Titanium (Ti) alloys have low thermal conductivity, suffer from tool wear and deformation of workpieces and are difficult-to-machine metals. This contributes to surface roughness, Sa > 240 nm of Ti alloys after mechanical polishing with a low material removal rate (MRR). With the addition of assisting energy fields, the MRR is usually lower than 7 μm h-1. Nevertheless, there is a high demand to achieve Sa < 50 nm on a free surface blade to save energy and reduce the resistance of fluids. To address this challenge, novel photocatalytic shear-thickening chemical mechanical polishing (PSTCMP) was developed using a custom-made polisher. The new PSTCMP slurry contained ceria, corn starch, sodium bicarbonate and deionized water. After PSTCMP, the Sa and thickness of the damaged layer of a free surface blade of a Ti alloy decreased from 501.71 to 38.46 nm and from 634.79 to 7.83 nm, respectively, representing reductions of 92% and 99%. The MRR is 12.52 μm h-1. To the best of our knowledge, both the Sa and MRR are the best published to date for a Ti alloy blade with a free surface. PSTCMP mechanisms were interpreted using first-principles molecular dynamics, X-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy. Hydroxyl radicals were generated under ultraviolet irradiation on ceria with a size of 4.2 nm, oxidizing the surface of the Ti alloy and forming Ti-OH and Ti-O groups. A Ce-O-Ti interface bridge was produced between Ti-OH and Ce-OH, induced by the hydrolysis of ceria. Our findings provide a new way to fabricate nanometer-scale surface roughness on a free surface blade of a Ti alloy with a high MRR.

Predicting prognosis using baseline clinical and genetic features remains critical in the tyrosine-kinase-inhibitor (TKI) era of chronic myeloid leukemia (CML). We retrospectively analyzed 944 chronic phase CML (CML-CP) patients treated at a single center in China, aiming to clarify treatment responses, long-term outcomes and baseline prognostic factors in real-world settings. Analyses were performed in available patient subsets depending on endpoint-specific data completeness. The study found that female patients had higher major molecular response (MMR) than males (P = 0.004). Age ≥ 45 years was associated with lower complete cytogenetic response (CCyR; p = 0.006), overall survival (OS; p = 0.011), and CML-related survival (p = 0.010). Initial white-blood-cell counts ≥ 118 × 10⁹/L predicted inferior CCyR and MMR (both P < 0.001). Conversely, baseline haemoglobin ≥ 110 g/L independently predicted superior CCyR, MMR (both P < 0.001), event-free survival (EFS; p = 0.009), progression-free survival (PFS; p = 0.008), OS (P = 0.001), and CML-related survival (p = 0.001). Compared to patients without ACAs, high-risk additional chromosomal abnormalities (HR-ACAs) conferred worse EFS (P = 0.042), PFS (P = 0.057), OS (P = 0.010) and CML-related survival (P = 0.006). Gender and initial WBC primarily influenced TKI treatment responses, while age and initial Hgb levels influenced both TKI responses and long-term survival. Additionally, HR-ACAs significantly predicted poorer long-term survival in CML-CP patients.

Measuring long-focal-length aspheric surfaces is susceptible to environmental disturbances, where a long testing optical path is needed. Thus, folding the testing path and using no phase-shifting methods would be appreciated. Conventional transmissive computer-generated holography (CGH) could not provide a folding test path. Meanwhile, conventional temporal phase-shifting methods could also be heavily influenced by the long path. To face this challenge, in this article, a wavefront measurement method is proposed, free-from phase-shifting by a novel reflective CGH and physics U-Net. Here, the reflective CGH solution is for aspheric null measurements, folding the testing path. A comparative analysis was conducted between reflective and transmissive CGHs under laboratory conditions. A root-mean-square (RMS) difference of 0.002 lambda was observed. Principal component consistency (PCC) was achieved at 0.9905. Notably, the working distance of the former configuration was found to approximate half that of the latter. Wavefront phase retrieval uses the physics-informed U-Net deep learning method. An average accuracy of 0.007 lambda is achieved by the phase retrieval results derived from two carrier interferograms using the proposed method. This advancement effectively mitigates environmental disturbances associated with extended working-distance measurements, providing a novel method for long-focal-length aspheric wavefront measurement in astronomical telescopes and related fields.

Venetoclax (VEN) combined with hypomethylating agents is approved for frontline therapy in older/unfit patients with acute myeloid leukemia (AML). However, prospective data on this low-intensity therapy in treatment-naive younger patients with AML are lacking. This study investigated the efficacy and safety of VEN plus decitabine (VEN-DEC) as induction in untreated young fit patients with AML in a randomized trial. Patients aged 18 to 59 years eligible for intensive chemotherapy were randomized 1:1 to receive VEN-DEC or IA-12 (idarubicin and cytarabine). All patients achieved composite complete remission (CRc) underwent high-dose cytarabine consolidation. The primary end point was CRc rate after induction. Of 255 screened, 188 were enrolled and randomly assigned, with 94 in each group. In the intention-to-treat population, CRc was 89% (84/94) in the VEN-DEC group vs 79% (74/94) in the IA-12 group (noninferiority P = .0021), with measurable residual disease negativity rates of 80% (67/84) vs 76% (56/74), respectively. VEN-DEC showed superior CRc in patients aged >= 40 years (91% vs 75%) and those with adverse risk (91% vs 42%) or epigenetic mutations (91% vs 67%), but lower CRc in RUNX1::RUNX1T1 fusion cases (44% vs 88%) than IA-12. Patients in the VEN-DEC group experienced fewer grade >= 3 infections (32% vs 67%) and shorter severe thrombocytopenia duration (median, 13 vs 19 days; P < .001). At a median follow-up of 12.1 months, overall and progression-free survival were similar between groups. In conclusion, VEN-DEC demonstrated noninferior response rates with superior safety over IA-12 in young patients with AML. The trial was registered at www.clinicaltrials.gov as #NCT05177731.

Introduction Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is a common hematological malignancy in adults, classified as a subtype of acute lymphoblastic leukemia (ALL). It accounts for approximately 20% to 30% of adult ALL patients, and reaches 50% among patients over 60 years old. Over the past two decades, the development of tyrosine kinase inhibitors (TKIs), particularly third-generation TKIs, along with advancements in novel therapies, has led to significant improvements in patient outcomes. The crucial role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) as a necessary treatment option is facing challenges. Methods We conducted a single-center observational study on 740 Ph+ ALL patients diagnosed from January 2009 to September 2024 for a total of 15 years, to summarize the clinical, cytogenetic, and molecular genetic characteristics; to analyze the data of patients undergoing allo-HSCT or chimeric antigen receptor T-cell (CAR-T) therapy; to analyze the impact of clinical laboratory characteristics, types of frontline TKIs, and treatment regimens on the survival of Ph+ ALL patients. Results Baseline characteristics of 740 patients with Ph+ ALL were analyzed, with a median age of 39 years and 51.0% male. The P190 type of BCR-ABL1 fusion gene transcripts was the most common (65.6%), and 11 rare BCR-ABL1 transcripts were detected. Treatment characterization revealed that 95.1% of patients received frontline TKIs and 91.8% achieved complete remission (CR) after induction therapy. 22.9% of patients achieved a complete molecular response (CMR), and 14.1% achieved a major molecular response (MMR). Among the frontline TKIs, the first-generation TKI imatinib has the highest usage rate (45.3%), followed by the second-generation TKIs dasatinib (32.3%) and flumatinib (8.7%). 4.8% of patients received frontline olverembatinib treatment. A total of 71.1% of patients received allo-HSCT or CAR-T, or CAR-T bridging allo-HSCT. Overall, patients had a 2-year overall survival (OS) rate of 73.8% and a 2-year relapse-free survival (RFS) rate of 59.1%. Patients undergoing allo-HSCT had superior survival, with the most common being haploidentical transplantation (50.9%), followed by matched sibling (26.1%) and matched unrelated (15.8%) transplantation, with no significant difference in OS and RFS among the three types. The optimal prognosis of transplant patients was achieved with transplantation in first complete remission and the attainment of CMR status. The molecular genetic alterations in Ph+ ALL were most frequent with RUNX1 mutations (11.4%), followed by SETD2 mutations (11.0%). The most common additional chromosomal abnormalities (ACAs) were complex karyotype (43.3%), +Ph (34.9%), -7/7q- (28.8%), and monosomal karyotype (27.0%). +Ph karyotype coexisted significantly with complex karyotype (p<0.001). Patients with ACAs had the worst prognosis compared to those with normal karyotype and Ph alone karyotype, but the prognostic difference was not significant among those undergoing allo-HSCT. Univariate analysis revealed that the diagnosis year between 2018 and 2024, frontline second-generation or third-generation TKIs, molecular response after induction, and CAR-T bridging allo-HSCT for consolidation were favorable factors for OS and RFS. Multivariate analysis showed that old age, high white blood cell count, and complex karyotype were independent unfavorable factors for OS and RFS. Conclusions In the era of TKIs, novel therapies provide deeper responses and improved survival when incorporated in frontline treatment. Transplant patients should achieve a deep molecular response before transplantation. +Ph karyotype coexisted significantly with complex karyotype. The most common genetic alterations in Ph+ ALL patients are RUNX1 and SETD2 mutations. Patients with ACAs have the worst prognosis compared to those with normal karyotype and Ph alone karyotype, and the impact is less significant under the allogeneic transplantation model. A complex karyotype is an independent unfavorable factor that significantly impacts the prognosis.

Introduction: Nucleoporin 98 (NUP98) rearrangement has been proposed as a type of acute myeloid leukemia (AML) with defining genetic abnormalities, occurring in approximately 2-3% of adult AML patients. While used to be reported with poor survival in children, adult AML with NUP98 rearrangement may present different genetic profiles and outcomes, particularly owing to targeted agents such as Bcl-2, FLT3 and Menin inhibitors in recent years. Method: We retrospectively collected the data of adult AML patients with NUP98 rearrangement who were diagnosed at 12 hospitals of East China Leukemia Alliance (ECLA) from June 2019 to February 2025, including baseline clinical features, laboratory examinations, morphological, chromosomal and genetic abnormalities (tested by next generation sequencing and RNA sequencing), treatment strategies and outcome. Rates of complete remission (CR) between groups were compared by Chi square test or Binary logistic regression, while median survival time was estimated by the Kaplan-Meier method and compared by log rank test. COX regression model was used to figure out independent favorable or risk factors for overall survival (OS). Results: A total of 71 (35 male and 36 female) AML patients with NUP98 rearrangement were enrolled in the ECLA database. The median age was 46 years old (range, 16~86). The median white blood cell count and bone marrow blast% were 31.1 (1.5-313.63) ×109/L and 64.5% (8.5%-93%), respectively. The FAB types were mainly concentrated in M2 (26 cases, 36.6%), M4 (20 cases, 28.2%) and M5 (17 cases, 23.9%), while 8 (11.3%) were unknown types. The most common abnormal karyotype was t(7;11)(p15;p15), carried by 19 patients. Among them, 17 were found with NUP98::HOXA9 fusion gene, and the other two with NUP98::HOXA6 and NUP98::HOXA13. Another 4 patients with NUP98::HOXA9 owned normal karyotype (2 cases), t(7;15) (1 case) and unknown type (1 case). A total of 15 fusion partners with NUP98 were detected, of which the most frequently occurring were NSD1 (occurred in 31 cases, 43.7%) and HOXA9 (21 cases, 29.6%), and the other 13 different partners were found in the rest 19 (26.8%) patients. NUP98 rearrangement often co-existed with several mutations, among which FLT3-ITD (40 cases, 56.3%) and WT1 (24, 33.8%) were most frequently detected. According to ELN 2022 risk classification, 55 (77.5%) were at intermediate risk and 16 (22.5%) at adverse risk. The induction therapy was divided into two types: targeted agents-based therapy (including Venetoclax or Gilteritinib, combining with low-intensity or intensive chemotherapy, however Menin inhibitors have not been available in China till now) or traditional chemotherapy (including 7+3, hypomethylation agents (HMA), Homoharringtonine-based therapy, et al.). A total of 55 (77.5%) patients achieved composite CR (CRc, CR+CRi+CRp) after 1-2 cycles of induction therapy. Age, gender, blast% in bone marrow, FAB types, karyotypes involving t(7;11) or not, fusion partners carrying NSD1, HOXA9 or others, ELN 2022 risk stratification, and chemo vs targeted therapies were calculated by univariate analysis to investigate the risk factors of non-remission individuals. Significant difference in CRc rates was only observed between different treatment groups (67.5% in chemotherapy vs 90.3% in targeted therapy, Chi-square 5.211, P=0.022). Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) was implemented in 36 (50.7%) patients, of whom 27 were transplanted in CR1. With a median follow-up time of 14.8 months, the median overall survival (OS) and event-free survival (EFS) of all patients were 50.9m and 13.3m, respectively. The estimated 4-year OS and EFS rates were 56.2% and 45.3%. Patients without HSCT would only reach a 2-year OS and EFS rate of 20.9% and 12.4%, respectively, comparable to that of the ELN 2022 adverse risk group. Univariate analysis (P<0.1) identified younger age, targeted therapy, reaching CRc and allo-HSCT as favorable factors for longer OS. But COX regression reserved younger age (OR 0.968 (95% CI: 0.939-0.998) P=0.037), CRc (OR 0.206 (95% CI: 0.08-0.53), P=0.001) and allo-HSCT (OR 0.024 (95% CI: 0.004-0.128), P<0.001) as independent favorable factors for OS. Conclusion: Adult AML with NUP98 rearrangement should be recognized as one of adverse risk subgroups, irrespective of different fusion partners. Targeted therapy had higher chance of achieving CRc, and bone marrow transplantation in CR1 was the key to long-term survival.

Background In 2022, the World Health Organization (WHO) and the International Consensus Classification of Myeloid and Lymphoma ( ICC-MLN ) defined a group of rare hematopoietic tumors driven by specific tyrosine kinase gene fusions (PDGFRA/B, FGFR1, JAK2, FLT3, or ETV6::ABL1) as myeloid/lymphoid tumors with eosinophilia and tyrosine kinase gene fusion (MLN-TK). Significant phenotypic and prognostic heterogeneity poses challenges to clinical diagnosis and targeted therapy. The purpose of this study was to analyze the clinical characteristics and treatment outcomes of MLN-TK patients, and to provide reference for clinical diagnosis and treatment. Methods This retrospective, multi-center study included a total of 71 MLN-TK patients from five clinical centers. Tyrosine kinase gene fusions were detected by RNA-sequencing or FISH and confirmed by qPCR. Next-generation sequencing was performed in 47 patients. We assessed demographic and clinical variables, treatment, and outcomes. Results Demographic and clinical variables PDGFRA/B were the most commonly observed fusion genes (PDGFRA, n=27; PDGFRB, n=14), subsequently followed by FGFR1(n=12), JAK2(n=7), FLT3(n=2), ETV6::ABL1(n=8), and RANBP2::ALK(n=1). The median age was 43(6-69) years. 53(74.6%) patients were male.Both patients with PDGFRA and FLT3 fusion genes were male, while only 33% of the FGFR1 group were male (P＜0.01). 68 patients had eosinophil count at the initial diagnosis, of whom 55(80.9%) patients had eosinophilia, including 48(70.6%) diagnosed with hypereosinophilia(HE). Eosinophilia was observed in 5/8(62.5%, P=0.03) ETV6::ABL1 positive and 4/11(36.4%, P＜0.01) FGFR1 rearrangement patients, while more than 90% of patients in other subgroups had eosinophilia. Hypereosinophilia was more common in patients with PDGFRA rearrangement (24/26), FLT3 rearrangement (2/2), and RANBP2::ALK (1/1) positive, while only 4/11 in the FGFR1 rearrangement group(P＜0.01). Overall, a blast phase (BP) in bone marrow (BM) was diagnosed in 15/71 (21.13%) patients (myeloid, 40%; lymphoid, 40%; mixture phenotype, 13.3%; plasma cell leukemia, 6.67%), 5 patients(myeloid sarcoma, 1; T lymphoblastic lymphoma, 4) were diagnosed as extramedullary disease (EMD). Compared with other subgroups, the incidence of BP was higher in the FGFR1 rearrangement group(7/12, 58.33%). 37 mutations were detected in 21 patients, and RUNX1 mutations (8/37, 21.6 %) were the most commonly observed. The main organs involved included the spleen (32/55, 58.2%), lymph nodes (13/55, 23.6%), skin (12/55, 21.8%), liver (11/55, 20.0%) and heart (3/55, 5.4%); 21/55(38.2%) of the patients had two or more organ involvement. Treatments and outcomes Treatment follow-up data were available for 63 patients. At a median follow-up of 19.5 months, death occurred in 6 (9.8%) patients.. In MLN with PDGFRA fusion genes, 22 patients in chronic phase(CP) were treated with imatinib, 1 patient with AML received chemotherapy + imatinib, and 1 patient with ALL received dasatinib + chemotherapy. Except for 2 patients who did not reach the 3-month evaluation time, the remaining patients achieved complete molecular remission(CMR) in the 3-month evaluation. In MLN with PDGFRB fusion genes, CMR was obtained in 10 CP patients after 3 months of imatinib treatment; 2 AML patients failed to benefit from chemotherapy and died 1 month and 3 months after diagnosis;.another AML patient with persistent CR after chemotherapy. One patient with T-LBL received imatinib combined with chemotherapy and achieved CR, followed by allogeneic hematopoietic stem cell transplantation(Allo HSCT). In MLN with FGFR1, JAK2, FLT3, ETV6::ABL1 and RANBP2::ALK fusion genes (n=28), 11 patients received allo-HSCT after TKI combined with or without chemotherapy. Four patients died of disease progression(FGFR1, n=1; JAK2, n=1; ETV6::ABL1 n=1 and RANBP2::ALK n=1).Two cases of ZMYM2::FLT3 achieved complete hematological remission(CHR) after treatment with giretinib, but did not achieve CMR, and one of them progressed to ALL after 18 months of treatment. Conclusions: The clinical manifestations of MLN-TK are different, which may involve multiple organs. The increase of eosinophils is more common, and the prognosis of BP or secondary BP seems to be worse.

It is very important to calculate the starting surface shape before machining off-axis free-form surfaces. The three-point method is usually used to calculate the starting surface shape before machining. However, the material removal of the starting surface shape calculated by this method is large. Therefore, this paper proposes a calculation method that utilizes off-axis aspherical surfaces as the starting surface profile, which is named as best-fit off-axis aspheric method (BOAS). Off-axis Zernike polynomial surfaces made of glass are analyzed. Different types of workpieces are solved separately to obtain the starting surface type with the smallest possible removal. The methodological approach proposed in this paper is validated and analyzed by means of examples. The results show that: for the non-equal-thickness type of workpiece, the maximum asphericity of the BOAS can be less than 50 microns. Afterwards, the PV can be quickly reduced to less than 2 microns by combining with the CMM inspection technique for subsequent inspection using CGH. The results show that the use of BOAS as the starting surface of off-axis Zernike polynomial surfaces can effectively reduce the amount of material removal. An indispensable method of calculating the starting face pattern for machining methods with small material removal.

Systemic mastocytosis (SM) is a subset of rare neoplasms characterized by clonal proliferation of aberrant mast cells (MCs) and their accumulation in >= 1 extracutaneous organs, which typically associates with activating KIT mutations.(1) SM with an associated hematological neoplasm (AHN) is the second most common type of SM in Mayo series (similar to 40%),(2) with challenging diagnosis because the mast cell infiltration may hide behind the AHN component and vice versa.(3-5) This is particularly applicable to acute myeloid leukemia (AML) because the histological examination of bone marrow (BM) has not been established as a standard diagnostic tool. Moreover, the concomitant hematological neoplasm often shares a KIT mutation and/or other clonal genetic abnormalities with neoplastic MCs. AML with t(8;21) (q22;q22)/RUNX1::RUNX1T1 [t(8;21) AML] represents 4% to 8% of all AMLs, which is categorized to the genetically favorable risk group.(6) Meanwhile, KIT mutations, most frequently at position D816, are detectable in up to 20% to 47% of patients with t(8;21) AML and associate with decreased remission duration and inferior overall survival (OS).(7-10) Previous case reports, case-series, and/or literature reviews have described the potential association of KIT mutant t(8;21) AML [KITpos t(8;21) AML] with underlying SM.(11)(,)(12) Owing to a lack of literature on investigating similarities and differences between SM-t(8;21) AML and KITpos t(8;21) AML, we carried out this retrospective cohort study from multiple Chinese centers to compare clinical and molecular features between these 2 groups. Between January 2009 and December 2022, 24 patients with SM-t(8;21) AML and 212 with KITpos t(8;21) AML diagnosed and treated in 16 Chinese centers were eligible. All patients were screened for SM by BM smear, flow cytometry, and/or BM histological examination. Details of the study design, patient population, treatment regimen, and statistical analysis have been described in supplemental Data. This study was approved by the responsible ethics committees and performed in accordance with the Declaration of Helsinki.

Introduction Venetoclax plus hypomethylating agents (VEN+HMA) has shown remarkable efficacy in elderly and unfit AML patients. However, prospective studies comparing VEN+HMA to standard intensive chemotherapy in young and fit AML patients are lacking. We conducted a phase 2 study to compare the efficacy and safety of VEN+HMA versus the standard 7+3 regimen in newly diagnosed AML patients eligible for intensive chemotherapy. Preliminary results were reported at ASH 2023 (#970). The study, now complete with increased sample size and extended follow-up, presents the final analysis. Methods In this multicenter, randomized, open-label, controlled phase 2 trial, newly diagnosed Chinese AML patients aged 18-59 years and eligible for intensive chemotherapy were randomly assigned, in a 1:1 ratio to receive either venetoclax plus decitabine (VEN-DEC) or the idarubicin plus cytarabine (IA-12) as induction therapy. Patients in the VEN-DEC arm received venetoclax (orally, once daily, for 28 days, target dose 400 mg) and decitabine (20 mg/m² intravenously on days 1-5). Patients in the IA-12 arm received intravenous idarubicin (12 mg/m² on days 1-3) and cytarabine (100 mg/m² on days 1-7). The primary endpoint was composite complete remission (CRc), including complete remission and complete remission with incomplete hematologic recovery, aiming to demonstrate the non-inferiority of VEN-DEC as induction therapy compared to IA-12 with a non-inferiority margin of 5% and a one-sided type 1 error of 2.5%. Secondary endpoints included the incidence of grade 3 or worse infections during induction treatment, duration of severe myelosuppression, event-free survival (EFS), overall survival (OS), and the measurable residual disease (MRD) negativity rates post-induction therapy. The exploratory endpoint was the efficacy of the two treatment regimens in cytogenetic subgroups. The study was registered on ClinicalTrials.gov (NCT05177731), and the data cut-off date was 30 April, 2024. Results The intention-to-treat population comprised 188 patients (94 in each group). The median age was 45 years in the VEN-DEC group and 40 years in the IA-12 group. Composite complete remission was observed in 84 (89%) of 94 patients in the VEN-DEC group versus 74 (79%) of 94 patients in the IA-12 group (test for non-inferiority, p=0.0021). VEN-DEC demonstrated non-inferiority to IA-12 at the 2.5% significance level. The difference in CRc between VEN-DEC and IA-12 was estimated to be 10.6% (95% CI 0.2 to 21.3). The rate of MRD negativity in CRc patients after induction therapy was 80% in both the VEN-DEC (67/84) and the IA-12 groups (59/74). Subgroup analysis of CRc rates showed that compared to IA-12, patients aged ≥40 years (91% vs 75%), with ELN-2022 adverse risk factors (91% vs 42%), and with epigenetic modifier mutations (91% vs 67%) benefited more from VEN-DEC, whereas the RUNX1::RUNX1T1subgroup responded better to IA-12 (44% vs 88%). Fewer patients in the VEN-DEC group experienced grade 3 or worse infections compared to the IA-12 group (30 [32%] vs 63 [67%], χ² test, p<0.001). Key grade 3 or worse infections included pneumonia (16% in the VEN-DEC group vs 32% in the IA-12 group), sepsis (7% vs 25%), and septic shock (1% vs 6%). 82% of patients in the VEN-DEC group and 93% in the IA-12 group experienced grade 3-4 hematologic adverse events. The median duration of severe neutropenia (<0.5×109/L) was longer in the VEN-DEC group (23 days, IQR 17-28) compared to the IA-12 group (19 days, IQR 16-23) (p=0.001). Conversely, the median duration of severe thrombocytopenia (<25×109/L) was shorter in the VEN-DEC group (13 days, IQR 0-20) compared to the IA-12 group (19 days, IQR 14-26) (p<0.001). At a median follow-up of 12.1 months (range, 0.33 to 26.5), the median survival time was not reached in either group, with no significant difference in EFS (hazard ratio, HR=0.91, p=0.714) or OS (HR=1.15, p=0.705). However, in the VEN-DEC group, patients with CEBPAbZIP had a 1-year RFS rate of 52.5% (95% CI 33.2 to 83.0), significantly lower than 85.1% (95% CI 68.0 to 100) in the IA-12 group (HR for relapse or death, 5.43; 95% CI 1.14 to 25.75; p=0.017). Conclusions In newly diagnosed adult patients under 60 years old who are eligible for intensive chemotherapy, VEN+DEC showed comparable efficacy but improved safety compared to the standard 7+3 regimen. However, caution is warranted when using VEN+DEC in AML patients with RUNX1::RUNX1T1 or CEBPAbZIP mutations.

The prognostic impact of clonal hematopoiesis (CH) in complete molecular remission (CMR) in acute myeloid leukemia (AML) remains controversial. Here, we explored the prognosis of CH-related gene mutations (CH-mutation) at CMR in patients with AML with NPM1 mutation (NPM1c AML). Ninety-one patients with de novo NPM1c AML were included between June 2018 and June 2023, including 32 patients with CH-related mutation at CMR and 59 patients without. A cutoff of ≥ 2.0

In this report, we present an optimized prevention and treatment strategy for differentiation syndrome (DS). A total of 111 eligible patients with acute promyelocytic leukemia (APL) − 78 classified as low-risk and 33 as high-risk - received induction treatment consisting of all-trans retinoic acid (ATRA) in combination with an arsenic agent. Different doses of dexamethasone were administered based on the dynamics of white blood cell (WBC) counts to prevent DS. Ruxolitinib was used as a second-line therapy for DS. Among the patients, 41 (36.9%) experienced DS, with 16 having a severe form (14.4%) and 25 having a moderate form (22.5%). There was no significant difference in the incidence and severity of DS between the low-risk and high-risk patients (p = 0.057 and p = 0.056, respectively). The efficacy of ruxolitinib in cases of DS resistant to steroids was 67% without interruption of ATRA therapy. After discontinuing ATRA, the remaining DS cases were relieved through treatment with dexamethasone and ruxolitinib. The overall 30-day mortality rate was 1.8% (2/111), with two high-risk patients succumbing to intracranial hemorrhage. Complete remission (CR) was achieved in the remaining 109 patients. Our findings suggest that personalized prophylaxis against DS can mitigate the negative prognostic impact of hyperleukocytosis, and ruxolitinib is effective and well tolerated for refractory DS, ultimately decreasing early mortality in APL patients .(clinical trials.gov NCT04446806).

Introduction Blinatumomab, a bispecific T-cell antibody, has emerged as a novel therapy with a promising efficacy and tolerable safety in patients with B-cell acute lymphoblastic leukemia (B-ALL). However, there is a paucity of data on blinatumomab for patients with newly diagnosed and relapsed/refractory (R/R) B-ALL in frontline and relapsed settings outside the clinical trials. This study aimed to describe the treatment patterns, effectiveness and safety of blinatumomab in Chinese patients with B-ALL. Methods In this retrospective observational study, data of patients with B-ALL who received at least one dose of blinatumomab in frontline or relapsed settings between August 2021 and June 2023 were collected from electronic medical data of the Department of Haematology of the First Affiliated Hospital of Soochow, China. The primary endpoint of the study was the treatment pattern of blinatumomab therapy, including median treatment cycles. Secondary endpoints included complete remission (CR)/CR with incomplete blood cell recovery (CRi) rate, minimal residual disease (MRD) negativity (i.e., complete MRD remission, defined as MRD <0.01%), median event-free survival (EFS) and 1-year EFS rate, median overall survival (OS) and 1-year OS rate, duration of response (DOR) and adverse events (AEs). Results In total, 96 patients with B-ALL (53 males and 43 females) were included. Of these, 53 received frontline treatment (blinatumomab used for first line remission induction: n=6; first line consolidation: n=39; first line induction or consolidation unknown: n=8), and 43 were R/R patients (blinatumomab for remission re-induction: n=28; R/R consolidation: n=14; R/R re-induction or consolidation unknown: n=1). The median age was 34 years (range: 11-67). Among R/R patients, 18 (18.8%), 12 (12.5%) and 13 (13.5%) had received 2, 3, and ≥3 previous lines of treatments, respectively. Sixteen patients were refractory to the last treatment. Among patients using blinatumomab for consolidation, MRD status at the start of therapy was positive in 29 (30.2%), and negative in 23 (24.0%) patients. Most of the patients (66.7%) received 1 cycle of blinatumomab followed by 2 (20.8%), 3 (7.3%), 4 (4.2%), and 5 (1.0%) cycles of the drug. The median treatment cycle was 1 (range: 1-5) with a median follow-up of 205 days (range: 15-652). In frontline treatment, all those using blinatumomab for remission induction and first line unknown status achieved CR with the CR/CRi rate of 100% (14/14) after blinatumomab. In patients with evaluable MRD (n=47) in the frontline setting, 87.2% (n=41) achieved MRD negativity within the 2 cycles of blinatumomab. In the following cycles, 3 more patients achieved MRD remission with overall complete MRD remission rate of 93.6% (44/47). In R/R re-induction patients, the CR/CRi rate was 50% (14/28) after blinatumomab treatment. Complete MRD remission rate in R/R patients who achieved CR within 2 cycles of blinatumomab was 73% (19/26). Median EFS was not reached (NR) in both frontline and R/R patients and the 1-year EFS rate was 90.8% (95% CI: 67% - 97%) and 55.1% (95% CI: 30% - 74%), respectively (Figure 1). Stratification of EFS by CR status at blinatumomab initiation showed 1-year EFS rate of 93.8% and 100% in first line consolidation and remission induction patients, respectively, whereas, R/R consolidation and re-induction patients showed 1-year EFS rate of 66.8% and 59.3%, respectively. None of the frontline treated patients died until the last follow-up time. In R/R patients the median OS was not reached and the 1-year OS rate was 70.9% (95% CI: 50% - 84%). OS stratified by CR status in R/R patients showed 1-year OS of 87.5% in consolidation and 69.9% in re-induction patients. Median DOR was NR in both frontline and relapsed settings. Seven (7.3%), and 3 (3.1%) patients reported any grade, and grade ≥3 cytokine release syndrome, respectively. Immune effector cell-associated neurotoxicity syndrome was reported by 1 patient (grade ≥3). Infection of any grade and grade ≥3 was reported by 6 (6.2%) and 4 (4.2%) patients, respectively. Increase in liver enzymes and neutropenia were observed in 1 patient (grade ≥3) each. Conclusion This study showed that using blinatumomab for remission induction and consolidation with one to five cycles was effective in the treatment of patients with B-ALL in the frontline as well as relapsed settings and had a tolerable safety profile.

Background: More than 95% of acute promyelocytic leukemia (APL) patients can achieve complete remission by dual induction of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). However, early death is a treatment obstacle of APL. The main causes of early death in APL include hemorrhage, differentiation syndrome (DS) related to induction therapy, and infection. Currently, the mechanism of DS in APL largely remains unclear. This study aims to investigate the pathogenetic mechanism and treatment pattern for APL DS and find a suitable biomarker for DS using multiomics approaches. Methods: Eighty newly diagnosed APL patients were recruited through Jan 2019 to Jan 2021 from a clinical trial (NCT04446806). Matched RNA and plasma samples of APL at presentation and DS were studied by RNA-seq and Human Cytokine Array. Two matched peripheral blood samples at presentation and DS from 2 severe DS patients were selected for 10×scRNA-seq analysis, compared with 3 peripheral blood and 2 bone marrow controls. Results: The incidence of DS was 35.3% (29/80), including 21.3% (17/80) moderate DS and 15% (12/80) severe DS. Bulk RNA-seq suggested immune response and cytokines interaction might play important roles in the development of DS ( Figure 1A and B). Significant downregulation of immune checkpoint molecules was shown in the DS period, such as GAL-9, which plays a crucial role in regulating the immune response ( Figure 1C). The activated CD4 +T and CD8 +T cells were amplification at diagnosis period compared with the corresponding CR/CRi period, then declined dramatically at DS period ( Figure 1 D). 10×scRNA-seq analysis revealed the activation of neutrophils and monocytes through innate immune response and inflammatory response ( Figure 1 E). Consistent with bulk RNA-seq results, apparent elevated expression of multiple inflammatory storm-related cytokines/receptors are shown in the DS period in monocytes and neutrophils, which indicates they contribute to the inflammatory cytokine storm ( Figure 1 F). These results indicated that ATRA induction overcomes immune evasion and induces highly activated immune response through downregulating immune checkpoint molecules. Based on 10×scRNA-seq data, differentiated promyelocytic leukemic cell, neutrophils and monocytes are major cell populations and expressed significantly higher cytokine and chemokine in DS stage, indicating that these cells might be major sources of the cytokine storm ( data not shown). We found S100A8 and S100A9, which function as danger-associated molecular pattern (DAMP) molecules and activate innate immune responses via binding to PRRs, significantly upregulated among all known alarmins ( Figure 1G). S100A8/A9 can be induced by ATRA induction, and also activate ERK, JAK-STAT and NF-κB signaling pathways ( Figure 1H). S100A8/A9 expression can be repressed by ERK inhibitor ( Figure 1I). Knockdown of S100A9 induced lower phosphorylation level of STAT1 and P65 ( Figure 1J). These results indicated S100A8/A9 were regulated by the ERK signaling and controlled the JAK-STAT and NF-κB signaling pathway. As a result, JAK-STAT related cytokines could be regulated by S100A8/A9 signaling. Importantly, ROC analysis showed that S100A8/A9 displayed both high sensitivity and specificity as a biomarker for predicting APL DS ( Figure 1K). According to clinical and cytokine storm characteristics of APL DS patients, Dexamethasone (DEX) and Ruxolitinib (RUX) were applied in the treatment of APL DS patients. The percentage of severe DS reduced remarkably after DEX prevention ( Figure 1L, P<0.05). The early death rate of APL declined under the DEX prevention and RUX treatment, and no patient died due to DS ( Figure 1M). The expression of a series of inflammatory cytokines dramatically decreased, indicating that the cytokine storm was effectively suppressed by the treatment of DEX and/or RUX ( Figure 1N). Conclusion s : Our data indicate that ATRA induction could overcome immune evasion through downregulating immune checkpoint molecules. ATRA-induced upregulation of S100A8/A9 may contribute to the cytokine storm observed in the DS stage of APL patients by activating the JAK-STAT and NF-κB signaling pathway. S100A8/A9 is recommended as a biomarker for predicting APL DS. Dexamethasone and Ruxolitinib are appropriate prevention and treatment pattern for APL DS patients.

Xie et al present results of a multicenter, single-arm phase 2 trial of venetoclax and decitabine as frontline treatment in 42 younger adults (median age 39 years) with newly diagnosed adverse risk acute myeloblastic leukemia (AML). Remission was achieved in 39 of 42 patients (93%), 36 of whom went on to allogeneic stem cell transplant. Efficacy is encouraging, with estimated 12-month overall survival, event-free survival, and duration of response being 82%, 61%, and 65% respectively.