Publications by authors named "Depei Wu"

410 Publications

Bendamustine versus chlorambucil in treatment of chronic lymphocytic leukaemia in China: a randomized, open-label, parallel-controlled, phase III clinical trial.

Invest New Drugs 2022 Jan 15. Epub 2022 Jan 15.

Department of Hematology, Sun Yat-Sen University Cancer Center, Sun Yat-sen, China.

Background: Chronic lymphoblastic leukemia (CLL) is the most common adult leukemia and mainly affects the elderly. Chemoimmunotherapy still has a role in the standard frontline therapy for specific population. However, the clinical activity of bendamustine has not been investigated in unfit Chinese patients with CLL. This study aimed to compare the efficacy and safety of bendamustine versus chlorambucil for untreated Chinese patients with Binet stage B/C CLL.

Methods: In this multi-center, randomized, open-label, parallel-controlled, phase III trial, patients with previously untreated CLL were enrolled and randomly assigned (1:1) to receive bendamustine or chlorambucil. The primary endpoint was the objective response rate. Secondary endpoints included progression-free survival, the duration of response, and overall survival. Adverse events were recorded to evaluate safety.

Results: Of 158 screened patients, 147 were enrolled and randomly allocated to receive bendamustine (n = 72) or chlorambucil (n = 75). After a median follow-up of 25.6 months (IQR 12.5-27.7), 69.0% (95% CI, 56.9-79.5) of bendamustine-treated patients achieved objective response and 37.0% (95% CI, 26.0-49.1) of chlorambucil with a difference of 32.0% (95%CI: 16.6-47.5), demonstrating the superiority of bendamustine to chlorambucil (p < 0.001). The median progression-free survival was longer for bendamustine (16.5 months; 95% CI, 11.3-24.7) versus chlorambucil (9.6 months; 95% CI, 8.7-11.8; p < 0.001). A longer median duration of response was seen in those receiving bendamustine (19.2 months; 95% CI, 11.8-29.1) than chlorambucil (10.7 months; 95% CI, 5.6-13.6; p = 0.0018). Median overall survival was not reached in either group. Overall survival at 18 months was 88% for bendamustine versus 85% for chlorambucil. Most common adverse events in both groups were neutropenia and thrombocytopenia.

Conclusion: In untreated Chinese patients with Binet stage B/C CLL, bendamustine induced the better objective response and resulted in longer progression-free survival than chlorambucil. Overall, these results validate the role of bendamustine as an effective and safe first-line therapy in this population.
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http://dx.doi.org/10.1007/s10637-021-01206-2DOI Listing
January 2022

Characterization of m6A regulator-mediated methylation modification patterns and tumor microenvironment infiltration in acute myeloid leukemia.

Cancer Med 2022 Jan 13. Epub 2022 Jan 13.

National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.

Background: Previous studies have confirmed the existence of epigenetic regulation of immune responses in acute myeloid leukemia. However, the potential role of RNA N6-methyladenosine (m6A) remodeling in tumor microenvironment (TME) infiltration remains unclear.

Methods And Materials: m6A patterns of 469 AML patients (420 of which provided survival data) based on 18 m6A regulators were systematically evaluated. Based on the expression of 18 m6A regulators, unsupervised agglomerative cluster analysis was applied to recognize the various m6A modification types and to classify patients. We linked these patterns to TME infiltration characteristics and identified three distinct populations of m6A modifications.

Results: These three TME cell infiltration patterns are characterized by a high degree of concordance with the three tumor immunophenotypes, which include immunoinflammatory, immunorejection, and immune inert patterns. We showed that assessment of m6A modification patterns within individually neoplasms can forecast the stage of neoplasmic inflammation, TME basal activity, subtype, hereditary mutation, and clinical patient prognosis. Limited low m6Ascore, featuring increased mutational load and immune activation, indicates an inflammatory phenotype of TME with a 5-year survival rate at 14.4% compared to the high-m6Ascore group (40.9%).

Conclusions: Data from two different cohorts demonstrated that a higher m6Ascore showed a marked therapeutic superiority as well as clinical advantage. Assessing m6A modification patterns in AML patients could improve our knowledge of the TME infiltrative profile as well as directing effective immunotherapeutic approaches.
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http://dx.doi.org/10.1002/cam4.4531DOI Listing
January 2022

The differential effects of tumor burdens on predicting the net benefits of ssCART-19 cell treatment on r/r B-ALL patients.

Sci Rep 2022 Jan 10;12(1):378. Epub 2022 Jan 10.

Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, NO, 3663 North Zhongshan Road, Shanghai, 200065, China.

The tumor burden (TB) is significantly related to the severity of cytokine release syndrome (CRS) caused by CAR-T cells, but its correlation with therapeutic efficacy has not been systematically studied. This study focused on the effects of the TB level on both the safety and efficacy of ssCART-19 as a treatment for r/r B-ALL. Taking the 5% tumor burden as the boundary, the study participants were divided into 2 groups, high and low tumor burden groups. Under this grouping strategy, the impacts of differential r/r B-ALL TBs on the clinical therapeutic efficacy (CR rate and long-term survival) and safety profiles after ssCART-19 cell treatment were analysed. 78 patients were reported in this study. The differential B-ALL TBs significantly affected the complete remission (CR) rates of patients treated with ssCART-19, with rates of 93.94% and 75.56% in the low and high TB groups, respectively (P = 0.0358). The effects of TBs on long-term therapeutic efficacy were further studied based on event-free survival (EFS) and overall survival (OS) profiles; both the OS and EFS of the low TB group were better than those of the high TB group, but the differences were not statistically significant. Importantly, the time points of TB measurement did not significantly affect the OS and EFS profiles regardless of whether the TBs were measured before or after fludarabine-cyclophosphamide (FC) preconditional chemotherapy. On the other hand, the severity of CRS was significantly correlated with the TB level (P = 0.0080), and the incidence of sCRS was significantly related to the TB level (the sCRS incidence increased as the TB level increased, P = 0.0224). Unexpectedly, the ssCART-19 cell expansion peaks were not significantly different (P = 0.2951) between the study groups. Patients with a low r/r B-ALL TB yield more net benefits from CAR-T treatment than those with a high TB in terms of safety and CR rate. These findings are critical and valuable for determining the optimal CAR-T cell treatment window for r/r B-ALL patients and will further the development of comprehensive and reasonable CAR-T cell treatment plans for r/r B-ALL patients with differential TBs.Trial registration: ClinicalTrials.gov identifier, NCT03919240.
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http://dx.doi.org/10.1038/s41598-021-04296-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8748521PMC
January 2022

Pegylated Interferon Alpha-2b in Patients With Polycythemia Vera and Essential Thrombocythemia in the Real World.

Front Oncol 2021 21;11:797825. Epub 2021 Dec 21.

Department of Hematology, First Affiliated Hospital of Soochow University, Soochow University, Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, Suzhou, China.

Several clinical trials have shown promising efficacy of pegylated interferon (Peg-IFN) in the first- and second-line polycythemia vera (PV) and essential thrombocythemia (ET). However, the efficacy and safety of Peg-IFN in the real world have rarely been reported. Hence, we conducted a prospective, single-center, single-arm, open exploratory study, which aimed to explore the hematologic response, molecular response, safety, and tolerability of patients with PV and ET treated with Peg-IFN in the real world. This study included newly diagnosed or previously treated patients with PV and ET, aged 18 years or older, admitted to the Department of Hematology of the First Affiliated Hospital of Soochow University from November 2017 to October 2019. The results revealed that complete hematological response (CHR) was achieved in 66.7% of patients with PV and 76.2% of patients with ET, and the molecular response was obtained in 38.5% of patients with PV and 50% of patients with ET after 48 weeks of Peg-IFN treatment. Peg-IFN is safe, effective and well tolerated in most patients. In the entire cohort, 4 patients (9.1%) discontinued treatment due to drug-related toxicity. In conclusion, Peg-IFN is a promising strategy in myeloproliferative neoplasms (MPNs), and Peg-IFN alone or in combination with other drugs should be further explored to reduce treatment-related toxicity and improve tolerability.
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http://dx.doi.org/10.3389/fonc.2021.797825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8724125PMC
December 2021

N-acetyl-L-cysteine potentially inhibits complement activation in transplantation-associated thrombotic microangiopathy.

Transplant Cell Ther 2021 Dec 31. Epub 2021 Dec 31.

National clinical research center for hematologic diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China; Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China; Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Suzhou, China; State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China. Electronic address:

Transplant-associated thrombotic microangiopathy (TA-TMA) has a high mortality rate and lacks effective treatments. We searched the GEO database and analyzed RNA-seq data and whole-genome sequencing (WGS) data from patients' blood samples. We identified N-acetyl-L-cysteine (NAC) as a possible therapeutic target for TA-TMA. In vitro experiments showed that NAC reduced complement activation and VWF multimerization in HUVECs. We also treated a 36-year-old female TA-TMA patient with NAC. HB, PLT counts, LDH levels, and sC5b-9 levels and schistocytes were normalized after using NAC. It shows that NAC may be an effective drug to improve TA-TMA symptoms by inhibiting complement activation.
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http://dx.doi.org/10.1016/j.jtct.2021.12.018DOI Listing
December 2021

Maternal and Fetal Outcomes of Acute Leukemia in Pregnancy: A Retrospective Study of 52 Patients.

Front Oncol 2021 14;11:803994. Epub 2021 Dec 14.

Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Suzhou, China.

Acute leukemia during pregnancy (P-AL) is a rare disease with limited data regarding the management and outcomes of mothers and fetuses. We retrospectively analyzed the characteristics, pregnancy outcomes and maternal and neonatal prognoses of 52 patients with P-AL collected from January 2013 to December 2020 in our center. Seventeen (32.7%) patients received chemotherapy during pregnancy (exposed cohort), while 35 (67.3%) received chemotherapy after abortion/delivery (nonexposed cohort). Twenty-six (50.0%) pregnancies ended with abortion, and 26 (50.0%) babies were born through spontaneous delivery or cesarean section. Seven infants (26.9%) were born in the exposed cohort, while 19 infants (73.1%) were born in the nonexposed cohort. Fetuses in the exposed cohort had lower gestational ages (P=0.030) and birth weights (P=0.049). Considering the safety of the fetus, seven patients in the exposed cohort received low-dose chemotherapy, one patient received all-trans retinoic acid (ATRA) and one patient only received corticosteroids as induction therapy. Patients received low-dose chemotherapy as induction therapy had a lower complete remission (CR) rate (P=0.041), and more patients in this group received HSCT (P=0.010) than patients received intensive chemotherapy. Patients who delayed chemotherapy in the nonexposed cohort experienced a trend toward a higher mortality rate than patients who received timely chemotherapy (P=0.191). The CR (P = 0.488), OS (P=0.655), and DFS (P=0.453) were similar between the exposed and nonexposed cohorts. Overall, the 4-year overall survival (OS) and disease-free survival (DFS) rates were estimated at 49.1% and 57.8%, respectively. All newborns were living, without deformities, or developmental and intellectual disabilities. Our study indicated that P-AL patients in the first trimester might tend to receive chemotherapy after abortion. Both the status of disease and patients' willingness should be taken into consideration when clinicians were planning treatment strategies in the second or third trimester. Low-dose or delayed chemotherapy might decrease the efficacy of induction therapy and survival rate of patients, but HSCT could improve the prognosis.
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http://dx.doi.org/10.3389/fonc.2021.803994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8712699PMC
December 2021

Clinical Outcomes of B Cell Acute Lymphoblastic Leukemia Patients Treated with Haploidentical Stem Cells Combined with Umbilical Cord Blood Transplantation.

Transplant Cell Ther 2021 Dec 22. Epub 2021 Dec 22.

Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Suzhou, China; Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China. Electronic address:

Clinical outcomes of hematopoietic stem cell transplantation (HSCT) using a haploidentical stem cell graft and an unrelated umbilical cord blood unit (haplo-cord HSCT) for the treatment of B cell acute lymphoblastic leukemia (B-ALL) remain unclear. This study was conducted to explore the clinical outcomes of haplo-cord HSCT in patients with B-ALL. A total of 112 B-ALL patients who underwent haplo-cord HSCT and 64 B-ALL patients who underwent haploidentical HSCT (haplo-HSCT) at our center between 2010 and 2020 were retrospectively included in this study, and clinical outcomes and prognostic factors were further analyzed. Of the 112 haplo-cord HSCT recipients, 106 (94.6%) achieved complete haploidentical chimerism and 6 (5.4%) had mixed cord blood chimerism. No differences in neutrophil and platelet recovery or in the incidences of graft-versus-host disease, cytomegalovirus/Epstein-Barr virus viremia, bloodstream infection, or hemorrhagic cystitis were observed between the haplo-cord HSCT and haplo-HSCT groups. Compared with the haplo-HSCT group, the haplo-cord HSCT group had a higher absolute number of CD3 cells (P = .029) and a lower ratio of CD3CD4 /CD3CD8 cells (P = .049) at 1 month post-transplantation. Moreover, the haplo-cord HSCT group had lower minimal residual disease (MRD) levels at 1 month (P = .020) and 100 days (P = .038) post-transplantation and a better 3-year prognosis (overall survival, P = .016; disease-free survival, P = .041; cumulative incidence of relapse [CIR], P = .016). The CIRs in patients with adverse genomic features (P = .040) or flow cytometry-based MRD (FCM-MRD) ≥1 × 10 (P = .033) were improved by haplo-cord HSCT. Multivariate analysis revealed that haplo-cord HSCT could independently improve the 3-year OS, DFS, and CIR of B-ALL patients (OS, P = .029; DFS, P = .024; CIR, P = .024). In addition, allo-HSCT at first complete remission was an independent parameter associated with 3-year OS for B-ALL patients (P = .014). An FCM-MRD ≥1 × 10 pre-HSCT could independently predict unfavorable 3-year DFS and CIR (DFS, P = .020; CIR, P = .036) in B-ALL patients. Our data suggest that the use of haplo-cord HSCT can independently improve survival in patients with B-ALL.
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http://dx.doi.org/10.1016/j.jtct.2021.12.010DOI Listing
December 2021

Successful treatment of acquired amegakaryocytic thrombocytopenia with eltrombopag and immunosuppressant.

Platelets 2021 Dec 16:1-3. Epub 2021 Dec 16.

National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.

Acquired amegakaryocytic thrombocypenia (AAMT) is an extremely rare hematologic disorder and standard treatment strategy has not been established. We described herein two cases of AAMT who were fully responded to eltrombopag and immunosuppressant. Patient 1 was refractory to steroid, IVIG and recombinant human thrombopoietin (rhTPO). Patient 2 did not respond to high dosage of steroid, IVIG, rhTPO and rituximab. Moreover, his AAMT progressed to aplastic anemia in 5 months. Both patients took eltrombopag and immunosuppressant, then they achieved long-term remission without obvious side effects. Our findings suggest that this combination can be a valuable alternative in AAMT.
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http://dx.doi.org/10.1080/09537104.2021.2012140DOI Listing
December 2021

Molecular characterization of Novel fusions in chronic lymphocytic leukemia and T-cell prolymphocytic leukemia.

Leuk Lymphoma 2021 Dec 13:1-11. Epub 2021 Dec 13.

Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

deletions and/or mutations are recurrent in lymphoid neoplasms while rearrangements are rare. In this study, we used mate pair sequencing (MPseq) technology to characterize two novel rearrangements in one patient with chronic lymphocytic leukemia (CLL) and one patient with T-prolymphocytic leukemia (T-PLL). Both patients showed chromosome 11q22 aberrations encompassing by conventional karyotype and fluorescence hybridization: isolated t(11;13)(q22;q14) in CLL and a complex karyotype with apparent 11q deletion and unbalanced der(14)t(11;14)(q22;p11.2) in T-PLL. MPseq identified fusion in CLL and - in T-PLL, both of which led to ATM inactivation, confirmed by loss of immunohistochemical protein expression. Next-generation sequencing mutation analysis detected concurrent mutation(s) CLL patient, while T-PLL lacked mutation. rearrangements, not apparently detectable using standard laboratory technologies, represent another mechanism of loss-of-function. Recent high-throughput technologies such as MPseq can uncover novel pathogenic gene fusions and resolve complex chromosomal rearrangements in hematologic malignancies.
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http://dx.doi.org/10.1080/10428194.2021.2010061DOI Listing
December 2021

Graft-versus-Host Disease Prophylaxis with Post-Transplantation Cyclophosphamide versus Cyclosporine A and Methotrexate in Matched Sibling Donor Transplantation.

Transplant Cell Ther 2021 Nov 29. Epub 2021 Nov 29.

Department of Clinical Hematology and Cellular Therapy, Saint-Antoine Hospital, AP-HP, Sorbonne University, Paris, France; Sorbonne University, INSERM, Saint-Antoine Research Centre, Paris, France.

Cyclosporine A (CSA) and methotrexate (MTX) is the standard graft-versus-host disease (GVHD) prophylaxis regimen for matched sibling donor (MSD) allogeneic hematopoietic cell transplantation (allo-HCT). Recently, post-transplantation cyclophosphamide (PTCy) has been shown to be effective in GVHD prevention. In this registry-based study, we compared outcomes of 118 patients treated with PTCy and 1202 patients with CSA/MTX who underwent MSD allo-HCT for acute myelogenous leukemia. In a matched-pair analysis, PTCy was associated with a higher incidence of relapse at 2 years compared with CSA/MTX (41.1% versus 21.3%; P = .039). The incidences of day +180 grade II-IV acute GVHD and 2-year chronic GVHD were comparable in the PTCy and CSA/MTX arms (25.2% versus 25.4% [P = .90] and 42.6% versus 42.6% [P = .84], respectively). Similarly, 2-year leukemia-free survival (LFS; 54.4% versus 74.32%; P = .052), overall survival (OS; 70.6% versus 79.7%; P = .15), and GVHD-free relapse-free survival (GRFS; 38.1% versus 52.5%; P = .49) were not statistically different in the 2 arms. Our data show that GVHD prophylaxis with PTCy is feasible, resulting in similar incidences of GVHD, GRFS, LFS, and OS as seen with conventional CSA/MTX in patients undergoing allo-HCT from an MSD. The higher rate of relapse observed with PTCy needs further evaluation in a prospective study. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
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http://dx.doi.org/10.1016/j.jtct.2021.11.013DOI Listing
November 2021

The disulfide bond Cys2724-Cys2774 in the C-terminal cystine knot domain of von Willebrand factor is critical for its dimerization and secretion.

Thromb J 2021 Nov 27;19(1):94. Epub 2021 Nov 27.

Department of Hematology, Key Laboratory of Hematology of Hebei Province, The Second Hospital of Hebei Medical University, 050000, Shijiazhuang, China.

Background: Type 3 von Willebrand disease (VWD) exhibits severe hemorrhagic tendency with complicated pathogenesis. The C-terminal cystine knot (CTCK) domain plays an important role in the dimerization and secretion of von Willebrand factor (VWF). The CTCK domain has four intrachain disulfide bonds including Cys2724-Cys2774, Cys2739-Cys2788, Cys2750-Cys2804 and Cys2754-Cys2806, and the single cysteine mutation in Cys2739-Cys2788, Cys2750-Cys2804 and Cys2754-Cys2806 result in type 3 VWD, demonstrating the crucial role of these three disulfide bonds in VWF biosynthesis, however, the role of the remaining disulfide bond Cys2724-Cys2774 remains unclear.

Method And Results: In this study, by the next-generation sequencing we found a missense mutation a c.8171G>A (C2724Y) in the CTCK domain of VWF allele in a patient family with type 3 VWD. In vitro, VWF C2724Y protein was expressed normally in HEK-293T cells but did not form a dimer or secrete into cell culture medium, suggesting that C2724 is critical for the VWF dimerization, and thus for VWF multimerization and secretion.

Conclusions: Our findings provide the first genetic evidence for the important role of Cys2724-Cys2774 in VWF biosynthesis and secretion. Therefore, all of the four intrachain disulfide bonds in CTCK monomer contribute to VWF dimerization and secretion.
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http://dx.doi.org/10.1186/s12959-021-00348-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8626975PMC
November 2021

A comprehensive approach to stool donor screening for faecal microbiota transplantation in China.

Microb Cell Fact 2021 Nov 27;20(1):216. Epub 2021 Nov 27.

School of Medicine, Xiamen University, Xiamen, China.

Background: Faecal microbiota transplantation (FMT) is an effective therapy for recurrent Clostridium difficile infections and chronic gastrointestional infections. However, the risks of FMT and the selection process of suitable donors remain insufficiently characterized. The eligibility rate for screening, underlying microbial basis, and core ethical issues of stool donors for FMT are yet to be elucidated in China.

Results: The potential stool donors were screened from December 2017 to December 2019 with the help of an online survey, clinical assessments, and stool and blood testing. Bioinformatics analyses were performed, and the composition and stability of gut microbiota in stool obtained from eligible donors were dynamically observed using metagenomics. Meanwhile, we build a donor microbial evaluation index (DoMEI) for stool donor screening. In the screening process, we also focused on ethical principles and requirements. Of the 2071 participants, 66 donors were selected via the screening process (3.19% success rate). Although there were significant differences in gut microbiota among donors, we found that the changes in the gut microbiota of the same donor were typically more stable than those between donors over time.

Conclusions: DoMEI provides a potential reference index for regular stool donor re-evaluation. In this retrospective study, we summarised the donor recruitment and screening procedure ensuring the safety and tolerability for FMT in China. Based on the latest advances in this field, we carried out rigorous recommendation and method which can assist stool bank and clinicians to screen eligible stool donor for FMT.
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http://dx.doi.org/10.1186/s12934-021-01705-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8626716PMC
November 2021

Dose tapering to withdrawal stage and long-term efficacy and safety of hetrombopag for the treatment of immune thrombocytopenia: Results from an open-label extension study.

J Thromb Haemost 2021 Nov 25. Epub 2021 Nov 25.

Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Background: The efficacy of hetrombopag in Chinese patients with immune thrombocytopenia (ITP) has been demonstrated in a randomized, double-blind, placebo-controlled, multicenter, phase III trial (NCT03222843).

Objective: This study aimed to report comprehensive data on a ≤6-week dose tapering to withdrawal (Stage 3) and an additional 24-week long-term extension period (Stage 4) in this phase III trial.

Patients/methods: Patients who fulfilled the screening criteria were eligible to enter Stage 3 or 4. During Stage 3, hetrombopag was gradually tapered to withdrawal. During Stage 4, hetrombopag treatment was initiated at 2.5, 3.75, 5, or 7.5 mg once daily. The efficacy endpoints during Stage 3 or 4 and the safety profile during the entire treatment period were reported.

Results: Among 194 patients who entered Stage 3, 171 (88.1%) relapsed. The median time to the first relapse since the start of Stage 3 was 15.0 days (95% CI, 14.0-16.0). In Stage 4, 144 (42.5%) patients responded at ≥75% of their assessments and 254 (74.9%) patients achieved platelet count ≥30 × 10 /L at least once, which was at least twice their baseline platelet count in the hetrombopag group (n = 339). The most common adverse events were upper respiratory tract infection (53.1%), thrombocytopenia (27.1%), and urinary tract infection (21.2%) in the hetrombopag group.

Conclusion: The majority of patients who experienced dose tapering to withdrawal experienced a relapse. Long-term treatment with hetrombopag was effective in increasing and maintaining platelet count within the desired range in Chinese adults with ITP. Hetrombopag was well tolerated.
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http://dx.doi.org/10.1111/jth.15602DOI Listing
November 2021

High salt activates p97 to reduce host antiviral immunity by restricting Viperin induction.

EMBO Rep 2022 Jan 15;23(1):e53466. Epub 2021 Nov 15.

International Institute of Infection and Immunity, Institutes of Biology and Medical Sciences, Suzhou, China.

High-salt diets have recently been implicated in hypertension, cardiovascular disease, and autoimmune disease. However, whether and how dietary salt affects host antiviral response remain elusive. Here, we report that high salt induces an instant reduction in host antiviral immunity, although this effect is compromised during a long-term high-salt diet. Further studies reveal that high salt stimulates the acetylation at Lys663 of p97, which promotes the recruitment of ubiquitinated proteins for proteasome-dependent degradation. p97-mediated degradation of the deubiquitinase USP33 results in a deficiency of Viperin protein expression during viral infection, which substantially attenuates host antiviral ability. Importantly, switching to a low-salt diet during viral infection significantly enhances Viperin expression and improves host antiviral ability. These findings uncover dietary salt-induced regulation of ubiquitinated cellular proteins and host antiviral immunity, and could offer insight into the daily consumption of salt-containing diets during virus epidemics.
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http://dx.doi.org/10.15252/embr.202153466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8728598PMC
January 2022

Diagnosis and Treatment of Myeloproliferative Neoplasms With PCM1-JAK2 Rearrangement: Case Report and Literature Review.

Front Oncol 2021 11;11:753842. Epub 2021 Oct 11.

Department of Hematology, First Affiliated Hospital of Soochow University, National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, Soochow University, Suzhou, China.

Myeloproliferative neoplasm (MPN) with PCM1-JAK2 rearrangement is a rare disease with poor prognosis and lacks uniform treatment guidelines. Several studies confirmed the efficacy of ruxolitinib in hematological malignancies with PCM1-JAK2 fusion, but the efficacy is variable. Here, we report two patients diagnosed with MPN with PCM1-JAK2 fusion who were treated with ruxolitinib-based regimen, including the first case of ruxolitinib combined with pegylated interferon (Peg-IFN), and we conduct a literature review. We found that ruxolitinib combined with Peg-IFN is an effective treatment option in the case of poor efficacy of ruxolitinib monotherapy.
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http://dx.doi.org/10.3389/fonc.2021.753842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8542851PMC
October 2021

Roles of the intestinal microbiota and microbial metabolites in acute GVHD.

Exp Hematol Oncol 2021 Oct 27;10(1):49. Epub 2021 Oct 27.

National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, People's Republic of China.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is one of the most curative strategies for the treatment of many hematologic malignancies and diseases. However, acute graft-versus-host disease (GVHD) limits the success of allo-HSCT. The prevention and treatment of acute GVHD is the key issue for improving the efficacy of allo-HSCT and has become a research hotspot. The intestine is the primary organ targeted by acute GVHD, and the intestinal microbiota is critical for maintaining the homeostasis of the intestinal microenvironment and the immune response. Many studies have demonstrated the close association between the intestinal microbiota and the pathogenesis of acute GVHD. Furthermore, dysbiosis of the microbiota, which manifests as alterations in the diversity and composition of the intestinal microbiota, and alterations of microbial metabolites are pronounced in acute GVHD and associated with poor patient prognosis. The microbiota interacts with the host directly via microbial surface antigens or microbiota-derived metabolites to regulate intestinal homeostasis and the immune response. Therefore, intervention strategies targeting the intestinal microbiota, including antibiotics, prebiotics, probiotics, postbiotics and fecal microbiota transplantation (FMT), are potential new treatment options for acute GVHD. In this review, we discuss the alterations and roles of the intestinal microbiota and its metabolites in acute GVHD, as well as interventions targeting microbiota for the prevention and treatment of acute GVHD.
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http://dx.doi.org/10.1186/s40164-021-00240-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8555140PMC
October 2021

Bortezomib provides favorable efficacy in type 3 acquired von willebrand syndrome related to lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia.

Leuk Lymphoma 2021 Oct 20:1-4. Epub 2021 Oct 20.

National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.

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http://dx.doi.org/10.1080/10428194.2021.1992766DOI Listing
October 2021

Development of a Nomogram for Predicting the Cumulative Incidence of Disease Recurrence of AML After Allo-HSCT.

Front Oncol 2021 27;11:732088. Epub 2021 Sep 27.

Jiangsu Institute of Haematology, Key Laboratory of Thrombosis and Haemostasis of Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, China.

Using targeted exome sequencing, we studied correlations between mutations at diagnosis and transplant outcomes in 332 subjects with acute myeloid leukemia (AML) receiving allotransplantation. A total of 299 patients (299/332, 90.1%) had at least one oncogenic point mutation. In multivariable analyses, pretransplant disease status, minimal residual disease (MRD) before transplantation (pre-MRD), cytogenetic risk classification, and and mutations were independent risk factors for AML recurrence after allotransplantation (p < 0.05). A nomogram for the cumulative incidence of relapse (CIR) that integrated all the predictors in the multivariable model was then constructed, and the concordance index (C-index) values at 6, 12, 18, and 24 months for CIR prediction were 0.754, 0.730, 0.715, and 0.690, respectively. Moreover, calibration plots showed good agreements between the actual observation and the nomogram prediction for the 6, 12, 18, and 24 months posttransplantation CIR in the internal validation. The integrated calibration index (ICI) values were 0.008, 0.055, 0.094, and 0.136 at 6, 12, 18, and 24 months posttransplantation, respectively. With a median cutoff score of 9.73 from the nomogram, all patients could be divided into two groups, and the differences in 2-year CIR, disease-free survival (DFS), and overall survival (OS) between these two groups were significant (p < 0.05). Taken together, the results of our study indicate that gene mutations could help to predict the outcomes of patients with AML receiving allotransplantation.
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http://dx.doi.org/10.3389/fonc.2021.732088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8503644PMC
September 2021

Inefficacy of Immunosuppressive Therapy for Severe Aplastic Anemia Progressing From Non-SAA: Improved Outcome After Allogeneic Hematopoietic Stem Cell Transplantation.

Front Oncol 2021 21;11:739561. Epub 2021 Sep 21.

National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.

Background And Aims: This study aimed at comparing the efficacy and safety of severe aplastic anemia (SAA) cases that had met the criteria for SAA at the time of diagnosis (group A) with SAA that had progressed from non-SAA (NSAA) (group B), both undergoing first-line immunosuppressive therapy (IST). Additionally, group B was compared with SAA that had progressed from NSAA and who had been treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT) (group C).

Methods: We retrospectively compared 608 consecutive patients in group A (n = 232), group B (n = 229) and group C (n = 147) between June 2002 and December 2019. Six months after treatment, the rate of overall response and the fraction of patients who had achieved normal blood values, treatment-related mortality (TRM), secondary clonal disease, 5-year overall survival (OS) and failure-free survival (FFS) were indirectly compared between group A and group B, group B and group C.

Results: Six months after treatment, the rate of overall response and the fraction of patients who had achieved normal blood values in group A was higher than in group B (65.24% . 40.54%, < 0.0001; 23.33% . 2.25%, < 0.0001); the same was true for group C (92.50% . 2.25%, < 0.0001). The rate of relapse in group B was higher than in group C ( < 0.0001), but there were no differences in TRM and secondary clonal disease ( > 0.05). There were no differences in estimated 5-year OS between groups A and B (83.8% ± 2.6% . 85.8% ± 2.6%, = 0.837), or between B and C (85.8% ± 2.6% . 77.9% ± 3.4%, = 0.051). The estimated 5-year FFS in groups A and C was higher than for group B (57.1% ± 3.3% . 39.7% ± 3.4%, < 0.001; 76.7% ± 3.5% vs. 39.7% ± 3.4%, < 0.0001).

Conclusion: These results indicate that IST is less effective in SAA progressing from non-SAA but allo-HSCT can improve outcomes.
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http://dx.doi.org/10.3389/fonc.2021.739561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490923PMC
September 2021

TNF-α increases the risk of bleeding in patients after CAR T-cell therapy: A bleeding model based on a real-world study of Chinese CAR T Working Party.

Hematol Oncol 2021 Oct 4. Epub 2021 Oct 4.

National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.

Chimeric antigen receptor (CAR) T-cell therapy has shown excellent clinical efficacy in patients with hematologic malignancies. However, severe bleeding after this treatment is a life-threatening complication for most patients. This study evaluated the risk factors associated with bleeding in CAR T treatment and developed a predictive model for this complication. Analysis performed in the First Affiliated Hospital of Suzhou University and external validation launched in Suzhou Hongci Hematology Hospital (Jiangsu, China). We conducted a real-world study incorporating data from 400 patients with hematologic malignancies treated with CAR T between 1 November 2015 and 1 September 2019. Also, 39 patients from another hospital were selected for external validation. Patients with severe bleeding (hazard ratio [HR] 13.04, 95% confidence interval 5.82-29.18; p < 0.001) had a higher risk of death after CAR T. Stage III and IV cytokine release syndrome (CRS) (odds ratio [OR] 6.07, 95% CI 2.35-16.76; p < 0.001) and higher tumor necrosis factor-α (TNF-α) levels (OR 4.00, 95% CI 1.53-11.35; p < 0.001) were independent factors of bleeding in patients after CAR-T treatment. The predictive model developed by Lasso regression, which selected factors such as CRS period, transfusion volume, platelet percentage, platelet count, thrombinogen time, interleukin 6, and TNF-α levels, and showed Nomogram, yielded excellent agreement (C-statistics = 0.905) with the calibration curve, which improved clinical benefit with respect to established bleeding scores such as outpatient bleeding risk index (MOBRI). External validation was performed using 39 patients from another hospital with an AUC of 0.700. Patients with severe bleeding after Car-T therapy had increased the risk of death. A cross-validated bleeding risk score based on CRS stages and TNF-α level show significant prognostic value in patients undergoing CAR-T treatment.
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http://dx.doi.org/10.1002/hon.2931DOI Listing
October 2021

A comparative study of porcine antihuman lymphocyte globulin versus antithymocyte globulin-fresenius in an allogeneic hematopoietic cell transplantation conditioning regimen for severe aplastic anemia.

Hematology 2021 Dec;26(1):741-750

National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, People's Republic of China.

Objectives: To compare the outcomes of antihuman T lymphocyte globulin (ATG-F) and porcine antihuman lymphocyte globulin (p-ALG) as part of a conditioning regimen in hematopoietic stem cell transplantation (HSCT) for severe aplastic anemia (SAA).

Methods: we performed a retrospective analysis, evaluating the outcome of patients with SAA who received ATG-F based conditioning ( = 26) with those receiving p-ALG conditioning ( = 34).

Results: The median time to neutrophil engraftment was 11 days (range, 8 - 38) and 11 days (range, 9 - 24) in the p-ALG and ATG-F groups (= 0.857); the median platelet engraftment time was 15 (range, 9 - 330) days and 13 (range, 10 - 56) days (= 0.155). There were no significant differences in grades II - IV acute graft-versus-host disease (aGVHD), grades III - IV aGVHD, chronic GVHD (cGVHD), and the moderate-severe cGVHD between the ATG-F and p-ALG groups (>0.05).

Discussion: Patients in the ATG-F group functioned significantly better on role-physical ( = 0.006), general health ( = 0.029), and physical component summary ( = 0.009). The estimated overall survival and failure free survival rates at 5 years were 88.5% ± 6.3% vs. 82.4% ± 6.5% ( = 0.515), 84.6% ± 7.1% vs. 79.4% ± 6.9%, respectively ( = 0.579). The infection rates were 61.53% and 47.05%, respectively ( = 0.265).

Conclusion: As part of the conditioning regimen, p-ALG achieved a similar efficacy as ATG-F without increasing the incidence of transplantation complications in SAA patients.
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http://dx.doi.org/10.1080/16078454.2021.1974201DOI Listing
December 2021

Recurrent mutations in multiple components of the SWI/SNF complex in myelodysplastic syndromes and acute myeloid leukaemia.

Br J Haematol 2022 Jan 18;196(2):441-444. Epub 2021 Sep 18.

Jiangsu Institute of Hematology, the First Affiliated Hospital of Soochow University, Suzhou, China.

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http://dx.doi.org/10.1111/bjh.17795DOI Listing
January 2022

Quadruple-hit pleomorphic mantle cell lymphoma with MYC, BCL2, BCL6, and CCND1 gene rearrangements.

Br J Haematol 2021 11 16;195(4):634-637. Epub 2021 Sep 16.

National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, P.R. China.

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http://dx.doi.org/10.1111/bjh.17729DOI Listing
November 2021

Epstein-Barr virus and cytomegalovirus reactivation after allogeneic hematopoietic cell transplantation in patients with non-Hodgkin lymphoma: the prevalence and impacts on outcomes : EBV and CMV reactivation post allo-HCT in NHL.

Ann Hematol 2021 Nov 4;100(11):2773-2785. Epub 2021 Sep 4.

National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Shizi Street 188, Suzhou, 215006, China.

Epstein-Barr virus (EBV) and cytomegalovirus (CMV) reactivations are common complications after allogeneic hematopoietic cell transplantation (allo-HCT), but data focusing on non-Hodgkin lymphoma (NHL) are limited. We retrospectively analyzed the prevalence of EBV and CMV reactivation post-allo-HCT and the impacts on transplant outcomes in 160 NHL patients. The 1-year incidences of EBV and CMV reactivation were 22.58% and 25.55%, respectively. Independent impactors for EBV reactivation were more than 6 lines of chemotherapy (P = 0.030), use of rituximab (P = 0.004), and neutrophil recovery within 30 days post-HCT (P = 0.022). For T-cell lymphoblastic lymphoma patients, the International Prognostic Index (IPI) (P = 0.015) and chronic GVHD (P = 0.001) increased the risk of CMV reactivation. CMV reactivation was independently related to a lower risk of relapse (P = 0.027) but higher transplant-related mortality (TRM) (P = 0.038). Although viral reactivation had no significant impact on overall survival (OS) in the whole cohort, it led to an inferior 2-year OS (67.6% versus 92.5%, P = 0.005) and TRM (20.1% versus 4.7%, P = 0.020) in recipients surviving for more than 180 days. We concluded that EBV and CMV reactivation post-allotransplant still deserved concern particularly in NHL patients with high-risk factors, since it is generally related to a deteriorated prognosis. Large-scale studies are warranted to validate our findings.
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http://dx.doi.org/10.1007/s00277-021-04642-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8510926PMC
November 2021

The Prognostic Value of Early Detection of Minimal Residual Disease as Defined by Flow Cytometry and Gene Mutation Clearance for Myelodysplastic Syndrome Patients After Myeloablative Allogeneic Hematopoietic Stem-Cell Transplantation.

Front Oncol 2021 5;11:700234. Epub 2021 Aug 5.

Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Suzhou, China.

High relapse incidence remains a major problem for myelodysplastic syndrome (MDS) patients who have received an allogeneic hematopoietic stem-cell transplantation (allo-HSCT). We retrospectively analyzed the correlations between clinical outcomes and minimal residual disease (MRD) by using mutations (MUT) and flow cytometry (FCM) analysis of 115 MDS patients with allo-HSCT. We divided 115 MDS patients into four groups based on molecular genetics and FCM MRD results at day 30 post-HSCT. There were significant differences in the 2-year progression-free survival (PFS) between the FCM MUT and FCM MUT groups (20% vs 79%, P < 0.001). In addition, by univariate analysis, we found that an IPSS-R score ≥4 pre-HSCT (HR, 5.061; P=0.007), DNMT3A mutations (HR, 2.291; P=0.052), TP53 mutations (HR, 3.946; P=0.011), and poor and very poor revised International Prognostic Scoring System (IPSS-R) cytogenetic risk (HR, 4.906; P < 0.001) were poor risk factors for PFS. In multivariate analysis, we found that an IPSS-R score ≥ 4 pre-HSCT (HR, 4.488; P=0.015), DNMT3A mutations (HR, 2.385; P=0.049), positive FCM MRD combined with persistence gene mutations at day 30 (HR, 5.198; P=0.013) were independent risk factors for disease progression. In conclusion, our data indicated that monitoring MRD by FCM combined with gene mutation clearance at day 30 could help in the prediction of disease progression for MDS patients after transplantation.
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http://dx.doi.org/10.3389/fonc.2021.700234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374104PMC
August 2021

First-Line Unrelated Double-Unit Umbilical Cord Blood Transplantation for Acquired Severe Aplastic Anemia.

Transplant Proc 2021 Sep 17;53(7):2390-2396. Epub 2021 Aug 17.

National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation of Soochow University, Suzhou, China. Electronic address:

We analyzed the outcomes of 14 patients with severe aplastic anemia (SAA) who received first-line double-unit cord blood transplantation (dUCBT). Patients' median age was 24.5 years (range, 10-44 years). The median numbers of infused nucleated and CD34 cells were 5.48 × 10/kg (range, 3.33-7.96 × 10/kg) and 2.30 × 10/kg (range, 0.86-3.97 × 10/kg), respectively. One patient died 5 days after transplantation. Three of the 13 patients acquired autologous myeloid recovery. Neutrophil engraftment was observed in 10 patients (76.29%), and the median time of neutrophil recovery was 19 days (range, 15-40 days). Platelet engraftment was observed in 7 cases (53.8%), and 3 patients experienced platelet graft failure. The median time of platelet recovery was 32 days (range, 22-80 days). The cumulative incidence of grade II-IV acute graft-vs-host disease (GVHD) was 38.5%. One patient demonstrated mild chronic GVHD. After a median follow-up of 61 months (range, 18-102 months), 6 patients were alive. The predicted 5-year overall survival and GVHD-free, failure-free survival rates were 42.9% ± 13.2% and 14.3% ± 9.4%, respectively. The first-line dUCBT for SAA is still primarily evaluated through multicenter prospective clinical trials by an optimal conditioning regimen, cell dose, and other graft and transplantation-related factors.
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http://dx.doi.org/10.1016/j.transproceed.2021.07.004DOI Listing
September 2021

The clinical outcomes and genomic landscapes of acute lymphoblastic leukemia patients with E2A-PBX1: A 10-year retrospective study.

Am J Hematol 2021 11 4;96(11):1461-1471. Epub 2021 Sep 4.

Jiangsu Institute of Hematology, National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Suzhou, China.

The clinical outcomes and genomic features of E2A-PBX1 (TCF3-PBX1)-positive B-cell acute lymphoblastic leukemia (B-ALL) patients remain unclear. A total of 137 patients carrying E2A-PBX1 among 3164 B-ALL patients between 2009 and 2019 were retrospectively analyzed. The 5-year overall survival (OS) and disease-free survival (DFS) rates of the whole cohort were 68.6% and 61.0%, respectively. Age [DFS, p = 0.037; cumulative incidence of relapse (CIR), p = 0.005] and the level of minimal residual disease (MRD) after induction chemotherapy (OS, p = 0.020; DFS, p = 0.002; CIR, p = 0.006) were independent risk factors. In adolescents/adults, allogeneic hematopoietic stem cell transplantation (allo-HSCT) at first complete remission (CR1) significantly improved the 5-year prognosis (OS, p < 0.001; DFS, p < 0.001; CIR, p < 0.001). Haploidentical HSCT decreased the CIR compared with human leukocyte antigen-matched HSCT in adolescents/adults (p = 0.017). Mutations in PBX1, PAX5, CTCF and SETD2, amplification of AKT3, and deletion of CDKN2A/B were common in the total cohort, while transcriptome differences were found in the cell cycle, nerve growth factor (NGF) signaling pathway and transcriptional regulation by TP53 between adolescents/adults and children. Patients with multiple subclones at diagnosis tended to have unfavorable 3-year prognoses (DFS, p = 0.010; CIR, p = 0.021). Leukemia clones with DNA repair gene mutations showed aggressive and treatment-refractory phenotypes in this subtype of ALL. Our study indicated that age, the level of MRD and DNA repair gene mutations were associated with E2A-PBX1-positive B-ALL outcomes. Allo-HSCT, especially haploidentical HSCT, could improve the prognosis of adolescent/adult patients.
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http://dx.doi.org/10.1002/ajh.26324DOI Listing
November 2021

Real-world assessment of the effectiveness of posaconazole for the prophylaxis and treatment of invasive fungal infections in hematological patients: A retrospective observational study.

Medicine (Baltimore) 2021 Jul;100(30):e26772

Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China.

Abstract: The aim of the study was to analyze the efficacy of posaconazole for the prophylaxis and treatment of invasive fungal diseases (IFDs) in patients with hematological malignancies.In this retrospective observational multi-center study, 762 patients from 25 Chinese hematological centers were enrolled. Inclusion criteria were patients with hematological malignancy or they had undergone hematopoietic stem cell transplantation and received at least 1 dose of posaconazole. The primary endpoints were the observation of breakthrough rates and the clinical efficacy of posaconazole prophylaxis. The secondary endpoint was the efficacy of posaconazole for the treatment of IFDs.Of the 762 enrolled patients, 456 (59.8%) were prescribed posaconazole prophylactically while 243 (31.9%) received posaconazole as an IFD treatment (12 proven, 61 probable, 109 possible, and 61 unclassified IFD cases) for ≥7 days. The overall IFD breakthrough rate (probable cases) for the ≥4 days prophylactic treatment (n = 445) group was 1.6% (95% Cl: 0.6%-3.2%), with breakthrough rates of 2.6% for acute myeloid leukemia/myelodysplastic syndrome patients undergoing chemotherapy and 2.2% for hematopoietic stem cell transplantation patients. For primary antifungal prophylaxis, the breakthrough rate was 1.9% and for secondary antifungal prophylaxis 0%. The overall effective IFD remission rate of patients treated for ≥7 days with posaconazole was 56.0% and the effective remission rate of proven/probable/possible IFD cases was 59.3%. The effective remission rate of posaconazole as salvage therapy was 50% (95% CI: 32.4%-67.6%) including 75% (CI: 19.4%-99.4%) for Aspergillus infections.The present retrospective study confirmed posaconazole as IFD prophylaxis and medication for hematological malignancy patients undergoing various treatments in China.
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http://dx.doi.org/10.1097/MD.0000000000026772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322488PMC
July 2021

Evaluation of diagnostic performance of metagenomic next-generation sequencing when applied in patients after allogeneic hematopoietic stem cell transplant.

Bone Marrow Transplant 2021 Nov 10;56(11):2860-2861. Epub 2021 Aug 10.

National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.

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http://dx.doi.org/10.1038/s41409-021-01423-6DOI Listing
November 2021

SPOP-mediated ubiquitination and degradation of PDK1 suppresses AKT kinase activity and oncogenic functions.

Mol Cancer 2021 08 5;20(1):100. Epub 2021 Aug 5.

Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510275, Guangdong, China.

Background: 3-phosphoinositide-dependent protein kinase-1 (PDK1) acts as a master kinase of protein kinase A, G, and C family (AGC) kinase to predominantly govern cell survival, proliferation, and metabolic homeostasis. Although the regulations to PDK1 downstream substrates such as protein kinase B (AKT) and ribosomal protein S6 kinase beta (S6K) have been well established, the upstream regulators of PDK1, especially its degrader, has not been defined yet.

Method: A clustered regularly interspaced short palindromic repeats (CRISPR)-based E3 ligase screening approach was employed to identify the E3 ubiquitin ligase for degrading PDK1. Western blotting, immunoprecipitation assays and immunofluorescence (IF) staining were performed to detect the interaction or location of PDK1 with speckle-type POZ protein (SPOP). Immunohistochemistry (IHC) staining was used to study the expression of PDK1 and SPOP in prostate cancer tissues. In vivo and in vitro ubiquitination assays were performed to measure the ubiquitination conjugation of PDK1 by SPOP. In vitro kinase assays and mass spectrometry approach were carried out to identify casein kinase 1 (CK1) and glycogen synthase kinase 3 (GSK3)-mediated PDK1 phosphorylation. The biological effects of PDK1 mutations and correlation with SPOP mutations were performed with colony formation, soft agar assays and in vivo xenograft mouse models.

Results: We identified that PDK1 underwent SPOP-mediated ubiquitination and subsequent proteasome-dependent degradation. Specifically, SPOP directly bound PDK1 by the consensus degron in a CK1/GSK3β-mediated phosphorylation dependent manner. Pathologically, prostate cancer patients associated mutations of SPOP impaired PDK1 degradation and thus activated the AKT kinase, resulting in tumor malignancies. Meanwhile, mutations that occurred around or within the PDK1 degron, by either blocking SPOP to bind the degron or inhibiting CK1 or GSK3β-mediated PDK1 phosphorylation, could markedly evade SPOP-mediated PDK1 degradation, and played potently oncogenic roles via activating the AKT kinase.

Conclusions: Our results not only reveal a physiological regulation of PDK1 by E3 ligase SPOP, but also highlight the oncogenic roles of loss-of-function mutations of SPOP or gain-of-function mutations of PDK1 in tumorigenesis through activating the AKT kinase.
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http://dx.doi.org/10.1186/s12943-021-01397-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8340461PMC
August 2021
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