ABSTRACT:GPRC5D has emerged as a promising therapeutic target in relapsed/refractory multiple myeloma (R/R MM), particularly following progression after B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell (CAR-T) therapies. RD118 is a novel CAR-T therapy incorporating a fully human single-domain antibody fragment targeting GPRC5D. In this phase 1 study, 18 R/R patients (17 with MM and 1 with a history of primary plasma cell leukemia) received a single infusion of RD118 at 1.0 × 106, 2.0 × 106, or 3.0 × 106 CAR+ T cells per kg. At a median follow-up of 17.0 months, the overall response rate (ORR) was 94.4%, including 72.2% complete or stringent complete responses. Among the 7 patients previously exposed to BCMA-directed CAR-T therapy, ORR reached 85.7%. Median progression-free survival (PFS) was 18.2 months (95% confidence interval, 14.4 to not estimable), with 12-month PFS and overall survival rates of 82.1% and 93.3%, respectively. Cytokine release syndrome occurred in 88.9% of the patients, primarily grade 1 to 2. One patient developed grade 3 immune effector cell-associated neurotoxicity, which resolved within 72 hours. No cerebellar toxicities or treatment-related deaths were reported. These findings support that RD118 is a highly effective and safe therapeutic option for heavily pretreated R/R MM. This trial was registered at www.clinicaltrials.gov as #NCT05759793 and #NCT05219721.

OBJECTIVE:To retrospectively analyze the characteristics and influencing factors of COVID-19 infection in patients with multiple myeloma (MM) who underwent autologous hematopoietic stem cell transplantation (AHSCT). METHODS:The clinical data of MM patients who underwent AHSCT in Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from May 26, 2021 to December 26, 2022 were collected. The onset of COVID-19 infection, corresponding symptoms and laboratory tests were followed up in outpatient or by the means of telephone contact and online questionnaires. Related analysis was then performed. RESULTS:This study included 96 patients, and 72 cases among them were infected with COVID-19 while 24 cases were uninfected. Logistic regression analysis showed that vaccination did not significantly reduce the risk of COVID-19 infection, but patients who received two doses of the vaccine had a lower risk of developing moderate and severe disease than those who did not receive or received one dose (OR =0.06, P =0.029). Patients who received daratumumab before had a higher risk of COVID-19 infection (OR =5.78, P =0.039), while those with a history of immunomodulatory drugs (IMiDs) had the opposite effect (OR =0.31, P =0.028). The use of both drugs did not affect the severity of COVID-19 infection. CONCLUSION:For MM patients undergoing AHSCT as first-line chemotherapy, COVID-19 vaccination does not significantly reduce the infection rate, but it plays a role in preventing moderate and severe cases. The application of antineoplastic drugs with different mechanisms has a certain impact on the susceptibility to the COVID-19, which should be considered comprehensively when creating treatment plans.

Chimeric antigen receptor T-cell (CAR-T) therapy has been successfully applied in clinical treatment, especially for hematologic malignancies such as multiple myeloma (MM), but its broad application is limited by cytokine release syndrome (CRS), a potentially life-threatening complication. Although metabolic alterations are known to accompany CRS, predictive biomarkers for its onset, severity, and associated metabolic remodeling remain unknown, hindering proactive clinical management. Here, we analyzed longitudinal serum metabolic profiles from 19 patients with relapsed/refractory MM receiving CAR-T therapy, with validation in an independent cohort of 23 patients. We observed dysregulated arginine metabolism that progressed alongside clinical CRS. At pre-lymphodepletion (Day-5), over half of differentially abundant metabolites were enriched in unsaturated fatty acid (UFA) synthesis pathways, which were exclusively upregulated in patients who later developed severe CRS. Furthermore, two lysophosphatidylcholines, namely, lysoPC(16:0) and lysoPC(15:0), were significantly associated with delayed CRS onset, with elevated concentrations correlated with a prolonged time to onset; this association was independently validated. These findings revealed that arginine metabolism was a pathological axis in CRS, UFAs were severity predictors, and specific lysoPCs were modulators of onset time. Collectively, they provide proactive CRS management, addressing critical gaps in predictive biomarkers to advance the safe, broad CAR-T application in MM.

[18F]fluorodeoxyglucose (FDG)-PET is a powerful tool to evaluate prognosis in multiple myeloma (MM). The development of systematic and reproducible standard interpretation criteria is crucial for the effective application of FDG-PET in MM. A new set of criteria—Italian Myeloma criteria for PET Use (IMPeTUs)—has standardized PET evaluation in MM. However, the prognostic value of IMPeTUs score remains unknown. A total of 58 patients with newly diagnosed multiple myeloma (NDMM) who underwent both [18F]FDG-PET/MRI and PET/CT examinations at diagnosis were enrolled (ChiCTR1900022597). All patients completed a 42-month follow-up. The prognostic value of the PET/MRI (or PET/CT) IMPeTUs score in predicting progression-free (PFS) and overall (OS) survival was compared with that of individual laboratory parameters and the maximum standardized uptake value (SUVmax). Kaplan-Meier method was used for survival analysis. Univariate and multivariate analyses of prognostic factors were conducted using Cox regression. ROC curves demonstrated that the area under the curve for the PET/MRI IMPeTUs score was 0.760, exceeding that of the PET/CT IMPeTUs score (0.711), PET/CT BM SUVmax (0.649), PET/MRI BM SUVmax (0.575), bone marrow plasma cells (0.500), and β2-microglobulin (0.501). Univariate analysis and Kaplan-Meier analysis showed that a PET/MRI IMPeTUs score ≥ 13 and PET/CT IMPeTUs score ≥ 10 were significantly associated with worse PFS. Cox multivariate analysis showed that a PET/MRI IMPeTUs score ≥ 13 was an independent risk factor for PFS. IMPeTUs standardized [18F]FDG-PET/MRI and PET/CT readings in MM. The IMPeTUs score is crucial for predicting MM prognosis, performing better than SUVmax and clinical indicators. ChiCTR1900022597, Registered on 18 April 2019.

Background: Chimeric antigen receptor (CAR)-T cell therapies have produced durable antitumor response for the treatment of relapsed and refractory hematological malignancies. The remarkable efficacy is achieved through redirecting T cell activation and cytolytic activity to tumor associated antigens. However, due to large-scale and non-physiological T cell activation, CAR-T cells treatment can cause high incidence of potentially life-threatening cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), requiring frequent therapeutic intervention. While toxicity prevention and mitigation strategies have enhanced CAR-T therapy safety to make it more feasible and accessible to broader patients, development of novel CAR formats with favorable cellular and toxicity profiles remains the desired goal. NPB5005-V283 is a novel autologous BCMA targeting CAR-T. The CAR is made of an extracellular nanobody, a CD8 transmembrane domain, a truncated 3rd generation costimulatory domain (3.5 gen) composed of ICOS in tandem with N terminal-deleted 4-1BB signaling domains (ICOS-BBt, delivering more potent costimulatory signal than either 2nd or wild-type 3rd generation constructs), and a truncated CD3Zt containing one of three ITAM motifs to attenuate CAR-T cell overactivation, cytokine production, and exhaustion while maintaining active in vitro and in vivo antitumor activities. The novel combination of a 3.5-gen more potent costimulatory domain with a significantly truncated CD3Zt lays the foundation for the next generation of highly effective CAR Ts with controlled output of CRS and ICANS. Methods: Study NPB5005-V283 is an investigator-initiated, first-in-human, single center, single-arm, open-label, 3+3 dose-escalation clinical trial approved by Ruijin Hospital Ethics Committee of Shanghai Jiaotong University School of Medicine (2023, IRB Approval No. 446). The clinical study is to evaluate the safety, tolerability, and efficacy of NPB5005-V283 cell injection in the treatment of relapsed/refractory multiple myeloma patients. The patients have received at least 3 prior lines of therapy. The NPB5005-V283 CAR was introduced into autologous T cells through lentiviral transduction and cells were expanded ex-vivo to the intended dose. Patients are administered infusion of NPB5005-V283 following lymphodepletion by fludarabine 30 mg/m2 and cyclophosphamide 300 mg/m2 daily for 3 days. Three dose levels at 1.5, 3.0, and 6.0 x 106 CAR-Ts/kg are to be evaluated in 15 to 27 RRMM patients. The first patient in each dose group receives a split dose of 20%, 30%, and 50% on days 0, 2, and 6, respectively, while the rest receive a single dose. The primary endpoints assess the dose-limiting toxicities of CRS and ICANS using ASTCT consensus grading. The secondary endpoints include measurements of minimal residual disease (MRD), depth and duration of clinical response according to the IMWG Uniform Response Criteria, progression-free survival (PFS), and overall survival (OS). Results: As of July 31, 2025, 4 patients of Han ethnicity were enrolled. 2 male sex (50%), median age was 62 years (range 50–73), median time from MM diagnosis was 4.2 years (range 3.5-5), received median 4.5 prior lines of treatment (range 3-6), 2 (50%) patients had high-risk cytogenetics, 1(25%) had extramedullary disease, 1(25%) had high tumor burden of 81% BMPCs, Products had been successfully manufactured for all patients. Patients received bridging therapy between apheresis and infusion. Average time to infusion was 54 days (range 33-107). 3 patients received the dose of 1.5 x 106 CAR-T cells/kg per protocol. Patient 4 was the first to be enrolled in the escalating dose of 3.0 x 106 CAR-T cells/kg. The patient received first infusion of 20% dose after lymphodepletion per protocol. Next day, the patient had shown flu infection in the test, so the planned second infusion was postponed. The patient subsequently went through treatment of flu infection and emerging fever. 10 days after the first infusion, the patient received a non-conforming second infusion of 30% dose. In total, patient 4 ended up receiving a sum of half of the intended dose 3.0 x 106 CAR-T cells/kg. Median follow-up after NPB5005-V283 infusion was 3 months (range, 1-6 months). Enrollment and follow-up are ongoing and updated data will be presented.

Extramedullary myeloma disease (EMD) can present at disease relapse (secondary EMD, sEMD) and confers an aggressive clinical course. Identifying predictive markers for sEMD is crucial for clinical management. Our study, spanning February 2013 to October 2022, identified sEMD in 77 (12.5

Chimeric antigen receptor (CAR) T-cell therapy has demonstrated considerable promise in patients with late-line refractory multiple myeloma (MM), and there has been commercial approval for its use in treating relapsed and/or refractory MM (RR MM). B-cell maturation antigen remains the most extensively studied CAR T-cell target in this disease, although several alternative antigens are also under active investigation. Despite the notable success of CAR T-cell therapy in the treatment of RR MM, challenges remain in improving response rates, extending the durability of remission, and reducing relapse after CAR T-cell therapy. Notably, the presence of high-risk disease features is strongly associated with worse outcomes after CAR T-cell therapy for RR MM. This review explores the underlying mechanisms of CAR T-cell therapy failure and outlines potential salvage strategies. In addition, based on this mechanistic understanding, we discuss emerging technologies and platforms aimed at improving CAR designs, enhancing the quality of cellular products, increasing antitumor activity, and reducing relapse and/or resistance. Moreover, several approaches are being developed to improve the safety of CAR T-cell therapy. Finally, we consider the potential for earlier application of CAR T-cell therapy in high-risk patients and propose strategies to improve clinical outcomes. Ongoing research is expected to expand the therapeutic potential of CAR T-cell therapy, particularly in patients with high-risk RR MM.

Third-generation tyrosine kinase inhibitors (TKIs) have much potential for the treatment of BCR::ABL1 -positive leukaemia, particularly that harbouring the ABL1 T315I mutation. Olverembatinib (HQP1351), a novel third-generation TKI, has favourable efficacy and safety profiles in chronic myeloid leukaemia. Here, we present the clinical findings from 31 BCR::ABL1 -positive acute lymphoblastic leukaemia (ALL) patients who received olverembatinib. Among the 14 patients with overt relapsed/refractory (R/R) disease (including 10 with the T315I mutation), 71.4% achieved an overall response. Of the other 17 patients with minimal residual disease (MRD)-positive ALL (including 14 with the T315I mutation), 60.0% and 47.1% achieved MRD flow negativity and complete molecular remission, respectively. With a median follow-up time of 16.3 months, the median event-free survival and overall survival were 3.9 and 8.3 months respectively, in overt R/R patients, and 11.5 and 18.4 months in MRD-positive patients. Allogeneic haematopoietic stem cell transplantation further improved outcomes among responders. The safety profile was generally manageable. This study suggests that olverembatinib-based therapy is another promising option for BCR::ABL1 -positive ALL in addition to ponatinib, especially for patients with MRD-positive disease and a single T315I mutation.

Abstract Background Autologous stem-cell transplantation (ASCT) remains a beneficial approach for patients with newly diagnosed multiple myeloma (NDMM) in the age of novel therapeutic agents. Nevertheless, limited real-world data is available to establish criteria for identifying high-risk ASCT patients. Methods We analyzed outcomes for 168 NDMM patients who underwent ASCT at our center from December 2015 to December 2022. We investigated the impact of the number of high-risk cytogenetics (HRCA), defined as t(4;14), t(14;16), 1q21 gain/amplification, and del(17p), as well as the post-ASCT minimal residual disease (MRD) status as prognostic indicators. We assessed progression-free survival (PFS) and overall survival (OS), and focused on identifying risk factors. Results The cohort included 42% of patients (n = 71) with 0 HRCA, 42% (n = 71) with 1 HRCA, and 16% (n = 26) with ≥ 2 HRCA. After a median follow-up of 31 months, the median PFS was 53 months (95% CI, 37–69), and OS was not reached for the entire cohort. Despite similar rates of MRD-negativity post-ASCT, patients with ≥ 2 HRCA, termed “double hit” (DH), had a significantly higher risk of progression/mortality than those with 0 or 1 HRCA. Multivariate analysis highlighted DH (HR 4.103, 95% CI, 2.046–8.231) and MRD positivity post-ASCT (HR 6.557, 95% CI, 3.217–13.366) as adverse prognostic factors for PFS, with DH also linked to inferior OS. As anticipated, DH patients with post-ASCT MRD positivity displayed the poorest prognosis, with a median PFS of 7 months post-ASCT. Meanwhile, DH patients with MRD negativity post-ASCT showed improved prognosis, akin to MRD-negative non-DH patients. It is noteworthy to exercise caution, as DH patients who initially achieved MRD negativity experienced a 41% cumulative loss of that status within one year. Conclusions This study strongly advocates integrating DH genetic assessments for eligible ASCT patients and emphasizes the importance of ongoing MRD monitoring, as well as considering MRD-based treatment adaptation for those patients in real-world settings.

Background Second-generation Tyrosine kinase inhibitors (TKIs) further improved outcomes in BCR::ABL1-positive acute lymphoblastic leukemia (BCR::ABL1+ ALL). Flumatinib, an approved alternative second-generation TKI in China since 2019, has demonstrated favorable efficacy and safety profiles in chronic myeloid leukemia. However, limited studies have specifically investigated the utilization of flumatinib in BCR::ABL1+ ALL, particularly among elderly patients (pts). Herein, we present the clinical findings of flumatinib combined with a low-intensity chemotherapy regimen for ALL pts aged 65 years and older. Methods In this observational study, newly diagnosed BCR::ABL1+ ALL pts aged ≥ 65 years with adequate organ function were analyzed. All pts received flumatinib (600mg/day) and VP-based (Vincristine/Prednisone) chemotherapy; dose reduction was permitted according to the discretion of physicians. Central nervous system (CNS) prophylaxis is regularly performed by intrathecal injection of methotrexate, cytarabine, and dexamethasone after the induction course. No pts underwent allogeneic hematopoietic stem cell transplantation. Minimal residual disease (MRD) was monitored by both multiparameter flow cytometry at a sensitivity of at least 0.01% and real-time quantitative PCR at a sensitivity of 0.001%. Complete molecular remission (CMR) was defined as the absence of quantifiable BCR::ABL1 transcripts. IKZF1plus (IKZF1 deletions with CDKN2A, CDKN2B, PAX5, or PAR1 region deletions, in the absence of ERG deletion) was identified by multiplex ligation-dependent probe amplification. Adverse events (AEs) were assessed according to CTCAE v5.0. Results From January 2021 to April 2024, 25 pts with de novo BCR::ABL1+ ALL underwent flumatinib combined with VP-based chemotherapy. The median age was 68 years (range, 65-78), 56.0% of pts were females, and the median WBC count was 49.0 ×109/L (IQR, 16.0-105.2). BCR::ABL1 p190 fusion transcript was detected in 16 pts, while p190 and p210 were simultaneously found in 7 pts. For karyotype analysis and DNA sequencing, poor-risk cytogenetic and molecular alterations were identified in 17/24 pts, and additional cytogenetic aberrations were identified in 18/23 pts. With the MLPA method, 10/23 pts were found to have IKZF1plus. Besides, one pt had primary CNS leukemia. All 25 pts achieved CR/CRi at the end of induction, with no early death during the induction course. The MRD flow negative rate and the CMR rate were 72.0% (18/25) and 12.5% (3/24) at the end of induction and 72.7% (16/22) and 31.8% (7/22) at 3 months, respectively. With a median follow-up time of 22.3 months (range, 2.6-43.6), the estimated 2-year OS and PFS rates were 64.8% and 50.2%, with a median OS and PFS of 26.0 and 24.1 months, respectively. Among the 15 survived pts, 13 were in continuous remission, and 2 were relapsed. Among 10 deaths, 9 died of disease progression and 1 of pulmonary infection. There was a survival superiority in pts who achieved MRD flow negativity at 3 months ( OS: p=0.002, PFS: p=0.027). Among 24 pts evaluable for ABL1 mutations, one or more known mutations were found in 15 pts. T315I was most frequently identified, accounting for 66.7% (10/15), followed by Y253H of 53.3% (8/15). Among 11/24 pts with relapsed disease, 10 were associated with ABL1 mutations, including 8 with T315I and 4 with Y253H, and 8 with multiple mutations successively or simultaneously. Pts with T315I mutation showed a poorer outcome than non-T315I mutation (OS: p=0.022, PFS: p=0.033). Finally, the safety profiles of the flumatinib-based therapy were acceptable. Non-hematological AEs were primarily G1-2, reversible rapidly after symptomatic management. Most of the G3-4 AEs were hematological and infectious, possibly related to chemotherapy. No G3-4 pleural effusion, pericardial effusion, cardiovascular adverse events, or pancreatitis were found. No permanent discontinuation or death related to flumatinib was observed. Conclusion This study firstly reports the efficacy and safety of the second-generation TKI flumatinib combined with low-dose chemotherapy in newly-diagnosed elderly pts with BCR::ABL1+ ALL. The clinical outcomes observed for flumatnib were comparable to those reported for the classical second-generation TKI dasatinib. These findings will be further validated through long-term follow-up with an expanded sample size.

Background Despite the encouraging outcome of chimeric antigen receptor T cell (CAR-T) targeting B cell maturation antigen (BCMA) in managing relapsed or refractory multiple myeloma (RRMM) patients, the therapeutic side effects and dysfunctions of CAR-T cells have limited the efficacy and clinical application of this promising approach.Methods In this study, we incorporated a short hairpin RNA cassette targeting PD-1 into a BCMA-CAR with an OX-40 costimulatory domain. The transduced PD-1KD BCMA CAR-T cells were evaluated for surface CAR expression, T-cell proliferation, cytotoxicity, cytokine production, and subsets when they were exposed to a single or repetitive antigen stimulation. Safety and efficacy were initially observed in a phase I clinical trial for RRMM patients.Results Compared with parental BCMA CAR-T cells, PD-1KD BCMA CAR-T cell therapy showed reduced T-cell exhaustion and increased percentage of memory T cells in vitro. Better antitumor activity in vivo was also observed in PD-1KD BCMA CAR-T group. In the phase I clinical trial of the CAR-T cell therapy for seven RRMM patients, safety and efficacy were initially observed in all seven patients, including four patients (4/7, 57.1%) with at least one extramedullary site and four patients (4/7, 57.1%) with high-risk cytogenetics. The overall response rate was 85.7% (6/7). Four patients had a stringent complete response (sCR), one patient had a CR, one patient had a partial response, and one patient had stable disease. Safety profile was also observed in these patients, with an incidence of manageable mild to moderate cytokine release syndrome and without the occurrence of neurological toxicity.Conclusions Our study demonstrates a design concept of CAR-T cells independent of antigen specificity and provides an alternative approach for improving the efficacy of CAR-T cell therapy.

Background: Tyrosine kinase inhibitors (TKIs) have significantly improved outcomes of patients (pts) with Ph/BCR-ABL1-positive acute lymphoblastic leukemia (Ph/BCR-ABL1+ ALL). Compared to the first-generation TKIs, the second-generation result in a relatively better response rate and survival. Flumatinib is a novel second-generation TKI developed in China and approved in 2019. It has shown better efficacy compared to imatinib in clinical trials of CML, but few reports are available in ALL. Aims: Herein, we report the updated results of RJ-ALL2020.2A trial, which is the first reported registered clinical trial of flumatinib in Ph/BCR-ABL1+ ALL to evaluate its efficacy and safety in adult pts. Methods: In this prospective phase II study, pt eligibility mainly includes: 18 ≤ age < 65 years; newly diagnosed Ph/BCR-ABL+ ALL; and adequate organ function. Once the diagnosis is confirmed, combination of flumatinib (600mg/day) and VIP-based chemotherapy regimen (Vincristine/Idarubicin/Prednisone) is administered promptly. Allo-HSCT is recommended to all eligible pts. Central nervous system (CNS) prophylaxis is regularly performed after remission induction course. Multiparameter flow cytometry (MFC) and RT-qPCR are used to monitor minimal residual disease (MRD). The primary endpoints are MRD clearance, PFS and OS. (Clinical Trial Registration Number: ChiCTR2100042248) Results: From Dec. 2020 to Dec. 2022, 63 adult pts with de novo Ph/BCR-ABL1+ ALL were enrolled. Median age was 43 years (range, 19-63). Median WBC count at diagnosis was 41.1×109/L (0.6-675.3). And 4 pts had primary CNS leukemia. 60/63 (95.2%) pts achieved CR at the end of induction, with no early death during the induction course. MRD negative (MRD-, <10-4) rates by MFC were 66.1% (39/59) and 80% (44/55), while the CMR (BCR-ABL1 transcript<10-5) rates were 28.1% (16/57) and 51.9% (28/54) at the end of induction and 3 months, respectively. With a median follow-up time of 14 months (range, 2-23), the 1-year PFS and OS rates were 86.1% and 92.5%(Figure 1A, 1B). Among the 58 survived pts, 50 pts were in continuous remission and 8 were relapsed. Among 5 deaths, 4 died of disease progression, and 1 of pulmonary infection post-HSCT. There was a survival superiority in pts who achieved MRD- or CMR at 3 months (PFS: p=0.041, p=0.024; OS: p=0.001, p=0.190). 37 pts received allo-HSCT with a median time of 6 months (range, 1-10) from diagnosis, the median age was 43 years (range, 19-63). Before HSCT, MRD- and CMR rates were 80.6% (29/36) and 72.2% (26/36), respectively. PFS and OS were significantly improved in pts who underwent HSCT (PFS: p=0.008, OS: p=0.02) (Figure 1C, 1D). Among 61 pts evaluable for ABL1 mutations, 21 pts were mutated, and T315I was most frequently identified, accounting for 76.2%. Pts with T315I mutation showed a poorer outcome than non-T315I mutation (PFS: p<0.001, OS: p=0.013) (Figure 1E, 1F). Meanwhile, the combination of flumatinib and chemotherapy was well-tolerated. Non-hematological AEs were mostly grade 1-2, which could be recovered soon after symptomatic management. Most of the G3-4 AEs were hematological, possibly related to induction chemotherapy. No pt discontinued flumatinib due to toxicity.Summary/Conclusion: The combination of the novel second-generation TKI flumatinib and chemotherapy is quite effective and safe in newly-diagnosed Chinese adult pts with Ph/BCR-ABL1+ ALL. This clinical trial is still ongoing, and the long-term follow-up data will be further investigated. Keywords: Acute lymphoblastic leukemia, Tyrosine kinase inhibitor, BCR::ABL

Background Olverembatinib (HQP1351) is a novel third-generation tyrosine kinase inhibitor (TKI) that has shown remarkable efficacy and safety in chronic myeloid leukemia (CML). Still, few reports are available on BCR::ABL1-positive acute lymphoblastic leukemia (BCR::ABL1+ ALL). We first reported the early encouraging outcome of olverembatinib in BCR::ABL1+ ALL patients (pts) with T315I mutation or disease progression last year. Here, we enlarged the sample size and included a case of CML in lymphoid blast phase (CML-LBP) who also benefited from olverembatinib to a certain extent. Methods In this observational study, we retrospectively enrolled BCR::ABL1+ ALL or CML-LBP pts with T315I mutation, disease progression, or intolerant to previous TKIs in our institution from Dec. 2021 to May 2023. All pts received olverembatinib monotherapy (40mg qod) or combination therapy. Efficacy was assessed by CR rate, MRD negative (MRD <10 -4) rate by multiparameter flow cytometry (MFC), CMR (BCR-ABL1 transcript<10 -5) rate by RT-qPCR, as well as the survival data. PFS and OS were both calculated from the start of olverembatinib. Adverse events (AEs) were assessed and graded according to CTCAE v5.0. Results Totally, 30 pts with BCR::ABL1+ ALL (n=29) or CML-LBP (n=1) were analyzed. Among 29 BCR::ABL1+ ALL pts (median age of 60 years [range, 23-76]), 14 were in CR with molecular R/R disease, including 1 with MRD only detected by RT-qPCR. While the other 15 had hematological R/R disease, including 4 with central nervous system leukemia. T315I mutation was detected in 23 pts, including 8 with additional mutations. The baseline characteristics are detailed in Table 1. As for the 23-year-old female pt with CML-LBP, dasatinib was switched to olverembatinib when T315I, E255K, and E255V mutations were detected. T315I and E255V were eliminated rapidly after 1-month treatment of olverembatinib, while E255K still existed. At present, the patient maintained in CR, and blinatumomab will be used for MRD clearance before allo-HSCT. She was only included in the safety analysis. Among 14 pts with molecular R/R disease, 61.5% and 50% achieved MRD flow negativity and CMR with a median time of 1.3 months (range, 0.8-4.4) and 1.2 months (range, 0.9-4.4), respectively. Among 15 pts with hematological R/R disease, 80%, 53.3%, and 46.7% achieved CR/CRi, MRD flow negativity, and CMR, with a median time of 1 month (range, 0.2-2.5), 1 month (range, 0.2-3.3) and 2.1 months (range, 0.7-4.6), respectively. Totally, 8 pts underwent allo-HSCT with a median age of 48.5 years (range, 23-60), of which 6 pts achieved CMR before allo-HSCT, and all attained persistent CMR after allo-HSCT. By June 15, 2023, with a median follow-up time of 9.1 months (range, 1.7-16) in BCR::ABL1+ ALL pts, the median PFS was 7.8 months, and the median OS was not reached. For molecular R/R pts, the median PFS and OS were not reached, and for hematological R/R pts, the median PFS and OS were 6.5 and 8.6 months. MRD flow negativity or CMR responders had significantly better PFS and OS (PFS: p<0.001, p<0.001; OS: p<0.001, p<0.001), and bridging allo-HSCT after olverembatinib-based therapy showed a significant survival superiority (PFS: p=0.001; OS: p=0.017). Among the 23 pts with T315I mutation, the MRD flow negativity rate in pts with T315I single mutation was significantly higher than those with additional mutations (p=0.008), and the CMR rate tended to be better (p=0.089). Meanwhile, pts with T315I single mutation showed significant improvements in PFS and OS (Figure 1). As for safety analysis, the olverembatinib-based therapy was well-tolerated. Most non-hematological AEs were G1-2, and most G3-4 AEs were hematological, possibly related to chemotherapy. The incidence of G3-4 cardiovascular AEs was 6.7%. Five elderly pts (median age of 72 years [range, 63-76]) had temporary treatment suspension or dose reduction. No permanent discontinuation or death related to olverembatinib was observed. Conclusion This study further confirmed the efficacy of olverembatinib-based therapy in Chinese adults BCR::ABL1+ ALL pts with T315I mutation or R/R disease, especially in those with T315I single mutation. In addition, bridging allo-HSCT after deeper molecular remission could further improve survival. The safety profiles were manageable, but there is still a need to explore the optimal dose in elderly pts.

Background The introduction of the second-generation TKIs further improved outcomes in BCR::ABL1-positive acute lymphoblastic leukemia (BCR::ABL1+ ALL). Flumatinib is a novel second-generation TKI approved in China in 2019. It has shown better efficacy compared to imatinib in clinical trials of CML, but few reports are available in ALL. Herein, we report the updated results of the RJ-ALL2020.2A trial, which is the first reported registered clinical trial of flumatinib in adult BCR::ABL1+ ALL last year. The enrollment will be completed at the end of Aug. 2023. Methods In this prospective phase II study, patient (pt) eligibility mainly includes: 18≤age＜65 years; newly diagnosed BCR::ABL+ ALL; with adequate organ function. Once the diagnosis is confirmed, the combination of flumatinib (600mg/day) and VIP-based chemotherapy regimen (Vincristine/Idarubicin/Prednisone) is given promptly. Allo-HSCT is recommended for all eligible pts. Blinatumomab is allowed to administer for MRD clearance before allo-HSCT. All pts receive central nervous system (CNS) prophylaxis once achieving remission. The choice of subsequent salvage treatments is based on the discretion of physicians. Multiparameter flow cytometry (minimal residual disease[MRD]<10 -4) and RT-qPCR (BCR-ABL1 transcript<10 -5) are used to monitor MRD. The primary endpoints are MRD clearance, PFS, and OS. (Clinical Trial Registration Number: ChiCTR2100042248) Results From Dec. 2020 to Jun. 2023, 81 adult pts with de novo BCR::ABL1+ ALL were enrolled. Seventy-eight pts were included in the efficacy and safety assessment (3 were excluded due to the short duration of treatment), and 76 were available for survival analysis (2 withdrew). Median age was 42 years (range, 18-63). Median WBC count at diagnosis was 38.7×10 9/L (0.6-675.3). Four pts had primary CNS leukemia (Table 1). Among 78 pts, 75 (96.2%) achieved CR/CRi at the end of induction, and 78 (100%) achieved CR/CRi at any time. No early death occurred during the induction course. MRD flow negative rates were 67.1% (51/76) and 79.7% (55/69), while the CMR rates were 31.1% (23/74) and 52.2% (36/69) at the end of induction and 3 months, respectively. With a median follow-up time of 16.2 months (range, 1.8-29.2), the estimated 2-year PFS and OS rates were 64.8% and 81.3% (Figure 1). Among the 69 survived pts, 61 were in continuous remission, and 8 were relapsed (4 had CNS involvement). Among 7 deaths, 6 died of disease progression (4 had CNS involvement), and 1 of pulmonary infection post-HSCT. There was a survival superiority in pts who achieved MRD flow negativity (PFS: p=0.091, OS: p=0.005) or CMR (PFS: p=0.055; OS: p=0.033) at 3 months. With a median time of 6.4 months (range, 1.6-10.3) from diagnosis, 46 pts (median age of 39 years [range, 20-60]) received allo-HSCT with 45 pts in CR1. The MRD flow negativity and CMR rates were 82.2% (37/45) and 70.5% (31/44) before HSCT, respectively. PFS and OS significantly improved in patients who underwent HSCT (PFS: p<0.001, OS: p=0.012). In multivariate analysis for PFS and OS, MRD flow negativity at 3 months (PFS: HR: 0.129, p=0.016; OS: HR: 0.151, p=0.029) and allo-HSCT (PFS: HR: 0.247, p=0.036; OS: HR: 0.176, p=0.042) still had a significant effect on PFS and OS as protective factors. When including CMR as a variable, CMR at 3 months (PFS: HR: 0.221, p=0.02; OS: HR: 0.115, p=0.054) and allo-HSCT (PFS: HR: 0.169, p=0.01; OS: HR: 0.139, p=0.021) had the similar impact on survival. Among 75 pts evaluable for ABL1 mutations, 24 (32%) pts were mutated, and T315I was the most frequently identified (75%). Pts with T315I mutation showed a poorer outcome than non-T315I mutation (PFS: p<0.001, OS: p=0.01). Meanwhile, the safety profiles of the flumatinib-based therapy were acceptable. Non-hematological AEs were mostly G1-2, which were reversible rapidly after symptomatic management. Most of the G3-4 AEs were hematological, possibly related to chemotherapy. No permanent discontinuation or death related to flumatinib was observed. Conclusion This prospective study further confirmed the efficacy and safety of the promising second-generation TKI flumatinib combined with chemotherapy in newly-diagnosed Chinese adult pts with BCR::ABL1+ ALL. Achieving MRD flow negativity or CMR at 3 months and bridging allo-HSCT could further improve survival. The long-term follow-up data will be disclosed soon.

Background: Tyrosine kinase inhibitors (TKIs) have significantly improved the outcomes of patients (pts) with Ph/BCR-ABL1-positive acute lymphoblastic leukemia (Ph/BCR-ABL1+ ALL). Mutation of the ABL1 kinase domain, especially T315I, is the main mechanism of resistance to the first and second-generation TKIs. Olverembatinib is a novel third-generation TKI developed in China and approved in Dec. 2021, which has shown remarkable efficacy and safety in CML, but few reports are available in Ph/BCR-ABL1+ ALL. Aims: Herein, we report the updated results of olverembatinib in Ph/BCR-ABL1+ ALL pts with T315I mutation or relapsed/refractory (R/R) disease in our institution. Methods: In this exploratory study, adult Ph/BCR-ABL1+ ALL pts with T315I mutation or disease progression were treated with olverembatinib monotherapy (40mg, every 2 days) or in combination with VP based low intensive chemotherapy (Vincristine/Prednisone). Efficacy was assessed by CR rate, MRD negative (MRD-, <10-4) rate by multiparameter flow cytometry (MFC), CMR (BCR-ABL1 transcript<10-5) rate by RT-qPCR, as well as the survival data. PFS and OS were both calculated from the start of olverembatinib. Adverse events (AEs) were assessed and graded according to CTCAE v5.0. Results: From Dec. 2021 to Dec. 2022, 21 pts with Ph/BCR-ABL1+ ALL were treated with olverembatinib due to T315I mutation or R/R disease, with a median age of 60 years (range,23-76). Among 21 pts, 11 were in CR1, with molecular R/R disease detected by MFC or RT-qPCR. The other 10 had hematological R/R diseases, including 1 with refractory central nervous system leukemia. Median time from diagnosis to the administration of olverembatinib was 6 months (range, 2-41). T315I mutation was detected in 16 pts, including 6 with additional mutations. Among 11 pts with molecular R/R diseases, MRD- and CMR rates were 72.7% and 63.6%, with a median time of 1 month (range, 1-4) to achieve MRD-. Among 10 pts with hematological R/R disease, the CR, MRD- and CMR rates were 70%, 50% and 40%, respectively, with a median time of 2 months (range, 1-4) to achieve CR. ORR, MRD- and CMR rates for the entire cohort were 71.4%, 61.9% and 52.4%. In pts with T315I mutation, MRD- and CMR rates were 75% and 62%, and were both 20% in those without T315I mutation, suggesting that pts with T315I could achieve better molecular response (Figure 1A). Further comparison between pts with T315I single mutation and combined mutations showed that the former could respond better to olverembatinib (Figure 1B). By Jan. 15, 2023, the median follow-up time was 6 months (range, 1-10), and PFS and OS rates were 51.5% and 64.5%. Among 21 pts, 11 remained MRD- or CMR, 4 had no response or disease recurrence again, while 6 died due to disease progression. MRD- or CMR responders had significantly better PFS and OS (Figure 1C, 1D). All the 6 pts bridging allo-HSCT after Olverembatinib-based therapy achieved sustained CMR with a survival superiority (Figure 1E, 1F). As for safety analysis, all pts experienced at least 1 treatment-related AE. Most of the non-hematological AEs were G1-2, and most of the G3-4 AEs were hematological, possibly related to chemotherapy. The incidence of G3-4 cardiovascular AEs (CVEs) was 9.5% (2 pts), only 1 pt needed dose adjustment due to G4 CVE (hemorrhagic Infarct of the intestine). No death related to olverembatinib was observed.Summary/Conclusion: The novel third-generation TKI Olverembatinib is effective and safe in Chinese adult Ph/BCR-ABL1+ ALL with molecular or hematological R/R disease, especially in pts with T315I mutation. In addition, bridging allo-HSCT after MRD clearance could be a better choice to improve PFS and OS. These results laid an essential foundation for subsequent prospective clinical trials. Keywords: BCR::ABL, Tyrosine kinase inhibitor, Acute lymphoblastic leukemia

Background Olverembatinib (HQP1351) is a novel third-generation tyrosine kinase inhibitor (TKI) that has shown remarkable efficacy and safety in chronic myeloid leukemia (CML). Still, few reports are available on BCR::ABL1-positive acute lymphoblastic leukemia (BCR::ABL1+ ALL). We first reported the early encouraging outcome of olverembatinib in BCR::ABL1+ ALL patients (pts) with T315I mutation or disease progression last year. Here, we enlarged the sample size and included a case of CML in lymphoid blast phase (CML-LBP) who also benefited from olverembatinib to a certain extent. Methods In this observational study, we retrospectively enrolled BCR::ABL1+ ALL or CML-LBP pts with T315I mutation, disease progression, or intolerant to previous TKIs in our institution from Dec. 2021 to May 2023. All pts received olverembatinib monotherapy (40mg qod) or combination therapy. Efficacy was assessed by CR rate, MRD negative (MRD <10 -4) rate by multiparameter flow cytometry (MFC), CMR (BCR-ABL1 transcript<10 -5) rate by RT-qPCR, as well as the survival data. PFS and OS were both calculated from the start of olverembatinib. Adverse events (AEs) were assessed and graded according to CTCAE v5.0. Results Totally, 30 pts with BCR::ABL1+ ALL (n=29) or CML-LBP (n=1) were analyzed. Among 29 BCR::ABL1+ ALL pts (median age of 60 years [range, 23-76]), 14 were in CR with molecular R/R disease, including 1 with MRD only detected by RT-qPCR. While the other 15 had hematological R/R disease, including 4 with central nervous system leukemia. T315I mutation was detected in 23 pts, including 8 with additional mutations. The baseline characteristics are detailed in Table 1. As for the 23-year-old female pt with CML-LBP, dasatinib was switched to olverembatinib when T315I, E255K, and E255V mutations were detected. T315I and E255V were eliminated rapidly after 1-month treatment of olverembatinib, while E255K still existed. At present, the patient maintained in CR, and blinatumomab will be used for MRD clearance before allo-HSCT. She was only included in the safety analysis. Among 14 pts with molecular R/R disease, 61.5% and 50% achieved MRD flow negativity and CMR with a median time of 1.3 months (range, 0.8-4.4) and 1.2 months (range, 0.9-4.4), respectively. Among 15 pts with hematological R/R disease, 80%, 53.3%, and 46.7% achieved CR/CRi, MRD flow negativity, and CMR, with a median time of 1 month (range, 0.2-2.5), 1 month (range, 0.2-3.3) and 2.1 months (range, 0.7-4.6), respectively. Totally, 8 pts underwent allo-HSCT with a median age of 48.5 years (range, 23-60), of which 6 pts achieved CMR before allo-HSCT, and all attained persistent CMR after allo-HSCT. By June 15, 2023, with a median follow-up time of 9.1 months (range, 1.7-16) in BCR::ABL1+ ALL pts, the median PFS was 7.8 months, and the median OS was not reached. For molecular R/R pts, the median PFS and OS were not reached, and for hematological R/R pts, the median PFS and OS were 6.5 and 8.6 months. MRD flow negativity or CMR responders had significantly better PFS and OS (PFS: p<0.001, p<0.001; OS: p<0.001, p<0.001), and bridging allo-HSCT after olverembatinib-based therapy showed a significant survival superiority (PFS: p=0.001; OS: p=0.017). Among the 23 pts with T315I mutation, the MRD flow negativity rate in pts with T315I single mutation was significantly higher than those with additional mutations (p=0.008), and the CMR rate tended to be better (p=0.089). Meanwhile, pts with T315I single mutation showed significant improvements in PFS and OS (Figure 1). As for safety analysis, the olverembatinib-based therapy was well-tolerated. Most non-hematological AEs were G1-2, and most G3-4 AEs were hematological, possibly related to chemotherapy. The incidence of G3-4 cardiovascular AEs was 6.7%. Five elderly pts (median age of 72 years [range, 63-76]) had temporary treatment suspension or dose reduction. No permanent discontinuation or death related to olverembatinib was observed. Conclusion This study further confirmed the efficacy of olverembatinib-based therapy in Chinese adults BCR::ABL1+ ALL pts with T315I mutation or R/R disease, especially in those with T315I single mutation. In addition, bridging allo-HSCT after deeper molecular remission could further improve survival. The safety profiles were manageable, but there is still a need to explore the optimal dose in elderly pts.

Background Tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of patients(pts) with Ph/BCR-ABL1-positive (Ph/BCR-ABL1+) acute lymphoblastic leukemia (ALL). However, mutations in the ABL1 kinase domain, especially T315I, are the main mechanism of resistance to the first- or second-generation TKIs. Olverembatinib is a novel third-generation TKI developed in China and approved in Dec. 2021, which has been demonstrated great efficacy and safety in clinical trials of CML with T315I mutation. Our study is the first application of Olverembatinib in adult Ph/BCR-ABL1+ ALL with T315I mutation. Herein, we report the preliminary results. Methods In this exploratory study, adult Ph/BCR-ABL1+ ALL pts with T315I mutation or disease progression were treated with olverembatinib monotherapy (40 mg, every 2 days) or in combination with VP based low intensive chemotherapy (Vincristine/Prednisone) in our institution. Efficacy was assessed by complete remission (CR) rate, MRDneg (<0.01%) rate by multiparameter flow cytometry (MFC) and CMR (BCR-ABL1 transcript<10-5) rate by real-time quantitative polymerase chain reaction (RT-qPCR). Safety profiles were also monitored in this study. Results From December 2021 to June 2022, 10 Ph/BCR-ABL1+ ALL pts were treated with olverembatinib due to T315I mutation or disease recurrence, after prior TKIs combined with chemotherapy. Median age was 60.5 years (range, 37-65), and 6/10 were males. 5 pts had received 2 types of TKIs previously, of which 2 pts relapsed after ponatinib (Table 1). Among 10 pts, 6 were still in CR1 (pt 1-6), their T315I mutations were detected during regular follow-up. 4/6 pts were persistently molecular positive, while the other 2 had molecular relapse. Median time from diagnosis to the administration of olverembatinib was 5 months (range, 3-17). Among the 4 pts with hematologic relapse (pt 7-10), 2 (pt 7, 8) had T315I mutation. Because of the successive occurrence of G250E, Y253H, L248V mutations and L248 K274del, the 3rd one (pt 9) relapsed twice and failed to response to two kinds of TKIs and chemotherapy. As for the last pt (pt 10), although no ABL1 mutations were found, she was in 3rd relapse with CNS and BM involvement. Median time from diagnosis to the start of olverembatinib for these 4 relapsed pts was 28 months (range, 5-41). Among 6 pts with T315I mutation and persistent molecular diseases or molecular relapse, the CMR rate was 66.7%, with a median time of 3 months (range, 1-4) to achieve CMR. Then 2 pts underwent allo-HSCT (pt3, 4), who were still in CR. Among 4 hematological relapsed pts, the CR rate was 75%. 1 pt (pt8) with T315I was unresponsive, while another T315I positive patient achieved MRDneg by MFC after 1 month of treatment, with a complete disappearance of T315I mutation (pt7), though the BCR-ABL1 transcript was still positive. The remaining 2 relapsed pts without T315I mutation achieved hematologic CR after 1 month of olverembatinib monotherapy (pt9,10). Totally, overall response rate (ORR) was 70% and MRDneg rate by MFC was 71.4% (5/7), while the CMR rate by PCR was 57.1% (4/7). Notably, olverembatinib was ineffective in neither of the 2 pts who have been previously treated by ponatinib. Meanwhile, the olverembatinib-based therapy was well-tolerated, and the main adverse events of the third-generation TKIs, such as cytopenia, elevated transaminases, hypertension, and cardiovascular events, were less frequent than those reported relating to ponatinib. In addition, 4 patients developed grade 1 skin pigmentation (pt2,3,6,9). There were no drug-related death or permanent discontinuation due to toxicity. Conclusion This work suggests that Olverembatinib is a very promising 3rd-generation TKI. It is effective and safe in Chinese adult Ph/BCR-ABL1+ ALL with extremely poor prognosis, especially in T315I mutated or relapsed pts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

HaemophiliaVolume 24, Issue 2 p. e68-e70 LETTER TO THE EDITOR A novel missense mutation, p.Phe360Cys, in FIX gene results in haemophilia B in a female patient with skewed X-inactivation C. Yang, C. Yang orcid.org/0000-0002-0130-3949 Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis/Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, China Collaborative Innovation Center of Hematology, Soochow University, Suzhou, ChinaSearch for more papers by this authorZ. Yu, Corresponding Author Z. Yu yuziqiang@suda.edu.cn Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis/Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, China Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China Correspondence Ziqiang Yu, The First Affiliated Hospital of Soochow University, Suzhou, China. Email: yuziqiang@suda.edu.cnSearch for more papers by this authorW. Zhang, W. Zhang Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis/Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, China Collaborative Innovation Center of Hematology, Soochow University, Suzhou, ChinaSearch for more papers by this authorL. Cao, L. Cao Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis/Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, China Collaborative Innovation Center of Hematology, Soochow University, Suzhou, ChinaSearch for more papers by this authorW. Ouyang, W. Ouyang Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis/Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, China Collaborative Innovation Center of Hematology, Soochow University, Suzhou, ChinaSearch for more papers by this authorF. Hu, F. Hu Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis/Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, China Collaborative Innovation Center of Hematology, Soochow University, Suzhou, ChinaSearch for more papers by this authorP. Zhang, P. Zhang Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis/Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, China Collaborative Innovation Center of Hematology, Soochow University, Suzhou, ChinaSearch for more papers by this authorX. Bai, X. Bai Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis/Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, China Collaborative Innovation Center of Hematology, Soochow University, Suzhou, ChinaSearch for more papers by this authorC. Ruan, C. Ruan Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis/Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, China Collaborative Innovation Center of Hematology, Soochow University, Suzhou, ChinaSearch for more papers by this author C. Yang, C. Yang orcid.org/0000-0002-0130-3949 Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis/Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, China Collaborative Innovation Center of Hematology, Soochow University, Suzhou, ChinaSearch for more papers by this authorZ. Yu, Corresponding Author Z. Yu yuziqiang@suda.edu.cn Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis/Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, China Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China Correspondence Ziqiang Yu, The First Affiliated Hospital of Soochow University, Suzhou, China. Email: yuziqiang@suda.edu.cnSearch for more papers by this authorW. Zhang, W. Zhang Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis/Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, China Collaborative Innovation Center of Hematology, Soochow University, Suzhou, ChinaSearch for more papers by this authorL. Cao, L. Cao Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis/Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, China Collaborative Innovation Center of Hematology, Soochow University, Suzhou, ChinaSearch for more papers by this authorW. Ouyang, W. Ouyang Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis/Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, China Collaborative Innovation Center of Hematology, Soochow University, Suzhou, ChinaSearch for more papers by this authorF. Hu, F. Hu Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis/Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, China Collaborative Innovation Center of Hematology, Soochow University, Suzhou, ChinaSearch for more papers by this authorP. Zhang, P. Zhang Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis/Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, China Collaborative Innovation Center of Hematology, Soochow University, Suzhou, ChinaSearch for more papers by this authorX. Bai, X. Bai Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis/Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, China Collaborative Innovation Center of Hematology, Soochow University, Suzhou, ChinaSearch for more papers by this authorC. Ruan, C. Ruan Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis/Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, China Collaborative Innovation Center of Hematology, Soochow University, Suzhou, ChinaSearch for more papers by this author First published: 05 February 2018 https://doi.org/10.1111/hae.13423Citations: 5Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume24, Issue2March 2018Pages e68-e70 RelatedInformation