classification schemas. To comprehensively define the genomic landscape of pAML, we systematically categorized 887 pAML into 23 mutually distinct molecular categories, including new major entities such as UBTF or BCL11B, covering 91.4% of the cohort. These molecular categories were associated with unique expression profiles and mutational patterns. For instance, molecular categories characterized by specific HOXA or HOXB expression signatures showed distinct mutation patterns of RAS pathway genes, FLT3 or WT1, suggesting shared biological mechanisms. We show that molecular categories were strongly associated with clinical outcomes using two independent cohorts, leading to the establishment of a new prognostic framework for pAML based on these updated molecular categories and minimal residual disease. Together, this comprehensive diagnostic and prognostic framework forms the basis for future classification of pAML and treatment strategies.
Assuntos
Leucemia Mieloide Aguda , Humanos , Criança , Leucemia Mieloide Aguda/genética , Mutação , Prognóstico , Genômica , Fatores de Transcrição/genética , Proteínas Repressoras/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
Recent studies on pediatric acute myeloid leukemia (pAML) have revealed pediatric-specific driver alterations, many of which are underrepresented in the current classification schemas. To comprehensively define the genomic landscape of pAML, we systematically categorized 895 pAML into 23 molecular categories that are mutually distinct from one another, including new entities such as UBTF or BCL11B, covering 91.4% of the cohort. These molecular categories were associated with unique expression profiles and mutational patterns. For instance, molecular categories characterized by specific HOXA or HOXB expression signatures showed distinct mutation patterns of RAS pathway genes, FLT3, or WT1, suggesting shared biological mechanisms. We show that molecular categories were strongly associated with clinical outcomes using two independent cohorts, leading to the establishment of a prognostic framework for pAML based on molecular categories and minimal residual disease. Together, this comprehensive diagnostic and prognostic framework forms the basis for future classification of pAML and treatment strategies.
RESUMO
BACKGROUND: Lineage infidelity is characteristic of mixed phenotype acute leukemia and is also seen in blast phase of chronic myeloid leukemia (CML), myeloid/lymphoid neoplasia with eosinophilia and gene rearrangements, and subtypes of acute myeloid leukemia. Driver genetic events often occur in multipotent progenitor cells in myeloid neoplasms, suggesting that multilineage output may be more common than appreciated. This phenomenon is not well studied in myelodysplastic syndrome (MDS) and non-CML myeloproliferative neoplasms (MPN). METHODS: We systematically evaluated phenotypic lineage infidelity by reviewing bone marrow pathology and flow cytometry (FC) studies of 1262 consecutive patients with a diagnosis of MDS and/or non-CML MPN. We assessed B- and T-cells in these patients by FC. When abnormal B-lymphoblast (ABLB) populations were detected, we additionally evaluated immature B-cells using a high sensitivity FC assay for B-lymphoblastic leukemia/lymphoma (B-ALL). RESULTS: We identified 9 patients (7 MDS, 7/713, 1%; 2 non-CML MPN, 2/312, 0.6%; 0 in MDS/MPN) with low-level ABLB populations (0.012%-3.6% of WBCs in marrow) with abnormal immunophenotypes. Genetic studies on flow sorted cell populations confirmed that some ABLB populations were clonally related to myeloid blasts (4/6, 67%). On follow-up, ABLB populations in 8/9 patients remained stable or disappeared. Only 1 case progressed to B-ALL. CONCLUSIONS: These findings demonstrate that phenotypically detectable abnormal immature B lineage output occurs in MDS and non-CML MPN, albeit rarely. While presence of ABLB does not necessarily reflect blast crisis, the underlying disease biology of our findings may ultimately be relevant to patient management and warrants further investigation.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Transtornos Mieloproliferativos , Humanos , Citometria de Fluxo , Transtornos Mieloproliferativos/patologia , Síndromes Mielodisplásicas/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Crise Blástica/patologia , Leucemia Mieloide Aguda/patologiaRESUMO
Signaling through JAK1 and/or JAK2 is common among tumor and nontumor cells within peripheral T-cell lymphoma (PTCL). No oral therapies are approved for PTCL, and better treatments for relapsed/refractory disease are urgently needed. We conducted a phase 2 study of the JAK1/2 inhibitor ruxolitinib for patients with relapsed/refractory PTCL (n = 45) or mycosis fungoides (MF) (n = 7). Patients enrolled onto 1 of 3 biomarker-defined cohorts: (1) activating JAK and/or STAT mutations, (2) ≥30% pSTAT3 expression among tumor cells by immunohistochemistry, or (3) neither or insufficient tissue to assess. Patients received ruxolitinib 20 mg PO twice daily until progression and were assessed for response after cycles 2 and 5 and every 3 cycles thereafter. The primary endpoint was clinical benefit rate (CBR), defined as the combination of complete response, partial response (PR), and stable disease lasting at least 6 months. Only 1 of 7 patients with MF had CBR (ongoing PR > 18 months). CBR among the PTCL cases (n = 45) in cohorts 1, 2, and 3 were 53%, 45%, and 13% (cohorts 1 & 2 vs 3, P = .02), respectively. Eight patients had CBR > 12 months (5 ongoing), including 4 of 5 patients with T-cell large granular lymphocytic leukemia. In an exploratory analysis using multiplex immunofluorescence, expression of phosphorylated S6, a marker of PI3 kinase or mitogen-activated protein kinase activation, in <25% of tumor cells was associated with response to ruxolitinib (P = .05). Our findings indicate that ruxolitinib is active across various PTCL subtypes and support a precision therapy approach to JAK/STAT inhibition in patients with PTCL. This trial was registered at www.clincialtrials.gov as #NCT02974647.
Assuntos
Janus Quinases/metabolismo , Linfoma de Células T Periférico/tratamento farmacológico , Nitrilas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Fatores de Transcrição STAT/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Janus Quinases/antagonistas & inibidores , Linfoma de Células T Periférico/metabolismo , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/metabolismo , Resultado do Tratamento , Adulto JovemAssuntos
Leucemia de Células Pilosas/diagnóstico , Transtornos Linfoproliferativos/diagnóstico , Idoso , Antígenos CD5/biossíntese , Diagnóstico Diferencial , Feminino , Testes Genéticos , Humanos , Leucemia de Células Pilosas/genética , Leucemia de Células Pilosas/metabolismo , Leucemia de Células Pilosas/terapia , Transtornos Linfoproliferativos/metabolismo , Mutação , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
Pediatric therapy-related myeloid neoplasms (tMN) occur in children after exposure to cytotoxic therapy and have a dismal prognosis. The somatic and germline genomic alterations that drive these myeloid neoplasms in children and how they arise have yet to be comprehensively described. We use whole exome, whole genome, and/or RNA sequencing to characterize the genomic profile of 84 pediatric tMN cases (tMDS: n = 28, tAML: n = 56). Our data show that Ras/MAPK pathway mutations, alterations in RUNX1 or TP53, and KMT2A rearrangements are frequent somatic drivers, and we identify cases with aberrant MECOM expression secondary to enhancer hijacking. Unlike adults with tMN, we find no evidence of pre-existing minor tMN clones (including those with TP53 mutations), but rather the majority of cases are unrelated clones arising as a consequence of cytotoxic therapy. These studies also uncover rare cases of lineage switch disease rather than true secondary neoplasms.
Assuntos
Leucemia Mieloide Aguda/genética , Segunda Neoplasia Primária/genética , Criança , Regulação Neoplásica da Expressão Gênica , Genômica , Histona-Lisina N-Metiltransferase , Humanos , Leucemia Mieloide Aguda/terapia , Mutação , Síndromes Mielodisplásicas , Proteína de Leucina Linfoide-Mieloide , Segunda Neoplasia Primária/terapia , Prognóstico , Sequenciamento do ExomaRESUMO
Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare but increasingly important diagnosis as the incidence of breast implant placement, both elective and reconstructive, continues to rise. When detected and treated early, this indolent disease carries an excellent prognosis. However, because the clinical presentation is often nonspecific, it is crucial for radiologists to accurately identify the imaging findings associated with BIA-ALCL to facilitate a timely diagnosis. This article will provide radiologists with an overview of the diagnosis, imaging findings, and management of BIA-ALCL.
RESUMO
Inflammatory breast cancer (IBC) is a relatively rare and aggressive subtype, accounting for nearly 2.5% of all diagnosed breast cancers worldwide. It is usually characterised by an acute onset, rapid clinical progression, poor prognosis and micrometastasis at the time of presentation. Prompt recognition of clinical symptoms and identification of warning signs are vital in diagnosing and appropriately treating a patient with IBC.