Objectives Olverembatinib is a novel 3rd-generation tyrosine kinase inhibitor (TKI) for patients with chronic myeloid leukemia (CML). However, long-term therapy raises concerns about treatment-related adverse events including proteinuria, hypertriglyceridemia, hyperglycemia, hypoalbuminemia, hypertension, arterial and/or venous obstructive events. To investigate the pathogenesis of proteinuria, we performed renal biopsies in 5 TKI-resistant patients with CML receiving olverembatinib therapy. Methods Clinical and pathological data on TKI-resistant CML patients with proteinuria receiving olverembatinib therapy were analyzed retrospectively. Results 5 CML-CP patients who had failed at least one TKI, developed proteinuria during olverembatinib treatment, and performed renal biopsy evaluation were included in this study. Among them, 3 patients developed de novo proteinuria during olverembatinib therapy, while 2 had mild proteinuria prior to olverembatinib therapy and developed nephrotic-range proteinuria during therapy. Median age at the time of renal biopsy was 44 years (range, 31-48 years). None of them had cardiovascular or renal comorbidities before olverembatinib therapy. Median CML history and prior TKI duration before olverembatinib therapy were 119 months (range, 9-189 months) and 29 months (range, 9-101 months), respectively. 2 patients were in MR4, each patient was in CHR, MMR and MR4.5 before renal biopsy. Median interval from starting olverembatinib therapy to renal biopsy was 34 months (range, 25-59 months). Before renal biopsy the median serum creatinine and estimated glomerular filtration (eGFR) was 94 μmol/L (range, 59-101 μmol/L) and 78 ml/min/1.73m2 (range, 62-112 ml/min/1.73m2), respectively. All 5 patients developed hypertriglyceridemia during olverembatinib therapy. 4 patients were diagnosed nephrotic syndrome because of nephrotic-ranged proteinuria and hypoalbuminemia; one patient, isolated proteinuria. In renal biopsy, glomeruli ischemic obsolescence was observed in 4 patients; hyperplasia of endothelial cells, in 3 patients; increased intracapillary cellularity and ischemic wrinkling of basement membranes, in one patient each. Microthrombi were noted in 2 patients. Renal tubular epithelial cells displayed vacuolar and granular degeneration with focal atrophy in all 5 patients. Immunofluorescence microscopy examination demonstrated that Complement 1q or Complement 3 deposition was observed in each 3 patients, respectively. Under electron microscopy, thrombotic microangiopathy (TMA) -related renal involvement was observed in 2 patients; endocapillary proliferative glomerulonephritis accompanied by ischemic renal injury, ischemic renal injury, and sclerotic glomeruli, one patient each. The 4 patients diagnosed with nephrotic syndrome received angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), and resulted in partial reduction of proteinuria, however none achieved complete normalization of urinary protein. Conclusion The renal pathology of olverembatinib-associated proteinuria predominantly presented with microvascular occlusion or ischemic injury in CML patients. Proteinuria appears to persist throughout olverembatinib therapy despite optimal therapeutic management. These preliminary findings require validation through future studies with larger sample size.

Research on the comprehensive integration of clinical and genomic characteristics in patients with core binding factor acute myeloid leukemia (CBF-AML) is limited. Clinical and genomic data from consecutive patients with CBF-AML were reviewed. A Cox regression model was used to identify the variables associated with event-free survival (EFS), relapse-free survival (RFS) and overall survival (OS). A total of 346 CBF-AML patients (211 with RUNX1::RUNX1T1 and 135 with CBFB::MYH11) were included in this study. In the RUNX1::RUNX1T1 cohort, multivariate analyses revealed that KDM6A mutations were significantly associated with poor RFS (hazard ratio = 3.1 [1.4, 7.1], p = 0.007) and OS (HR = 11.5 [3.6, 37.0], p < 0.001); FLT3-TKD mutations, poor OS (HR = 4.9 [1.7, 14.3], p = 0.004); KIT mutation VAF > 25%, poor RFS (KITwt as ref, HR = 2.5 [1.1, 5.3], p = 0.022); ASXL1 mutations, favorable EFS (HR = 0.4 [0.2, 0.9], p = 0.016) and OS (HR = 0.2 [0.03, 0.8], p = 0.028). In the CBFB::MYH11 cohort, multivariate analyses revealed that a high mutation burden was significantly associated with inferior OS (HR = 1.4 [1.1, 1.8], p = 0.018); FLT3-ITD mutations, inferior OS (HR = 6.8 [1.3, 36.0], p = 0.024). In addition, increasing age, nonintensive chemotherapy, and high MRD levels predict poor outcomes in the RUNX1::RUNX1T1 cohort. In addition to the adverse impact of high KIT mutation burden and FLT3-ITD or FLT3-TKD mutations on prognosis in CBF-AML, KDM6A mutations predicted poor outcomes in patients with RUNX1::RUXN1T1; however, ASXL1 mutations, favourable outcomes; high mutation burden, poor outcomes in those with CBFB::MYH11.

Objectives To compare the outcomes of FLT3-ITD mutated AML patients who underwent allo-HSCT in first complete remission (CR1) with those who remained on continuous chemotherapy plus a FLT3-targeted inhibitor as consolidation therapy. Methods Consecutive patients newly diagnosed with FLT3-ITD mutated AML and treated at Peking University Institute of Hematology between January 2018 and January 2025 were enrolled; last follow-up was 1 July 2025. Induction therapy comprised chemotherapy plus a FLT3-targeted inhibitor or azacitidine plus venetoclax. MRD relapse was defined as conversion from MRD negativity to positivity detected by multiparameter flow cytometry. Events were hematologic relapse, MRD relapse, or death from any cause. Event-free survival (EFS) was measured from diagnosis to the first event or last follow-up; relapse-free survival (RFS) was calculated from the date of CR/CRi to hematologic relapse or last follow-up/death from other causes; overall survival was calculated from diagnosis to death or last follow-up. Kaplan–Meier estimates were compared by log-rank test. Propensity-score matching (PSM) adjusted for baseline covariates; uni- and multivariable Cox regression identified covariates associated with EFS, RFS, and overall survival. Results Data on 303 consecutive newly diagnosed AML patients with FLT3-ITD mutation classified as ELN intermediate-risk cohort were collected. 150 subjects receiving chemotherapy plus sorafenib or venetoclax plus azacitidine as induction therapy, achieving CR/CRi and received 1 or 2 cycles of consolidation were included in this study. The median age was 46 years (range, 16-74 years). With a median follow-up of 30 months (range, 6-83 months) in surviving patients, 80 patients chose to remain on chemotherapy plus FLT3 inhibitor and 70 received allo-HSCT. In multivariate analysis allo-HSCT was associated with favorable EFS (p = 0.02) and RFS (p = 0.001). 102 patients were included in the PSM analysis, 51 patients chose to remain on chemotherapy plus FLT3 inhibitor and 51 received allo-HSCT. There were no difference in EFS (p = 0.005), RFS (p = 0.002) and survival (p = 0.41) between the 2 cohorts. In 120 CR1 subjects with negative MRD after 1-2 cycle of consolidation, 66 chose to remain on chemotherapy plus FLT3 inhibitor and 54 received allo-HSCT. In PSM analysis, 41 patients chose to remain on chemotherapy plus FLT3 inhibitor and 41 received allo-HSCT. 2 cohorts had comparable EFS (p = 0.15), RFS (p = 0.17) and survival (p = 0.63). However, in the 30 CR1 subjects with positive MRD after 1-2 cycle of consolidation, 14 chose to remain on chemotherapy plus FLT3 inhibitor and 16 received allo-HSCT. Allo-HSCT cohort had significant advantage in EFS (p < 0.001) and RFS (p < 0.001), but did not show significant difference in survival (p = 0.12). ConclusionIn the era of FLT3-targeting inhibition therapy, FLT3-ITD mutated AML patients who achieve MRD negativity after 1-2 cycles receiving chemotherapy plus FLT3 inhibitor exhibit comparable outcomes to those undergoing allo-HSCT in CR1; however, those with positive MRD still can benefit from allo-HSCT. These findings require validation through larger prospective studies to establish definitive treatment guidelines.

BACKGROUND:NPM1 mutacute myeloid leukemia (AML) patients have greater heterogeneity. However, data on the comprehensive integration of clinical and genetic data in NPM1mutAML patients are limited, especially in the FLT3 inhibitor era. METHODS:Data from consecutive AML patients with NPM1mut/FLT3-ITDwt (n = 203) and NPM1mut/FLT3-ITDmut (n = 115) were reviewed. RESULTS:In NPM1mut/FLT3-ITDwt patients, in multivariate analyses male sex, WBC count ≥19 × 109/L, bone marrow blasts ≥ 70%, NPM1 non-A/B/D type mutation, TET2 mutation and measurable residual disease (MRD) positivity after the first cycle of consolidation were significantly-associated with poor relapse-free survival (RFS) and survival. Based on the adverse prognostic covariates, patients were classified into low-risk (score 0-2, n = 113, 64%), intermediate-risk (score 3, n = 43, 25%) and high-risk (score ≥4, n = 20, 11%) subgroups, with significant differences in 3-year probabilities of RFS and survival (all P values < .001). In NPM1mut/FLT3-ITDmut patients who did not undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT) in CR1, single FLT3-ITD mutation, NPM1 non-A/B/D type mutation, TET2 mutation and MRD positivity after the first cycle of consolidation, poor RFS; platelet ≤60 × 109/L and albumin <40 g/L, poor survival. Patients were classified into low-risk (score 0-2) allo-HSCT (n = 9, 11%) or non-allo-HSCT (n = 26, 31%), and high-risk (score ≥ 3) allo-HSCT (n = 8, 10%) or non-allo-HSCT (n = 40, 48%). The first 3 subgroups had comparable outcomes, but were significantly superior to the high-risk non-allo-HSCT subgroup (all P values for trend = .001-.010). CONCLUSIONS:We identified high-risk AML patients with NPM1mut/FLT3-ITDwt or NPM1mut/FLT3-ITDmut who might consider more intensive therapy.

Background/Objectives: The role of KDM6A gene mutations in acute myeloid leukemia (AML) remains poorly understood. This study aimed to evaluate the impact of KDM6A mutations on relapse risk, cumulative incidence of relapse (CIR), relapse-free survival (RFS), and overall survival (OS) in adult AML patients, with a particular focus on those with RUNX1::RUNX1T1 fusion. Methods: the retrospective analysis was conducted on 1970 adult AML patients treated at Peking University People's Hospital. Of these, 1676 patients who achieved complete remission (CR) were included. Among them, 27 harbored KDM6A mutations. Propensity score matching (PSM) was used (1:10 ratio) to compare outcomes between patients with and without KDM6A mutations. Further analysis focused on 207 patients with RUNX1::RUNX1T1 fusion, among whom 13 had KDM6A mutations (PSM 1:5). Results: In the overall cohort, KDM6A variants (n = 27) had a higher 2-year CIR (45.7% vs. 28.6%, p = 0.04). Fine-Gray analysis showed KDM6A variants independently increased relapse risk (HR = 1.98 [1.08-3.63], p = 0.03). KDM6A mutations were associated with inferior 2-year RFS (36.3% vs. 60.9%, p = 0.044). Multivariable analysis confirmed KDM6A mutations as independent predictors of poor RFS (HR = 3.08 [1.56-6.08], p = 0.001). Among RUNX1::RUNX1T1 patients, KDM6A mutations significantly increased relapse risk (75.0% vs. 21.7%, p < 0.001), raised 2-year CIR (46.9% vs. 24.0%, p = 0.05), worsened 2-year RFS (31.3% vs. 71.9%, p < 0.001), and lowered 2-year OS (63.3% vs. 86.4%, p = 0.002). They were also independent predictors of CIR (HR = 2.46 [1.11-5.47], p = 0.03), RFS (HR = 5.1, [2.5-10.5], p < 0.001) and OS (HR = 12.9, [4.3-38.7], p < 0.001). Conclusions: KDM6A mutations are significantly associated with increased relapse risk and poor prognosis in AML, especially in patients with RUNX1::RUNX1T1 fusion, and may serve as a valuable prognostic biomarker.

Whether there is really a distinct accelerated phase (AP) at diagnosis in chronic myeloid leukaemia (CML) in the context of tyrosine kinase-inhibitor (TKI)-therapy is controversial. We studied 2122 consecutive subjects in chronic phase (CP, n = 1837) or AP (n = 285) at diagnosis classified according to the 2020 European LeukemiaNet (ELN) classification. AP subjects with increased basophils only had similar transformation-free survival (TFS) and survival compared with CP subjects classified as ELTS intermediate-risk. Those with increased blasts only had worse TFS but similar survival compared with CP subjects classified as ELTS high-risk. AP subjects with decreased platelets only had similar TFS but worse survival compared with subjects classified as ELTS high-risk. Proportions of CP and AP subjects meeting the 2020 ELN TKI-response milestones were similar. However, worse TFS at 3-month and survival at 6- or 12-month were only in AP subjects failing to meet ELN milestones. Findings were similar using the 2022 International Consensus Classification (ICC) criteria for AP replacing decreased platelets with additional cytogenetic abnormalities. Our data support the 2022 WHO classification of CML eliminating AP. We suggest adding a very high-risk cohort to the ELTS score including people with increased blasts or decreased platelets and dividing CML into 2 phases at diagnosis: CP and acute or blast phases.

Whether there is really a distinct accelerated phase (AP) at diagnosis in chronic myeloid leukemia (CML) in the context of tyrosine kinase-inhibitor (TKI)-therapy and whether co-variates identified as characterizing AP are simply adverse co-variates for outcomes, we studied 2,122 consecutive subjects in chronic phase (CP, n = 1,837) or AP (n = 285) according to the European LeukemiaNet (ELN) classification. AP subjects with increased basophils only had similar transformation-free survival (TFS) and survival compared with CP subjects in ELTS intermediate-risk. AP subjects with increased blasts only had worse TFS but similar survival compared with CP subjects in the ELTS high-risk; AP subjects with decreased platelets only, similar TFS but worse survival. Proportions of CP and AP subjects meeting the 2020 ELN TKI-response milestones were similar. However, worse outcomes were only seen in AP subjects failing to meet ELN milestones. Findings were similar using the 2022 International Consensus Classification (ICC) criteria replacing decreased platelets with additional cytogenetic abnormalities. Our data support the 2022 WHO classification of CML eliminating AP. We suggest adding a very high-risk cohort to the ELTS score including people with increased blasts or decreased platelets and dividing CML into 2 phases: CP and acute phase.

The application of tyrosine kinase inhibitors (TKIs) and novel immunotherapies has improved outcomes in patients with Ph + acute lymphoblastic leukaemia (ALL), and the issue of whether there is still a need for stem cell transplantation has become controversial. We performed a retrospective study to explore whether stem cell transplantation still held a place in patients with Ph + ALL if only imatinib and 2nd generation TKIs are available and affordable. A total of 292 patients were included. The median age was 38 years [range 14–64, IQR 28–48]. Patients receiving transplants (n = 216) had better rates of 4-year disease-free survival (DFS, 68

BackgroundCardiovascular disease (CVD) is a prevalent non-communicable disease globally and holds the position of being the primary cause of mortality worldwide. Consequently, considerable focus has been directed towards the prevention and management of CVD. PCSK9, a frequently targeted element in the treatment and prevention of CVD, can reduce cardiovascular risk by effectively lowering lipid levels even in the context of statin therapy. It also exhibits substantial potential in the diagnosis and treatment of familial hypercholesterolemia from genetic aspects. This bibliometric study aims to analyze and visualize the global trends and emerging hotspots of PCSK9 and CVD researches and provide researchers with new perspectives in further studies.MethodsThe data was obtained from the Web of Science Core Collection database. A total of 2,474 publications related to PCSK9 and CVD published between January 2006 and July 2023 were included. The VOSviewer was used to analyze most-cited references, co-authorship, co-citation, co-occurrence and generate a collaborative network map of authors, countries, and institutions. CiteSpace was used to analyze author and institution centroids, keyword bursts, and timeline graphs.ResultA total of 2,474 articles related to CVD and PCSK9 were included. The number of articles and citations show an increasing trend from year to year. Publications were mainly from the United States. The most active institution was Amgen Inc. Watts, Gerald F. was the most prolific author. Atherosclerosis was the most published journal. Literature co-citation and keyword co-occurrence revealed that early studies focused on the lipid-lowering effects of PCSK9 inhibitors in the context of statins therapy, long-term efficacy, adverse effects, LDLR, diagnosis and treatment of familial hypercholesterolemia. In recent years, myocardial ischemic protection, CRISPR-based editing, and new therapeutic strategies for arteriosclerotic cardiovascular disease have gotten wide attention. The protein convertase, inflammation, beta-polyacetate, and inclisiran may be the important future research directions.ConclusionThis study analyses the current status and global trends in the CVD and PCSK9 studies comprehensively, which may provide researchers and policymakers with new and comprehensive perspectives on in this field of research.

Blood basophils ≥ 20 percent is reportedly associated with a poor prognosis and used to define accelerated phase of chronic myeloid leukaemia (CML) in some classifications. However, quantification of blood basophils is by percentage is inaccurate. Using a Patient Similarity Network (PSM) approach we identified basophil concentration rather than percentage as the more accurate predictive co-variate. To test this observation we interrogated data for a possible correlation between blood basophils quantified by concentration in a training cohort of 131 subjects with newly-diagnosed chronic phase CML receiving tyrosine kinase-inhibitor (TKI)-therapy. Subjects with a basophil concentration ≥ 12.2 x 10E + 9/L had poorer event-free survival (EFS, Odds Ratio [OR] = 12.3 [95% Confidence Interval [CI]. 4.2, 36.1]; p < 0.0001) and failure-free survival (FFS; OR = 10.4 [3.89, 27.72]; p < 0.0001). TKI switch-free survival and progression-free survival were also correlated with basophil concentration. The negative impact of a high basophil concentration was validated in an independent cohort of 1,870 subjects. We explain why basophil concentration is a more accurate co-variate. Our data indicate blood basophil concentration at diagnosis rather than percentage is a more accurate predictor of outcomes in persons with newly-diagnosed chronic phase CML receiving TKI-therapy.

Background Meeting “failure” milestones as defined by the ELN2020 recommendations predicts poor outcomes in CML patients on TKI therapy. However, there are limited data exploring which “failure” events are the high-risk indicators that most significantly impact survival in patients with CML. Aims To identify which “failure” events during TKI-therapy are more robust and important predictors of survival in CML. Methods Data from consecutive adults with newly-diagnosed CML-CP receiving initial TKI therapy and regular monitoring at Peking University People's Hospital were interrogated. In this study, the “failure” events of interest were defined by the ELN 2020 recommendations. Survival was calculated using the Kaplan-Meier method with the log-rank test. The X-tile software was used to determine optimal cut-off values of continuous co-variates for predicting survival which could visualize the best cut-points for creating such divisions by calculating at each division by a variety of standard statistical tests, including the log-rank test for survival and means tests and so on. Cox regression models were used for uni- and multi-variable analyses to identify co-variates associated with survival. Results A total of 2,092 patients were enrolled in this study. 1,359 (65%) patients were male. Median age was 42 years (IQR: 36-58). 1,109 (53%), 502 (24%) and 230 (11%) patients were identified as ELTS low-, intermediate- and high-risk, respectively. 251 (12%) patients had unknown ELTS score. 1,632 (78%) patients received initial imatinib therapy; 460 (22%), 2G-TKI therapy (nilotinib, n = 313; dasatinib, n = 78; flumatinib, n = 69). Median follow-up was 60 months (IQR: 33-94 months). At the last follow-up, 16 patients did not achieve CHR by 3 months. 202 patients experienced BCR::ABL transcript level >10% at 3 months and confirmed within 1-3 months; 100 patients, >10% at 6 months; 50 patients, >10% at 12 months; 55 patients, >1% at 12 months; 186 patients, detected TKI-resistant ABL mutation; 68 patients, harbored Ph+ ACAs; 15, 38 and 136 patients, loss of CCyR, MMR and CHR alone or combined at the first episode of failure events occurred. Kaplan-Meier analyses showed that patients with BCR::ABL transcript levels >10% at 3, 6, or 12 months, >1% at 12 months, loss of MMR and detected ABL mutations had the similar outcome to those with no failure event occurred (all p values > 0.2), but significantly superior than those with no CHR by 3 months, loss of CHR or CCyR, or harboring Ph+ ACA (p = 0.001-0.03). Moreover, there were no significant differences in survival among the patients who failed to achieve CHR by 3 months, lost CHR or CCyR, or harbored Ph+ ACA (p = 0.69). Multi-variable Cox analyses further confirmed these results. Therefore, we defined these four events as high-risk “failure” events on TKI therapy. In patients with the high-risk “failure” events, multi-variable Cox analyses were further performed to identify co-variates associated with worse survival. The analyses revealed that the 2G- or 3G-TKI used, HB < 110 g/L, PLT < 35×109/L, blasts in PB or BM ≥10%, and blood basophils < 5% were significantly-associated with worse survival. Based on the number of adverse prognostic co-variates, patients were classified into low- (0-1 co-variate, n = 95, 59%), intermediate- (2-3 co-variates, n = 49, 30%) and high-risk (4-5 co-variates, n = 17, 11%) groups with significant different outcome (2-year survival rates: 96% [95%CI: 93-99%] versus 56% [48-64%] versus 17% [9-25%], p < 0.001). Conclusions Failure to achieve CHR by 3 months, loss of CHR or CCyR and the emergence of Ph+ ACA are robust predictors of worse survival in patients with CML during TKI-therapy. In patients with the high-risk “failure” events, certain clinical co-variates such as the 2G- or 3G-TKI used, the lower HB, PLT and blood basophils, and the higher blasts can further predict the worse survival. These insights emphasize the need for vigilant monitoring the patients with high-risk “failure” events to implement tailored treatment strategies.

Background Basophilia is common in chronic myeloid leukaemia (CML) and is associated with a poor prognosis. Previously it was quantified by percentage and a binary < or ≥ 20%. However, blood basophil concentration at diagnosis may be a better prognostic co-variate. Methods The hypothesis generating cohort was a 135 newly-diagnosed subjects with BCR::ABL1-positive CML receiving a tyrosine kinase-inhibitor (TKI). Median follow-up was 6.3 years (range, 4-16 years). Data were analyzed by Kaplan-Meier curves and multi-variable patient similarity network (PSN). A cohort of 1919 subjects was used to validate the test hypothesis. Subject gave informed consent for non-interventional data collection and the study was approved by Ethics Committees. Results Multi-variable PSNs of the hypothesis generating cohort indicated 5 subject clusters. Incidence of TKI switch was highest in clusters 1 (45%), 5 (40%) and 4 (30%) which were characterized by the increased basophil concentrations at diagnosis compared with clusters 2 (13%) and 3 (14%) with the low basophil concentrations at diagnosis. PSNs identified the combination of basophil concentration ≥ 8x10E+9/L, basophil percentage ≥ 5 % and WBC ≥ 164x10E+9/L to be associated with significantly worse FFS (p < 0.001) and PFS ( p = 0.02) but not survival ( p = 0.18). Basophil concentration ≥ 8x10E+9/L and WBC concentration ≥ 164x10E+9/L were associated with worse EFS (p < 0.001), (FFS (p < 0.001; Figure 1) but not PFS or survival. Basophil percentage at diagnosis had no impact on outcomes using ≥ 5% or ≥ 20% cutoffs. In the validation cohort the combination of basophil concentration ≥ 8x10E+9/L, basophil percentage ≥ 5% and WBC ≥ 164x10E+9/L at diagnosis was associated with worse FFS ( p < 0.001) but not PFS or survival. Basophils ≥ 5% was associated with worse survival ( p = 0.04) and ≥ 20% with worse FFS ( p = 0.04) and survival ( p = 0.009). Basophil concentration ≥ 8×10E+9/L was associated with worse PFS ( p < 0.001; Figure 1) and survival ( p = 0.03). There was no effect of WBC concentration on any outcome. Conclusion We show blood basophil concentration at diagnosis correlates with diverse outcomes in newly-diagnosed persons with CML receiving TKI-therapy. Support IGA_LF_2023_05, MH_CZ-DRO (FNOL, 00098892)

Background Some data, albeit controversial, suggest people with chronic myeloid leukaemia (CML) presenting in accelerated phase have the same prognosis as people with CML presenting in chronic phase but with high-risk co-variates. Objectives Interrogate the heterogeneity of subjects presenting in accelerated phase and compare their outcomes with persons presenting in high-risk chronic phase. Methods We interrogated data from 2132 consecutive subjects ≥ 18 years with CML presenting in accelerated (N = 274) or chronic phase (N = 1858). Subjects were seen at Peking University People's Hospital from January, 2006 to June, 2023. Criteria for accelerated phase according to the European LeukemiaNet (ELN) 2020 criteria included: ≥ 1 of the following: (1) blood or bone marrow blasts ≥ 15% but < 30%; (2) blood basophils ≥ 20%; and (3) platelet concentration < 100 × 10E + 9/L unrelated to therapy. Chronic phase was defined according to the ELN 2020 criteria. For subjects in chronic phase ELTS score at diagnosis was calculated and used to classify subjects into risk cohorts. Transformation was defined as blood or bone marrow blasts ≥ 30% during TKI-therapy. Transformation-free survival (TFS) was calculated as the interval from starting TKI-therapy to transformation, death or censored at a transplant or last follow-up. We then compared therapy responses and outcomes between defined accelerated phase cohorts and chronic phase risk cohorts using competing risk models and Kaplan-Meier survival analyses. Cox regression analyses were used to further explore the co-variates associated with therapy responses and outcomes. Results Amongst the 274 subjects presenting in accelerated phase 205 (75%), 39 (14%) and 31 (11%) were classified based on basophilia, excess blasts or thrombocytopenia. Amongst the 1858 subjects presenting in chronic phase 1220 (66%), 461 (25%) and 176 (9%) were ELTS low-, intermediate- and high-risk. In multi-variable analyses we use chronic phase subjects in ELTS low-, intermediate- and high-risk cohort as reference. Subjects in accelerated phase with basophilia had better therapy responses (MMR, HR = 1.2 [1.0, 1.5], p = 0.05; MR 4, HR = 1.7 [1.3, 2.2], p < 0.001; MR 4.5, HR = 2.0 [1.5, 2.6], p < 0.001) and similar TFS and survival (TFS, HR = 0.9 [0.5, 1.6], p = 0.60; survival, HR = 1.4 [0.6, 3.2], p = 0.45) compared with the ELTS intermediate-risk cohort. Accelerated phase subjects with excess blasts and with thrombocytopenia therapy responses like chronic phase subjects with the ELTS intermediate- and high-risk cohorts. TFS and survival were similar with ELTS high-risk cohort. These comparisons held in subjects receiving initial imatinib-therapy but were less clear in subjects receiving initial 2 nd generation TKI therapy. Similar findings were also obtained using the WHO 2016 criteria. Conclusions Subjects presenting in accelerated phase defined by basophilia had better therapy responses but similar TFS and survival compared with subjects presenting in chronic phase in the ELTS intermediate-risk cohort. Subjects presenting in accelerated phase with excess blasts or thrombocytopenia had comparable therapy responses compared with subjects presenting in chronic phase in the ELTS intermediate- and high-risk cohorts whereas their TFS and survival were like those or worse compared with subjects presenting in chronic phase in the ELTS high-risk cohort. The implication of our findings is presenting in accelerated phase per se does not always confer a worse prognosis compared with subjects presenting in chronic phase.

To the Editor: Nowadays, imatinib and second generation tyrosine kinase inhibitors (2G-TKIs) as initial therapy are used in newly-diagnosed chronic myeloid leukemia (CML) present in the accelerated phase. However, rare data compared responses and outcomes between them. Data from 430 consecutive subjects with CML presenting in accelerated phase from 37 medical centers across China from May 2009 to March 2022 were interrogated. The diagnosis of accelerated phase and TKI-dose adjustment were based on European LeukemiaNet recommendations. Last follow-up was in September 2022. Transformation was defined as blood or bone marrow blasts ≥30% during TKI therapy. Transformation-free survival (TFS) was calculated as the interval from starting TKI-therapy to transformation, death, or censored at a transplant or last follow-up. Survival was calculated as the interval from starting TKI-therapy to death from any cause or censored at a transplant or last follow-up. Cumulative incidences of complete cytogenetic response (CCyR), major molecular response (MMR), and molecular response 4.5 (MR) were calculated using the Fine-Gray test considering competing events defined as switching to another TKI or therapy, transplant, or death. TFS and survival were calculated by the Kaplan–Meier method and compared by the logrank test, subjects were censored at switching to another TKI or therapy, a transplant, or the last follow-up. Propensity-score matching (PSM) was done to adjust for differences in baseline covariates between the cohorts including sex, age, splenomegaly on physical exam, comorbidity(ies) (based on Charlson Comorbidity Index), WBC counts, hemoglobin concentration, platelet concentration, percentages of blood and/or bone marrow blasts and blood basophils, high-risk additional chromosomal abnormality(ies) in Ph-chromosome positive cells between subjects receiving initial imatinib or a 2G-TKI and balance evaluated using the standardized absolute mean difference where score <0.02 was considered balanced. A 2-sided p < .05 was considered significant. SPSS 22.0 (SPSS, Chicago, IL) and R version 4.0.2 (R Core Team, Vienna, Austria) were used for analysis and graphing. Patients' characteristics were displayed in Table S1. At the last follow-up, 166 subjects in the imatinib cohort (62%) and 121 in the 2G-TKI cohort (74%) remained on their first TKI (p = .02). Hundred subjects (38%) initially receiving imatinib switched to nilotinib (n = 43), dasatinib (n = 46), ponatinib (n = 1), olverembatinib (n = 1), flumatinib (n = 6), chemotherapy (n = 3) because of therapy-failure (n = 82), adverse events (AEs, n = 7) or subject and/or physician's preference (n = 11). Forty three subjects (26%) receiving initial 2G-TKI switched to imatinib (n = 5), nilotinib (n = 3), dasatinib (n = 25), ponatinib (n = 3), olverembatinib (n = 3), interferon (n = 1) or flumatinib (n = 3) because of therapy failure (n = 31), AEs (n = 8) or cost (n = 4). Grade 3/4 haematologic AEs occurred in 38 subjects in the imatinib cohort (14%) and 42 in the 2G-TKI cohort (26%) during the first 3 months of TKI therapy (p = .03). Fifty four subjects in the imatinib cohort (20%) and 54 in the 2G-TKI cohort (33%) had a dose reduction and/or -discontinuation (p = .03). Among them, 73 (68%) were because of grade 3/4 thrombocytopenia (n = 46), leukopenia (n = 10), or both (n = 17); 28 (26%), non-haematologic toxicity. With a median follow-up of 39 (IQR, 18–73) months. 382 (90%) subjects achieved complete hematologic response (CHR) in 3 months. 5-year cumulative incidences of CCyR, MMR, and MR were 89% (95% Confidential Interval [CI], 85, 92%), 81% (76, 86%), and 53% (47, 59%). In the cohort of subjects with excess blasts, basophils ≥20%, platelet <100 10E+9/L and those with ≥2 of these co-variates 5-year cumulative incidences of CCyR were 79% (67, 92%), 95% (92, 99%), 78% (67, 89%), 69% (41, 98%, p-value for trend = .01), cumulative incidences of MMR, 75% (63, 88%), 85% (79, 91%), 74% (59, 90%), 74% (49, 99%, p-value for trend = .13) and cumulative incidences of MR, 56% (41, 72%), 56% (47, 64%), 47% (33, 62%), 34% (8, 61%, p-value for trend = .14). During follow-up 135 subjects (31%) failed ≥1 TKIs and 43 (10%) transformed to the blast phase. Twenty four subjects (6%) died of leukemia progression (n = 22) or other causes (n = 2). 5-year probabilities of TFS and survival were 88% (85, 91%) and 93% (90, 96%). In the cohort of subjects with excess blasts, basophils ≥20%, platelet <100 10E+9/L or ≥2 criteria, 5-year probabilities of TFS were 82% (72, 92%), 93% (90, 97%), 86% (78, 94%), 65% (37, 94%, p-value for trend = .01); survival, 92% (81, 100%), 95% (92, 98%), 93% (86, 99%), 74% (46, 100%, p-value for trend = .19). Results of uni-variable and multi-variable analyses were displayed in Tables S2–S7. In the total population and cohort with basophils >20% receiving 2G-TKI was associated with higher cumulative incidences of CCyR, MMR, and MR, whereas in the cohort with platelet <100 10E+9/L receiving 2G-TKI was associated with worse TFS. We did not analyze subjects with ≥2 criteria because of too few subjects. Received: 13 March 2023 Revised: 12 April 2023 Accepted: 18 April 2023

To compare efficacy between homoharringtonine combined with cytarabine and aclarubicin (HAA) and idarubicin and cytarabine (IA) regimens as first induction chemotherapy in patients with core binding factor acute myeloid leukemia (CBF-AML). Cox regression model and propensity score matching (PSM) were used to identify the regimen associated with a better remission rate and outcomes. In total, 374 patients with CBF-AML (243 with RUNX1::RUXN1T1 and 131 with CBFB::MYH11) were included in this study. The patients received the HAA or IA regimen (187 each) as the first induction therapy. For patients with RUNX1::RUXN1T1, multivariate analyses showed that the HAA regimen was significantly associated with a higher CR/CRi rate after the first induction (hazard ratio [HR] = 5.3 [95% CI 2.3, 12.2]; p < 0.001) and more favorable relapse-free survival (RFS) (HR = 0.5 [0.3, 0.8], p = 0.01). In PSM analysis, the HAA regimen also had a higher CR/CRi rate (96% vs. 77%, p < 0.001), especially for those harboring wild-type KIT (KITWT) (96% vs. 83%, p = 0.02) or non-D816 KIT mutation (100% vs. 63%, p = 0.002), as well as more favorable RFS (p = 0.01), compared with the IA regimen. However, there was no difference in the remission rate or outcomes between the two regimens for patients with CBFB::MYH11. The HAA regimen as first induction chemotherapy resulted in a higher CR/CRi rate in AML patients with RUNX1::RUNX1T1, especially those harboring KITWT and non-D816 KIT mutation, and a more favorable RFS compared with the IA regimen. The efficacy between the two regimens did not differ in those with CBFB::MYH11.

Objectives Compare the treatment responses and outcomes between persons with chronic myeloid leukemia (CML) presenting in accelerated phase receiving a 2nd-generation tyrosine kinase inhibitor (2G-TKI) and imatinib as initial therapy. Methods Data from 442 consecutive subjects with CML presenting in accelerated phase according to the European LeukemiaNet (ELN) 2020 criteria from 32 centers were retrospectively collected. Propensity score matching (PSM) was performed to adjust for differences in baseline co-variates between subjects receiving a 2G-TKI or imatinib as initial therapy. Cumulative incidences of CCyR, MMR and MR4.5 were calculated using the Fine-Gray model. Transformation was defined as blood or bone marrow blasts ≥ 30% during TKI-therapy. Transformation-free survival (TFS) and survival were calculated by the Kaplan-Meier model. Results 442 subjects with CML presenting in accelerated phase were reviewed, including 147 (33%) received 2G-TKI and 295 (67%) received imatinib as initial therapy. 270 (61%) were male, median age was 43 years (Interquartile range [IQR], 31-55 years), median follow-up was 28 months (IQR, 13 - 53 months) in the 2G-TKI cohort and 51 months (IQR, 25 - 94 months) in the imatinib cohort reflecting the later availability of 2G-TKIs (p < 0.001), median treatment duration was 19 months (IQR, 9 - 41 months) in the 2G-TKI cohort and 32 months (IQR, 12 - 68 months) in the imatinib cohort (p < 0.001). 28 (26%) receiving 2G-TKI and 100 (34%) subjects receiving imatinib switched to another TKI during treatment. 379 subjects were identified by a 2:1 propensity-score matching in the 2G-TKI (n = 139; 37%) and imatinib (n = 240; 63%) cohorts. In the 2G-TKI and imatinib cohorts, the cumulative incidence of 2-year CCyR was 87% (95% Confidential Interval [CI], 86%, 87%) vs. 84% (84%, 84%, p < 0.001); MMR, 83% (82%, 83%) vs. 65% (65%, 65%, p < 0.001); MR4.5, 43% (42%, 44%) vs. 29% (28%, 29%, p = 0.006) when switching to another TKI, a transplantation and death were considered as competing events. When switching to another TKI was not considered as a competing event, cumulative incidences of 2-year CCyR were 91% (91%, 92%) vs. 83% (83%, 83%, p < 0.001); MMR, 80% (80%, 81%) vs. 66% (66%, 66%, p = 0.002); MR4.5, 40% (40%, 41%) vs. 28% (27%, 28%, p = 0.005) in the 2G-TKI and imatinib cohorts. The 2-year probabilities of TFS were 88% (81%, 94%) vs. 92% (88%, 96%, p = 0.116); survival, 97% (94%, 100%) vs. 98% (96%, 100%, p = 0.530) in the 2G-TKI and imatinib cohorts when censored at switching to another TKI, a transplantation or at last follow-up. Similarly, 2-year probabilities of TFS were 94% (89%, 98%) vs. 93% (90%, 96%, p = 0.868); survival, 97% (94%, 100%) vs. 96% (93%, 98%, p = 0.562) in the 2G-TKI and imatinib cohorts when censored at a transplantation or at last follow-up. Conclusions Persons with CML presenting in accelerated phase receiving a 2G-TKI as initial therapy achieved higher cumulative incidences of MMR and MR4.5 than those receiving imatinib, but similar TFS and survival. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

BackgroundPulmonary hypertension (PH) is a rare but life-threatening adverse event (AE) of dasatinib, but the associated variables are not clear. This study aimed to explore the variables associated with PH by echocardiography in patients with chronic myeloid leukemia in the chronic phase (CML-CP) receiving dasatinib therapy.MethodsEchocardiography was performed to estimate the probability of PH and pulmonary artery systolic pressure (PASP). Binary logistic analysis and Fine–Gray hazard model were used to identify the variables associated with PH by using cross-sectional and longitudinal data.ResultsAmong the 243 patients in the cross-sectional dataset, with a median dasatinib therapy duration of 27 months, 30 (12.3%) were classified as having a high probability of PH. Increasing age (OR = 1.7, p = 0.002; OR = 1.5, p = 0.003) and pericardial effusion (OR = 4.3, p = 0.004; OR = 3.2, p = 0.014) were significantly associated with a high probability of PH and PASP ≥ 40 mmHg, respectively. Among the 161 patients in the longitudinal dataset, the 3-year cumulative incidences of a high probability of PH and PASP ≥ 40 mmHg were 9.3% and 22.1%, respectively. Pericardial effusion (HR = 3.8, p = 0.005) and cardiopulmonary comorbidities (HR = 3.2, p = 0.021) were significantly associated with a high probability of PH; increasing age (HR = 1.5, p < 0.001) and dasatinib as ≥ 3rd-line therapy (p = 0.032; 2nd-line vs. 1st-line, HR = 2.0, p = 0.200; ≥ 3rd-line vs. 1st-line, HR = 3.4, p = 0.047) were significantly associated with PASP ≥ 40 mmHg.ConclusionIncreasing age, pericardial effusion, cardiopulmonary comorbidities, and dasatinib as ≥ 3rd-line TKI therapy were associated with PH in the patients with CML-CP on dasatinib therapy.

We interrogated data from 278 consecutive subjects with chronic myeloid leukaemia (CML) presenting in accelerated phase diagnosed by European LeukemiaNet (ELN) criteria receiving initial imatinib (n = 187) or a 2nd-generation tyrosine kinase-inhibitor (2G-TKI; n = 91). In multi-variable analyses, blood and/or bone marrow blasts ≥15% (Hazard ratio [HR] = 3.7 [1.6, 8.5], p = 0.003) and blood basophils <3% (HR = 4.6 [2.0, 10.7], p < 0.001) were significantly-associated with worse transformation-free survival (TFS). Age ≥60 years (HR = 4.3 [1.7, 11.4], p = 0.003), platelet concentration <230 × 10E + 9/L (HR = 4.7 [2.0, 10.7], p < 0.001) and blood and/or bone marrow blasts ≥9% (HR = 3.9 [1.7, 8.7], p = 0.001) were significantly-associated with worse survival. Based on number of adverse prognostic co-variates of TFS and survival, respectively, subjects were classified into the low- (none), intermediate- (one) and high-risk (≥2) cohorts with significant difference in TFS and survival (all p < 0.001). In propensity-score matching analysis subjects initially receiving a 2G-TKI had higher cumulative incidences of cytogenetic and molecular responses but similar TFS and survival to those receiving imatinib. Our data should help inform physicians treating person with CML initially presenting in accelerated phase.