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Leukemias are currently subclassified based on the presence of recurrent cytogenetic abnormalities and gene mutations. These molecular findings are the basis for risk-adapted therapy; however, such data are generally obtained by disparate methods in the clinical laboratory, and often rely on low-resolution techniques such as fluorescent in situ hybridization. Using targeted next generation sequencing, we demonstrate that the full spectrum of prognostically significant gene mutations including translocations, single nucleotide variants (SNVs), and insertions/deletions (indels) can be identified simultaneously in multiplexed sequence data. As proof of concept, we performed hybrid capture using a panel of 20 genes implicated in leukemia prognosis (covering a total of 1 Mbp) from five leukemia cell lines including K562, NB4, OCI-AML3, kasumi-1, and MV4–11. Captured DNA was then sequenced in multiplex on an Illumina HiSeq. Using an analysis pipeline based on freely available software we correctly identified DNA-level translocations in three of the three cell lines where translocations were covered by our capture probes. Furthermore, we found all published gene mutations in commonly tested genes including NPM1, FLT3, and KIT. The same methodology was applied to DNA extracted from the bone marrow of a patient with acute myeloid leukemia, and identified a t(9;11) translocation with single base accuracy as well other gene mutations. These results indicate that targeted next generation sequencing can be successfully applied in the clinical laboratory to identify a full spectrum of DNA mutations ranging from SNVs and indels to translocations. Such methods have the potential to both greatly streamline and improve the accuracy of DNA-based diagnostics.

Background: The established clinical staging systems (Rai/Binet) of chronic lymphocytic leukemia (CLL) cannot accurately predict the appropriate treatment of patients in the earlier stages. In the past two decades, several prognostic factors have been identified to predict the outcome of patients with CLL, but only a few studies investigated more markers together. To predict the time to first treatment (TTFT) in patients of early stages, we evaluated the prognostic role of conventional markers as well as cytogenetic abnormalities and combined them together in a new prognostic scoring system, the CLL prognostic index (CLL-PI). Methods: Taking advantage of a population of 406 untreated Chinese patients with CLL at early and advanced stage of disease, we identified the strongest prognostic markers of TTFT and, subsequently, in a cohort of 173 patients who had complete data for all 3 variables, we integrated the data of traditional staging system, cytogenetic aberrations, and mutational status of immunoglobulin heavy chain variable region (IGHV) in CLL-PI. The median follow-up time was 45 months and the end point was TTFT. Results: The median TTFT was 38 months and the 5-year overall survival was 80%. According to univariate analysis, patients of advanced Rai stages (P < 0.001) or with 11q- (P = 0.002), 17p- (P < 0.001), unmutated IGHV (P < 0.001), negative 13q- (P = 0.007) and elevated lactate dehydrogenase levels (P = 0.001) tended to have a significantly shorter TTFT. And subsequently, based on multivariate Cox regression analysis, three independent factors for TTFT were identified: advanced clinical stage (P = 0.002), 17p- (P = 0.050) and unmutated IGHV (P = 0.049). Applying weighted grading of these independent factors, a CLL-PI was constructed based on regression parameters, which could categorize four different risk groups (low risk [score 0], intermediate low [score 1], intermediate high [score 2] and high risk [score 3-6]) with significantly different TTFT (median TTFT of not reached (NR), 65.0 months, 36.0 months and 19.0 months, respectively, P < 0.001). Conclusions: This study developed a weighted, integrated CLL-PI prognostic system of CLL patients which combines the critical genetic prognostic markers with traditional clinical stage. This novel modified PI system could be used to discriminate among groups and may help predict the TTFT and prognosis of patients with CLL.

Background：The postremission therapics for adult patients generally contain consolidation chemotherapy,allogeneic hematopoietic stem cell transplantation and autologous hematopoietic stem cell transplantation （auto-HSCT）.Because of the various results from different centers,the optimal therapy for adult acute lymphoblastic leukemia （ALL） patients is still uncertain.This study aimed to better understand predictive factors and role of auto-HSCT in the postremission thcrapy for adult ALL patients.Methods：The outcomes of 135 adult patients with ALL,who received the first auto-HSCT in Hematopoietic Stem Cell Transplantation Center of Blood Diseases Hospital,Chinese Academy of Medical Sciences from January 1,1994 to February 28,2014,were retrospectively analyzed.Survival curves were estimated using the Kaplan-Meier method and simultaneous effects of multiple covariates were estimated with the Cox model.Results：Overall survival （OS） and disease-free survival （DFS） at 5 years for the whole cohort were 59.1 ± 4.5% and 59.0 ± 4.4%,respectively.The cumulative nonrelapse mortality and relapse rate at 5 years were 4.5 ± 0.03% and 36.6 ± 0.19%.For both OS and DFS,acute T-cell lymphoblastic leukemia,high lactate dehydrogenase （LDH） at diagnosis,blast cell proportion ≥5% on the 15th day of induction therapy,and extramedullary infiltration before HSCT were the poor prognosis factors.In addition,age ≥35 years predicted poor DFS.Only T-ALL and high LDH were the independent undesirable factors associated with OS and DFS in Cox regression model.For 44 patients who had results of pretransplantation minimal residual disease （MRD）,positive MRD （MRD ≥0.01%） indicated poor OS （P =0.044） and DFS （P =0.008）.Furthermore,for the standard risk group,the patients with negative MRD （MRD 〈0.01%） had better results （OS at 18 months was 90.0 ± 9.5%,while for the patients with positive MRD OS was 50.0 ± 35.4%,P =0.003;DFS at 18 months was 90.0 ± 9.5%,while for the positive MRD group DFS was 0%,P 〈 0.001）.Conclusions：This study confirmed that auto-HSCT combined with posttransplantation maintenance chemotherapy could be an option for adult ALL patients and pretransplantation MRD may play a significant role in the direction of therapy for adult ALL patients.

Among adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia, treatment with the bispecific anti-CD19 and anti-CD3 monoclonal antibody blinatumomab resulted in longer overall survival and higher remission rates than did chemotherapy. The prognosis for adults with newly diagnosed acute lymphoblastic leukemia (ALL) has improved over the past three decades. With the use of intensive chemotherapy regimens, complete remission rates are 85 to 90% and long-term survival rates are 30 to 50%. 1 – 4 Still, most adults with B-cell precursor ALL will have a relapse and will die from complications of resistant disease or associated treatment. Among adults with relapsed or refractory ALL, remission rates are 18 to 44% with the use of standard salvage chemotherapy, but the duration of remission is typically short. 5 – 10 A major goal in this population is to . . .

Analysis of 2668 children with acute lymphoblastic leukemia (ALL) treated in two successive Nordic clinical trials (Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL-92 and ALL-2000) showed that 75% of all patients are cured by first-line therapy, and 83% are long-term survivors. Improvements in systemic and intrathecal chemotherapy have reduced the use of central nervous system (CNS) irradiation to <10% of the patients and provided a 5-year risk of isolated CNS relapse of 2.6%. Improved risk stratification and chemotherapy have eliminated the previous independent prognostic significance of gender, CNS leukemia and translocation t(1;19)(q23;p13), whereas the post-induction level of minimal residual disease (MRD) has emerged as a new risk grouping feature. Infant leukemia, high leukocyte count, T-lineage immunophenotype, translocation t(4;11)(q21;q23) and hypodiploidy persist to be associated with lower cure rates. To reduce the overall toxicity of the treatment, including the risk of therapy-related second malignant neoplasms, the current NOPHO ALL-2008 protocol does not include CNS irradiation in first remission, the dose of 6-mercaptopurine is reduced for patients with low thiopurine methyltransferase activity, and the protocol restricts the use of hematopoietic stem cell transplantation in first remission to patients without morphological remission after induction therapy or with high levels of MRD after 3 months of therapy.

The bone marrow microenvironment influences acute myeloid leukemia (AML) progression. Mesenchymal stem cell–like (MSC-l) populations may exert tumor-modulating effects, but their prognostic role remains uncertain. We retrospectively analyzed 65 adult AML patients (excluding acute promyelocytic leukemia) treated with intensive chemotherapy between 2017 and 2024 at four Spanish institutions. MSC-l cells were identified in BM aspirates at end of treatment by multiparameter flow cytometry (CD13 bright /CD45 low /CD34 neg /CD117 neg /CD11b neg /CD16 neg /CD71 neg /CD64 neg ). Patients were stratified using a 0.265%cutoff (MSC-l HIGH  ≥ 0.265% and MSC-l LOW  < 0.265%). Survival was assessed with Kaplan–Meier and Cox regression, adjusting for age and ELN 2017 risk. MSC-l HIGH patients had inferior overall survival (OS) (median 0.66 years vs. not reached; P  < 0.001) and relapse-free survival (RFS) (median 1.27 years vs. 1.49 years; P  = 0.027). These associations persisted across ELN risk groups. Multivariate analysis confirmed MSC-l HIGH status as an independent predictor of worse OS (HR = 6.43; 95% CI 2.53–16.33; P  < 0.001) and RFS (HR = 4.8; 95% CI 1.71–13.47; P  = 0.003). MSC-l levels were lower in patients receiving myeloablative conditioning compared with non-transplanted patients, suggesting transplant intensity may influence MSC dynamics. Higher post-treatment MSC-l proportions are associated with poorer survival, independent of ELN risk and age, supporting their potential as a prognostic biomarker in AML.

Acute Lymphoblastic Leukemia (ALL) is the most common cancer in children worldwide. In the present investigation, the circulating RNAs (circRNAs) HOTAIR, NEAT1, H19, PCAT1, and SNHG1 were selected as potential biomarkers for childhood ALL (pALL) based on their predicted interactions with miR-326, a recognized tumor suppressor implicated in pALL, along with comprehensive in silico analyses. Subsequently, the expression levels of the circRNAs were examined in 50 pALL samples and 20 healthy controls using RT-qPCR. Notably, HOTAIR was identified as a 95% specific biomarker of cancer susceptibility, exhibiting a substantial increase in expression within the bone marrow plasma and peripheral blood samples. 22 B-ALL patients with elevated relative expression levels of circHOTAIR (≥ 1.87) were then monitored at three distinct time intervals during chemotherapy. Results demonstrated a significant decrease in HOTAIR expression only among treatment-sensitive patients ( P <  0.0001). This finding positions HOTAIR as a novel prognostic factor (AUC = 0.955), which may be used for monitoring the efficacy of chemotherapy in a non-invasive, cost-effective manner. Additionally, the regulatory inter-connection between HOTAIR and miR-326 was investigated by transfecting B-ALL RN-95 cells with exogenous miR-326. Data showed a time-dependent increase in cytoplasmic HOTAIR levels, alongside RAB35, resulting in a corresponding reduction in the cytoplasmic and exosomal miR-326 levels. While the results are preliminary due to the sample size, this study is the first to identify circHOTAIR as both a prognostic and diagnostic biomarker in B-ALL. Furthermore, it elucidates the role of HOTAIR as a sponge for miR-326, orchestrating its efflux from the cell via exosomes through RAB35.

Researches on the immune checkpoint molecule and its clinical application in acute myeloid leukemia (AML) fall behind solid tumors. The expression patterns and prognostic significance of immune checkpoint molecules across T cells and T-cell differentiated subsets in AML require further elucidation. In the present study, bone marrow (BM) samples from 165 newly diagnosed AML patients and 12 healthy donors (HDs) were tested PD-1 and TIM-3 expression on CD4 + and CD8 + T cells as well as their differentiated subsets by multi-parameter flow cytometry. Compared with HDs, PD-1 was significantly overexpressed on total CD4 + T cells and their major constituent subsets (naïve, central memory, and effector memory T cells; all P  < 0.05), whereas TIM-3 was overexpressed on both total CD4 + and CD8 + T cells, as well as all differentiated subsets (all P  < 0.05). Both high expressions of PD-1 on CD8 + T and TIM-3 on CD4 + T cells were associated with poor relapse-free survival (RFS) and event-free survival (EFS) (all P  < 0.05). In addition, high PD-1 expression on CD8 + T cells independently predicted poorer RFS and EFS ( P  = 0.010 and 0.0011). Further stratification by T-cell subsets revealed that high PD-1 expression on naïve CD4 + T cells and TIM-3 on effector CD4 + T cells emerged as independent adverse prognostic factors for RFS ( P  = 0.018 and P  = 0.034, respectively), replacing the prognostic impact of PD-1 on total CD8 + T cells. However, high PD-1 expression on CD8 + T cells remained the sole independent predictor of EFS ( P  = 0.0065). In conclusion, the expression patterns of PD-1 and TIM-3 in the BM T cells and their differentiated sub-populations in newly diagnosed AML patients were distinct from HDs, and predicted outcomes.

We analyzed the long-term outcome of 1011 patients treated in five successive clinical trials (Total Therapy Studies 11, 12, 13A, 13B, and 14) between 1984 and 1999. The event-free survival improved significantly ( P =0.003) from the first two trials conducted in the 1980s to the three more recent trials conducted in the 1990s. Approximately 75% of patients treated in the 1980s and 80% in the 1990s were cured. Early intensive triple intrathecal therapy, together with more effective systemic therapy, including consolidation and reinduction treatment (Studies 13A and 13B) as well as dexamethasone (Study 13B), resulted in a very low rate of isolated central nervous system (CNS) relapse rate (<2%), despite the reduced use of cranial irradiation. Factors consistently associated with treatment outcome were age, leukocyte count, immunophenotype, DNA index, and minimal residual disease level after remission induction treatment. Owing to concerns about therapy-related secondary myeloid leukemia and brain tumors, in our current trials we reserve the use of etoposide for patients with refractory or relapsed leukemia undergoing hematopoietic stem cell transplantation, and cranial irradiation for those with CNS relapse. The next main challenge is to further increase cure rates while improving quality of life for all patients.

Background This study aimed to evaluate the prognostic significance and clinical impact of the revised 2022 European LeukemiaNet (ELN) classification for acute myeloid leukemia (AML), focusing particularly on patients harboring fms-like tyrosine kinase 3- internal tandem duplication (FLT3- ITD ) mutations. Methods A retrospective, multicenter observational study was conducted by the Turkish Society of Hematology-Acute Leukemias Working Group, analyzing 312 adult patients newly diagnosed with AML from January 2012 to December 2022. Patients with acute promyelocytic leukemia were excluded . FLT3 -ITD mutations were detected using polymerase chain reaction and, when available, next-generation sequencing. Patients were classified according to the 2017 ELN risk stratification, and FLT3- ITD - positive cases were reclassified based on the updated 2022 ELN criteria. Endpoints were complete remission (CR), disease-free survival (DFS), and overall survival (OS). Results FLT3- ITD mutations were identified in 54 (17.3%) patients. According to the 2022 ELN classification, 29 patients previously categorized as the favorable ( n  = 6) or adverse-risk ( n  = 23) groups were reclassified into the intermediate-risk group, highlighting the substantial impact of removing the FLT3- ITD allelic ratio from risk stratification. With a median follow-up of 31.8 months, OS significantly differed among the 2017 ELN favorable-, intermediate-, and adverse-risk categories (not reached, 21.6 months, and 9.5 months, respectively, p  < 0.001). FLT3- ITD - positive patients demonstrated significantly inferior DFS ( p  = 0.038) and OS ( p  = 0.009) compared to FLT3- ITD - negative patients. In patients achieving first CR, allogeneic hematopoietic stem cell transplantation (HSCT) improved OS in intermediate-risk ( p  = 0.003), showed a trend in adverse-risk ( p  = 0.098), and no benefit in favorable-risk ( p  = 0.351). Among reclassified FLT3- ITD - positive patients, survival outcomes aligned closely with the original intermediate-risk group defined by the 2017 ELN, supporting the rationale behind the ELN revision. Conclusions Our findings validate the prognostic utility of the revised 2022 ELN guidelines, especially regarding FLT3- ITD - positive AML, emphasizing that the exclusion of the FLT3- ITD allelic ratio yields a more biologically consistent risk categorization. Furthermore, the data support tailored ELN-based risk stratification for older AML patients. Given the modest benefit of HSCT in adverse-risk patients, future refinements should further stratify this group to address their unmet therapeutic needs and enhance survival outcomes. Trial registration The study was registered at ClinicalTrials.gov (NCT05979675).