Publications by authors named "Jie Jin"

773 Publications

Daratumumab, Bortezomib, and Dexamethasone Versus Bortezomib and Dexamethasone in Chinese Patients with Relapsed or Refractory Multiple Myeloma: Phase 3 LEPUS (MMY3009) Study.

Clin Lymphoma Myeloma Leuk 2021 Apr 24. Epub 2021 Apr 24.

Peking University People's Hospital, National Clinical Research Center for Hematologic Disease, Beijing, China; Collaborative Innovation Center of Hematology, Soochow, China. Electronic address:

Background: Daratumumab plus bortezomib/dexamethasone (D-Vd) significantly improved outcomes versus Vd in patients with relapsed or refractory multiple myeloma (RRMM) in the phase 3 CASTOR study. We report the results of a prespecified interim analysis of the phase 3 LEPUS study of D-Vd versus Vd in Chinese patients with RRMM.

Patients And Methods: Chinese patients with ≥ 1 prior line of therapy were randomized 2:1 to receive 8 cycles (21 days/cycle) of bortezomib (1.3 mg/m subcutaneously) and dexamethasone (20 mg orally/intravenously) ± daratumumab (16 mg/kg intravenously). The primary endpoint was progression-free survival (PFS).

Results: A total of 211 patients were randomized (D-Vd, 141; Vd, 70). After an 8.2-month median follow-up, D-Vd significantly prolonged PFS versus Vd (median, not reached vs. 6.3 months; hazard ratio, 0.28; 95% confidence interval, 0.17-0.47; P < .00001) and significantly improved the rates of overall response (83% vs. 65%; P = .00527), ≥ very good partial response (65% vs. 33%; P = .00002), ≥ complete response (33% vs. 11%; P = .00079), and minimal residual disease negativity (10 sensitivity; 22% vs. 3%; P = .0002). The PFS benefit of D-Vd versus Vd was maintained across prespecified subgroups, including patients with prior bortezomib treatment and with high-risk cytogenetics. Thrombocytopenia (D-Vd, 51%; Vd, 37%), lymphopenia (44%; 29%), and lung infection (30%; 22%) were the 3 most common grade 3/4 treatment-emergent adverse events. Although patients in both treatment groups experienced higher rates of grade 3/4 lymphopenia and infections versus patients in CASTOR, the safety profile was generally consistent with that of CASTOR.

Conclusion: These data support the use of D-Vd in Chinese patients with RRMM.
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http://dx.doi.org/10.1016/j.clml.2021.04.012DOI Listing
April 2021

Adolescents experienced more treatment failure than children with chronic myeloid leukemia receiving imatinib as frontline therapy: a retrospective multicenter study.

Ann Hematol 2021 Jun 5. Epub 2021 Jun 5.

Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China.

To explore the differences in the clinical features, treatment responses, and outcomes among children, adolescents, and adults with chronic myeloid leukemia in the chronic phase (CML-CP) receiving imatinib as first-line therapy. Data from children (0-8 years for girls and 0-10 years for boys), adolescents (9-19 years for girls and 11-19 years for boys), and adults (age ≥ 20 years) with newly diagnosed CML-CP receiving imatinib as first-line therapy between 2006 and 2019 were retrospectively reviewed. In total, 135 children (cohort 1), 189 adolescents (cohort 2), and 658 adults (cohort 3: age 20-39 years, n = 305; cohort 4: age 40-59 years, n = 270; and cohort 5: age 60-83 years, n = 83) were included in this study. When compared with children, adolescents showed a significantly higher white blood cell count (P = 0.033) and basophil percentage in peripheral blood (P = 0.002) and a significantly higher prevalence of splenomegaly (P = 0.004). Both children and adolescents presented with more aggressive clinical features than adults. During median follow-ups of 28 months (range, 3-161 months) in children, 33 months (range, 3-152 months) in adolescents, and 48 months (range, 3-157 months) in adults, multivariate analysis showed that children and adolescents had higher probabilities of achieving complete cytogenetic response, major molecular response, and molecular response. Notably, compared with not only adults (cohort 3 vs. cohort 1: HR = 2.03 [1.03, 3.98], P = 0.040; cohort 4 vs. cohort 1: HR = 2.15 [1.07, 4.33], P = 0.033; cohort 5 vs. cohort 1: HR = 4.22 [1.94, 9.15], P < 0.001) but also adolescents (cohort 2 vs. cohort 1: HR = 2.36 [1.18, 4.72], P = 0.015), children had significantly longer failure-free survival. Age was not associated with progression-free survival or overall survival. Although they exhibited more aggressive clinical features at diagnosis, both children and adolescents achieved superior treatment responses than adults. Adolescents showed even more adverse features and a poor FFS than children.
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http://dx.doi.org/10.1007/s00277-021-04544-6DOI Listing
June 2021

Anchoring Al- and/or Mg-oxides to magnetic biochars for Co-uptake of arsenate and fluoride from water.

J Environ Manage 2021 May 31;293:112898. Epub 2021 May 31.

Collaborative Innovation Center of Atmospheric Environment and Equipment Technology, Jiangsu Key Laboratory of Atmospheric Environment Monitoring and Pollution Control, School of Environmental Science and Engineering, Nanjing University of Information Science and Technology, 219 Ningliu Road, Nanjing, 210044, China; NUIST-UoR International Research Institute, Nanjing University of Information Science and Technology, 219 Ningliu Road, Nanjing, 210044, China. Electronic address:

The co-occurrence of arsenic and fluoride in the water environment has led to many health concerns for living beings. Simultaneous removal of such ions is crucial to the safety of water resources, and biochar has been extensively engaged to address this issue. Here four magnetic biochars (mBCs) including pristine magnetic biochar and three aluminum (Al) and/or magnesium (Mg) oxides-anchored magnetic biochar (i.e., Al-mBC, Mg-mBC, and MgAl-mBC) were prepared via a facile pyrolysis method and then comprehensively evaluated as adsorbents for enhanced co-uptake of arsenate (As) and fluoride (F) from synthetic water. The mBC shows a high specific surface area of 205 m g, which dropped to 116, 80, and 114 m g upon the anchoring of Al, Mg, and Mg + Al, respectively. Our results suggest that the adsorption of either As or F is highly pH-dependent, and pH 4-6 is the optimal range for maximum adsorption. The adsorption isotherm data indicate that the MgAl-mBC adsorbent outranks all other mBCs for co-uptake of both As and F. The adsorption capacity maxima of MgAl-mBC are 34.45, and 21.59 mg g for As and F, respectively (pH = 5, T = 10 °C), also highly outstripping other biochars reported in the literature. The magnetic feature of these mBCs enables us to fast reclaim and regenerate the exhausted adsorbents by an external magnet and dilute NaOH. The Al- and Mg-anchored mBCs are expected to be used as highly efficient adsorbents for environmental remediation of waters contaminated by both As and F.
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http://dx.doi.org/10.1016/j.jenvman.2021.112898DOI Listing
May 2021

Increases the Tolerance of to Low-P Stress by Modulating Amino Acids Metabolism and Phosphorus Utilization Efficiency.

J Fungi (Basel) 2021 May 17;7(5). Epub 2021 May 17.

State Key Laboratory of Grassland Agro-Ecosystems, Center for Grassland Microbiome, Key Laboratory of Grassland Livestock Industry Innovation, Ministry of Agriculture and Rural Affairs, Engineering Research Center of Grassland Industry, Ministry of Education, College of Pastoral Agriculture Science and Technology, Lanzhou University, Lanzhou 730000, China.

In the long-term evolutionary process, and seed-borne endophytic fungi, , formed a mutually beneficial symbiosis relationship, and has an important biological role in improving the tolerance of host grasses to abiotic stress. In this work, we first assessed the effects of on dry weight, the content of C, N, P and metal ions, and metabolic pathway of amino acids, and phosphorus utilization efficiency (PUE) of at low P stress. Our results showed that the dry weights, the content of alanine, arginine, aspartic acid, glycine, glutamine, glutamic acid, L-asparagine, lysine, phenylalanine, proline, serine, threonine, and tryptophan were higher in leaves of -infected (E+) than -uninfected (E-) at low P stress. Further, increased C content of roots compared to the root of E- plant at 0.01 mM P and 0.5 mM P; increased K content of leaves compared to the leaf of E- plant at 0.01 mM P and 0.5 mM P. reduced Ca content of roots compared to the root of E- plant at 0.01 mM P and 0.5 mM P; reduced the content of Mg and Fe in leaves compared to the leaf of E- plant at 0.01 mM P and 0.5 mM P. In addition, at low P stress, most probably influenced aspartate and glutamate metabolism; valine, leucine, and isoleucine biosynthesis in leaves; and arginine and proline metabolism; alanine, aspartate, and glutamate metabolism in roots. also affected the content of organic acid and stress-related metabolites at low P stress. In conclusion, improves growth at low P stress by regulating the metabolic pathway of amino acids, amino acids content, organic acid content, and increasing PUE.
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http://dx.doi.org/10.3390/jof7050390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156409PMC
May 2021

A Novel Fenestrating Device, "Quick Fenestrater," for Reconstructing Supra-aortic Arteries In Situ during Thoracic Endovascular Aortic Repair.

Can J Cardiol 2021 May 11. Epub 2021 May 11.

Department of Vascular and Endovascular Surgery, Changzheng Hospital, Naval Medical University, Shanghai, 200001, China. Electronic address:

Background: In situ fenestration (ISF) is an effective approach for reconstructing supra-aortic branches during thoracic endovascular aortic repair (TEVAR). A dedicated device is needed for ISF.

Methods: The "Quick Fenestrater" (QF) underwent in vitro, animal-based, and initial clinical testing. In vitro, the polytetrafluoroethylene and Dacron aortic endografts were fenestrated using the QF, and the structure of the graft, fenestration hole, and shed particulate material were evaluated. Eight white swine had QF-aided ISF combined with TEVAR and bridge stent implantation. The outcomes were assessed using intraoperative angiography and biopsy. Finally, 13 patients were treated with QF-assisted ISF, combined with TEVAR, and the success rate, technical details, and intra- and post-operative complications were recorded.

Results: The endograft structure was not damaged during in vitro testing. The fenestration hole was clean, and no particulate material was detected. In animal studies, all animals survived, the supra-aortic arteries were patent, and the endografts and bridge stents had normal morphology. In clinical studies, the technical success rate was 100%, and no fenestration-related neurological complications or death occurred. One patient had a local access-related hematoma perioperatively and recovered after conservative treatment. Three patients had type III endoleaks, which resolved with no additional treatment. During a mean follow-up of 22.1±6 months, no thoracic complications were identified, and the bridge stents were patent with no endoleaks. No adverse cerebrovascular events, cardiovascular events, or death occurred.

Conclusions: QF-assisted ISF is a safe and effective method for the reconstruction of supra-aortic branches during TEVAR. Intermediate-term follow-up results validate the application of the novel fenestration device.
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http://dx.doi.org/10.1016/j.cjca.2021.04.024DOI Listing
May 2021

Bendamustine treatment of Chinese patients with relapsed indolent non-Hodgkin lymphoma: a multicenter, open-label, single-arm, phase 3 study.

Chin Med J (Engl) 2021 May 6;134(11):1299-1309. Epub 2021 May 6.

Department of Drug Metabolism and Pharmacokinetics, Teva Branded Pharmaceutical Products R&D Inc., West Chester, PA 19380, USA.

Background: Bendamustine was approved in China on May 26th, 2019 by the National Medical Product Administration for the treatment of indolent B-cell non-Hodgkin lymphoma (NHL). The current study was the registration trial and the first reported evaluation of the efficacy, safety, and pharmacokinetics of bendamustine in Chinese adult patients with indolent B-cell NHL following relapse after chemotherapy and rituximab treatment.

Methods: This was a prospective, multicenter, open-label, single-arm, phase 3 study (NCT01596621; C18083/3076) with a 2-year follow-up period. Eligible patients received bendamustine hydrochloride 120 mg/m2 infused intravenously on days 1 and 2 of each 21-day treatment cycle for at least six planned cycles (and up to eight cycles). The primary endpoint was the overall response rate (ORR); and secondary endpoints were duration of response (DoR), progression-free survival (PFS), safety, and pharmacokinetics. Patients were classified according to their best overall response after initiation of therapy. Proportions of patients in each response category (complete response [CR], partial response [PR], stable disease, or progressive disease) were summarized along with a two-sided binomial exact 95% confidence intervals (CIs) for the ORR.

Results: A total of 102 patients were enrolled from 20 centers between August 6th, 2012, and June 18th, 2015. At the time of the primary analysis, the ORR was 73% (95% CI: 63%-81%) per Independent Review Committee (IRC) including 19% CR and 54% PR. With the follow-up period, the median DoR was 16.2 months by IRC and 13.4 months by investigator assessment; the median PFS was 18.6 months and 15.3 months, respectively. The most common non-hematologic adverse events (AEs) were gastrointestinal toxicity, pyrexia, and rash. Grade 3/4 neutropenia was reported in 76% of patients. Serious AEs were reported in 29 patients and five patients died during the study. Pharmacokinetic analysis indicated that the characteristics of bendamustine and its metabolites M3 and M4 were generally consistent with those reported for other ethnicities.

Conclusion: Bendamustine is an active and effective therapy in Chinese patients with relapsed, indolent B-cell NHL, with a comparable risk/benefit relationship to that reported in North American patients.

Clinical Trial Registration: ClinicalTrials.gov, No. NCT01596621; https://clinicaltrials.gov/ct2/show/NCT01596621.
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http://dx.doi.org/10.1097/CM9.0000000000001463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183773PMC
May 2021

Current views on the genetic landscape and management of variant acute promyelocytic leukemia.

Biomark Res 2021 May 6;9(1):33. Epub 2021 May 6.

Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, #79 Qingchun Rd, Zhejiang, 310003, Hangzhou, China.

Acute promyelocytic leukemia (APL) is characterized by the accumulation of promyelocytes in bone marrow. More than 95% of patients with this disease belong to typical APL, which express PML-RARA and are sensitive to differentiation induction therapy containing all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), and they exhibit an excellent clinical outcome. Compared to typical APL, variant APL showed quite different aspects, and how to recognize, diagnose, and treat variant APL remained still challenged at present. Herein, we drew the genetic landscape of variant APL according to recent progresses, then discussed how they contributed to generate APL, and further shared our clinical experiences about variant APL treatment. In practice, when APL phenotype was exhibited but PML-RARA and t(15;17) were negative, variant APL needed to be considered, and fusion gene screen as well as RNA-sequencing should be displayed for making the diagnosis as soon as possible. Strikingly, we found that besides of RARA rearrangements, RARB or RARG rearrangements also generated the phenotype of APL. In addition, some MLL rearrangements, NPM1 rearrangements or others could also drove variant APL in absence of RARA/RARB/RARG rearrangements. These results indicated that one great heterogeneity existed in the genetics of variant APL. Among them, only NPM1-RARA, NUMA-RARA, FIP1L1-RARA, IRF2BP2-RARA, and TFG-RARA have been demonstrated to be sensitive to ATRA, so combined chemotherapy rather than differentiation induction therapy was the standard care for variant APL and these patients would benefit from the quick switch between them. If ATRA-sensitive RARA rearrangement was identified, ATRA could be added back for re-induction of differentiation. Through this review, we hoped to provide one integrated view on the genetic landscape of variant APL and helped to remove the barriers for managing this type of disease.
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http://dx.doi.org/10.1186/s40364-021-00284-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101136PMC
May 2021

Coagulation profile in newly diagnosed T-cell acute lymphoblastic leukemia.

Thromb Res 2021 Apr 19;203:69-71. Epub 2021 Apr 19.

Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Province Key Laboratory of Hematology Oncology Diagnosis and Treatment, Hangzhou, Zhejiang, China. Electronic address:

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http://dx.doi.org/10.1016/j.thromres.2021.04.013DOI Listing
April 2021

Not BCL2 mutation but dominant mutation conversation contributed to acquired venetoclax resistance in acute myeloid leukemia.

Biomark Res 2021 May 1;9(1):30. Epub 2021 May 1.

Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, #79 Qingchun Rd, Hangzhou, 310003, Zhejiang, China.

Venetoclax (VEN) plus azacitidine has become the first-line therapy for elderly patients with acute myeloid leukemia (AML), and has a complete remission (CR) plus CR with incomplete recovery of hemogram rate of ≥70%. However, the 3-year survival rate of these patients is < 40% due to relapse caused by acquired VEN resistance, and this remains the greatest obstacle for the maintenance of long-term remission in VEN-sensitive patients. The underlying mechanism of acquired VEN resistance in AML remains largely unknown. Therefore, in the current study, nine AML patients with acquired VEN resistance were retrospectively analyzed. Our results showed that the known VEN resistance-associated BCL2 mutation was not present in our cohort, indicating that, in contrast to chronic lymphocytic leukemia, this BCL2 mutation is dispensable for acquired VEN resistance in AML. Instead, we found that reconstructed existing mutations, especially dominant mutation conversion (e.g., expanded FLT3-ITD), rather than newly emerged mutations (e.g., TP53 mutation), mainly contributed to VEN resistance in AML. According to our results, the combination of precise mutational monitoring and advanced interventions with targeted therapy or chemotherapy are potential strategies to prevent and even overcome acquired VEN resistance in AML.
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http://dx.doi.org/10.1186/s40364-021-00288-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088697PMC
May 2021

Inhibition of CPT1a as a prognostic marker can synergistically enhance the antileukemic activity of ABT199.

J Transl Med 2021 04 29;19(1):181. Epub 2021 Apr 29.

Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, No. 79 Qingchun Road, Hangzhou, Zhejiang, People's Republic of China.

Background: Fatty acid oxidation (FAO) provides an important source of energy to promote the growth of leukemia cells. Carnitine palmitoyltransferase 1a(CPT1a), a rate-limiting enzyme of the essential step of FAO, can facilitate cancer metabolic adaptation. Previous reports demonstrated that CPT1a acts as a potential molecular target in solid tumors and hematologic disease. However, no systematic study was conducted to explore the prognostic value of CPT1a expression and possible treatment strategies with CPT1a inhibitor on acute myeloid leukemia (AML).

Methods: The expression of CPT1a in 325 cytogenetically normal AML (CN-AML) patients was evaluated using RT-PCR. The combination effects of ST1326 and ABT199 were studied in AML cells and primary patients. MTS was used to measure the cell proliferation rate. Annexin V/propidium iodide staining and flow cytometry analysis was used to measure the apoptosis rate. Western blot was used to measure the expression of Mcl-1. RNAseq and GC-TOFMS were used for genomic and metabolic analysis.

Results: In this study, we found AML patients with high CPT1a expression (n = 245) had a relatively short overall survival (P = 0.01) compared to patients in low expression group (n = 80). In parallel, downregulation of CPT1a inhibits proliferation of AML cells. We also conducted genomic and metabolic interactive analysis in AML patients, and found several essential genes and pathways related to aberrant expression of CPT1a. Moreover, we found downregulation of CPT1a sentitized BCL-2 inhibitor ABT199 and CPT1a-selective inhibitor ST1326 combined with ABT199 had a strong synergistic effect to induce apoptosis in AML cells and primary patient blasts for the first time. The underlying synergistic mechanism might be that ST1326 inhibits pGSK3β and pERK expression, leading to downregulation of Mcl-1.

Conclusion: Our study indicates that overexpression of CPT1a predicts poor clinical outcome in AML. CPT1a-selective inhibitor ST1326 combined with Bcl-2 inhibitor ABT199 showed strong synergistic inhibitory effects on AML.
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http://dx.doi.org/10.1186/s12967-021-02848-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082622PMC
April 2021

A Novel Vascular-Friendly Thoracic Stent Graft for Endovascular Repair of Acute Complicated Type B Aortic Dissection.

Ann Thorac Cardiovasc Surg 2021 Apr 14. Epub 2021 Apr 14.

Department of Vascular and Endovascular Surgery, Changzheng Hospital, Naval Medical University, Shanghai, China.

Purpose: To evaluate the safety and efficacy of a novel vascular-friendly thoracic stent graft for patients with acute complicated type B aortic dissection (ac-TBAD).

Methods: A multicenter retrospective study was undertaken in which we prospectively collected data in consecutive ac-TBAD patients treated by thoracic endovascular aortic repair (TEVAR) with the Ankura Thoracic Stent. Complications, true lumen rate (TLR), and mortality were recorded. Follow-up computed tomography angiography (CTA) was performed at 1, 6, and 12 months postoperatively and yearly thereafter.

Results: Altogether, 63 patients with ac-TBAD in four medical centers were included. No deaths or serious complications occurred during the perioperative period. The mean follow-up time was 30.1 ± 18.9 months. All-cause mortality rate was 3.1% (n = 2). TEVAR-related mortality rate was 1.6% (n = 1) because of retrograde type A dissection (RTAD) at 6 months. The other death was caused by acute myocardial infarction (AMI) during the third postoperative month. A distal endoleak detected at 3 months in one patient (1.6%) was treated by reintervention. The use of this novel vascular-friendly thoracic stent graft in ac-TBAD postoperative patients significantly improved their TLR.

Conclusion: The novel vascular-friendly thoracic stent graft showed satisfactory results, with favorable stability of the aortic diameter during follow-up.
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http://dx.doi.org/10.5761/atcs.oa.20-00383DOI Listing
April 2021

Copanlisib plus rituximab versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (CHRONOS-3): a double-blind, randomised, placebo-controlled, phase 3 trial.

Lancet Oncol 2021 05 10;22(5):678-689. Epub 2021 Apr 10.

IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", and Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy.

Background: Copanlisib, an intravenous pan-class I PI3K inhibitor, showed efficacy and safety as monotherapy in patients with relapsed or refractory indolent non-Hodgkin lymphoma who had received at least two therapies. The CHRONOS-3 study aimed to assess the efficacy and safety of copanlisib plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma.

Methods: CHRONOS-3 was a multicentre, double-blind, randomised, placebo-controlled, phase 3 study in 186 academic medical centres across Asia, Australia, Europe, New Zealand, North America, Russia, South Africa, and South America. Patients aged 18 years and older with an Eastern Cooperative Oncology Group performance status of no more than 2 and histologically confirmed CD20-positive indolent B-cell lymphoma relapsed after the last anti-CD20 monoclonal antibody-containing therapy and progression-free and treatment-free for at least 12 months, or at least 6 months for patients unwilling or unfit to receive chemotherapy, were randomly assigned (2:1) with an interactive voice-web response system via block randomisation (block size of six) to copanlisib (60 mg given as a 1-h intravenous infusion on an intermittent schedule on days 1, 8, and 15 [28-day cycle]) plus rituximab (375 mg/m given intravenously weekly on days 1, 8, 15, and 22 during cycle 1 and day 1 of cycles 3, 5, 7, and 9) or placebo plus rituximab, stratified on the basis of histology, progression-free and treatment-free interval, presence of bulky disease, and previous treatment with PI3K inhibitors. The primary outcome was progression-free survival in the full analysis set (all randomised patients) by masked central review. Safety was assessed in all patients who received at least one dose of any study drug. This study is registered with ClinicalTrials.gov, NCT02367040 and is ongoing.

Findings: Between Aug 3, 2015, and Dec 17, 2019, 652 patients were screened for eligibility. 307 of 458 patients were randomly assigned to copanlisib plus rituximab and 151 patients were randomly assigned to placebo plus rituximab. With a median follow-up of 19·2 months (IQR 7·4-28·8) and 205 total events, copanlisib plus rituximab showed a statistically and clinically significant improvement in progression-free survival versus placebo plus rituximab; median progression-free survival 21·5 months (95% CI 17·8-33·0) versus 13·8 months (10·2-17·5; hazard ratio 0·52 [95% CI 0·39-0·69]; p<0·0001). The most common grade 3-4 adverse events were hyperglycaemia (173 [56%] of 307 patients in the copanlisib plus rituximab group vs 12 [8%] of 146 in the placebo plus rituximab group) and hypertension (122 [40%] vs 13 [9%]). Serious treatment-emergent adverse events were reported in 145 (47%) of 307 patients receiving copanlisib plus rituximab and 27 (18%) of 146 patients receiving placebo plus rituximab. One (<1%) drug-related death (pneumonitis) occurred in the copanlisib plus rituximab group and none occurred in the placebo plus rituximab group.

Interpretation: Copanlisib plus rituximab improved progression-free survival in patients with relapsed indolent non-Hodgkin lymphoma compared with placebo plus rituximab. To our knowledge, copanlisib is the first PI3K inhibitor to be safely combined with rituximab and the first to show broad and superior efficacy in combination with rituximab in patients with relapsed indolent non-Hodgkin lymphoma.

Funding: Bayer.
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http://dx.doi.org/10.1016/S1470-2045(21)00145-5DOI Listing
May 2021

Hepatic sinusoidal obstruction syndrome caused by the ingestion of in a patient with alcoholic cirrhosis: a case report.

J Int Med Res 2021 Apr;49(4):300060520980649

Department of Infectious Diseases, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.

Hepatic sinusoidal obstruction syndrome (HSOS) is a rare hepatic vascular disorder characterized by intrahepatic congestion, liver injury, and post-sinusoidal portal hypertension, and it is frequently associated with hematopoietic stem cell transplantation. In this study, we observed a case of HSOS associated with the ingestion of , a pyrrolizidine alkaloid (PA)-containing Chinese herb, in a patient with alcoholic cirrhosis. The patient was a 43-year-old man with chief complaints of physical asthenia and a loss of appetite for more than a month. The diagnosis of HSOS combined with alcoholic cirrhosis was confirmed via the histopathological examination of liver tissues. With proper supportive and symptomatic care and anticoagulation therapy using low-molecular-weight heparin, the patient's condition was stabilized. Because of its nonspecific symptoms in the early stage and a lack of information about PA consumption, PA-induced HSOS (PA-HSOS) has been long neglected, especially in patients with underlying liver diseases. Early identification and intervention are critical for optimizing outcomes. Further efforts are needed to supervise the use of PA-containing herbal medicines and identify accurate biomarkers for PA-HSOS.
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http://dx.doi.org/10.1177/0300060520980649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047090PMC
April 2021

Clinical risk score for predicting invasive fungal disease after allogeneic hematopoietic stem cell transplantation: Analysis of the China Assessment of Antifungal Therapy in Hematological Diseases (CAESAR) study.

Transpl Infect Dis 2021 Apr 7:e13611. Epub 2021 Apr 7.

Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University Institute of Hematology, Peking University, People's Hospital, Beijing, People's Republic of China.

Background And Objective: Invasive fungal disease (IFD) is associated with a high mortality for patients with hematological malignancies undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study aimed not only to develop a proven/probable IFD risk-scoring model but to identify high-risk populations that would benefit from anti-fungal prophylaxis.

Methods: Data from the China Assessment of Antifungal Therapy in Hematological Diseases (CAESAR) study were retrieved, and all patients (n = 1053) undergoing allo-HSCT were randomly divided into the training set (n = 685) for model development and the validation set (n = 368) for model verification. A weighted risk score for proven or probable IFD was established through multivariate logistic regression analysis.

Results: The study population had a mean age of 28.95 years and the majority underwent myeloablative transplantation in complete remission 1 (53.4%). Five risk factors of IFD were identified, namely neutropenia lasting longer than 14 days, corticosteroid use, diabetes, haploidentical donor, and unrelated donor. Based on the risk score for IFD, the patients were categorized into three groups: low risk (score 0-4, 1.5%-4.0%), intermediate risk (score 5-8, 9.8%), and high risk (score>8, 24.7%-14.0%). Anti-fungal prophylaxis may provide benefits for patients with intermediate (8.5% vs. 18.5%, P = .0085) or high risk (19.4% vs. 30.8%, P = .4651) but not low risk (2.1% vs. 3.8%, P = .6136) of IFD.

Conclusion: A practical weighted risk score for IFD in patients receiving allo-HSCT was established, which can aid decision-making regarding the administration of anti-fungal prophylaxis.
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http://dx.doi.org/10.1111/tid.13611DOI Listing
April 2021

Global, regional, and national burdens of leukemia from 1990 to 2017: a systematic analysis of the global burden of disease 2017 study.

Aging (Albany NY) 2021 04 4;13(7):10468-10489. Epub 2021 Apr 4.

Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

We described the spatial and temporal trends of the annual leukemia incidence, prevalence, mortality, and disability-adjusted life years (DALYs) from 1990 to 2017. Leukemia case numbers and age-standardized rates (ASRs) were extracted from the Global Burden of Disease (GBD) study 2017. The estimated annual percentage change (EAPC) in the ASR was calculated using a generalized linear model with a Gaussian distribution. The risk factors for death and DALYs due to leukemia were estimated within the comparative risk assessment framework of the GBD study. Globally, the prevalence, age-standardized prevalence rate (ASPR), and EAPC in leukemia cases in 2017 were 2.43 (95% uncertainty interval (UI) 2.19 to 2.59) million, 32.26 (95% UI 29.02 to 34.61), and 0.22% (95% CI 0.13 to 0.31, P<0.01), respectively, during 1990-2017. The trends of the age-standardized incidence, deaths, and DALY rate all significantly decreased globally. The burden of leukemia was higher in males than in female. An increasing leukemia burden was found in high-middle-sociodemographic index (SDI) countries and territories. The burden of leukemia tended to be lower in high-SDI regions than that in lower SDI regions. The rapid increases in the prevalent cases and prevalence rate of leukemia is urgent to be solved in the future.
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http://dx.doi.org/10.18632/aging.202809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064161PMC
April 2021

Positive Effect of Andrographolide Induced Autophagy on Random-Pattern Skin Flaps Survival.

Front Pharmacol 2021 16;12:653035. Epub 2021 Mar 16.

Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.

Random-pattern skin flap replantation is generally used in the reconstruction of surgical tissues and covering a series of skin flap defects. However, ischemia often occurs at the flap distal parts, which lead to flap necrosis. Previous studies have shown that andrographolide (Andro) protects against ischemic cardiovascular diseases, but little is known about the effect of Andro on flap viability. Thus, our study aimed to building a model of random-pattern skin flap to understand the mechanism of Andro-induced effects on flap survival. In this study, fifty-four mice were randomly categorized into the control, Andro group, and the Andro+3-methyladenine group. The skin flap samples were obtained on postoperative day 7. Subsequently, the tissue samples were underwent a series of evaluations such as changes in the appearance of flap tissue, the intensity of blood flow, and neovascularization density of skin flap. In our study, the results revealed that Andro enhanced the viability of random skin flaps by enhancing angiogenesis, inhibiting apoptosis, and reducing oxidative stress. Furthermore, our results have also demonstrated that the administration of Andro caused an elevation in the autophagy, and these remarkable impact of Andro were reversed by 3-methyladenine (3-MA), the most common autophagy inhibitor. Together, our data proves novel evidence that Andro is a potent modulator of autophagy capable of significantly increasing random-pattern skin flap survival.
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http://dx.doi.org/10.3389/fphar.2021.653035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008123PMC
March 2021

Minimal residual disease level determined by flow cytometry provides reliable risk stratification in adults with T-cell acute lymphoblastic leukaemia.

Br J Haematol 2021 Mar 25. Epub 2021 Mar 25.

Department of Hematology, School of Medicine, the First Affiliated Hospital, Zhejiang University, Hangzhou, China.

Minimal residual disease (MRD) is an important independent prognostic factor for relapse and survival in acute lymphoblastic leukaemia (ALL). Compared with adult B-cell ALL, reports of adult T-cell ALL (T-ALL) MRD have been scarce and mostly based on molecular methods. We evaluated the prognostic value of multiparameter flow cytometry (FCM)-based MRD at the end of induction (EOI-MRD). The present retrospective study included 94 adult patients with T-ALL. MRD was detected by six- to eight-colour FCM. Patients who were EOI-MRD positive had a higher cumulative incidence of relapse (CIR) (87·6% vs. 38·8%, P = 0·0020), and a lower relapse-free survival (RFS) (5·4% vs. 61·0%, P = 0·0005) and overall survival (OS) (32·7% vs. 69·7%, P < 0·0001) than those who were EOI-MRD negative. Moreover, for patients who received allogeneic haematopoietic stem cell transplantation (allo-HSCT) at their first remission, EOI-MRD positivity was predictive of post-transplant relapse (2-year CIR: 68·2% vs. 4·0%, P = 0·0003). Multivariate analysis showed that EOI-MRD was an independent prognostic factor for CIR [hazard ratio (HR) 2·139, P = 0·046], RFS (HR 2·125, P = 0·048) and OS (HR 2·987, P = 0·017). In conclusion, EOI-MRD based on FCM was an independent prognostic factor for relapse and survival in adult T-ALL. For patients who underwent HSCT, EOI-MRD could be used to identify patients with a high risk of relapse after allo-HSCT.
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http://dx.doi.org/10.1111/bjh.17424DOI Listing
March 2021

A study on eccentric occluder via ultra minimal incision of doubly committed subarterial ventricular septal defects.

J Card Surg 2021 Jun 11;36(6):2055-2060. Epub 2021 Mar 11.

Department of Cardiac Surgery and Heart Center, The Childern's Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou, China.

Object: To compare the clinical data of sternotomy and left intercostals incision, combined with the literature, to provide the best surgical incision for committed subarterial ventricular septal defect (DCS-VSD).

Methods: From July 2016 to July 2020, a total of 117 cases of occlusion surgeries for DCSVSD, which guided by transoesophagel echocardiography (TEE) were completed, including 34 cases with sternotomy incision and 83 cases with left intercostal incision. Statistics and analysis of the operation and follow-up.

Results: A total of 115 cases successfully occluded, the successful rate was 98.29%, and 1 case failed in each group. Pericardial effusion occurred in five children after the drainage device was removed, and the pericardial effusion disappeared after diuretic treatment. There was no statistical difference between the two groups in operation time, occlusion time, thoracotomy time and postoperative hospital stay. All the children recovered and were discharged from the hospital, and were followed-up for 2-30 months after operation.

Conclusion: TEE-guided intercostal DCS-VSD occlusion is safe and effective. There is no statistical difference between two approach with the operation time, chest opening and closing time, occluder placing time, and postoperative hospital staying. At the same time, the surgical incision by intercostal incisionis smaller and the operation invasion is less, it is a surgical approach which worth to develop.
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http://dx.doi.org/10.1111/jocs.15484DOI Listing
June 2021

Vorolanib, an oral VEGFR/PDGFR dual tyrosine kinase inhibitor for treatment of patients with advanced solid tumors: An open-label, phase I dose escalation and dose expansion trial.

Chin J Cancer Res 2021 Feb;33(1):103-114

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.

Objective: This study evaluated the safety and preliminary efficacy of vorolanib, a novel tyrosine kinase inhibitor, for treatment of patients with advanced solid tumors.

Methods: During dose escalation, patients received increasing doses of oral vorolanib (50-250 mg once daily) in cycles of four weeks for up to one year. During dose expansion, patients received recommended doses (100 and 200 mg) in 4-week cycles. The primary endpoint was to determine the safety and maximum tolerated dose and/or the recommended phase II dose (RP2D). The severity and type of adverse drug reactions (ADRs) were assessed using the Common Terminology Criteria for Adverse Events version 4.0. The second endpoint was preliminary efficacy in terms of objective response and progression-free survival (PFS).

Results: No dose-limiting toxicity occurred during dose escalation (50-250 mg). Five (26.3%) patients in the escalation cohort (n=19) and 12 (48.0%) in the expansion cohort (n=25) experienced grade 3 ADRs. The most common ADRs were hair color changes, fatigue, portal hypertension, hypertriglyceridemia, and proteinuria. During dose expansion, the patients treated with 200 mg and 100 mg (once daily) showed an objective response rate of 22.2% and 5.9%, respectively; the disease control rate was 88.9% and 73.3%, respectively; the median PFS was 9.9 [95% confidence interval (95% CI): 7.4-not reached] months and 3.8 (95% CI: 1.9-not reached) months, respectively.

Conclusions: Oral vorolanib at a dose of 200 mg (once daily) exhibited an acceptable safety profile and favorable clinical benefit for patients with advanced solid tumors. The RP2D for vorolanib was determined to be 200 mg as a daily regimen.
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http://dx.doi.org/10.21147/j.issn.1000-9604.2021.01.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941683PMC
February 2021

Decitabine combined with low dose idarubicin and cytarabine (D-IA) followed by allo-HSCT improves acute myeloid leukemia and higher-risk myelodysplastic syndrome patient outcomes: results from a retrospective study.

Leuk Lymphoma 2021 Mar 7:1-18. Epub 2021 Mar 7.

Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, PR China.

Treatment for acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy is a major challenge for clinicians. We enrolled 154 patients ineligible for intensive chemotherapy who were prescribed D-IA regimen (decitabine 15-20 mg/m days 1 to 3-5, followed by idarubicin 3 mg/m for 5-7 days and cytarabine 30 mg/m for 7-14 days). For AML and MDS patients, the overall response rate after two cycles was 66.4% and 76.6%, respectively, and the 2-year overall survival rates were 29% and 31%, respectively. Fourteen (13.1%) AML and five (10.6%) MDS patients underwent allo-HSCT after complete remission. The allo-HSCT group survival time was significantly longer than the control group (median survival time not reached in HSCT group, 13 and 18.5 months in non-HSCT AML and MDS group). We concluded that D-IA regimen was effective and well tolerated for patients with AML or higher-risk MDS ineligible for intensive chemotherapy.
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http://dx.doi.org/10.1080/10428194.2021.1891230DOI Listing
March 2021

HIR V2: a human interactome resource for the biological interpretation of differentially expressed genes via gene set linkage analysis.

Database (Oxford) 2021 Mar;2021

Institute of Big Data and Artificial Intelligence in Medicine, School of Electronics and Information Engineering, Taizhou University, 1139 Shifu Avenue, Taizhou City, Zhejiang Province, Taizhou 318000, China.

To facilitate biomedical studies of disease mechanisms, a high-quality interactome that connects functionally related genes is needed to help investigators formulate pathway hypotheses and to interpret the biological logic of a phenotype at the biological process level. Interactions in the updated version of the human interactome resource (HIR V2) were inferred from 36 mathematical characterizations of six types of data that suggest functional associations between genes. This update of the HIR consists of 88 069 pairs of genes (23.2% functional interactions of HIR V2 are in common with the previous version of HIR), representing functional associations that are of strengths similar to those between well-studied protein interactions. Among these functional interactions, 57% may represent protein interactions, which are expected to cover 32% of the true human protein interactome. The gene set linkage analysis (GSLA) tool is developed based on the high-quality HIR V2 to identify the potential functional impacts of the observed transcriptomic changes, helping to elucidate their biological significance and complementing the currently widely used enrichment-based gene set interpretation tools. A case study shows that the annotations reported by the HIR V2/GSLA system are more comprehensive and concise compared to those obtained by the widely used gene set annotation tools such as PANTHER and DAVID. The HIR V2 and GSLA are available at http://human.biomedtzc.cn.
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http://dx.doi.org/10.1093/database/baab009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937034PMC
March 2021

Synthesis, characterization, and targeted chemotherapy of SCT200-linker-monomethyl auristatin E conjugates.

Eur J Med Chem 2021 Apr 24;216:113297. Epub 2021 Feb 24.

Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address:

Antibody-drug conjugates (ADCs) are currently among the most successful and important strategies for treating patients with solid tumors. ADCs are composed of a monoclonal antibody and warhead, which are conjugated via a linker. Currently, monomethyl auristatin E (MMAE) is the most widely applied warhead in the development of ADCs. However, MMAE-based ADCs are generally constructed using the MC-VC-PABC linker, and this design has limited structural diversity and some disadvantages. Accordingly, in this study, we generated three types of novel linker-MMAE (with alterations in the spacer, catabolizing area, and self-immolative compared with MC-VC-PABC-MMAE) in ADCs, termed SCT200-linker-MMAE conjugates, and then evaluated the linker-drug plasma stability and the rate of drug release by cathepsin B. The binding ability, internalization rates, and efficacy of all SCT200-linker-MMAE ADCs were systematically studied, and the expression of apoptosis-associated proteins and the therapeutic efficacies of SCT200-M-2, -C-2, and -C-4 were evaluated. The results showed that the activities of some of these ADCs were increased for epidermal growth factor receptor-positive tumors. Moreover, the novel linkers designed in this study can be linked with other antibodies to treat other types of cancer. Overall, these findings provide important insights into the application of SCT200-based linkers in ADCs.
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http://dx.doi.org/10.1016/j.ejmech.2021.113297DOI Listing
April 2021

The response mechanism to salt stress in Arabidopsis transgenic lines over-expressing of GmG6PD.

Plant Physiol Biochem 2021 May 21;162:74-85. Epub 2021 Feb 21.

Key Laboratory of Cell Activities and Stress Adaptations, Ministry of Education, School of Life Sciences, Lanzhou University, Lanzhou, Gansu, 730000, PR China. Electronic address:

Glucose-6-phosphate dehydrogenase (G6PD or G6PDH) plays an important role in response to salt stress in plants. However, much less is known about G6PD proteins in soybean (Glycine max L.). Here, we found that a soybean cytosolic G6PD gene, GmG6PD7, was induced by NaCl. We generated Arabidopsis transgenic lines overexpressing GmG6PD7. The seed germination rate and primary root length of Arabidopsis thaliana over-expressing GmG6PD7 under NaCl treatment were enhanced. Salt stress induced an obvious increase of the total and cytosolic G6PD activity and the marked decrease of ROS levels in the transgenic plants. At the same time, over-expressing GmG6PD7 in Arabidopsis affected the glutathione and NADPH level and activated ROS scavengers, suggesting that GmG6PD7 contributes to increase salinity tolerance by decreasing ROS accumulation. What's more, we found GmG6PD7 overexpression led to the up-regulation of abscisic acid (ABA) degradation gene and the down-regulation of ABA synthesis and ABA-responsive genes, which finally reduced ABA content to improve seed germination rate under salinity stress. It was noteworthy that GmG6PD7 can rescue the seed and root phenotype of Arabidopsis cytosolic G6PD mutant (Atg6pd5 and Atg6pd6) under salt stress, suggesting cytosolic G6PD may have a conserved function in soybean and Arabidopsis.
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http://dx.doi.org/10.1016/j.plaphy.2021.02.021DOI Listing
May 2021

A multicenter, randomized phase III trial of hetrombopag: a novel thrombopoietin receptor agonist for the treatment of immune thrombocytopenia.

J Hematol Oncol 2021 Feb 25;14(1):37. Epub 2021 Feb 25.

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

Background: Hetrombopag, a novel thrombopoietin receptor agonist, has been found in phase I studies to increase platelet counts and reduce bleeding risks in adults with immune thrombocytopenia (ITP). This phase III study aimed to evaluate the efficacy and safety of hetrombopag in ITP patients.

Methods: Patients who had not responded to or had relapsed after previous treatment were treated with an initial dosage of once-daily 2.5 or 5 mg hetrombopag (defined as the HETROM-2.5 or HETROM-5 group) or with matching placebo in a randomized, double-blind, 10-week treatment period. Patients who received placebo and completed 10 weeks of treatment switched to receive eltrombopag, and patients treated with hetrombopag in the double-blind period continued hetrombopag during the following open-label 14-week treatment. The primary endpoint was the proportion of responders (defined as those achieving a platelet count of ≥ 50 × 10/L) after 8 weeks of treatment.

Results: The primary endpoint was achieved by significantly more patients in the HETROM-2.5 (58.9%; odds ratio [OR] 25.97, 95% confidence interval [CI] 9.83-68.63; p < 0.0001) and HETROM-5 (64.3%; OR 32.81, 95% CI 12.39-86.87; p < 0.0001) group than in the Placebo group (5.9%). Hetrombopag was also superior to placebo in achieving a platelet response and in reducing the bleeding risk and use of rescue therapy throughout 8 weeks of treatment. The durable platelet response to hetrombopag was maintained throughout 24 weeks. The most common adverse events were upper respiratory tract infection (42.2%), urinary tract infection (17.1%), immune thrombocytopenic purpura (17.1%) and hematuria (15%) with 24-week hetrombopag treatment.

Conclusions: In ITP patients, hetrombopag is efficacious and well tolerated with a manageable safety profile. Trial registration Clinical trials.gov NCT03222843 , registered July 19, 2017, retrospectively registered.
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http://dx.doi.org/10.1186/s13045-021-01047-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905908PMC
February 2021

ROBUST: A Phase III Study of Lenalidomide Plus R-CHOP Versus Placebo Plus R-CHOP in Previously Untreated Patients With ABC-Type Diffuse Large B-Cell Lymphoma.

J Clin Oncol 2021 Apr 23;39(12):1317-1328. Epub 2021 Feb 23.

Division of Hematology, A.O.U. Città della Salute e della Scienza Hospital and University, Torino, Italy.

Purpose: Patients with the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) historically showed inferior survival with standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Phase II studies demonstrated that adding the immunomodulatory agent lenalidomide to R-CHOP improved outcomes in ABC-type DLBCL. The goal of the global, phase III ROBUST study was to compare lenalidomide plus R-CHOP (R2-CHOP) with placebo/R-CHOP in previously untreated, ABC-type DLBCL.

Methods: Histology and cell-of-origin type were prospectively analyzed by central pathology prior to random assignment and study treatment. Patients with ABC-DLBCL received lenalidomide oral 15 mg/d, days 1-14/21 plus standard R-CHOP21 versus placebo/R-CHOP21 for six cycles. The primary end point was progression-free survival (PFS) per independent central radiology review.

Results: A total of 570 patients with ABC-DLBCL (n = 285 per arm) were stratified by International Prognostic Index score, age, and bulky disease, and randomly assigned to R2-CHOP or placebo/R-CHOP. Baseline demographics were similar between arms. Most patients completed six cycles of treatment: 74% R2-CHOP and 84% placebo/R-CHOP. The most common grade 3/4 adverse events for R2-CHOP versus placebo/R-CHOP were neutropenia (60% 48%), anemia (22% 14%), thrombocytopenia (17% 11%), and leukopenia (14% 15%). The primary end point of PFS was not met, with a hazard ratio of 0.85 (95% CI, 0.63 to 1.14) and = .29; median PFS has not been reached for either arm. PFS trends favoring R2-CHOP over placebo/R-CHOP were seen in patients with higher-risk disease.

Conclusion: ROBUST is the first DLBCL phase III study to integrate biomarker-driven identification of eligible ABC patients. Although the ROBUST trial did not meet the primary end point of PFS in all patients, the safety profile of R2-CHOP was consistent with individual treatments with no new safety signals.
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http://dx.doi.org/10.1200/JCO.20.01366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078325PMC
April 2021

Oral Realgar-Indigo Naturalis Formula Plus Retinoic Acid for Acute Promyelocytic Leukemia.

Front Oncol 2020 5;10:597601. Epub 2021 Feb 5.

Department of Hematology, Leukemia Center, The First Affiliated Hospital of Zhejiang University, College of Medicine, Key Laboratory of Hematopoietic Malignancies in Zhejiang Province, Hangzhou, China.

Treatment paradigm of acute promyelocytic leukemia (APL) is by no mean the most remarkable story of cancer therapy. Recently, the advent of oral arsenic formulations (oral-arsenic trioxide and Realgar-Indigo Naturalis formula (RIF)) based regimens may provide a therapeutic advance by curing APL with two oral agents. Indeed, the oral RIF plus all-trans-retinoic acid (ATRA) without chemotherapy display highly efficacy in patients with APL. The safety profile of RIF plus ATRA make possible to treat APL patients in a home-based manner during postremission therapy. To our knowledge, RIF was the first commercially available oral arsenic agent approved in China. The RIF plus ATRA regimens are becoming a preferred frontline care for APL in China. In this review, we will discuss the history, current evidences and challengers of RIF-based strategies in APL. More and more APL patients may enjoy a cure with a normal quality-of-life after induction in the near future.
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http://dx.doi.org/10.3389/fonc.2020.597601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892950PMC
February 2021

Clinical significance of cytogenetic and molecular genetic abnormalities in 634 Chinese patients with myelodysplastic syndromes.

Cancer Med 2021 03 20;10(5):1759-1771. Epub 2021 Feb 20.

Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

Purpose: To explore the relevance of cytogenetic or molecular genetic abnormalities to clinical variables, including clinical and laboratory characteristics and prognosis in Chinese patients with myelodysplastic syndromes (MDS).

Methods: A total of 634 consecutive patients diagnosed with MDS at The First Affiliated Hospital, Zhejiang University School of Medicine from June 2008 to May 2018 were retrospectively included in this study. All patients had evaluable cytogenetic analysis, and 425 patients had MDS-related mutations sequencing.

Results: 38.6% of patients displayed abnormal karyotypes. The most common cytogenetic abnormality was +8 (31%). Sole +8 was related to female (p = 0.002), hemoglobin >10 g/dL (p = 0.03), and <60 years old (p = 0.046). TP53 mutations were associated with complex karyotype (CK) (p < 0.001). DNMT3A mutations correlated with -Y (p = 0.01) whereas NRAS mutations correlated with 20q- (p = 0.04). The overall survival (OS) was significantly inferior in patients with +8 compared with those with normal karyotype (NK) (p = 0.003). However, the OS of sole +8 and +8 with one additional karyotypic abnormality was not different from NK (p = 0.16), but +8 with two or more abnormalities had a significantly shorter OS than +8 and +8 with one additional karyotypic abnormality (p = 0.02). In multivariable analysis, ≥60 years old, marrow blasts ≥5% and TP53 mutations were independent predictors for poor OS (p < 0.05), whereas SF3B1 mutations indicated better prognosis. Male IDH1 and IDH2 mutations and marrow blasts ≥5% were independent risk factors for worse leukemia free survival (LFS) (p < 0.05).

Conclusion: In this population of Chinese patients, trisomy 8 is the most common karyotypic abnormality. Patients with +8 showed a poorer OS compared with patients with NK. Sole +8 and +8 with one additional karyotypic abnormality had similar OS with NK, whereas +8 with two or more abnormalities had a significantly shorter OS. DNMT3A mutations correlated with -Y and NRAS mutations correlated with 20q-. TP53 mutations were associated with CK and had a poor OS. SF3B1 mutations indicated a favorable OS. IDH1 and IDH2 mutations independently indicated inferior LFS.
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http://dx.doi.org/10.1002/cam4.3786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940222PMC
March 2021

Daratumumab monotherapy for patients with relapsed or refractory natural killer/T-cell lymphoma, nasal type: an open-label, single-arm, multicenter, phase 2 study.

J Hematol Oncol 2021 Feb 15;14(1):25. Epub 2021 Feb 15.

Division of Hematology/Oncology, Department of Medicine, Sungkyunkwan University School of Medicine, Samsung Medical Center, 81 Irwon-ro, Irwon-dong, Gangnam-gu, Seoul, 06351, South Korea.

Background: Natural killer/T-cell lymphoma (NKTCL) is a disease with limited treatment options and poor outcomes. Daratumumab monotherapy demonstrated clinical activity in a single-patient case report. We present data from the primary analysis of a phase 2 study of daratumumab monotherapy in relapsed or refractory (R/R) NKTCL.

Methods: This phase 2 study with Simon's two-stage design evaluated daratumumab in patients with histologically confirmed extranodal NKTCL, nasal type, per WHO classification that was refractory to or relapsed after ≥ 1 line of chemotherapy, who were not candidates for other treatment modalities. All patients received daratumumab 16 mg/kg intravenously once weekly for Cycles 1 and 2, every other week for Cycles 3 through 6, and every 4 weeks thereafter until progression or unacceptable toxicity; all cycles were 28 days. The primary end point was objective response rate (ORR) based on blinded independent central review per Revised Criteria for Response Assessment of Hodgkin and non-Hodgkin Lymphoma (Lugano classification).

Results: In total, 32 Asian patients received daratumumab. The ORR was 25.0% (95% confidence interval [CI] 11.5-43.4); all 8 responders had a partial response; and the median duration of response was 55.0 days (95% CI 29-339). At 10.2 months of median follow-up, median progression-free survival (PFS) was 53.0 days (95% CI 43-106); the 4-month PFS rate was 13.0%. Median overall survival (OS) was 141.0 days (95% CI 94-438); the 6-month OS rate was 42.9%. Nineteen (59.4%) patients had grade 3/4 treatment-emergent adverse events (TEAEs); the most common was thrombocytopenia (25.0%; n = 8). TEAEs leading to death occurred in 4 patients (death, respiratory failure, septic shock, and pneumonia); all were unrelated to daratumumab.

Conclusions: In patients with R/R NKTCL, daratumumab monotherapy was well tolerated with no new safety concerns and achieved an ORR of 25.0%. However, no patients achieved complete response, and duration of response was short. Trial registration ClinicalTrials.gov, NCT02927925. Registered 7 October 2016.
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http://dx.doi.org/10.1186/s13045-020-01020-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885403PMC
February 2021

Phase 4 Safety and Efficacy Study of Antihemophilic Factor (Recombinant) in Previously Treated Chinese Patients With Severe/Moderately Severe Hemophilia A.

Clin Appl Thromb Hemost 2021 Jan-Dec;27:1076029621989811

Baxalta Innovations GmbH, a Takeda Company, Vienna, Austria.

Antihemophilic factor (recombinant) (rAHF; ADVATE; Baxalta US Inc., a Takeda company, Lexington, MA, USA) is indicated for the treatment and prevention of bleeding in patients with hemophilia A. We aimed to assess the safety and efficacy of standard prophylaxis versus on-demand treatment with rAHF in previously treated Chinese patients with severe/moderately severe hemophilia A. This open-label, sequential, interventional, postapproval study (NCT02170402) conducted in China included patients of any age with hemophilia A with factor VIII (FVIII) level ≤2%. Patients received 6 months' on-demand rAHF then 6 months' rAHF prophylaxis (20-40 IU/kg every 48 ± 6 hours). The primary objective was percentage reduction in annualized bleeding rate (ABR) in the per-protocol analysis set (PPAS); secondary objectives included ABR by bleeding subtype, hemostatic efficacy, immunogenicity, and safety. Of 72 patients who received ≥1 rAHF dose, 61 were included in the PPAS. Total ABR was lower during prophylaxis (mean 2.5, 95% CI 1.5-3.7; median 0) versus on-demand treatment (mean 58.3, 95% CI 52.5-64.7; median 53.9), representing a 95.9% risk reduction. Similar findings in favor of prophylaxis were observed for all types of bleeding event by cause and location. rAHF hemostatic efficacy was rated as "excellent"/"good" in 96.1% of treated bleeding events. Transient FVIII inhibitors (0.6-1.7 BU) in 4 patients resolved before study end; no unexpected safety issues were observed. rAHF prophylaxis in this study of previously treated Chinese patients with severe/moderately severe hemophilia A resulted in a clear reduction in bleeding events versus rAHF on-demand treatment, with no change in safety profile.
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http://dx.doi.org/10.1177/1076029621989811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890741PMC
February 2021

Mixed phenotype acute leukemia with PML-RARα positive: a case report and literature review.

Mol Cytogenet 2021 Feb 11;14(1):10. Epub 2021 Feb 11.

Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, #79 Qingchun Road, Hangzhou, 310003, Zhejiang Province, People's Republic of China.

Mixed phenotype acute leukemia (MPAL) is an uncommon type of leukemia. It is one kind of malignant clonal diseases that expresses more than one genealogical specific antigen simultaneously. Most MPAL patients are associated with clonal chromosomal abnormalities and molecular genetic changes, such as t(9;22) (q34;q11) and KMT2A (MLL) rearrangement. These specific abnormalities usually have important guiding significance in MPAL diagnosis, targeted therapy and prognosis judgment. In this paper, we reported a case of MPAL, T/myeloid (M5) with an unfrequent combination of PML-RARα positivity and t(15;17). The treatment was successful with chemotherapy for both AML and ALL with daunorubicin, cytarabine (DA) and vincristine, prednisone (VP). We reported here this suggestive MPAL case of rare disease condition and effective treatment, in order to provide experience for the early diagnosis and treatment of similar patients.
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http://dx.doi.org/10.1186/s13039-021-00530-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879616PMC
February 2021