Background:Asciminib, a novel BCR::ABL1 inhibitor that functions by specifically targeting the myristoyl pocket, has shown superior efficacy and favorable safety and tolerability compared with adenosine triphosphate-competitive tyrosine kinase inhibitors (TKIs) in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Flumatinib, a second-generation TKI available exclusively in China, does not have a head‑to‑head comparison with asciminib till date with asciminib. Therefore, this study aimed to conduct an anchored matching‑adjusted indirect comparison using data from the ASC4FIRST and FESTnd trials to fill this evidence gap. Methods:Imatinib was the common comparator across the ASC4FIRST (NCT04971226) and FESTnd (NCT02204644) trials. To match the two populations, effect modifiers and baseline variables were identified. Adjusted estimates were derived from individual patient-level data (ASC4FIRST) for asciminib and imatinib and from aggregate data for flumatinib (FESTnd). Outcomes were compared based on early molecular response (EMR), major molecular response (MMR), and treatment discontinuation due to adverse events (AEs). Results:Asciminib demonstrated significantly higher EMR rates at 12 weeks (adjusted: 90.0%) than did flumatinib (82.1%), yielding a significantly higher odds ratio [odds ratio (OR): 1.95; 95% confidence interval (CI): 1.05-3.73; P=0.03]. MMR rates, both at 48 and 96 weeks, were significantly higher for asciminib (adjusted: 66.5% and 74.0%, respectively) than for flumatinib (an estimated 52.6% and 61.3%, respectively), with an OR of 1.79 (95% CI: 1.17-2.75; P=0.006). Safety analysis showed fewer discontinuations due to AEs at 48 weeks with asciminib (5.5%) than with flumatinib (10.2%), corresponding to a significantly lower risk of discontinuation due AEs (risk ratio: 0.29; 95% CI: 0.10-0.84; P=0.02). Conclusions:A robust statistical model indicated that asciminib provides consistently superior efficacy and safety over flumatinib, supporting its value as a first-line treatment option for patients with CML-CP.

Fms-like tyrosine kinase 3 (FLT3) mutations occur in approximately 30

Although acute myeloid leukemia (AML) with CBFB::MYH11 rearrangement is classified as favorable-risk, approximately 40% of patients experience relapse. We evaluated the prognostic impact of CBFB::MYH11 transcript levels and the optimal timing of allogeneic hematopoietic cell transplantation (allo-HCT) at first complete remission (CR1). A total of 186 patients with CBFB::MYH11-rearranged AML treated with intensive induction chemotherapy were included. CBFB::MYH11 levels after cycles 2 and 3 were strongly correlated (P < 0.001). The post-cycle 2 CBFB::MYH11 transcript level emerged as the strongest prognostic marker for both disease-free survival (DFS) and overall survival (OS), outperforming assessments after cycles 1 or 3. CBFB::MYH11 ≥ 1% after cycle 2 was independently associated with inferior DFS (HR 3.84, P < 0.001) and OS (HR 3.98, P = 0.003). Among patients with post-cycle 2 CBFB::MYH11 ≥ 1.0%, the 3-year DFS and OS were both 91.7% in patients who received allo-HCT at CR1, compared with 47.8% and 72.9%, respectively, in the chemotherapy consolidation group. Multivariate analysis indicated that allo-HCT in CR1 improved 3-year DFS compared with chemotherapy consolidation (HR 0.24; P = 0.023). However, no significant improvement in OS was observed during follow-up. These findings suggest that post-cycle 2 CBFB::MYH11 level ≥1.0% identifies a high-risk subgroup that may benefit from allo-HCT in CR1.

The BCL-2 inhibitor venetoclax has shown promise in acute lymphoblastic leukemia (ALL), but its role in first-line therapy for newly diagnosed (ND) Philadelphia chromosome-negative (Ph⁻) ALL is undefined. In this prospective phase 2 study, 167 adolescents and adults (aged 14-60 years) with ND Ph⁻ ALL received venetoclax combined with pediatric-inspired chemotherapy. The primary endpoint was the rate of measurable residual disease (MRD) negativity by multiparameter flow cytometry (MFC) after induction. The complete remission rate was 91.0%, and 73.0% of responders achieved MFC-MRD negativity, meeting the primary endpoint. After a median follow-up of 19.3 months, median overall and disease-free survival were not reached; estimated 2-year survival rates were 78.5% and 76.7%, respectively. Propensity score-matched analysis confirmed superior survival compared with historical chemotherapy-only controls. Grade ≥ 3 adverse events were primarily hematologic toxicities and infections, with an incidence comparable to that of the historical cohort. These results demonstrate that adding venetoclax to pediatric-inspired chemotherapy significantly improves MRD response and survival outcomes in ND Ph⁻ ALL, with a manageable safety profile. This trial was registered with ClinicalTrials.gov under the identifier NCT05660473.

Background Homoharringtonine (HHT) suppresses the expression of the CCAAT/enhancer-binding protein alpha (CEBPA). Our previous retrospective analysis indicated that favorable outcomes were observed in acute myeloid leukemia (AML) with double-mutated CEBPA (CEBPAdm) when patients received an HHT-based induction regimen. To confirm these observations, we performed a prospective multicenter, single-arm trial to assess the efficacy of homoharringtonine, daunorubicin, and cytarabine (HAD) induction regimen in patients with CEBPAdm AML. Methods This prospective multicenter single-arm trial enrolled patients with newly diagnosed CEBPAdm AML who received the HAD induction regimen between June 1, 2020, and October 1, 2023. Consolidation therapy comprised three cycles of high-dose cytarabine (HDAC). The trial was registered at ClinicalTrials.gov (NCT04415008). The primary outcomes were event-free survival (EFS) and relapse-free survival (RFS). Secondary endpoints included complete remission (CR) rate, 30-day mortality, and overall survival (OS). Survival outcomes were estimated using the Kaplan-Meier method and compared with the log-rank test. Results A total of 61 patients with newly diagnosed CEBPAdm AML (median age 40 years, interquartile range [IQR] 30–47 years) were enrolled. After one course of HAD induction, 57 patients (93.44%) achieved complete remission (CR), and the overall CR rate after one or two courses reached 95.08% (58/61). Among the 58 responders, 46 patients (79.31% [46/58]) achieved measurable residual disease (MRD) negativity after the first induction. The 30-day mortality rate was 3.28% (2/61). At a median follow-up of 31.97 months (IQR 21.27–37.77), the estimated 3-year EFS, RFS, and OS rates were 77.86%, 82.16%, and 87.27%, respectively. Exploratory subgroup analyses showed a numerical trend toward inferior RFS in patients with the co-occurring colony stimulating factor 3 receptor (CSF3R)T618I mutation (P = 0.064); however, given the small subgroup size, these findings are hypothesis-generating only and require validation in larger cohorts. Conclusions The HAD regimen demonstrated promising clinical activity and an acceptable safety profile in young adult patients with CEBPAdm AML, with 3-year EFS and RFS rates that met the predetermined objectives of 72% and 75%, respectively. Trial registration No. NCT04415008; https://classic.clinicaltrials.gov.

Acute leukemias of ambiguous lineage (ALAL) is a rare type of hematologic malignancies with poor outcomes. Currently, the treatment for this type of leukemia lack standardized protocols and exhibit significant heterogeneity, necessitating the exploration of novel, targeted approaches. We retrospectively analyzed the clinical characteristics, efficacy, and safety of 13 newly diagnosed Philadelphia chromosome (Ph)-negative ALAL patients between May 2022 and March 2025, who received induction therapy with the mini-CVD regimen (cyclophosphamide, vincristine, dexamethasone) combined with venetoclax and azacitidine. The cohort comprised 8 males and 5 females, with a median age of 53 years (range, 28–73 years). Among this cohort, 92.3

Germline variants of DDX41 were broadly investigated in myeloid neoplasms (MNs), while there is a lack of a larger cohort of Chinese patients report, and impact of donor-derived DDX41 variants on transplant outcomes has not been fully explored. We retrospectively analyzed 460 patients carrying DDX41 variants among 41 290 individuals. Although most of patients (65%) were diagnosed with MNs (mostly MDS/AML), other rarer diseases, such as AA, ALL, and lymphoma, can occur. A total of 417 germline and 262 somatic DDX41 variants were identified. The predominant pathogenic/likely pathogenic (P/LP) germline variants were P258L (26%) and Y259C (20%), followed by loss-of-function variants (25%) and c.935+4A>T (5%), which can cause aberrant intron retention. The most common somatic variants were R525H (53%), then G530D (7%) and T227M (4%). Germline variants in MNs were more often P/LP than in AA or ALL. GO (germline only) and GS (germline+somatic) mutations were distinctly distributed among diseases. Among thirteen donors included in this cohort, nine underwent transplantation. Four out of five recipients with donor-derived DDX41-VUS variants continued to be in complete remission at 18 or 19 months after transplantation, compared to two out of four patients with donor-derived DDX41-P/LP variants. For the first time, this study identified P258L/Y259C as predominant Chinese-specific germline DDX41 variants, expanding disease spectrum to include non-myeloid disorders, and established GS genotype as a key biomarker for myeloid malignancies. In addition, our results suggested that pre-transplant DDX41 germline screening in related donors may be beneficial for mitigating donor-derived leukemia and achieving better clinical outcomes.

Bacterial and fungal pulmonary infections (BFPI) are common in hematological patients and pose significant diagnostic challenges. Metagenomic next-generation sequencing (mNGS) is valuable for diagnosing BFPI. However, for hematological patients with limited access to lower respiratory tract samples (LRTS), the clinical value of blood-mNGS compared to LRTS-mNGS requires further investigation. A retrospective analysis was conducted on 160 cases with suspected pneumonia who underwent both blood-mNGS and LRTS-mNGS within one week. Diagnostic performance and impacts on antimicrobial adjustments were evaluated using clinical composite diagnosis (CCD) as the reference. Compared to CCD, LRTS-mNGS showed significantly higher positive percent agreement (PPA) than blood-mNGS [93.7

Acute myeloid leukemia (AML) is a hematological malignancy with a high mortality rate and heterogeneous prognosis. Traditional risk stratification is based on the genetic classification in the 2022 guidelines of the European Leukemia Net. However, the risks of some patients remain unclear, and other prognostic assessment methods are required to improve the risk assessment of these patients. Apoptosis-related genes (ARGs) play critical roles in regulating the survival and drug resistance of AML cells. Therefore, we collected gene expression and clinical data from patients with AML from The Cancer Genome Atlas Acute Myeloid Leukemia (TCGA-LAML) datasets to develop a risk assessment model based on 5 ARGs. Using the least absolute shrinkage and selection operator Cox regression (LASSO-Cox) model, we identified 5 key ARGs (DDIT4, HSP90B1, ENO1, SOD1, and SLC7A11) and constructed a 5-ARG prognostic model. Using this model, we successfully stratified patients in both TCGA-LAML training and independent external validation cohorts, with high-risk patients consistently exhibiting significantly poorer clinical outcomes. In addition, high-risk patients exhibited significant enrichment in pathways related to TP53 dysfunction, mechanistic target of rapamycin complex 1 (mTORC1) signaling activation, and pro-inflammatory responses, which were closely correlated with NPM1c-FLT3 co-mutations. Decitabine, sunitinib, and MK-1775 were identified as potential therapeutic agents. In summary, we established a 5-ARG prognostic model that may facilitate risk stratification and inform therapeutic decision-making in AML.

Daunorubicin dose optimization remains crucial for AML treatment. While 90 mg/m2 benefits younger adults and 45 mg/m2 remains standard for older patients, the optimal dose for patients aged 55-65 years is unclear. We evaluated whether intermediate dose escalation to 60 mg/m2 would improve outcomes compared to that of standard 45 mg/m2 in this population. In this prospective, randomized, open-label, single-center trial, newly diagnosed AML patients aged 55-65 years were randomly assigned 1:1 to receive daunorubicin 45 mg/m2 (Group S) or 60 mg/m2 (Group M) on days 1-3, combined with cytarabine for the induction. At median follow-up of 35.9 months, no significant difference in OS was observed between the two groups (HR 1.24, 95% CI 0.80-1.91; p = 0.333). Median OS was 48.7 months (95% CI 28.2-NR) in Group S vs. 33.0 months (95% CI 22.2-71.6) in Group M. Five-year survival rates were comparable (45.2% vs. 39.8%). CR rates after first induction were equivalent (47.1% vs. 44.4%; RD +2.7%, 95% CI -17.4 to 12.0; p = 0.720). MRD-negative CR rates showed no difference (35.6% vs. 32.2%; p = 0.632). RFS (HR 1.38, 95% CI 0.84-2.26; p = 0.201) and EFS (HR 1.18, 95% CI 0.81-1.74; p = 0.389) were similar in both arms. Regarding safety, while overall infection rates were similar, Group M showed a significantly higher incidence of documented intestinal infections compared to Group S (22.5% vs. 8.0%; p = 0.011). Exploratory subgroup analyses revealed no consistent patterns favoring either strategy across clinical or molecular subgroups. Daunorubicin dose escalation from 45 to 60 mg/m2 provides no clinical benefit but significantly increases mucosal toxicity. Therefore, 45 mg/m2 should remain the preferred regimen for this population. Trial Registration: ClinicalTrials.gov identifier: NCT02432872.

BACKGROUND:KMT2A rearrangements are a frequent genetic abnormality associated with Acute myeloid leukemia (AML), historically linked to varied prognoses and outcomes. The prognosis for patients with this rearrangement remains controversial, necessitating further research to stratify risk and guide treatment. METHODS:In this retrospective study, a total of 3468 adolescent and adult AML patients were screened, and 181 patients harboring KMT2A rearrangements were analyzed. We used FISH, RT-PCR, and next-generation sequencing, including transcriptome and targeted panels, for diagnosis and mutation profiling. All patients received intensive chemotherapy. We evaluated overall survival and event-free survival using Kaplan-Meier and Cox regression models, with HSCT analyzed as a time-dependent variable. RESULTS:The incidence of KMT2A-rearranged AML in our newly diagnosed cohort was 5.9%. Among the 181 patients included in the final analysis, 89 (49.2%) were male and 92 (50.8%) were female, with a median age of 33 years (range: 13-65). The distribution of fusion partners included KMT2A::MLLT3 (n = 39), KMT2A::AFDN (n = 27), KMT2A::MLLT10 (n = 25), KMT2A::ELL (n = 24), and others (n = 12). Seventy-four patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1). The median follow-up for survivors was 17.53 months (range 1.47-112.57), and the 3-year overall survival (OS) and event-free survival (EFS) for the entire cohort were 42.0% and 32.1%, respectively. Patients with KMT2A::ELL exhibited superior OS compared to other subtypes (3-year OS [ELL vs. non-ELL]: 59.8% vs. 39.3%, p = 0.023). Concomitant mutations did not significantly impact the prognosis of KMT2A-rearranged AML patients. In multivariate analysis, age and HSCT in CR1 were independently associated with OS and EFS (OS: HR = 1.022, p = 0.026 [age]; HR = 0.238, p < 0.001 [HSCT]; EFS: HR = 1.027, p = 0.002 [age]; HR = 0.155, p < 0.001 [HSCT]). Patients aged over 20 years were more likely to benefit from HSCT than those aged 20 years or younger (p < 0.001 [age > 20], p = 0.780 [age ≤ 20]). CONCLUSIONS:Our study revealed the heterogeneous outcomes of KMT2A-rearranged AML patients and clarified the impact of HSCT across different age groups.

To investigate the clinical features and outcomes of measurable residual disease recurrence (MRD-R) by multiparameter flow cytometric in acute myeloid leukemia (AML). We retrospectively analyzed clinical characteristic, residual disease status and outcomes of 767 newly diagnosed AML patients achieving complete remission within two cycles of induction at our center. Totally, 171 (22.3%) patients experienced MRD-R during follow-up. Patients with MRD-R had inferior outcomes compared to those without MRD-R, with 3-year cumulative incidence of morphologic relapse (CIR), relapse-free survival (RFS) and overall survival (OS) at 63.6% vs. 30.6% (P

BACKGROUND AND AIMS:Crohn's disease (CD) is a chronic, immune-mediated inflammatory disorder. Its pathophysiology involves dysregulation of both innate and adaptive immune responses, which can occur in clonal hematopoiesis of indeterminate potential (CHIP) individuals. Therefore, we hypothesize that CHIP may influence CD incidence. However, no study has explored the association between CHIP and incident CD. We analyzed UK Biobank data to investigate the association between CHIP and incident CD. METHODS:CHIP was defined based on whole-exome sequencing data. The outcome was incident CD. Cox regression models were used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for CD in relation to CHIP. RESULTS:This study included 461 913 participants, of whom 14 339 (3.1%) had CHIP. The incidence rate of CD was 21.6 and 37.7 per 100 000 person-years for individuals without and with CHIP, respectively. We found a statistically significant increased risk of CD among individuals with CHIP (HR, 1.68; 95% CI, 1.30-2.16), compared with the reference group. This association was particularly stronger in individuals with JAK2-mutant CHIP (HR, 7.28; 95% CI, 1.82-29.13), ASXL1-mutant CHIP (HR, 3.07; 95% CI, 1.74-5.44), and DNMT3A-mutant CHIP (HR, 1.73; 95% CI, 1.24-2.42). Additionally, the association did not vary greatly by demographic, socioeconomic, lifestyle factors, CHIP clone size, or cancer comorbidity. CONCLUSIONS:CHIP was associated with a markedly increased risk of subsequent CD. The association was particularly stronger in JAK2-mutant CHIP, ASXL1-mutant CHIP, and DNMT3A-mutant CHIP. The findings of this study may offer potential insights for future investigations into the mechanistic underpinnings of CD.

BACKGROUND:Evidence is scarce for the association between social isolation and loneliness and prognosis of any cancer or other common cancer types. METHODS:To address this gap, we performed a cohort study from 2006 to 2022 using data from the UK Biobank (UKB). Social isolation and loneliness were identified based on the questionnaire of the UKB. Cases of death were obtained from the death registry, where both primary and contributory causes were recorded using ICD-10 codes. The Cox proportional hazard models were used to estimate hazard ratios (HRs) and associated 95% confidence intervals (CIs) of death in relation to social isolation and loneliness among patients with cancer. RESULTS:Among cancer patients studied, 6206 (9.6%) were socially isolated and 3130 (4.8%) reported loneliness. Over a median follow-up of 6.7 years, there were 2378 deaths (38.3%) among exposed patients and 16,566 deaths (29.1%) among unexposed patients. Social isolation was associated with poorer cancer prognosis overall (HR 1.21, 95% CI 1.16-1.26, P < 0.001), while loneliness correlated with a similar risk (HR 1.18, 95% CI 1.11-1.25, P < 0.001). Social isolation specifically impacted survival in colon, melanoma, breast, prostate, kidney, and bladder cancers, as well as myeloproliferative neoplasms. Loneliness was linked to poorer outcomes in breast, prostate, and bladder cancers. CONCLUSIONS:Our findings suggested that social support for these vulnerable patients might have the potential to improve prognosis.

Tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL1 fusion tyrosine kinase have revolutionized the treatment of chronic myeloid leukaemia (CML). However, the development of TKI resistance and the subsequent transition from the chronic phase (CP) to blast crisis (BC) threaten patients with CML. Accumulating evidence suggests that translational control is crucial for cancer progression. Our high-throughput CRISPR-Cas9 screening identified poly(A) binding protein cytoplasmic 1 (PABPC1) as a driver for CML progression in the BC stage. PABPC1 preferentially improved the translation efficiency of multiple leukaemogenic mRNAs with long and highly structured 5' untranslated regions by forming biomolecular condensates. Inhibiting PABPC1 significantly suppressed CML cell proliferation and attenuated disease progression, with minimal effects on normal haematopoiesis. Moreover, we identified two PABPC1 inhibitors that inhibited BC progression and overcame TKI resistance in murine and human CML. Overall, our work identifies PABPC1 as a selective translation enhancing factor in CML-BC, with its genetic or pharmacological inhibition overcoming TKI resistance and suppressed BC progression.