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2.
Blood ; 2024 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-38996210

RESUMEN

Clonal cytopenia of undetermined significance (CCUS) represents a distinct disease entity characterized by myeloid-related somatic mutations with a variant allele fraction of ≥2% in individuals with unexplained cytopenia(s) but without a myeloid neoplasm (MN). Notably, CCUS carries a risk of progressing to MN, particularly in cases featuring high-risk mutations. Understanding CCUS requires dedicated studies to elucidate its risk factors and natural history. Our analysis of 357 CCUS patients investigated the interplay between clonality, cytopenia, and prognosis. Multivariate analysis identified 3 key adverse prognostic factors: the presence of splicing mutation(s) (score = 2 points), platelet count <100×109/L (score = 2.5), and ≥2 mutations (score = 3). Variable scores were based on the coefficients from the Cox proportional hazards model. This led to the development of the Clonal Cytopenia Risk Score (CCRS), which stratified patients into low- (score <2.5 points), intermediate- (score 2.5-<5), and high-risk (score ≥5) groups. The CCRS effectively predicted 2-year cumulative incidence of MN for low- (6.4%), intermediate- (14.1%), and high- (37.2%) risk groups, respectively, by Gray's test (P <.0001). We further validated the CCRS by applying it to an independent CCUS cohort of 104 patients, demonstrating a c-index of 0.64 (P =.005) in stratifying the cumulative incidence of MN. Our study underscores the importance of integrating clinical and molecular data to assess the risk of CCUS progression, making the CCRS a valuable tool that is practical and easily calculable. These findings are clinically relevant, shaping the management strategies for CCUS and informing future clinical trial designs.

4.
Curr Treat Options Oncol ; 25(8): 993-1010, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38916714

RESUMEN

OPINION STATEMENT: For adult patients diagnosed with relapsed B cell-ALL (B-ALL), there have been significant improvements in available treatment options following the FDA approval of novel cellular and immunotherapy approaches - blinatumomab, chimeric antigen receptor (CAR) T therapy, and inotuzumab. For the last several years, research has focused on gaining a better understanding of the effects of specific disease and patient characteristics on long-term outcomes with each of the FDA-approved agents. In combination with the better prevention and management of unique, treatment-specific toxicities, providers can now select the best available treatment option for each individual patient diagnosed with relapsed, adult B-ALL needing therapy. This has allowed more patients to proceed to consolidative hematopoietic stem cell transplant (HSCT), and long-term data has even brought into question the need for HSCT for long-term durable remission for all patients. However, with the adoption of blinatumomab, CAR T therapy, and inotuzumab in front-line treatment regimens, it remains unclear what effects this will have on patients with relapsed B-ALL following exposure to these novel cellular and immunotherapy therapies. Unlike B-ALL, similar advances have unfortunately not yet been realized in T cell-ALL (T-ALL). Currently, new therapeutic approaches are underway to utilize similar targeting strategies that have been successful in B-ALL - monoclonal antibodies, bispecific T-cell engagers (BiTE), and CAR T therapy. Like B-ALL, the only existing approved therapy for relapsed T-ALL, nelarabine, is now used in the upfront treatment setting potentially limiting its utility in relapsed disease. Over the next several years, the hope is for patients diagnosed with T-ALL to experience the drastic improvement in outcomes as has been seen for patients diagnosed with B-ALL over the last decade.


Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Manejo de la Enfermedad , Adulto , Inmunoterapia Adoptiva/métodos , Terapia Combinada/métodos , Anticuerpos Biespecíficos/uso terapéutico , Recurrencia , Resultado del Tratamiento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Recurrencia Local de Neoplasia/terapia
5.
Hemasphere ; 8(5): e69, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38774655

RESUMEN

Notable treatment advances have been made in recent years for patients with myelodysplastic syndromes/neoplasms (MDS), and several new drugs are under development. For example, the emerging availability of oral MDS therapies holds the promise of improving patients' health-related quality of life (HRQoL). Within this rapidly evolving landscape, the inclusion of HRQoL and other patient-reported outcomes (PROs) is critical to inform the benefit/risk assessment of new therapies or to assess whether patients live longer and better, for what will likely remain a largely incurable disease. We provide practical considerations to support investigators in generating high-quality PRO data in future MDS trials. We first describe several challenges that are to be thoughtfully considered when designing an MDS-focused clinical trial with a PRO endpoint. We then discuss aspects related to the design of the study, including PRO assessment strategies. We also discuss statistical approaches illustrating the potential value of time-to-event analyses and their implications within the estimand framework. Finally, based on a literature review of MDS randomized controlled trials with a PRO endpoint, we note the PRO items that deserve special attention when reporting future MDS trial results. We hope these practical considerations will facilitate the generation of rigorous PRO data that can robustly inform MDS patient care and support treatment decision-making for this patient population.

7.
Blood Rev ; 62: 101128, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37704469

RESUMEN

The guidelines for classification, prognostication, and response assessment of myelodysplastic syndromes/neoplasms (MDS) have all recently been updated. In this report on behalf of the International Consortium for MDS (icMDS) we summarize these developments. We first critically examine the updated World Health Organization (WHO) classification and the International Consensus Classification (ICC) of MDS. We then compare traditional and molecularly based risk MDS risk assessment tools. Lastly, we discuss limitations of criteria in measuring therapeutic benefit and highlight how the International Working Group (IWG) 2018 and 2023 response criteria addressed these deficiencies and are endorsed by the icMDS. We also address the importance of patient centered care by discussing the value of quality-of-life assessment. We hope that the reader of this review will have a better understanding of how to classify MDS, predict clinical outcomes and evaluate therapeutic outcomes.


Asunto(s)
Síndromes Mielodisplásicos , Neoplasias , Humanos , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/terapia , Medición de Riesgo , Calidad de Vida , Pronóstico
8.
Lancet Haematol ; 10(9): e767-e776, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37572683

RESUMEN

The existence of two acute myeloid leukaemia classification systems-one put forth by WHO and one by the International Consensus Classification in 2022-is concerning. Although both systems appropriately move towards genomic disease definitions and reduced emphasis on blast enumeration, there are consequential disagreements between the two systems on what constitutes a diagnosis of acute myeloid leukaemia. This fundamental problem threatens the ability of heath-care providers to diagnose acute myeloid leukaemia, communicate with patients and other health-care providers, and deliver appropriate and consistent management strategies for patients with the condition. Clinical trial eligibility, standardised response assessments, and eventual drug development and regulatory pathways might also be negatively affected by the discrepancies. In this Viewpoint, we review the merits and limitations of both classification systems and illustrate how the coexistence, as well as application of both systems is an undue challenge to patients, clinicians, hematopathologists, sponsors of research, and regulators. Lastly, we emphasise the urgency and propose a roadmap, by which the two divergent classification systems can be harmonised.


Asunto(s)
Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/diagnóstico
10.
Nat Commun ; 14(1): 3136, 2023 05 30.
Artículo en Inglés | MEDLINE | ID: mdl-37253784

RESUMEN

Genomic mutations drive the pathogenesis of myelodysplastic syndromes and acute myeloid leukemia. While morphological and clinical features have dominated the classical criteria for diagnosis and classification, incorporation of molecular data can illuminate functional pathobiology. Here we show that unsupervised machine learning can identify functional objective molecular clusters, irrespective of anamnestic clinico-morphological features, despite the complexity of the molecular alterations in myeloid neoplasia. Our approach reflects disease evolution, informed classification, prognostication, and molecular interactions. We apply machine learning methods on 3588 patients with myelodysplastic syndromes and secondary acute myeloid leukemia to identify 14 molecularly distinct clusters. Remarkably, our model shows clinical implications in terms of overall survival and response to treatment even after adjusting to the molecular international prognostic scoring system (IPSS-M). In addition, the model is validated on an external cohort of 412 patients. Our subclassification model is available via a web-based open-access resource ( https://drmz.shinyapps.io/mds_latent ).


Asunto(s)
Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Trastornos Mieloproliferativos , Humanos , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/patología , Mutación , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología
11.
Cancer J ; 29(3): 160-167, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37195772

RESUMEN

ABSTRACT: Myelodysplastic syndromes or myelodysplastic neoplasms (both abbreviated MDSs) (Leukemia 2022;36:1703-1719) have historically been challenging diseases to treat owing to their complex biology, molecular diversity, and a patient population that is elderly with comorbidities. As the patients are living longer, incidence of MDSs is rising, and challenges in selecting MDS treatments or lack thereof have been becoming more apparent. Fortunately, with better understanding of molecular underpinnings of this heterogeneous syndrome, numerous clinical trials reflecting the biology of disease and catering to the advanced age of MDS patients are in development to maximize the likelihood of identifying active drugs. Addressing this diverse nature of genetic abnormalities, novel agents, and combinations are in development to formulate personalized treatment approaches for MDS patients. Myelodysplastic syndrome is categorized into subtypes that are associated with lower or higher risk for leukemic evolution, and that knowledge helps with therapy selection. Currently, as it stands, for those with higher-risk MDSs, hypomethylating agents are the first-line therapy. Allogenic stem cell transplantation represents the only potential cure for our patients with MDSs and should be considered for all eligible patients with higher-risk MDSs at the time of diagnosis. This review discusses current MDS treatment landscape, as well as new approaches in development.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Humanos , Anciano , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/terapia
12.
Nat Commun ; 14(1): 3153, 2023 05 31.
Artículo en Inglés | MEDLINE | ID: mdl-37258544

RESUMEN

Graft-versus-leukemia (GvL) reactions are responsible for the effectiveness of allogeneic hematopoietic cell transplantation as a treatment modality for myeloid neoplasia, whereby donor T- effector cells recognize leukemia neoantigens. However, a substantial fraction of patients experiences relapses because of the failure of the immunological responses to control leukemic outgrowth. Here, through a broad immunogenetic study, we demonstrate that germline and somatic reduction of human leucocyte antigen (HLA) heterogeneity enhances the risk of leukemic recurrence. We show that preexistent germline-encoded low evolutionary divergence of class II HLA genotypes constitutes an independent factor associated with disease relapse and that acquisition of clonal somatic defects in HLA alleles may lead to escape from GvL control. Both class I and II HLA genes are targeted by somatic mutations as clonal selection factors potentially impairing cellular immune responses and response to immunomodulatory strategies. These findings define key molecular modes of post-transplant leukemia escape contributing to relapse.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia , Humanos , Leucemia/genética , Leucemia/terapia , Antígenos HLA/genética , Enfermedad Crónica , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Recurrencia
13.
Res Sq ; 2023 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-37066269

RESUMEN

Graft-versus-leukemia (GvL) reactions are responsible for the effectiveness of allogeneic hematopoietic cell transplantation as a treatment modality for myeloid neoplasia, whereby donor T- effector cells recognize leukemia neoantigens. However, a substantial fraction of patients experience relapses because of the failure of the immunological responses to control leukemic outgrowth. Here, through a broad immunogenetic study, we demonstrate that germline and somatic reduction of human leucocyte antigen (HLA) heterogeneity enhances the risk of leukemic recurrence. We show that preexistent germline-encoded low evolutionary divergence of class II HLA genotypes constitutes an independent factor associated with disease relapse and that acquisition of clonal somatic defects in HLA alleles may lead to escape from GvL control. Both class I and II HLA genes are targeted by somatic mutations as clonal selection factors potentially impairing cellular immune reactions and response to immunomodulatory strategies. These findings define key molecular modes of post-transplant leukemia escape contributing to relapse.

14.
Oncologist ; 28(10): 901-910, 2023 10 03.
Artículo en Inglés | MEDLINE | ID: mdl-37120291

RESUMEN

BACKGROUND: Older patients with myelodysplastic syndromes (MDS), particularly those with no or one cytopenia and no transfusion dependence, typically have an indolent course. Approximately, half of these receive the recommended diagnostic evaluation (DE) for MDS. We explored factors determining DE in these patients and its impact on subsequent treatment and outcomes. PATIENTS AND METHODS: We used 2011-2014 Medicare data to identify patients ≥66 years of age diagnosed with MDS. We used Classification and Regression Tree (CART) analysis to identify combinations of factors associated with DE and its impact on subsequent treatment. Variables examined included demographics, comorbidities, nursing home status, and investigative procedures performed. We conducted a logistic regression analysis to identify correlates associated with receipt of DE and treatment. RESULTS: Of 16 851 patients with MDS, 51% underwent DE. patients with MDS with no cytopenia (n = 3908) had the lowest uptake of DE (34.7%). Compared to patients with no cytopenia, those with any cytopenia had nearly 3 times higher odds of receiving DE [adjusted odds ratio (AOR), 2.81: 95% CI, 2.60-3.04] and the odds were higher for men than for women [AOR, 1.39: 95%CI, 1.30-1.48] and for Non-Hispanic Whites [vs. everyone else (AOR, 1.17: 95% CI, 1.06-1.29)]. The CART showed DE as the principal discriminating node, followed by the presence of any cytopenia for receiving MDS treatment. The lowest percentage of treatment was observed in patients without DE, at 14.6%. CONCLUSION: In this select older patients with MDS, we identified disparities in accurate diagnosis by demographic and clinical factors. Receipt of DE influenced subsequent treatment but not survival.


Asunto(s)
Anemia , Síndromes Mielodisplásicos , Masculino , Humanos , Femenino , Anciano , Estados Unidos/epidemiología , Medicare , Síndromes Mielodisplásicos/terapia , Síndromes Mielodisplásicos/tratamiento farmacológico , Comorbilidad
15.
Blood Rev ; 60: 101072, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-36934059

RESUMEN

Biological events that contribute to the pathogenesis of myelodysplastic syndromes/neoplasms (MDS) are becoming increasingly characterized and are being translated into rationally designed therapeutic strategies. Herein, we provide updates from the first International Workshop on MDS (iwMDS) of the International Consortium for MDS (icMDS) detailing recent advances in understanding the genetic landscape of MDS, including germline predisposition, epigenetic and immune dysregulation, the complexities of clonal hematopoiesis progression to MDS, as well as novel animal models of the disease. Connected to this progress is the development of novel therapies targeting specific molecular alterations, the innate immune system, and immune checkpoint inhibitors. While some of these agents have entered clinical trials (e.g., splicing modulators, IRAK1/4 inhibitors, anti-CD47 and anti-TIM3 antibodies, and cellular therapies), none have been approved for MDS. Additional preclinical and clinical work is needed to develop a truly individualized approach to the care of MDS patients.


Asunto(s)
Síndromes Mielodisplásicos , Neoplasias , Animales , Humanos , Síndromes Mielodisplásicos/etiología , Síndromes Mielodisplásicos/terapia , Epigenómica , Tratamiento Basado en Trasplante de Células y Tejidos , Procesamiento Proteico-Postraduccional
16.
Blood ; 141(17): 2047-2061, 2023 04 27.
Artículo en Inglés | MEDLINE | ID: mdl-36724453

RESUMEN

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.


Asunto(s)
Hematología , Síndromes Mielodisplásicos , Humanos , Resultado del Tratamiento , Consenso , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/tratamiento farmacológico , Evaluación de Resultado en la Atención de Salud
19.
Best Pract Res Clin Haematol ; 35(4): 101415, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36517125

RESUMEN

The advances and progress in the understanding and management of acute leukemia and myelodysplasia continue to occur at an exponential rate. While this has led to more therapy options, clinicians and researchers are now facing more challenges in terms of clinical decision-making and more unanswered questions. This paper has outlined some conundrums in acute leukemia and myelodysplasia, and the efforts that are underway to address these.


Asunto(s)
Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Humanos , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/terapia , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Enfermedad Aguda
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