From December 6–9, 2025, the 67th American Society of Hematology (ASH) Annual Meeting was held in Orlando, USA. As the largest and most influential global conference in hematology, ASH annually gathers experts from around the world to present cutting-edge advances and breakthrough research across malignant and non-malignant blood disorders.
At this year’s meeting, multiple studies from Prof. Jian Huang’s team at the First Affiliated Hospital, Zhejiang University School of Medicine, were selected for presentation. Their work spans essential thrombocythemia (ET), myelofibrosis (MF), chronic myeloid leukemia (CML), and related therapeutic innovations. Below is a summary of several key studies from Prof. Huang’s group.
1. Efficacy and Safety of OB756 (a Novel Selective JAK2 Inhibitor) in Hydroxyurea/Interferon-Resistant or -Intolerant Essential Thrombocythemia: A Phase II, Open-Label, Multicenter Study Abstract No.: 5530
Background OB756 is a novel, orally available small-molecule Janus kinase 2 (JAK2) inhibitor that has already shown significant clinical activity in patients with myeloproliferative neoplasms (MPN) in phase I trials. Although essential thrombocythemia (ET) generally has a relatively favorable prognosis within MPN, patients may still carry a substantial disease burden, and many are resistant or intolerant to hydroxyurea (HU) or interferon (IFN).
Objective To evaluate the safety and efficacy of the new oral JAK2 inhibitor OB756 in ET patients who are resistant or intolerant to HU and/or intolerant to IFN.
Methods Eligible patients received OB756 at 16 mg (exploratory subgroup, n = 5) or 20 mg (n = 45), orally twice daily in 28-day cycles until disease progression or unacceptable toxicity.
The primary endpoint was complete hematologic response (CHR) at week 24. Secondary endpoints included hematologic response (HR) rate, safety and tolerability, molecular response rates, proportion of patients achieving at least 35% spleen volume reduction from baseline at week 24 (SVR35), and changes in disease-related symptoms.
Results Between November 3, 2020, and May 16, 2024, a total of 96 patients were screened at 12 centers, and 50 were enrolled and treated. Median follow-up was 11.23 months. Median age was 59 years, and 42% were male.
OB756 produced a rapid reduction in platelet and white cell counts. In the 16 mg BID group, platelets decreased from 825 to 605 × 10⁹/L by week 6. In the 20 mg BID group, platelets reached a nadir of 512 × 10⁹/L at week 4. White blood cells decreased from 6.9 to 5.7 × 10⁹/L by week 2, while hemoglobin levels remained stable.
At week 24, the CHR rate was 23.7%, and the overall HR rate was 65.6%. Among patients with spleen enlargement, 94.7% experienced a reduction in spleen volume, with a median decrease of 35%. Among patients with evaluable JAK2 variant allele frequency (VAF), 84.6% showed a reduction. The TSS50 response rate (≥50% reduction in total symptom score) was 74.2%.
Treatment-emergent adverse events (TEAEs) were mostly grade 1–2. Anemia was the most common hematologic AE, occurring in 52% (26/50), with grade ≥3 anemia in 10% (5/50). Among non-hematologic AEs, infections were the most frequent grade ≥3 event, seen in 16% (8/50). No cases of acute leukemic transformation or progression to myelofibrosis were observed during the study. Overall, OB756 toxicity was predominantly mild to moderate and clinically manageable.
Conclusion OB756 demonstrated good tolerability and meaningful clinical activity in ET patients who were resistant or intolerant to HU and/or intolerant to IFN. It rapidly induced hematologic responses, reduced spleen volume, and lowered JAK2 V617F allele burden. CHR could be durably maintained, and the incidence of non-hematologic toxicity was low, making OB756 a highly promising new treatment option for this difficult-to-treat ET population.
2. BCL-2 Inhibitor TQB3909 Combined with JAK Inhibitors in Intermediate- or High-Risk Myelofibrosis: A Two-Cohort, Open-Label, Phase Ib/II Multicenter Study Abstract No.: 2034 (internal: abs25-8764)
Background Overexpression of BCL-2/BCL-XL is common in the malignant clone of MF patients. JAK inhibitors can downregulate BCL-XL and MCL-1, whereas BCL-2 inhibitors directly block BCL-2 function. Combining these agents may enhance apoptosis and restore sensitivity to JAK2 inhibition. Previous studies have suggested that BCL-2 inhibition combined with ruxolitinib (RUX) can improve efficacy. TQB3909 is a novel BCL-2 inhibitor; this Ib/II trial explores TQB3909 in combination with JAK inhibitors in MF.
Objective To evaluate the safety, tolerability, and preliminary efficacy of TQB3909 combined with JAK inhibitors (ruxolitinib or ropeginterferon-like JAKi rovatinib, ROV) in intermediate- or high-risk MF patients.
Methods This is a multicenter, open-label phase Ib/II trial (NCT06245941) conducted at 5 centers. Eligible patients were ≥18 years old with DIPSS intermediate-1 or higher-risk MF, either JAK inhibitor–naïve or JAKi-resistant, with palpable splenomegaly or spleen volume ≥450 cm³ on imaging.
Per investigator decision, patients received either RUX or ROV in combination with TQB3909. In the RUX cohort, TQB3909 doses were escalated (100/200/300 mg QD). In the ROV cohort, a 3+3 design was used for ROV (10 mg or 15 mg BID). Key assessments included spleen size reduction, total symptom score (TSS) changes, hemoglobin and platelet dynamics, and adverse events.
Results From May 13, 2024 to April 22, 2025, 16 patients were enrolled (11 primary MF, 4 post-PV MF, 1 post-ET MF). Seven patients received RUX + TQB3909, and 9 received ROV + TQB3909. Thirteen patients (81.3%) harbored JAK2 mutations; 5 (31.3%) were JAKi-naïve, and 11 (68.8%) were RUX-resistant.
Among 11 evaluable patients, 9 (81.8%) achieved spleen size reduction, with 6 (54.5%) achieving >20% reduction. The rate of >35% spleen volume reduction (SVR35) was 66.7% (4/6) in the ROV cohort versus 20.0% (1/5) in the RUX cohort. All evaluable patients (12/12, 100%) had improvement in TSS, and the TSS50 rate reached 75.0% (9/12). Hemoglobin increased by ≥15 g/L in 50% (8/16) of patients, with a more pronounced trend in the ROV cohort. Platelet and hemoglobin declines were smaller and recovery faster in the ROV cohort.
In terms of safety, in the RUX cohort there were three discontinuations due to RUX withdrawal syndrome and cryptococcal infection. In the ROV cohort, two dose-limiting toxicities (DLTs) of grade 4 thrombocytopenia were observed. Excluding one patient who withdrew because of RUX withdrawal syndrome, 10 of 14 patients (71.4%) experienced grade ≥3 treatment-related AEs, most commonly lymphopenia, anemia, thrombocytopenia, and diarrhea.
Conclusion TQB3909 in combination with JAK inhibitors yielded clinically meaningful benefits in MF, particularly with ROV, where spleen reduction, symptom relief, and potential hemoglobin improvement were more pronounced. Hematologic toxicity was the main safety concern. Ongoing dose optimization aims to balance efficacy with tolerability.
3. Multiple ASXL1 Mutations and G646fs Alterations Confer Increased Risk of Leukemic Transformation in Patients with Myelofibrosis Abstract No.: 3800 (internal: abs25-8764)
Background ASXL1 is one of the most common high-molecular-risk genes in myeloid neoplasms and is strongly associated with poor prognosis. Most prior studies simply compared ASXL1-mutated versus wild-type patients. However, some MF patients harbor multiple ASXL1 mutations (multi-ASXL1), and the clinical impact of this pattern has not been fully clarified.
Objective To evaluate the impact of multi-ASXL1 and specific high-risk variants (such as G646fs) on leukemic transformation (LT) in MF patients.
Methods A targeted next-generation sequencing panel of 155 genes was used to characterize MF patients. A total of 222 MF patients with available NGS data were retrospectively analyzed. Multi-ASXL1 was defined as the presence of at least two distinct ASXL1 mutation sites.
Chi-square and Kruskal–Wallis tests were used to compare clinical features. Leukemia-free survival (LFS) was assessed using Kaplan–Meier and log-rank tests, with a 2-year landmark analysis. Enrichment and prognostic impact of the ASXL1 G646fs variant were also evaluated.
Results Sixty-nine patients (31.1%) carried ASXL1 mutations; 76.8% had a single ASXL1 mutation and 23.2% had multiple ASXL1 mutations. Compared with wild-type, ASXL1-mutated patients were older and had higher WBC, LDH levels, and higher MF grade. These differences remained significant when stratifying into three groups (wild-type, single ASXL1, multi-ASXL1). Complex karyotype was most frequent in the multi-ASXL1 group (43.8%).
The most common hotspot variant, G646fs, was significantly enriched in the multi-ASXL1 group (31.3% vs 18.9%, P<0.001). Leukemic transformation rates showed an increasing trend across groups: 13.8% in wild-type, 26.5% in single-mutant, and 31.3% in multi-ASXL1 (P=0.045). Median LFS was not reached in the wild-type group, 114 months in the single-mutant group, and 54 months in the multi-ASXL1 group.
Compared with wild-type, multi-ASXL1 significantly increased LT risk (HR = 4.25, P = 0.027), while the difference between multi- and single-mutant groups was not statistically significant overall. However, in a 2-year landmark analysis, multi-ASXL1 was associated with significantly worse long-term LFS compared with single-mutant ASXL1 (P = 0.024). Among ASXL1-mutated patients, those carrying G646fs had inferior LFS (HR = 4.06, P = 0.006).
Conclusion Multi-ASXL1 is an independent adverse factor for leukemic transformation in MF, particularly evident in long-term follow-up. Its poor prognostic impact appears partly driven by enrichment of high-risk variants such as G646fs.
4. ASXL1 and NOTCH1 Mutations Independently Predict TKI Treatment Failure in Chronic Myeloid Leukemia Abstract No.: 5551
Background Tyrosine kinase inhibitors (TKIs) have dramatically improved the prognosis of CML, yet a subset of patients still fail to achieve optimal responses. Mutations in the ABL1 kinase domain explain only about half of TKI resistance, suggesting additional genetic mechanisms. The role of non-ABL1 mutations in TKI failure has not been systematically studied.
Objective To assess the impact of high-risk gene mutations identified by NGS on TKI treatment failure in CML.
Methods Ninety-four CML patients who underwent NGS at diagnosis were retrospectively analyzed. TKI treatment failure was defined according to ELN 2020 criteria. Mutation status and variant allele frequency (VAF), as well as functional categories of genes (e.g., histone methylation, transcription factors), were evaluated. Uni- and multivariable logistic regression models were used to identify clinical and genetic predictors of TKI failure.
Results Median age was 45.5 years, and 52.1% were male. Compared with responders, patients with TKI failure had significantly lower hemoglobin (105 vs 123 g/L, P<0.001) and platelet counts (401 vs 542 × 10⁹/L, P=0.003), and a higher proportion of intermediate/high-risk Sokal scores (76.7% vs 66.7%, P=0.033).
The total number of mutations was higher in the failure group (median 3 vs 2, P<0.001). Excluding ABL1, the most frequently mutated genes in the failure group were ASXL1 (30.2%), NOTCH1 (16.3%), WT1 (14.0%), CSMD1 (11.6%), KMT2C (9.3%), and TCF3 (9.3%), with higher ASXL1 VAF. Mutations in histone methylation–related genes were more common in the failure group (20% vs 13%, P=0.033).
Patients ≥50 years had more mutations (3 vs 2, P=0.031). Those initially treated with first-generation TKIs had more mutations than those starting with later-generation TKIs (3 vs 1, P<0.001). Patients who failed to achieve MMR at 12 months also carried more mutations (3 vs 2, P=0.014).
In univariable analysis, ASXL1 (OR 3.99, P=0.016) and NOTCH1 (OR 9.72, P=0.037) mutations were significantly associated with TKI failure. After multivariable adjustment, both ASXL1 (OR 4.17, P=0.025) and NOTCH1 (OR 12.61, P=0.029) remained independent predictors. Functionally, histone methylation–related genes retained predictive value in both uni- and multivariable models, while transcription factor mutations were significant in univariable analysis.
Conclusion ASXL1 and NOTCH1 mutations are independent predictors of TKI treatment failure in CML, suggesting that non-ABL1 genetic alterations play important roles in resistance mechanisms and should be incorporated into future risk stratification and treatment decision-making.
Expert Profile
Prof. Jian Huang First Affiliated Hospital, Zhejiang University School of Medicine
MD, Chief Physician, Doctoral Supervisor Deputy Director of the Department of Hematology, First Affiliated Hospital, Zhejiang University Zhejiang Provincial “551” High-Level Innovation Talent Deputy Director of Zhejiang Provincial Clinical Research Center for Hematologic Diseases and Head of the MPN Subgroup Head of the Zhejiang CML/MPN Collaborative Group Standing Committee Member and Head of the Platelet Disorders Group, Targeted Therapy Committee, Chinese Medical Women’s Association Former visiting scholar at the University of Western Australia and the University of Alberta (Canada) Member of the National Health Science Popularization Expert Panel (2024)
Committee roles include: Member, Rare Disease Group, 12th Committee of the Hematology Branch, Chinese Medical Association Member, Red Cell Disorders Group, 11th Committee of the Hematology Branch, Chinese Medical Association Standing Committee Member, Hematology Committee, Chinese Medical Women’s Association Standing Council Member, Hematology Branch, Chinese National Medical Association of Ethnic Medicine Standing Member, Hemophilia Group, China Alliance for Rare Diseases Vice-Chair, Hematology Branch, Zhejiang Association of Integrative Medicine Standing Member and Head of the Rare Disease Group, Hematology Physician Branch, Zhejiang Medical Doctor Association; Vice-Head of the MDS/MPN Group Member, Translational Hematology Committee, Chinese Anti-Cancer Association Member, MDS/MPN Working Group, Hematologic Oncology Branch, Chinese Anti-Cancer Association Member, Hematology and Rare Disease Branches, Zhejiang Medical Association
She has published around 30 SCI-indexed papers as first or corresponding author (including in eClinicalMedicine), led 10 national and provincial research projects (including National Natural Science Foundation and provincial key R&D programs), and received multiple science and technology awards, including participation in a National Science and Technology Progress Second Prize and two provincial First Prizes.
In 2018, she was named one of Zhejiang Province’s first “Outstanding Hematologists.” From 2014 to 2022, she served as Director of the Department of Hematology at the Fourth Affiliated Hospital of Zhejiang University and was the academic lead for key hematology disciplines in Jinhua and Yiwu.
