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1.
Blood ; 2024 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-38687605

RESUMO

Mutations in UBA1, which are disease-defining for VEXAS syndrome, have been reported in patients diagnosed with myelodysplastic syndromes (MDS). Here, we define the prevalence and clinical associations of UBA1 mutations in a representative cohort of patients with MDS. Digital droplet PCR profiling of a selected cohort of 375 male patients lacking MDS disease-defining mutations or established WHO disease classification identified 28 patients (7%) with UBA1 p.M41T/V/L mutations. Using targeted sequencing of UBA1 in a representative MDS cohort (n=2,027), we identified an additional 27 variants in 26 patients (1%), which we classified as likely/pathogenic (n=12) and unknown significance (n=15). Among the total 40 patients with likely/pathogenic variants (2%), all were male and 63% were classified by WHO2016 as MDS-MLD/SLD. Patients had a median of one additional myeloid gene mutation, often in TET2 (n=12), DNMT3A (n=10), ASXL1 (n=3), or SF3B1 (n=3). Retrospective clinical review where possible showed that 83% (28/34) UBA1-mutant cases had VEXAS-associated diagnoses or inflammatory clinical presentation. The prevalence of UBA1-mutations in MDS patients argues for systematic screening for UBA1 in the management of MDS.

2.
Blood ; 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38958467

RESUMO

Myelodysplastic syndromes/neoplasms (MDS) are clonal hematologic disorders characterized by morphologic abnormalities of myeloid cells and peripheral cytopenias. While genetic abnormalities underlie the pathogenesis of these disorders and their heterogeneity, current classifications of MDS rely predominantly on morphology. We performed genomic profiling of 3,233 patients with MDS or related disorders to delineate molecular subtypes and define their clinical implications. Gene mutations, copy-number alterations (CNAs), and copy-neutral loss of heterozygosity (cnLOH) were derived from targeted sequencing of a 152-gene panel, with abnormalities identified in 91, 43, and 11% of patients, respectively. We characterized 16 molecular groups, encompassing 86% of patients, using information from 21 genes, 6 cytogenetic events, and LOH at the TP53 and TET2 loci. Two residual groups defined by negative findings (molecularly not-otherwise specified, absence of recurrent drivers) comprised 14% of patients. The groups varied in size from 0.5% to 14% of patients and were associated with distinct clinical phenotypes and outcomes. The median bone marrow blast percentage across groups ranged from 1.5 to 10%, and the median overall survival from 0.9 to 8.2 years. We validated 5 well-characterized entities, added further evidence to support 3 previously reported subsets, and described 8 novel groups. The prognostic influence of bone marrow blasts depended on the genetic subtypes. Within genetic subgroups, therapy-related MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) had comparable clinical and outcome profiles to primary MDS. In conclusion, genetically-derived subgroups of MDS are clinically relevant and may inform future classification schemas and translational therapeutic research.

3.
Blood ; 142(26): 2247-2257, 2023 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-37774372

RESUMO

ABSTRACT: Myelodysplastic syndromes (MDSs) are neoplastic myeloid proliferations characterized by ineffective hematopoiesis resulting in peripheral blood cytopenias. MDS is distinguished from nonneoplastic clonal myeloid proliferations by the presence of morphologic dysplasia and from acute myeloid leukemia by a blast threshold of 20%. The diagnosis of MDS can be challenging because of the myriad other causes of cytopenias: accurate diagnosis requires the integration of clinical features with bone marrow and peripheral blood morphology, immunophenotyping, and genetic testing. MDS has historically been subdivided into several subtypes by classification schemes, the most recent of which are the International Consensus Classification and World Health Organization Classification (fifth edition), both published in 2022. The aim of MDS classification is to identify entities with shared genetic underpinnings and molecular pathogenesis, and the specific subtype can inform clinical decision-making alongside prognostic risk categorization. The current MDS classification schemes incorporate morphologic features (bone marrow and blood blast percentage, degree of dysplasia, ring sideroblasts, bone marrow fibrosis, and bone marrow hypocellularity) and also recognize 3 entities defined by genetics: isolated del(5q) cytogenetic abnormality, SF3B1 mutation, and TP53 mutation. It is anticipated that with advancing understanding of the genetic basis of MDS pathogenesis, future MDS classification will be based increasingly on genetic classes. Nevertheless, morphologic features in MDS reflect the phenotypic expression of the underlying abnormal genetic pathways and will undoubtedly retain importance to inform prognosis and guide treatment.


Assuntos
Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Transtornos Mieloproliferativos , Humanos , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Medula Óssea/patologia , Transtornos Mieloproliferativos/patologia , Prognóstico , Leucemia Mieloide Aguda/patologia
4.
Blood ; 141(17): 2047-2061, 2023 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-36724453

RESUMO

Myelodysplastic syndromes/myelodysplastic neoplasms (MDS) are associated with variable clinical presentations and outcomes. The initial response criteria developed by the International Working Group (IWG) in 2000 have been used in clinical practice, clinical trials, regulatory reviews, and drug labels. Although the IWG criteria were revised in 2006 and 2018 (the latter focusing on lower-risk disease), limitations persist in their application to higher-risk MDS (HR-MDS) and their ability to fully capture the clinical benefits of novel investigational drugs or serve as valid surrogates for longer-term clinical end points (eg, overall survival). Further, issues related to the ambiguity and practicality of some criteria lead to variability in interpretation and interobserver inconsistency in reporting results from the same sets of data. Thus, we convened an international panel of 36 MDS experts and used an established modified Delphi process to develop consensus recommendations for updated response criteria that would be more reflective of patient-centered and clinically relevant outcomes in HR-MDS. Among others, the IWG 2023 criteria include changes in the hemoglobin threshold for complete remission (CR), the introduction of CR with limited count recovery and CR with partial hematologic recovery as provisional response criteria, the elimination of marrow CR, and specific recommendations for the standardization of time-to-event end points and the derivation and reporting of responses. The updated criteria should lead to a better correlation between patient-centered outcomes and clinical trial results in an era of multiple emerging new agents with novel mechanisms of action.


Assuntos
Hematologia , Síndromes Mielodisplásicas , Humanos , Resultado do Tratamento , Consenso , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde
5.
Mod Pathol ; 37(4): 100440, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38290600

RESUMO

Primary bone lymphoma (PBL) is rare and mostly represented by diffuse large B-cell lymphomas (DLBCL). Follicular lymphoma (FL), albeit commonly disseminating to the bone marrow, rarely presents primarily as bone lesions. Here, we studied 16 patients (12 men:4 women, median age 60 years) who presented with bone pain and/or skeletal radiologic abnormalities revealing bone FL. Lesions were multifocal in 11 patients (spine ± appendicular skeleton), and unifocal in 5 patients (femoral, tibial, or vertebral). An infiltrate of centrocytes and centroblasts (CD20+ CD5- CD10+ BCL2+ BCL6+) with abundant reactive T cells and an increased reticulin fibrosis massively replaced the marrow spaces between preserved bone trabeculae. The pattern was diffuse ± nodular, often with paratrabecular reinforcement and/or peripheral paratrabecular extension. Ki-67 was usually <15%. Two cases had necrosis. BCL2 rearrangement was demonstrated in 14 of 14 evaluable cases (with concomitant BCL6 rearrangement in one). High-throughput sequencing revealed BCL2, KMT2D, and TNFRSF14 to be the most frequently mutated genes. After staging, 5 qualified for PBL (3 limited stage) and 11 had stage IV systemic FL. All patients received rituximab ± polychemotherapy as firstline treatment, and 7 received local therapy (6 radiotherapy and 2 surgery). Three patients experienced transformation to DLBCL. At the last follow-up (15/16, median 48 months), 11 patients achieved complete remission, including all cases with PBL and most patients with limited extraosseous disease (3-year progression-free survival 71%). One patient died of unrelated cause (3-year overall survival 91%). FL may manifest as a localized or polyostotic bone disease. A minority represent PBL, whereas most reveal systemic disease.


Assuntos
Linfoma Folicular , Linfoma Difuso de Grandes Células B , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Linfoma Folicular/genética , Linfoma Folicular/terapia , Linfoma Folicular/patologia , Linfoma Difuso de Grandes Células B/patologia , Rituximab , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas c-bcl-2/genética
6.
Mod Pathol ; 37(1): 100352, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37839675

RESUMO

In this study, we performed a comprehensive molecular analysis of paired skin and peripheral blood/bone marrow (BM) samples from 17 patients with cutaneous myeloid or cutaneous histiocytic-dendritic neoplasms. The cutaneous manifestations included 10 patients with cutaneous acute myeloid leukemia (c-AML), 2 patients with full or partial Langerhans cell differentiation, 2 patients with blastic plasmacytoid dendritic cell neoplasms (BPDCN), 1 patient with both Langerhans cell differentiation and BPDCN, and 2 patients with full or partial indeterminate dendritic cell differentiation. Seven of the 10 c-AML patients (70%) exhibited concurrent or subsequent marrow involvement by acute myeloid leukemia, with all 7 cases (100%) demonstrating shared clonal mutations in both the skin and BM. However, clonal relatedness was documented in one additional case that never had any BM involvement. Nevertheless, NPM1 mutations were identified in 7 of the 10 (70%) of these c-AML cases while one had KMT2A rearrangement and one showed inv(16). All 3 patients (100%) with Langerhans cell neoplasms, 2 patients with BPDCN (100%), and one of the 2 patients (50%) with other cutaneous dendritic cell neoplasms also demonstrated shared mutations between the skin and concurrent or subsequent myeloid neoplasms. Both BM and c-AML shared identical founding drivers, with a predominance of NPM1, DNMT3A, and translocations associated with monocytic differentiation, with common cutaneous-only mutations involving genes in the signal transduction and epigenetic pathways. Cutaneous histiocytic-dendritic neoplasms shared founding drivers in ASXL1, TET2, and/or SRSF2. However, in the Langerhans cell histiocytosis or histiocytic sarcoma cases, there exist recurrent secondary RAS pathway hits, whereas cutaneous BPDCN cases exhibit copy number or structural variants. These results enrich and broaden our understanding of clonally related cutaneous manifestations of myeloid neoplasms and further illuminate the highly diverse spectrum of morphologic and immunophenotypic features they exhibit.


Assuntos
Neoplasias Hematológicas , Leucemia Mieloide Aguda , Transtornos Mieloproliferativos , Neoplasias Cutâneas , Humanos , Medula Óssea/patologia , Células Dendríticas/metabolismo , Mutação , Leucemia Mieloide Aguda/patologia , Neoplasias Hematológicas/patologia , Neoplasias Cutâneas/patologia , Transtornos Mieloproliferativos/patologia , Proteínas Nucleares/genética
7.
Blood ; 139(3): 323-332, 2022 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-34111285

RESUMO

Patients with acute myeloid leukemia (AML) have conventionally received more intense therapy than patients with myelodysplastic syndrome (MDS). Although less intense therapies are being used more often in AML, the dichotomy between AML and MDS remains, with the presence of ≥20% myeloblasts in marrow or peripheral blood generally regarded as defining AML. Consequently, patients with 19% blasts are typically ineligible for AML studies, and patients with 21% blasts are ineligible for MDS studies. Here we cite biologic and clinical data to question this practice. Biologically, abnormalities in chromosome 3q26 and mutations in NPM1 and FLT3, regarded as AML associated, also occur in MDS. The genetic signatures of MDS, particularly cases with 10% to 19% blasts (MDS-EB2), resemble those of AML following a preceding MDS (secondary AML). Mutationally, secondary AML appears at least as similar to MDS-EB2 as to de novo AML. Patients presenting with de novo AML but with secondary-type AML mutations seem to have the same poor prognosis associated with clinically defined secondary AML. Seattle data indicate that after accounting for European LeukemiaNet 2017 risk, age, performance status, clinically secondary AML, and treatment including allogeneic transplantation, patients with World Health Organization-defined AML (n = 769) have similar rates of overall survival, event-free survival, and complete remission (CR)/CR with incomplete hematologic recovery as patients with MDS-EB2 (n = 202). We suggest defining patients with 10% to 30% blasts (AML/MDS) as eligible for both AML and MDS studies. This would permit empiric testing of the independent effect of blast percentage on outcome, allow patients access to more therapies, and potentially simplify the regulatory approval process.


Assuntos
Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Aberrações Cromossômicas , Diagnóstico Diferencial , Feminino , Rearranjo Gênico , Humanos , Leucemia Mieloide Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/diagnóstico , Nucleofosmina/genética , Adulto Jovem
8.
Blood ; 140(12): 1345-1377, 2022 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-35797463

RESUMO

The 2010 and 2017 editions of the European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML) in adults are widely recognized among physicians and investigators. There have been major advances in our understanding of AML, including new knowledge about the molecular pathogenesis of AML, leading to an update of the disease classification, technological progress in genomic diagnostics and assessment of measurable residual disease, and the successful development of new therapeutic agents, such as FLT3, IDH1, IDH2, and BCL2 inhibitors. These advances have prompted this update that includes a revised ELN genetic risk classification, revised response criteria, and treatment recommendations.


Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Adulto , Antineoplásicos/uso terapêutico , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Mutação , Neoplasia Residual/diagnóstico , Neoplasia Residual/tratamento farmacológico , Nucleofosmina , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/genética
9.
Blood ; 139(15): 2273-2284, 2022 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-35167654

RESUMO

Cytogenetics has long represented a critical component in the clinical evaluation of hematologic malignancies. Chromosome banding studies provide a simultaneous snapshot of genome-wide copy number and structural variation, which have been shown to drive tumorigenesis, define diseases, and guide treatment. Technological innovations in sequencing have ushered in our present-day clinical genomics era. With recent publications highlighting novel sequencing technologies as alternatives to conventional cytogenetic approaches, we, an international consortium of laboratory geneticists, pathologists, and oncologists, describe herein the advantages and limitations of both conventional chromosome banding and novel sequencing technologies and share our considerations on crucial next steps to implement these novel technologies in the global clinical setting for a more accurate cytogenetic evaluation, which may provide improved diagnosis and treatment management. Considering the clinical, logistic, technical, and financial implications, we provide points to consider for the global evolution of cytogenetic testing.


Assuntos
Neoplasias Hematológicas , Aberrações Cromossômicas , Análise Citogenética , Citogenética , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Humanos
10.
Blood ; 140(11): 1200-1228, 2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-35767897

RESUMO

The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CACs) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As a continuation of this CAC-based process, the authors, a group with expertise in the clinical, pathologic, and genetic aspects of these disorders, developed the International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias. Using a multiparameter approach, the main objective of the consensus process was the definition of real disease entities, including the introduction of new entities and refined criteria for existing diagnostic categories, based on accumulated data. The ICC is aimed at facilitating diagnosis and prognostication of these neoplasms, improving treatment of affected patients, and allowing the design of innovative clinical trials.


Assuntos
Neoplasias Hematológicas , Leucemia , Transtornos Mieloproliferativos , Doença Aguda , Consenso , Genômica , Neoplasias Hematológicas/patologia , Humanos , Leucemia/diagnóstico , Leucemia/genética , Leucemia/patologia , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Organização Mundial da Saúde
11.
Blood ; 140(21): 2228-2247, 2022 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-36130297

RESUMO

Myeloid neoplasms and acute leukemias derive from the clonal expansion of hematopoietic cells driven by somatic gene mutations. Although assessment of morphology plays a crucial role in the diagnostic evaluation of patients with these malignancies, genomic characterization has become increasingly important for accurate diagnosis, risk assessment, and therapeutic decision making. Conventional cytogenetics, a comprehensive and unbiased method for assessing chromosomal abnormalities, has been the mainstay of genomic testing over the past several decades and remains relevant today. However, more recent advances in sequencing technology have increased our ability to detect somatic mutations through the use of targeted gene panels, whole-exome sequencing, whole-genome sequencing, and whole-transcriptome sequencing or RNA sequencing. In patients with myeloid neoplasms, whole-genome sequencing represents a potential replacement for both conventional cytogenetic and sequencing approaches, providing rapid and accurate comprehensive genomic profiling. DNA sequencing methods are used not only for detecting somatically acquired gene mutations but also for identifying germline gene mutations associated with inherited predisposition to hematologic neoplasms. The 2022 International Consensus Classification of myeloid neoplasms and acute leukemias makes extensive use of genomic data. The aim of this report is to help physicians and laboratorians implement genomic testing for diagnosis, risk stratification, and clinical decision making and illustrates the potential of genomic profiling for enabling personalized medicine in patients with hematologic neoplasms.


Assuntos
Neoplasias Hematológicas , Leucemia Mieloide Aguda , Transtornos Mieloproliferativos , Neoplasias , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Mutação , Genômica , Neoplasias/genética , Neoplasias Hematológicas/genética , Tomada de Decisão Clínica
12.
Cancer ; 129(2): 175-180, 2023 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-36397669

RESUMO

TP53-altered myelodysplastic syndrome with excess blasts and TP53-altered acute myeloid leukemia should be considered under one unifying classification term for their study in clinical trials. Ultimately, such a unification would simplify the screening processes for clinical trials and allow a focus on treating the patient for a genetically defined disorder rather than one based on an arbitrary blast threshold.


Assuntos
Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Síndromes Mielodisplásicas/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucócitos , Proteína Supressora de Tumor p53/genética
13.
Mod Pathol ; 36(3): 100016, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36788093

RESUMO

Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm driven by canonical gene mutations in JAK2, CALR, or MPL in >80% of the cases. PMF that lacks these canonical alterations is termed triple-negative PMF (TN-PMF). The pathologic and genetic characteristics of TN-PMF compared with those of conventional PMF with canonical driver mutations (DM-PMF) have not been well studied. We aimed to identify clinicopathologic and molecular genetic differences between patients with TN-PMF (n = 56) and DM-PMF (n = 89), all of whom fulfilled the 2016 World Health Organization diagnostic criteria for PMF. Compared with the control group, patients in the TN-PMF group were more likely to have thrombocytopenia and less likely to have organomegaly. The bone marrow in patients with TN-PMF showed fewer granulocytic elements and more frequent dyserythropoiesis. Cytogenetic analysis showed a higher incidence of trisomy 8. Targeted next-generation sequencing revealed a lower frequency of ASXL1 mutations but enrichment of ASXL1/SRSF2 comutations. Our findings demonstrated several clinicopathologic and molecular differences between TN-PMF and DM-PMF. These findings, particularly the observed mutation profile characterized by a higher frequency of ASXL1 and SRSF2 comutation, suggest that at least a subset of TN-PMF may be pathogenetically different from DM-PMF, with potential prognostic implications.


Assuntos
Transtornos Mieloproliferativos , Mielofibrose Primária , Humanos , Medula Óssea/patologia , Mielofibrose Primária/genética , Mielofibrose Primária/patologia , Transtornos Mieloproliferativos/genética , Mutação , Prognóstico , Janus Quinase 2/genética , Fatores de Transcrição/genética
14.
Blood ; 138(19): 1870-1884, 2021 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-34424946

RESUMO

B-cell acute lymphoblastic leukemia (B-ALL) occurs most commonly in children, whereas chronic myeloid leukemia is more frequent in adults. The myeloid bias of hematopoiesis in elderly individuals has been considered causative, but the age of the bone marrow microenvironment (BMM) may be contributory. Using various murine models of B-ALL in young vs old mice, we recapitulated B-ALL preponderance in children vs adults. We showed differential effects of young vs old BM macrophages on B-ALL cell function. Molecular profiling using RNA- and ATAC-sequencing revealed pronounced differences in young vs old BMM-derived macrophages and enrichment for gene sets associated with inflammation. In concordance with the role of C-X-C motif chemokine (CXCL) 13 for disease-associated B-cell chemoattraction, we found CXCL13 to be highly expressed in young macrophages on a translational compared with a transcriptional level. Inhibition of CXCL13 in BM macrophages impaired leukemia cell migration and decreased the proliferation of cocultured B-ALL cells, whereas recombinant CXCL13 increased pAKT and B-ALL cell expansion. Pretreatment of B-ALL-initiating cells with CXCL13 accelerated B-ALL progression. Deficiency of Cxcr5, the receptor for CXCL13, on B-ALL-initiating cells prolonged murine survival, whereas high expression of CXCR5 in pediatric B-ALL may predict central nervous system relapse. CXCL13 staining was increased in bone sections from pediatric compared with adult patients with B-ALL. Taken together, our study shows that the age of the BMM and, in particular, BM macrophages influence the leukemia phenotype. The CXCR5-CXCL13 axis may act as prognostic marker and an attractive novel target for the treatment of B-ALL.


Assuntos
Quimiocina CXCL13/genética , Regulação Leucêmica da Expressão Gênica , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Receptores CXCR5/genética , Microambiente Tumoral , Envelhecimento , Animais , Medula Óssea/metabolismo , Medula Óssea/patologia , Linhagem Celular Tumoral , Progressão da Doença , Humanos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia
15.
Haematologica ; 108(10): 2730-2742, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37165840

RESUMO

Pentraxin 2 (PTX-2; serum amyloid P component), a circulating endogenous regulator of the inflammatory response to tissue injury and fibrosis, is reduced in patients with myelofibrosis (MF). Zinpentraxin alfa (RO7490677, PRM-151) is a recombinant form of PTX-2 that has shown preclinical antifibrotic activity and no dose-limiting toxicities in phase I trials. We report results from stage 1 of a phase II trial of zinpentraxin alfa in patients with intermediate-1/2 or high-risk MF. Patients (n=27) received intravenous zinpentraxin α weekly (QW) or every 4 weeks (Q4W), as monotherapy or an additional therapy for patients on stable-dose ruxolitinib. The primary endpoint was overall response rate (ORR; investigatorassessed) adapted from International Working Group-Myeloproliferative Neoplasms Research and Treatment criteria. Secondary endpoints included modified Myeloproliferative Neoplasm-Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) change, bone marrow (BM) MF grade reduction, pharmacokinetics, and safety. ORR at week 24 was 33% (n=9/27) and varied across individual cohorts (QW: 38% [3/8]; Q4W: 14% [1/7]; QW+ruxolitinib: 33% [2/6]; Q4W+ruxolitinib: 50% [3/6]). Five of 18 evaluable patients (28%) experienced a ≥50% reduction in MPN-SAF TSS, and six of 17 evaluable patients (35%) had a ≥1 grade improvement from baseline in BM fibrosis at week 24. Most treatment-emergent adverse events (AE) were grade 1-2, most commonly fatigue. Among others, anemia and thrombocytopenia were infrequent (n=3 and n=1, respectively). Treatment-related serious AE occurred in four patients (15%). Overall, zinpentraxin alfa showed evidence of clinical activity and tolerable safety as monotherapy and in combination with ruxolitinib in this open-label, non-randomized trial (clinicaltrials gov. Identifier: NCT01981850).


Assuntos
Mielofibrose Primária , Proteínas Recombinantes , Humanos , Anemia , Fibrose , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/tratamento farmacológico , Resultado do Tratamento , Proteínas Recombinantes/efeitos adversos , Quimioterapia Combinada/efeitos adversos
16.
Haematologica ; 2023 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-37981812

RESUMO

STAT5B has been reported as a recurrent mutation in myeloid neoplasms (MNs) with eosinophilia, but the overall frequency and importance across a spectrum of MNs are largely unknown. We conducted a multicenter study on a series of 82 MNs with STAT5B mutations detected by next-generation sequencing. The estimated frequency of STAT5B mutation in MNs was low.

17.
Am J Hematol ; 98(8): 1286-1306, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37283522

RESUMO

Based on new data and increased understanding of disease molecular genetics, the international consensus classification (ICC) has made several changes in the diagnosis and classification of eosinophilic disorders and systemic mastocytosis. Myeloid/lymphoid neoplasms with eosinophilia (M/LN-eo) and gene rearrangements have been renamed as M/LN-eo with tyrosine kinase gene fusions (M/LN-eo-TK). The category has been expanded to include ETV6::ABL1 and FLT3 fusions, and to accept PCM1::JAK2 and its genetic variants as formal members. The overlaps and differences between M/LN-eo-TK and BCR::ABL1-like B-lymphoblastic leukemia (ALL)/de novo T-ALL sharing the same genetic lesions are addressed. Besides genetics, ICC for the first time has introduced bone marrow morphologic criteria in distinguishing idiopathic hypereosinophilia/hypereosinophilic syndrome from chronic eosinophilic leukemia, not otherwise specified. The major diagnostic criteria for systemic mastocytosis (SM) in the ICC remain largely based on morphology, but several minor modifications/refinements have been made in criteria related to diagnosis, subclassification, and assessment of disease burden (B- and C-findings). This review is to focus on the ICC updates related to these disease entities, illustrated through changes related to morphology, molecular genetics, clinical features, prognosis, and treatment. Two practical algorithms are provided in navigating through the diagnosis and classification systems of hypereosinophilia and SM.


Assuntos
Síndrome Hipereosinofílica , Leucemia , Mastocitose Sistêmica , Transtornos Mieloproliferativos , Humanos , Mastocitose Sistêmica/diagnóstico , Mastocitose Sistêmica/genética , Consenso , Leucemia/genética , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/tratamento farmacológico , Síndrome Hipereosinofílica/diagnóstico , Síndrome Hipereosinofílica/genética , Síndrome Hipereosinofílica/patologia
18.
Int J Gynecol Pathol ; 42(4): 390-397, 2023 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-36044301

RESUMO

Follicular dendritic cell sarcoma is a rare dendritic/histiocytic tumor of intermediate malignant potential, which often involves extranodal sites, most commonly the gastrointestinal tract and mediastinum with only 5 cases reported in the female genital tract. We present the clinical and pathologic features of 2 such examples arising in the uterine corpus. Both patients (63 and 72-yr old) presented with postmenopausal bleeding and underwent an endometrial biopsy diagnostic of follicular dendritic cell sarcoma that was followed by hysterectomy. The tumors were polypoid, 3.5 and 5.0 cm, and were confined to the endometrium. Microscopically, ovoid to round to spindled tumor cells with pale eosinophilic cytoplasm and vesicular nuclei were arranged predominantly in sheets with an accompanying lymphocyte-rich inflammatory infiltrate. The tumor cells were positive for CD35, CD23, D2-40 in both tumors and additionally positive for CD21 in 1 tumor, all highlighting cell bodies and processes. Patients were alive without evidence of disease at 1 and 4 years with no adjuvant treatment. These cases highlight the importance of entertaining a broad differential diagnosis in lesions with epithelioid and/or spindled morphology involving the uterus.


Assuntos
Sarcoma de Células Dendríticas Foliculares , Humanos , Feminino , Sarcoma de Células Dendríticas Foliculares/diagnóstico , Sarcoma de Células Dendríticas Foliculares/cirurgia , Sarcoma de Células Dendríticas Foliculares/patologia , Útero/patologia , Histerectomia , Biópsia , Endométrio/patologia , Biomarcadores Tumorais/análise
19.
Oncologist ; 27(11): 930-939, 2022 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-35852437

RESUMO

BACKGROUND: Precision oncology relies on molecular diagnostics, and the value-proposition of modern healthcare networks promises a higher standard of care across partner sites. We present the results of a clinical pilot to standardize precision oncology workflows. METHODS: Workflows are defined as the development, roll-out, and updating of disease-specific molecular order sets. We tracked the timeline, composition, and effort of consensus meetings to define the combination of molecular tests. To assess clinical impact, we examined order set adoption over a two-year period (before and after roll-out) across all gastrointestinal and hepatopancreatobiliary (GI) malignancies, and by provider location within the network. RESULTS: Development of 12 disease center-specific order sets took ~9 months, and the average number of tests per indication changed from 2.9 to 2.8 (P = .74). After roll-out, we identified significant increases in requests for GI patients (17%; P < .001), compliance with testing recommendations (9%; P < .001), and the fraction of "abnormal" results (6%; P < .001). Of 1088 GI patients, only 3 received targeted agents based on findings derived from non-recommended orders (1 before and 2 after roll-out); indicating that our practice did not negatively affect patient treatments. Preliminary analysis showed 99% compliance by providers in network sites, confirming the adoption of the order sets across the network. CONCLUSION: Our study details the effort of establishing precision oncology workflows, the adoption pattern, and the absence of harm from the reduction of non-recommended orders. Establishing a modifiable communication tool for molecular testing is an essential component to optimize patient care via precision oncology.


Assuntos
Neoplasias , Humanos , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/terapia , Medicina de Precisão/métodos , Fluxo de Trabalho , Oncologia/métodos , Atenção à Saúde
20.
Mod Pathol ; 35(4): 470-479, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34775472

RESUMO

Classification of myeloid neoplasms with isolated isochromosome i(17q) [17p deletion with inherent monoallelic TP53 loss plus 17q duplication] is controversial. Most cases fall within the WHO unclassifiable myelodysplastic/myeloproliferative neoplasms (MDS/MPN-U) category. The uniformly dismal outcomes warrant better understanding of this entity. We undertook a multi-institutional retrospective study of 92 adult MDS/MPN-U cases from eight institutions. Twenty-nine (32%) patients had isolated i(17q) [MDS/MPN-i(17q)]. Compared to MDS/MPN without i(17q), MDS/MPN-i(17q) patients were significantly younger, had lower platelet and absolute neutrophil counts, and higher frequency of splenomegaly and circulating blasts. MDS/MPN-i(17q) cases showed frequent bilobed neutrophils (75% vs. 23%; P = 0.03), hypolobated megakaryocytes (62% vs. 20%; P = 0.06), and a higher frequency of SETBP1 (69% vs. 5%; P = 0.002) and SRSF2 (63% vs. 5%; P = 0.006) mutations that were frequently co-existent (44% vs. 0%; P = 0.01). TP53 mutations were rare. The mutation profile of MDS/MPN-U-i(17q) was similar to other myeloid neoplasms with i(17q) including atypical chronic myeloid leukemia, chronic myelomonocytic leukemia, myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis, myelodysplastic syndrome and acute myeloid leukemia, with frequent concomitant SETBP1/SRSF2 mutations observed across all the diagnostic entities. Over a median follow-up of 52 months, patients with MDS/MPN-i(17q) showed a shorter median overall survival (11 vs. 28 months; P < 0.001). The presence of i(17q) retained independent poor prognostic value in multivariable Cox-regression analysis [HR 3.686 (1.17-11.6); P = 0.026] along with splenomegaly. We suggest that MDS/MPN-i(17q) warrants recognition as a distinct subtype within the MDS/MPN-U category based on its unique clinico-biologic features and uniformly poor prognosis.


Assuntos
Produtos Biológicos , Isocromossomos , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa , Adulto , Medula Óssea/patologia , Humanos , Isocromossomos/genética , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/diagnóstico , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/genética , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/patologia , Mutação , Estudos Retrospectivos
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