RESUMEN
Donor-derived haematological neoplasms, in which recipients present with haematological malignancies that have evolved from transplant donor stem cells, have previously been described for myelodysplastic syndrome, myeloproliferative neoplasms, acute myeloid leukaemia and less often, leukaemias of lymphoid origin. Here we describe a rare and complex case of donor-derived T-cell acute lymphoblastic leukaemia with a relatively short disease latency of less than 4 years. Through genomic and in vitro analyses, we identified novel mutations in NOTCH1 as well as a novel activating mutation in STAT5B; the latter targetable with the clinically available drugs, venetoclax and ruxolitinib.
Asunto(s)
Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Masculino , Femenino , Hermanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Donantes de Tejidos , Linfocitos TRESUMEN
Azacitidine (AZA) is commonly used hypomethylating agent for higher risk myelodysplastic syndromes and acute myeloid leukemia (AML). Although some patients achieve remission, eventually most patients fail AZA therapy. Comprehensive analysis of intracellular uptake and retention (IUR) of carbon-labeled AZA (14C-AZA), gene expression, transporter pump activity with or without inhibitors, and cytotoxicity in naïve and resistant cell lines provided insight into the mechanism of AZA resistance. AML cell lines were exposed to increasing concentrations of AZA to create resistant clones. 14C-AZA IUR was significantly lower in MOLM-13- (1.65 ± 0.08 ng vs. 5.79 ± 0.18 ng; p < 0.0001) and SKM-1- (1.10 ± 0.08 vs. 5.08 ± 0.26 ng; p < 0.0001) resistant cells compared to respective parental cells. Importantly, 14C-AZA IUR progressively reduced with downregulation of SLC29A1 expression in MOLM-13- and SKM-1-resistant cells. Furthermore, nitrobenzyl mercaptopurine riboside, an SLC29A inhibitor, reduced 14C-AZA IUR in MOLM-13 (5.79 ± 0.18 vs. 2.07 ± 0.23, p < 0.0001) and SKM-1-naive cells (5.08 ± 2.59 vs. 1.39 ± 0.19, p = 0.0002) and reduced efficacy of AZA. As the expression of cellular efflux pumps such as ABCB1 and ABCG2 did not change in AZA-resistant cells, they are unlikely contribute to AZA resistance. Therefore, the current study provides a causal link between in vitro AZA resistance and downregulation of cellular influx transporter SLC29A1.
Asunto(s)
Azacitidina , Resistencia a Antineoplásicos , Tranportador Equilibrativo 1 de Nucleósido , Leucemia Mieloide Aguda , Humanos , Azacitidina/farmacología , Azacitidina/uso terapéutico , Línea Celular Tumoral/efectos de los fármacos , Línea Celular Tumoral/metabolismo , Regulación hacia Abajo , Resistencia a Antineoplásicos/genética , Tranportador Equilibrativo 1 de Nucleósido/efectos de los fármacos , Tranportador Equilibrativo 1 de Nucleósido/metabolismo , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismoRESUMEN
Up to 90% of patients with a myelodysplastic syndrome require red blood cell transfusion; nevertheless, comprehensive data on red cell alloimmunization in such patients are limited. This study evaluates the incidence and clinical impact of red cell alloimmunization in a large cohort of patients with myelodysplastic syndrome registered in the statewide South Australian-MDS registry. The median age of the 817 patients studied was 73 years, and 66% were male. The cumulative incidence of alloimmunization was 11%. Disease-modifying therapy was associated with a lower risk of alloimmunization while alloimmunization was significantly higher in patients with a revised International Prognostic Scoring System classification of Very Low, Low or Intermediate risk compared to those with a High or Very High risk (P=0.03). Alloantibodies were most commonly directed against antigens in the Rh (54%) and Kell (24%) systems. Multiple alloantibodies were present in 49% of alloimmunized patients. Although 73% of alloimmunized patients developed alloantibodies during the period in which they received their first 20 red cell units, the total number of units transfused was significantly higher in alloimmunized patients than in non-alloimmunized patients (90±100 versus 30±52; P<0.0001). In individual patients, red cell transfusion intensity increased significantly following alloimmunization (2.8±1.3 versus 4.1±2.0; P<0.0001). A significantly higher proportion of alloimmunized patients than non-alloimmunized patients had detectable autoantibodies (65% versus 18%; P<0.0001) and the majority of autoantibodies were detected within a short period of alloimmunization. In conclusion, this study characterizes alloimmunization in a large cohort of patients with myelodysplastic syndrome and demonstrates a signficant increase in red cell transfusion requirements following alloimmunization, most probably due to development of additional alloantibodies and autoantibodies, resulting in subclinical/clinical hemolysis. Strategies to mitigate alloimmunization risk are critical for optimizing red cell transfusion support.
Asunto(s)
Transfusión de Eritrocitos , Eritrocitos/inmunología , Síndromes Mielodisplásicos/sangre , Anciano , Australia , Autoanticuerpos/biosíntesis , Humanos , Isoanticuerpos , Masculino , Síndromes Mielodisplásicos/inmunología , Síndromes Mielodisplásicos/metabolismo , Síndromes Mielodisplásicos/terapiaRESUMEN
RBC-transfusion dependency (RBC-TD) is an independent prognostic factor for poor overall survival (OS) in the WHO classification-based prognostic scoring system (WPSS) for MDS patients. However, WPSS did not include cytopenia, whereas revised International Prognostic Scoring System (IPSS-R) did not include RBC-TD. Thus, neither of these prognostic scoring systems incorporates both cytopenia and RBC-TD. We aimed to test whether RBC-TD adds prognostic value to the IPSS-R. We analyzed MDS patients not treated with disease-modifying therapy, and enrolled in SA-MDS Registry (derivation cohort; n = 295) and Dusseldorf registry (Germany; validation cohort; n = 113) using time-dependent Cox proportional regression and serial landmark analyses. In the derivation cohort, RBC-TD patients had inferior OS compared to RBC transfusion-independent (RBC-TI) patients (P < 0.0001) at 6- (18 vs. 64 months), 12- (24 vs. 71 months), and 24-months (40 vs. 87 months). In a Cox proportional regression analysis, RBC-TD was an independent adverse prognostic marker in addition to age, sex, and IPSS-R variables (P < 0.0001). A prognostic index (PI) was derived using these Cox-proportional regression model variables. In the validation cohort, this PI classified patients into four prognostic groups with significantly different OS (P < 0.001) as in the derivation cohort. In conclusion, multivariate analysis by Cox proportional hazards regression and serial landmark analyses clearly demonstrates that development of RBC-TD at any time during the course of MDS is associated with poor OS, independent of IPSS-R. This study demonstrates that dynamic assessment of RBC-TD provides additional prognostic value to IPSS-R and should be included in treatment decision algorithms for MDS patients.
Asunto(s)
Transfusión de Eritrocitos , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/terapia , Adulto , Anciano , Anciano de 80 o más Años , Australia , Causas de Muerte , Terapia Combinada , Manejo de la Enfermedad , Transfusión de Eritrocitos/métodos , Femenino , Alemania , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/diagnóstico , Pronóstico , Modelos de Riesgos Proporcionales , Sistema de Registros , Reproducibilidad de los Resultados , Resultado del Tratamiento , Adulto JovenAsunto(s)
Transfusión de Eritrocitos , Inmunización , Isoanticuerpos , Síndromes Mielodisplásicos , Reacción a la Transfusión , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Isoanticuerpos/sangre , Isoanticuerpos/inmunología , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/sangre , Síndromes Mielodisplásicos/epidemiología , Síndromes Mielodisplásicos/inmunología , Síndromes Mielodisplásicos/terapia , Prevalencia , Reacción a la Transfusión/sangre , Reacción a la Transfusión/epidemiología , Reacción a la Transfusión/inmunología , Reacción a la Transfusión/terapiaRESUMEN
Therapy-related myeloid neoplasm (tMN) is considered a direct consequence of DNA damage in hematopoietic stem cells. Despite increasing recognition that altered stroma can also drive leukemogenesis, the functional biology of the tMN microenvironment remains unknown. We performed multiomic (transcriptome, DNA damage response, cytokine secretome and functional profiling) characterization of bone marrow stromal cells from tMN patients. Critically, we also compared (i) patients with myeloid neoplasm and another cancer but without cytotoxic exposure, (ii) typical primary myeloid neoplasm, and (iii) age-matched controls to decipher the microenvironmental changes induced by cytotoxics vs. neoplasia. Strikingly, tMN exhibited a profoundly senescent phenotype with induction of CDKN1A and ß-Galactosidase, defective phenotype, and proliferation. Moreover, tMN stroma showed delayed DNA repair and defective adipogenesis. Despite their dormant state, tMN stromal cells were metabolically highly active with a switch toward glycolysis and secreted multiple pro-inflammatory cytokines indicative of a senescent-secretory phenotype that inhibited adipogenesis. Critically, senolytics not only eliminated dormant cells, but also restored adipogenesis. Finally, sequential patient sampling showed senescence phenotypes are induced within months of cytotoxic exposure, well prior to the onset of secondary cancer. Our data underscores a role of senescence in the pathogenesis of tMN and provide a valuable resource for future therapeutics.
Asunto(s)
Antineoplásicos , Células Madre Mesenquimatosas , Neoplasias , Humanos , Senescencia Celular/genética , Secretoma , Células Madre Mesenquimatosas/metabolismo , Antineoplásicos/farmacología , Citocinas/metabolismo , Microambiente TumoralRESUMEN
The majority of studies assessing the contribution of pathogenic germline variants (PGVs) to cancer predisposition have focused on patients with single cancers. We analyzed 45 known cancer predisposition genes (CPGs) in germline samples of 202 patients with hematological malignancies (HMs) plus one or more other independent cancer managed at major tertiary medical centers on two different continents. This included 120 patients with therapy-related myeloid neoplasms (t-MNs), where the HM occurred after cytotoxic treatment for a first malignancy, and 82 patients with multiple cancers in which the HM was not preceded by cytotoxic therapy (MC-HM). Using American College of Medical Genetics/Association for Molecular Pathology variant classification guidelines, 13% of patients had PGVs, most frequently identified in CHEK2 (17% of PGVs), BRCA1 (13%), DDX41 (13%), and TP53 (7%). The frequency of PGVs in MC-HM was higher than in t-MN, although not statistically significant (18 vs. 9%; p = 0.085). The frequency of PGVs in lymphoid and myeloid HM patients was similar (19 vs. 17.5%; p > 0.9). Critically, patients with PGVs in BRCA1, BRCA2 or TP53 did not satisfy current clinical phenotypic criteria for germline testing. Our data suggest that a personal history of multiple cancers, one being a HM, should trigger screening for PGVs.
Asunto(s)
Proteína BRCA1/genética , Proteína BRCA2/genética , Biomarcadores de Tumor/genética , Mutación de Línea Germinal , Neoplasias Hematológicas/patología , Neoplasias/patología , Proteína p53 Supresora de Tumor/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Neoplasias Hematológicas/epidemiología , Neoplasias Hematológicas/genética , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/epidemiología , Neoplasias/genética , Pronóstico , Estudios Retrospectivos , Estados Unidos/epidemiología , Adulto JovenAsunto(s)
Enfermedades Autoinmunes , Metotrexato , Humanos , Metotrexato/uso terapéutico , Metotrexato/efectos adversos , Femenino , Masculino , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/inducido químicamente , Persona de Mediana Edad , Anciano , Enfermedades Reumáticas/tratamiento farmacológico , Adulto , Antirreumáticos/uso terapéutico , Antirreumáticos/efectos adversosRESUMEN
Therapy-related myeloid neoplasms (T-MN) are poorly characterized secondary hematological malignancies following chemotherapy/radiotherapy exposure. We compared the clinical and mutational characteristics of T-MN (n = 129) and primary myelodysplastic syndrome (P-MDS, n = 108) patients. Although the somatic mutation frequency was similar between T-MN and P-MDS patients (93% in both groups), the pattern was distinct. TP53 mutations were more frequent in T-MN (29.5 vs. 7%), while spliceosomal complex mutations were more common in P-MDS (56.5 vs. 25.6%). In contrast to P-MDS, the ring sideroblasts (RS) phenotype was not associated with better survival in T-MN, most probably due to genetic association with TP53 mutations. SF3B1 was mutated in 96% of P-MDS with ≥15% RS, but in only 32% T-MN. TP53 mutations were detected in 92% T-MN with ≥15% RS and SF3B1 wild-type cases. Interestingly, T-MN and P-MDS patients with "Very low" or "Low" Revised International Prognostic Scoring System (IPSS-R) showed similar biological and clinical characteristics. In a Cox regression analysis, TP53 mutation was a poor prognostic factor in T-MN, independent of IPSS-R cytogenetics, disease-modifying therapy, and NRAS mutation. Our data have direct implications for T-MN management and provide evidence that, in addition to conventional disease parameters, mutational analysis should be incorporated in T-MN risk stratification.