Next-generation sequencing reveals relapse and leukemia-free survival risks in newly diagnosed acute myeloid leukemia treated with CAG regimen combined with decitabine.

Background: Acute myeloid leukemia (AML) is a heterogeneous hematopoietic malignancy whose prognosis is associated with several biomarkers. Decitabine, a deoxyribonucleic acid (DNA) methyltransferase (DNMT) inhibitor, combined with cytarabine, aclarubicin hydrochloride, and granulocyte colony-stimulating factor (DCAG), has been used in patients newly diagnosed with AML. This regimen has been especially used in older and fragile patients who are immunocompromised or have co-morbidities, as well as those with specific gene mutations. However, the integration of molecular risk stratification and treatment guidance for the DCAG regimen has not been well defined. Therefore, this study aimed to investigate the genetic mutations associated with AML and establish appropriate treatment strategies for patients newly diagnosed with AML. Methods: This study analyzed the clinical data and genetic mutations based on next-generation sequencing (NGS) in 124 newly diagnosed patients with AML who received the DCAG regimen at the People's Liberation Army (PLA) General Hospital from January 2008 to August 2020. Factors associated with the cumulative incidence of relapse (CIR) and leukemia-free survival (LFS) in patients newly diagnosed with AML were analyzed. Results: The most adverse prognosis of DCAG-treated patients was observed in those with FLT3-ITD, KIT, PTPN11, GATA2, or IDH1 mutations during univariable analysis, whereas PTPN11 mutation was solely significant in multivariable analysis, with an increased likelihood of CIR (P = 0.001) and reduced LFS duration (P = 0.077). Hyperleukocytosis was maintained as an independent risk factor for increased CIR risk (P = 0.044) and decreased LFS duration (P = 0.042) in multivariable analysis. In this study, we validated the risk classification of patients with AML receiving an epigenetic modifier-based induction regimen across a broad age range. Conclusion: NGS demonstrated a dismal overall outcome in patients with the rare PTPN11 mutations, indicating the need for new therapies that target this high-risk subtype of AML. These results offer a potential molecular stratification and treatment guidance for patients with AML.

Next-generation sequencing revealed factors associated with cumulative incidence of relapse and leukemia-free survival in patients with newly diagnosed acute myeloid leukemia.

Background: Several prognostic biomarkers have been validated for acute myeloid leukemia (AML), a heterogeneous hematopoietic malignancy. However, the factors associated with the cumulative incidence of relapse (CIR) and leukemia-free survival (LFS) in real-world patients with AML have not been well defined. Methods: This study examined clinical and mutational data of 246 patients with newly diagnosed AML who received the traditional "3 â€‹+ â€‹7" regimen in PLA General Hospital from January 2008 to August 2020. Factors associated with CIR and LFS in patients newly diagnosed with AML were analyzed using next-generation sequencing. Results: Additional sex combs-like 1 (ASXL1) and Serine/arginine-rich splicing factor 2 (SRSF2) mutations were found to be associated with an increased risk of CIR and a reduced LFS in univariate analysis, while only SRSF2 mutations were associated with these factors in the multivariate analysis. Hyperleukocytosis maintained an independent effect on LFS in the multivariate analysis. Hematopoietic stem cell transplantation conferred a significant prognostic benefit on both CIR and LFS in our cohort. Furthermore, we validated the risk classification of patients with AML receiving traditional induction regimens across a broad age range. Based on next-generation sequencing results, we concluded that SRSF2 mutations were predictive of an increased risk of relapse, inferior LFS rates, and non-relapse mortality in patients with newly diagnosed AML. Conclusion: These findings indicate that patients with SRSF2 mutations might not benefit from the conventional "3 â€‹+ â€‹7" regimen. Our results may help in developing molecular stratification strategies and could guide treatment decisions for patients with newly diagnosed AML.

High Risk of Recurrence of Malignancy Noted in Four-day rATG Regimen After Allogeneic PBSCT From Matched Sibling Donors.

Hitherto, the optimal timing of rabbit anti-thymocyte globulin (rATG) in matched sibling donor peripheral blood stem cell transplantation (MSD-PBSCT) remains to be elucidated. We wanted to evaluate the effect of a new timing strategy of rATG in MSD-PBSCT patients on transplantation outcomes. In this prospective single-arm phase 2 clinical trial, 45 consecutive MSD-PBSCT patients were enrolled from February 1, 2019, to January 31, 2021. The rATG was administered intravenously at a total dose of 5 mg/kg from day -5 to day -2 before graft infusion (4d-ATG group). Thirty-seven MSD-PBSCT patients receiving rATG at the same total dose of 5 mg/kg from day -5 to day -4 before graft infusion from December 1, 2014, to January 31, 2019 served as historical control (2d-ATG group). No graft failure occurred in either group. In the 4d-ATG group, median timing to neutrophil and platelet engraftment was 12 days. The cumulative incidences (CI) of grade 2-4 and grade 3-4 acute graft-versus-host disease (GVHD) at day 100 were 37.8% and 4.4%. The 2-year CIs of severe chronic GVHD and extensive chronic GVHD were 2.2% and 9.6%. The rates of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) reactivation at day 180 were 24.4% and 37.8%, respectively. No patients died of non-relapse causes. Twenty-one patients relapsed at a median of 203 days after transplantation, and the 2-year cumulative incidence of relapse (CIR) was 51.4%. The 2-year probabilities of overall survival (OS), disease-free survival (DFS), and GVHD-free and relapse-free survival (GRFS) were 72.4%, 48.6%, and 40.8%, respectively. There were no significant differences between the 4d-ATG group and 2d-ATG group with regard to timing of neutrophil and platelet engraftment, incidences of CMV reactivation, EBV reactivation, acute GVHD, chronic GVHD, probabilities of OS, and GRFS. The 2-year CIR was significantly increased, and the 2-year DFS was significantly reduced in 4d-ATG group compared with the control group (CIR: 51.4% versus 13.5%, P < .001; DFS: 48.6% versus 75.7%, P = .014). High CIR and worse DFS were noted in MSD-PBSCT receiving 4d-ATG regimen compared with historical control (2d-ATG regimen). Inappropriate rATG timing may increase the risk of relapse after MSD-PBSCT in patients with hematologic malignancies. © 2023 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Ruxolitinib-corticosteroid as first-line therapy for newly diagnosed high-risk acute graft versus host disease: study protocol for a multicenter, randomized, phase II controlled trial.

BACKGROUND: The response rate of the first-line therapy with corticosteroid for acute graft versus host disease (aGVHD) is about 50%, and steroid-refractory disease is associated with high mortality. The improved response rate to the first-line therapy of newly diagnosed aGVHD patients would result in therapeutic benefits. Ruxolitinib, a selective Janus kinase (JAK) 1/2 inhibitor, has been approved for the treatment of steroid-refractory acute GVHD. The addition of ruxolitinib to the first-line therapy may improve the efficacy of corticosteroids. METHODS: This investigator-initiated, open-label, multicenter, prospective randomized, and controlled two-arm phase II study compares the efficacy and safety of ruxolitinib combined with 1 mg/kg methylprednisolone versus 2 mg/kg methylprednisolone alone in newly diagnosed aGVHD patients. Patients with intermediate or high-risk aGVHD, as defined by the Minnesota aGVHD high-risk score and biomarker algorithm, are eligible for this study. A total of 198 patients will be randomized at a 1:1 ratio and assigned a GVHD risk (intermediate versus high risk) and disease status before transplantation (complete remission versus no complete remission). The primary endpoint is the overall response rate on day 28, which is defined as an improvement of at least one stage in the severity of aGVHD in one organ without deterioration in any other organ or disappearance of any GVHD signs from all organs without requiring new systemic immunosuppressive treatment. The secondary objectives consist of response time, response duration, overall survival, disease-free survival, non-relapse mortality, failure-free survival, and changes in serum levels of proinflammatory cytokines and GVHD-related biomarkers. DISCUSSION: This open-label, multicenter, two-arm randomized trial will evaluate whether the addition of ruxolitinib combined with corticosteroid is superior to corticosteroid alone in newly diagnosed high-risk aGVHD. TRIAL REGISTRATION: ClinicalTrials.gov NCT04061876 (version number: 2019.5.18). Registered on July 16, 2019.

Co-Administration with Voriconazole Doubles the Exposure of Ruxolitinib in Patients with Hematological Malignancies.

Background: Ruxolitinib is newly approved for glucocorticoid-refractory acute graft-versus-host disease (GVHD) in patients undergoing allo-geneic hematopoietic stem-cell transplantation (allo-HSCT), and voriconazole is commonly used in allo-HSCT recipients for the prophylaxis or treatment of invasive fungal infections (IFIs). Drug-drug interaction (DDI) may occur between them because their metabolic pathways overlap and can be inhibited by voriconazole, including cytochrome P450 (CYP) isozymes 3A4 and 2C9. Objective: In the present study, we aimed to investigate the DDI between ruxolitinib and voriconazole in patients with hematological malignancies. Methods: A total of 12 patients with hematologic malignancies were enrolled in this single-arm, single-center, Phase I/II, fixed sequence self-control study. All subjects received 5 mg ruxolitinib alone, followed by the co-administration of ruxolitinib and voriconazole. The plasma concentrations of the two drugs were determined by two well-validated high-performance liquid chromatography-tandem mass spectrometry methods. Phoenix WinNonlin software was used to compare the differences in maximum plasma concentration (Cmax), time to Cmax (Tmax), terminal elimination half-life (T1/2), and apparent plasma clearance (CL/F), as well as area under the curve from time zero to last (AUClast) and AUC from time zero to infinity (AUCinf) between the two periods. Results: After pre-treatment with voriconazole, no significant change existed in Tmax, while Cmax, T1/2, AUClast, and AUCinf of ruxolitinib were significantly increased by 50.4%, 81.3%, 110.1%, and 118.3%, respectively, and CL/F was significantly decreased to 43.6% compared with patients receiving ruxolitinib alone. Conclusion: Our findings confirmed a moderate inhibitory DDI between ruxolitinib and voriconazole as voriconazole decreased the elimination and increased the exposure of ruxolitinib in patients with hematologic malignancies. We recommended a dose reduction regimen when voriconazole and ruxolitinib were coadministered. Drug monitoring might help determine the ruxolitinib treatment concentration for aGVHD patients, improve efficacy, and reduce toxicity.

Elevated REG3α predicts refractory aGVHD in patients who received steroids-ruxolitinib as first-line therapy.

We started a single-arm, phase II, open-label, prospective clinical trial using steroids-ruxolitinib as the first-line therapy for intermediate- to high-risk aGVHD (NCT04397367). Here, we report the association of a biomarker panel (sST2, REG3α, sTNFR1, IL-6 and IL-8) with responses to GVHD therapy. The novel first-line therapy for 39 patients with newly diagnosed aGVHD consisted of 1 mg/kg methylprednisolone and 5 mg/day ruxolitinib. The serum concentrations of the biomarkers were prospectively detected at planned time points. Of the 39 patients, the complete response rate at day 28 was 82.05%. In patients who achieved CR, the concentrations of REG3α (P14 = 0.01; P28 = 0.10) and sTNFR1 (P14 = 0.42; P28 = 0.04) declined at day 14 and day 28 compared with the pre-enrolment levels. In refractory patients, the levels of REG3α at day 14 were higher than those pre-enrolment (P = 0.04). REG3α (P = 0.02) was elevated in the refractory patients compared with the patients achieving CR at day 14 after enrolment, while there was no significant difference in the levels of sST2, sTNFR1 or IL-6. Elevated REG3α levels may predict refractory aGVHD after novel first-line therapy with steroids-ruxolitinib.

Semi­random mutagenesis profile of BCR­ABL during imatinib resistance acquirement in K562 cells.

Although imatinib is effective in chronic myeloid leukemia treatment, imatinib resistance due to the T315I mutation and/or other mutations is a challenge to be overcome. However, how DNA mutation occurs, particularly the T315I mutation, remains unclear. In the current study, the mutagenesis of BCR­ABL was analyzed via focusing on the process of drug resistance, rather than the final results. Clone sequencing of the BCR­ABL gene and other control genes was applied in two imatinib­resistant cell models. The results have indicated that imatinib actively and selectively causes sporadic mutations in the BCR­ABL gene, however not in the control genes. The majority of the mutations of BCR­ABL were not the clinically observed T315I mutation, suggesting that the T315I mutation may be due to clonal expansion of cells with survival advantages. Taken together, the results of the current study elucidated the mutagenesis process during drug resistance and thus aids in the management of chemotherapy.

Association between Dietary Vitamin A Intake and the Risk of Glioma: Evidence from a Meta-analysis.

The results from epidemiological studies between dietary vitamin A intake and glioma risk is not consistent. Thus, a meta-analysis was conducted to confirm the exact relationship between them. PubMed and Web of Knowledge were used to search the relevant articles up to May 2015. Pooled relative risk (RR) with 95% confidence interval (CI)was calculated using random-effect model. Egger's test was used to assess the small-study effect. At the end, seven articles with eight case-control studies involving 1841 glioma cases and 4123 participants were included. Our study indicated that highest category of dietary vitamin A intake was significantly associated with reduced risk of glioma (RR = 0.80, 95% CI = 0.62-0.98, p = 0.014, I² = 54.9%). Egger's test did not find any publication bias. In conclusion, our study indicated that higher category of dietary vitamin A intake could reduce the glioma risk. However, we could not do a dose-response analysis for vitamin A intake with glioma risk due to the limited data in each reported individual article. Due to this limitation, further studies with detailed dose, cases and person-years for each category is wanted to assess this dose-response association.

Asymmetric Total Synthesis of Propindilactone G.

A concise total synthesis of (+)-propindilactone G, a nortriterpenoid isolated from the stems of Schisandra propinqua var. propinqua, has been achieved for the first time. The key steps of the synthesis include an asymmetric Diels-Alder reaction, a Pauson-Khand reaction, a Pd-catalyzed reductive hydrogenolysis reaction, and an oxidative heterocoupling reaction. These reactions enabled the synthesis of (+)-propindilactone G in only 20 steps. As a consequence of our synthetic studies, the structure of (+)-propindilactone G has been revised.

Highly regioselective syntheses of substituted triphenylenes from 1,2,4-trisubstituted arenes via a co-catalyzed intermolecular alkyne cyclotrimerization.

Herein, we report the development of a new method for the syntheses of substituted triphenylenes from the corresponding 1,2,4-trisubstituted arenes, which were themselves generated in a highly regioselective manner according to an intermolecular alkyne cyclotrimerization reaction that was catalyzed by a novel Co-TMTU complex. This highly regioselective reaction for the formation of 1,2,4-trisubstituted arenes will be a valuable addition to the plethora of tools already available to synthetic chemists and encourage further mechanistic studies of this important alkyne trimerization process.

Total synthesis of (±)-decinine via an oxidative biaryl coupling with defined axial chirality.

The total synthesis of (±)-decinine has been achieved. The key steps in the synthesis involved the formation of lasubine II via a gold catalyzed annulation of 1-(but-3-yn-1-yl)piperidine and the formation of the 12-membered ring of decinine (1) with complementary atropselectivity via a VOF3-mediated oxidative biaryl coupling reaction.

Diastereoselective total synthesis of (±)-schindilactone†A, Part†1: Construction of the ABC and FGH ring systems and initial attempts to construct the CDEF ring system.

First-generation synthetic strategies for the diastereoselective total synthesis of schindilactone A (1) are presented and methods for the synthesis of the ABC, FGH, and CDEF moieties are explored. We have established a method for the synthesis of the ABC moiety, which included both a Diels-Alder reaction and a ring-closing metathesis as the key steps. We have also developed a method for the synthesis of the FGH moiety, which involved the use of a Pauson-Khand reaction and a carbonylative annulation reaction as the key steps. Furthermore, we have achieved the construction of the central 7-8 bicyclic ring system by using a [3,3]-rearrangement as the key step. However, unfortunately, when this rearrangement reaction was applied to the construction of the more advanced CDEF moiety, the anticipated annulation reaction did not occur and the development of an alternative synthetic strategy would be required for the construction of this central core.

Diastereoselective total synthesis of (±)-schindilactone†A, Part†2: Construction of the fully functionalized CDEFGH ring system.

The successful synthesis of the highly complex model compound (2) of the CEFGH ring system of schindilactone A (1) is described. Several synthetic methodologies were developed and applied to achieve this goal, including ring-closing metathesis (RCM) and Co-thiourea-catalyzed Pauson-Khand reactions. Furthermore, two independent approaches were developed for the construction of the GH ring of model compound 2, the key steps of which included Pd-thiourea-catalyzed carbonylative annulation, methylation, and sequential RCM/oxa-Michael-addition reactions. The chemistry developed herein has provided a greater understanding of the synthesis of schindilactone A (1) and its analogous compounds of the same family.

Diastereoselective total synthesis of (±)-schindilactone†a, Part†3: The final phase and completion.

The final phase for the total synthesis of (±)-schindilactone A (1) is described herein. Two independent synthetic approaches were developed that featured Pd-thiourea-catalyzed cascade carbonylative annulation reactions to construct intermediate 3 and a RCM reaction to make intermediate 4. Other important steps that enabled the completion of the synthesis included: 1) A Ag-mediated ring-expansion reaction to form vinyl bromide 17 from dibromocyclopropane 30; 2) a Pd-catalyzed coupling reaction of vinyl bromide 17 with a copper enolate to synthesize ketoester 16; 3) a RCM reaction to generate oxabicyclononenol 10 from diene 11; 4) a cyclopentenone fragment in substrate 8 was constructed through a Co-thiourea-catalyzed Pauson-Khand reaction (PKR); 5) a Dieckmann-type condensation to successfully form the A ring of schindilactone A (1). The chemistry developed for the total synthesis of schindilactone A (1) will shed light on the synthesis of other family members of schindilactone A.

CoBr2-TMTU-zinc catalysed-Pauson-Khand reaction.

A cobalt-TMTU complex, derived from the in situ reduction of CoBr(2) with Zn in the presence of TMTU, can catalyze Pauson-Khand reaction at a balloon pressure of CO, which enables the synthesis of structurally diverse cyclopentenones. This catalytic system works efficiently for both intermolecular and intramolecular PK reactions.

Organopalladium(IV) chemistry.

Although the chemistry of Pd(0), Pd(I) and Pd(II) is well established, high oxidation state Pd(IV) complexes are less well-known. This situation has highly changed in recent years. Many well-defined Pd(IV) complexes has been isolated and characterized, providing evidence for a series of proposed Pd(II)/Pd(IV) catalytic reactions. A deep understanding of the behavior of Pd(IV) complexes could lead to the design and development of novel reactions that could not be accessed by traditional Pd(0)/Pd(II) chemistry. This critical review describes the stoichiometric reactions of Pd(IV) complexes and discusses their potential mechanism in catalytic reactions (137 references).

[Experimental study of DNA synthesis in the airway cells and airway remodeling in asthmatic rats].

OBJECTIVE: To study the DNA synthesis in the airway cells of asthmatic rats after allergen stimulation in association with airway remodeling. METHODS: Double staining immunohistochemical techniques was used to determine DNA synthesis of the airway cells of 12 asthmatic and 12 normal rats. BrdU incorporation into the airway smooth muscle (ASM) and epithelium was quantified by employment of computer-assisted image analysis. RESULTS: BrdU indices in both the ASM and the epithelium of asthmatic model group were higher than those of the control group (P<0.01, P<0.05), and positive linear correlation of the BrdU indices in the ASM and epithelium with the airway diameter was observed (r=0.7828, P<0.01; r=0.5852, P<0.05), which was not found in the control group (r=-0.3755, P>0.05; r=-0.5208, P>0.05). The epithelial thickness of the model group was significantly greater than that of the control group (P<0.01). There was no significant difference in terms of airway diameter, thickness of the ASM and the area positive of alpha-smooth muscle actin between the 2 groups (P>0.05). CONCLUSION: Increased DNA synthesis and accelerated proliferation of ASM and epithelial cells in sensitized SD rats following repeated allergen challenges may lead to airway remodeling.