Estudio clínico y biológico de la leucemia mielomonocítica crónica

La leucemia mielomonocítica crónica (LMMC) es un trastorno hematológico poco frecuente con una expresión clínica y morfológica muy heterogénea, sin embargo, hasta ahora no se ha aceptado ningún sistema pronóstico para los pacientes con LMMC. Los principales objetivos de este estudio fueron evaluar el impacto pronóstico de las alteraciones citogenéticas e identificar los factores pronósticos más relevantes tanto para supervivencia global (SG) como para el riesgo de evolución a leucemia mieloblástica aguda (LMA) en una serie de pacientes con LMMC de novo. Además se desarrolló y validó en una cohorte externa un nuevo sistema de pronóstico específico para la LMMC (CPSS). Para desarrollar el CPSS se utilizó una cohorte de 558 pacientes con LMMC del Grupo Español de Síndromes Mielodisplásicos. El valor pronóstico del CPSS fue evaluado en una cohorte independiente de 274 pacientes. Las variables más relevantes para el resultado fueron los subtipos morfológicos según las clasificaciones FAB y WHO, la citogenética según el riesgo citogenético específico de LMMC (bajo riesgo: cariotipo normal o pérdida del cromosoma Y como anomalía única; alto riesgo: presencia de trisomia 8 o anormalidades del cromosoma 7 o cariotipo complejo; y riesgo intermedio: el resto de anormalidades) y la dependencia transfusional. El CPSS permitió clasificar a los pacientes en cuatro grupos de riesgo claramente diferenciados para la SG (P< .001) y para el riesgo de evolución a LMA (P< .001) y su capacidad de predicción fue confirmada en la cohorte de validación. Este estudio confirma el impacto pronóstico en los subtipos de las clasificaciones FAB y WHO, y reconoce la importancia de la dependencia transfusional y de la citogenética en la LMMC, además ofrece un nuevo sistema de clasificación pronóstica simple y robusto para evaluar con precisión el pronóstico y para facilitar la planificación terapéutica mas apropiada para la LMMC.The natural course of chronic myelomonocytic leukemia (CMML) is highly variable but a widely accepted prognostic scoring system for patients with CMML is not available. The main aims of this study were to evaluate the independent prognostic impact of cytogenetic abnormalities, to identify prognostic factors for overall survival (OS) and risk of evolution to acute myeloblastic leukemia (AML) in a large series of patients with de novo CMML and to develop and validate in an external cohort a new CMML-specific prognostic scoring system (CPSS). A training cohort consisting of 558 patients with CMML from the Spanish Group of Myelodysplastic Syndromes. was used to develop the CPSS. The prognostic value of the CPSS was evaluated in an independent cohort of 274 patients. The most relevant variables for outcome were FAB and WHO morphological subtypes, and cytogenetic according to CMML-specific cytogenetic risk classification (low risk: normal karyotype or loss of Y chromosome as a single anomaly), high risk (presence of trisomy 8 or abnormalities of chromosome 7,or complex karyotype), and intermediate risk (all other abnormalities), and RBC-transfusion dependence. CPSS was able to segregate patients into four clearly different risk groups for both OS (P< .001) and risk of AML evolution (P< .001) and its predictive capability was confirmed in the validation cohort. This study confirms the prognostic impact of FAB and WHO subtypes, recognizes the importance of RBC-transfusion dependency and cytogenetic and offers a simple and powerful CPSS for accurately assessing prognosis and planning therapy in CMML

Prognostic heterogeneity of adult B-cell precursor acute lymphoblastic leukaemia patients with t(1;19)(q23;p13)/TCF3-PBX1 treated with measurable residual disease-oriented protocols

Acute lymphoblastic leukaemia; Cytogenetic alterations; PrognosisLeucemia linfoblástica aguda; Alteraciones citogenéticas; PronósticoLeucèmia limfoblàstica aguda; Alteracions citogenètiques; PronòsticThe prognosis of t(1;19)(q23;p13)/transcription factor 3-pre-B-cell leukaemia homeobox 1 (TCF3-PBX1) in adolescent and adult patients with acute lymphoblastic leukaemia (ALL) treated with measurable residual disease (MRD)-oriented trials remains controversial. In the present study, we analysed the outcome of adolescent and adult patients with t(1;19)(q23;p13) enrolled in paediatric-inspired trials. The patients with TCF3-PBX1 showed similar MRD clearance and did not have different survival compared with other B-cell precursor ALL patients. However, patients with TCF3-PBX1 had a significantly higher cumulative incidence of relapse, especially among patients aged ≥35 years carrying additional cytogenetic alterations. These patients might benefit from additional/intensified therapy (e.g. immunotherapy in first complete remission with or without subsequent haematopoietic stem cell transplantation).This work was supported in part by CERCA/Generalitat de Catalunya SGR 2017 288 (GRC), a restricted grant from ‘La Caixa’ and Healthcare Alliance for Resourceful Medicine Offensive against Neoplasms (HARMONY)

Complex Variant t(9;22) Chromosome Translocations in Five Cases of Chronic Myeloid Leukemia

The Philadelphia (Ph1) chromosome arising from the reciprocal t(9;22) translocation is found in more than 90% of chronic myeloid leukemia (CML) patients and results in the formation of the chimeric fusion gene BCR-ABL. However, a small proportion of patients with CML have simple or complex variants of this translocation, involving various breakpoints in addition to 9q34 and 22q11. We report five CML cases carrying variant Ph translocations involving both chromosomes 9 and 22 as well as chromosomes 3, 5, 7, 8, or 10. G-banding showed a reciprocal three-way translocation involving 3q21, 5q31, 7q32, 8q24, and 10q22 bands. BCR-ABL fusion signal on der(22) was found in all of the cases by FISH

Mutational Profile Enables the Identification of a High-Risk Subgroup in Myelodysplastic Syndromes with Isolated Trisomy 8

Simple Summary Trisomy 8 (+8) is one of the most frequent cytogenetic alterations found in myelodysplastic syndromes (MDS). MDS patients harboring isolated +8 show clinical heterogeneity, and life expectancy varies between several months and several years after diagnosis. We aimed to investigate whether the mutational profile of isolated +8 MDS patients could help to clarify the heterogeneous prognosis of these patients. In fact, we found that mutations in STAG2, SRSF2 and RUNX1 are independent prognostic factors, enough to define the course of the disease in terms of overall survival and leukemic transformation in isolated +8 MDS. Therefore, these findings might help to identify patients at a high risk of evolving disease and open new horizons by changes in the management of a high subset of patients within MDS with isolated +8. Trisomy 8 (+8) is the most frequent trisomy in myelodysplastic syndromes (MDS) and is associated with clinical heterogeneity and intermediate cytogenetic risk when found in isolation. The presence of gene mutations in this group of patients and the prognostic significance has not been extensively analyzed. Targeted deep sequencing was performed in a cohort of 79 MDS patients showing isolated +8. The most frequently mutated genes were: TET2 (38%), STAG2 (34.2%), SRSF2 (29.1%) and RUNX1 (26.6%). The mutational profile identified a high-risk subgroup with mutations in STAG2, SRSF2 and/or RUNX1, resulting in shorter time to acute myeloid leukemia progression (14 months while not reached in patients without these mutations, p < 0.0001) and shorter overall survival (23.7 vs. 46.3 months, p = 0.001). Multivariate analyses revealed the presence of mutations in these genes as an independent prognostic factor in MDS showing +8 isolated (HR: 3.1; p < 0.01). Moreover, 39.5% and 15.4% of patients classified as low/intermediate risk by the IPSS-R and IPSS-M, respectively, were re-stratified as a high-risk subgroup based on the mutational status of STAG2, SRSF2 and RUNX1. Results were validated in an external cohort (n = 2494). In summary, this study validates the prognosis significance of somatic mutations shown in IPSS-M and adds STAG2 as an important mutated gene to consider in this specific subgroup of patients. The mutational profile in isolated +8 MDS patients could, therefore, offer new insights for the correct management of patients with a higher risk of leukemic transformation

CYP2C8 gene polymorphism and bisphosphonate-related osteonecrosis of the jaw in patients with multiple myeloma

Osteonecrosis of the jaw is an uncommon but potentially serious complication of bisphosphonate therapy in multiple myeloma. Previous studies showed that the presence of one or two minor alleles of the cytochrome P450, subfamily 2C polypeptide 8 gene (CYP2C8) polymorphism rs1934951 was an independent prognostic marker associated with development of osteonecrosis of the jaw in multiple myeloma patients treated with bisphosphonates. The aim of this study was to validate the frequency of SNP rs193451 in 79 patients with multiple myeloma. In 9 (22%) patients developing osteonecrosis of the jaw, a heterozygous genotype was found, in contrast with those who did not develop osteonecrosis of the jaw (n=4, 11%) or healthy individuals (n=6, 13%). We found no differences in the cumulative risk of developing osteonecrosis of the jaw between patients homozygous and heterozygous for the major allele. We were unable to confirm a significant association between this polymorphism and the risk of developing osteonecrosis of the jaw

The modular network structure of the mutational landscape of Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is associated with the sequential accumulation of acquired genetic alterations. Although at diagnosis cytogenetic alterations are frequent in AML, roughly 50% of patients present an apparently normal karyotype (NK), leading to a highly heterogeneous prognosis. Due to this significant heterogeneity, it has been suggested that different molecular mechanisms may trigger the disease with diverse prognostic implications. We performed whole-exome sequencing (WES) of tumor-normal matched samples of de novo AML-NK patients lacking mutations in NPM1, CEBPA or FLT3-ITD to identify new gene mutations with potential prognostic and therapeutic relevance to patients with AML. Novel candidate-genes, together with others previously described, were targeted resequenced in an independent cohort of 100 de novo AML patients classified in the cytogenetic intermediate-risk (IR) category. A mean of 4.89 mutations per sample were detected in 73 genes, 35 of which were mutated in more than one patient. After a network enrichment analysis, we defined a single in silico model and established a set of seed-genes that may trigger leukemogenesis in patients with normal karyotype. The high heterogeneity of gene mutations observed in AML patients suggested that a specific alteration could not be as essential as the interaction of deregulated pathways

Prognostic heterogeneity of adult B-cell precursor acute lymphoblastic leukaemia patients with t(1;19)(q23;p13)/TCF3-PBX1 treated with measurable residual disease-oriented protocols

Programa para el Tratamiento de Hemopatias Malignas (PETHEMA) Group (Spanish Society of Hematology, SEHH).The prognosis of t(1;19)(q23;p13)/transcription factor 3-pre-B-cell leukaemia homeobox 1 (TCF3-PBX1) in adolescent and adult patients with acute lymphoblastic leukaemia (ALL) treated with measurable residual disease (MRD)-oriented trials remains controversial. In the present study, we analysed the outcome of adolescent and adult patients with t(1;19)(q23;p13) enrolled in paediatric-inspired trials. The patients with TCF3-PBX1 showed similar MRD clearance and did not have different survival compared with other B-cell precursor ALL patients. However, patients with TCF3-PBX1 had a significantly higher cumulative incidence of relapse, especially among patients aged ≥35 years carrying additional cytogenetic alterations. These patients might benefit from additional/intensified therapy (e.g. immunotherapy in first complete remission with or without subsequent haematopoietic stem cell transplantation).This work was supported in part by CERCA/Generalitat de Catalunya SGR 2017 288 (GRC), a restricted grant from ‘La Caixa’ and Healthcare Alliance for Resourceful Medicine Offensive against Neoplasms (HARMONY)

Prognostic heterogeneity of adult B-cell precursor acute lymphoblastic leukaemia patients with t(1;19)(q23;p13)/TCF3-PBX1 treated with measurable residual disease-oriented protocols

The prognosis of t(1;19)(q23;p13)/transcription factor 3-pre-B-cell leukaemia homeobox 1 (TCF3-PBX1) in adolescent and adult patients with acute lymphoblastic leukaemia (ALL) treated with measurable residual disease (MRD)-oriented trials remains controversial. In the present study, we analysed the outcome of adolescent and adult patients with t(1;19)(q23;p13) enrolled in paediatric-inspired trials. The patients with TCF3-PBX1 showed similar MRD clearance and did not have different survival compared with other B-cell precursor ALL patients. However, patients with TCF3-PBX1 had a significantly higher cumulative incidence of relapse, especially among patients aged ≥35 years carrying additional cytogenetic alterations. These patients might benefit from additional/intensified therapy (e.g. immunotherapy in first complete remission with or without subsequent haematopoietic stem cell transplantation). 40 __ $u https://creativecommons.org/licenses/by-nc-nd/4.0

ALL-268 genetic classification of B-Cell precursor adult acute lymphoblastic leukemia patients enrolled in LAL19 trial from the pethema group: response to treatment and survival

Context: B-cell precursor acute lymphoblastic leukemia (BCP ALL) is a genetically heterogeneous neoplasm with >20 biologic subtypes. Each subtype shows specific genetic traits that determine relapse risk and patients' survival. Objectives: To establish the genetic subtype (primary alteration) of adult BCP ALL patients enrolled in the PETHEMA LAL19 trial (NCT 04179929) and to correlate them with measurable residual disease (MRD) level and survival. Patients and Methods: In the LAL19 trial (NCT04179929), Ph-negative patients (18–65 y) with MRD≥0.01% at day+35 or high-risk genetics receive alloHSCT and MRD<0.01% patients with standard-risk genetics receive maintenance chemotherapy. The genetic analyses are centralized: FISH and NGS DNA panel (Hospital de Salamanca), RNAseq panel (Hospital 12 de Octubre), FISH panel (Hospital La Fe), and SNP array (Josep Carreras Institute/ICO-Hospital Germans Trias i Pujol). MRD determinations are centrally done by next-generation flow cytometry in the Cytometry Service, NUCLEUS, University of Salamanca. Results: The genetic subtype was identified in 54% (82/152) of patients. The most recurrent subtypes were KMT2Ar (11%), Ph-like (mostly CRLF2::IGH, 11%), low-hypodiploid (7%), PAX5 P80R (7%), high-hyperdiploid (6%), and t(1;19)/TCF3::PBX1 (6%). In addition, t(12;21)/ETV6::RUNX1, ZNF384r, and iAMP21 subtypes (1.5% each) and MEF2Dr, MYCr, IDH1 R132 subtypes (<1% each) were found. Regarding secondary alterations, NRAS (15%), TP53 (13%), PAX5 (13%), and KRAS (10%) mutations were the most frequently observed. Twelve patients were refractory (mainly low-hypodiploid, Ph-like, MYCr, and B-other/unclassified patients). Statistically significant differences were observed for day+35 MRD levels between genetic subtypes. Ph-like, low-hypodiploid, and KMT2Ar showed lower frequencies of MRD<0.01% (17%, 33%, and 57%, respectively) than patients with PAX5P80R (100%), t(1;19)/TCF3::PBX1 (83%), and high-hyperdiploid (75%) (P=0.006). Despite the short median follow-up (11 months), differences in response to treatment were reflected in patients' survival. Significant differences in survival were observed between poor-response subtypes (Ph-like, KMT2Ar, and low-hypodiploid) and good-response subtypes (PAX5 P80R, t(1;19)/TCF3::PBX1, and high-hyperdiploid). Conclusions: Knowing the genetic subtype of each ALL is crucial to better predict relapse risk and offer the best (personalized) treatment for each patient

Outcomes and effect of somatic mutations after erythropoiesis stimulating agents in patients with lower-risk myelodysplastic syndromes

Background: Erythropoiesis stimulating agents (ESAs) are the first-line therapy in patients with lower-risk myelodysplastic syndromes (LR-MDS). Some predictive factors for ESAs response have been identified. Type and number of somatic mutations have been associated with prognosis and response to therapies in MDS patients.Objectives: The objective was to evaluate the outcomes after ESAs in patients with LR-MDS and to address the potential predictive value of somatic mutations in ESAs-treated patients.Design: Multi-center retrospective study of a cohort of 722 patients with LR-MDS included in the SPRESAS (Spanish Registry of Erythropoietic Stimulating Agents Study) study. Retrospective analysis of 65 patients with next generation sequencing (NGS) data from diagnosis.Methods: ESAs' efficacy and safety were evaluated in patients receiving ESAs and best supportive care (BSC). To assess the potential prognostic value of somatic mutations in erythroid response (ER) rate and outcome, NGS was performed in responders and non-responders.Results: ER rate for ESAs-treated patients was 65%. Serum erythropoietin (EPO) level = 3; p = 0.170). The presence of >= 3 mutated genes was also significantly associated with worse OS (hazard ratio, 2.8; p= 0.015), even in responders. A higher cumulative incidence of acute myeloid leukemia progression at 5 years was also observed in patients with >= 3 mutated genes versus<3 (33.3% and 10.7%, respectively; p< 0.001).Conclusion: This large study confirms the beneficial effect of ESAs and the adverse effect of somatic mutations in patients with LR-MDS