Development and validation of a nomogram to predict poor efficacy of imatinib in the treatment of newly diagnosed chronic phase chronic myeloid leukemia patients.

Background: Imatinib is the most widely used tyrosine kinase inhibitor (TKI) in patients with newly diagnosed chronic-phase chronic myeloid leukemia(CML-CP). However, failure to achieve optimal response after imatinib administration, and subsequent switch to second-generation TKI therapy results in poor efficacy and induces drug resistance. In the present study, we developed and validated a nomogram to predict the efficacy of imatinib in the treatment of patients newly diagnosed with CML-CP in order to help clinicians truly select patients who need 2nd generation TKI during initial therapy and to supplement the risk score system. Methods: We retrospectively analyzed 156 patients newly diagnosed with CML-CP who met the inclusion criteria and were treated with imatinib at the Second Affiliated Hospital of Xi'an Jiao Tong University from January 2012 to June 2022. The patients were divided into a poor-response cohort (N = 60)and an optimal-response cohort (N = 43) based on whether they achieved major molecular remission (MMR) after 12 months of imatinib treatment. Using univariate and multivariate logistic regression analyses, we developed a chronic myeloid leukemia imatinib-poor treatment (CML-IMP) prognostic model using a nomogram considering characteristics like age, sex, HBG, splenic size, and ALP. The CML-IMP model was internally validated and compared with Sokal, Euro, EUTOS, and ELTS scores. Results: The area under the curve of the receiver operator characteristic curve (AUC)of 0.851 (95% CI 0.778-0.925) indicated satisfactory discriminatory ability of the nomogram. The calibration plot shows good consistency between the predicted and actual observations. The net reclassification index (NRI), continuous NRI value, and the integrated discrimination improvement (IDI) showed that the nomogram exhibited superior predictive performance compared to the Sokal, EUTOS, Euro, and ELTS scores (P < 0.05). In addition, the clinical decision curve analysis (DCA) showed that the nomogram was useful for clinical decision-making. In predicting treatment response, only Sokal and CML-IMP risk stratification can effectively predict the cumulative acquisition rates of CCyR, MMR, and DMR (P<0.05). Conclusion: We constructed a nomogram that can be effectively used to predict the efficacy of imatinib in patients with newly diagnosed CML-CP based on a single center, 10-year retrospective cohort study.

Pharmacokinetics and Bioequivalence of Vardenafil Hydrochloride in Healthy Chinese Volunteers.

Vardenafil hydrochloride tablet is an inhibitor of phosphodiesterase type 5, primarily for the treatment of erectile dysfunction. This postprandial study evaluated the pharmacokinetics and bioequivalence of the test and reference formulations of vardenafil hydrochloride tablets in healthy Chinese volunteers. An open, randomized, single-center, single-dose, 2-period, 2-sequence bioequivalence test was conducted on 66 healthy subjects under fed conditions. Subjects were randomly assigned to a 20-mg test or reference formulation with a 7-day washout period. Venous blood samples (4 mL) were collected from each subject 25 times spanning predose (0 hour) to 24 hours after dosing. The plasma concentration of vardenafil was determined by high-performance liquid chromatography-tandem mass spectrometry. Sixty-two volunteers completed the study. Under fed conditions, the maximum plasma concentration was 29.1 ng/mL, the area under the concentration-time curve (AUC) from time 0 to the time of the last measurable concentration was 85.3 ng•h/mL, and AUC from time 0 to infinity was 87.1 ng•h/mL. The 90% confidence intervals of the geometric mean ratio of AUC time 0 to the time of the last measurable concentration and AUC from time 0 to infinity were within the bioequivalence acceptance range of 0.80-1.25. The test formulation was a bioequivalent alternative to the reference formulation when taken under fed conditions in healthy Chinese subjects.

Outcomes in patients with multiple myeloma receiving salvage treatment after BCMA-specific CAR-T therapy: A retrospective analysis of LEGEND-2.

Chimeric antigen receptor T-cell (CAR-T) therapy targeting B-cell maturation antigen (BCMA) has shown profound efficacy and manageable toxicity in patients with relapsed/refractory multiple myeloma (RRMM). However, determining the best course of treatment for post-CAR-T therapy relapse remains a significant challenge. We conducted a retrospective analysis of patients from the phase I LEGEND-2 study (NCT03090659) enrolled at the Xi'an site, analysing the first salvage line of therapy and outcomes in patients with RRMM who progressed after receiving LCAR-B38M CAR-T therapy. Of 45 eligible patients, 34 (76%) had progressive disease (PD). Overall response rate (ORR) to salvage treatment was 50.0%. Median progression-free survival (PFS) after starting salvage treatment was 16.3 months. Median PFS of patients receiving proteasome inhibitor (PI)-based combination therapy was longer (28.2 months) than that of patients receiving a second BCMA CAR-T (including LCAR-B38M; 3.9 months, p = 0.0022) or chemotherapy (1.67 months, p = 0.0001). All patients with extramedullary disease at baseline (n = 11) progressed after CAR-T therapy; ORR to salvage therapy was 25.0% and median PFS was 9.7 months. In conclusion, salvage therapy in patients with PD after receiving LCAR-B38M CAR-T cells produced moderate efficacy, with better outcomes for PI-based salvage regimens.

Synthesis of Hierarchical CdS/NiS Photocatalysts Using Ni-MOF-74 as Template for Efficient Ethanol Conversion and Hydrogen Production under Visible Light.

The conversion of ethanol into high-valuable chemicals and H2 by photocatalytic process provides a sustainable approach to produce carbon-chain-prolonged chemicals and hydrogen energy. In this article, Ni-MOF-74 was added to fabricate the hierarchical CdS/NiS-N composites with an elevated specific surface area during the hydrothermal synthesis of CdS microsphere, and the Ni-MOF-74 facilitate the self-assemble growth of CdS and provide a source of Ni for the formation of NiS. The as-prepared photocatalyst was subjected to photocatalytic ethanol conversion, and the hierarchical composite material CdS/NiS-N (100) formed by adding 100 mg of Ni-MOF-74 exhibits the highest photocatalytic activity and stability in an ethanol aqueous solution with a water content of 10 %. Under visible light irradiation, the conversion rate of ethanol reached 15.2 % at the photocatalytic reaction of 5 h. The selectivity of 2,3-butanediol(2,3-BDO) was 25 %, and the selectivity of acetaldehyde(AA) was 63 %. Through various characterizations, it has been proven that a large specific surface area and the coupling interface between CdS and NiS are key factors in improving photocatalytic performance. This work provides an effective strategy for constructing photocatalysts with coupled cocatalysts/semiconductors and large specific surface areas.

A high-performance, all-solid-state Na+ selective sensor printed with eco-friendly conductive ink.

In recent years, the integration of flexible printed electronics and electrochemical sensors has emerged as a new approach for developing wearable biochemical detecting devices. Among the materials utilized in flexible printed electronics, carbon-based conductive inks are considered to be crucial. In this study, we propose a cost-effective, highly conductive, and environmentally friendly ink formulation utilizing graphite and carbon black (CB) as conductive fillers, resulting in a very low sheet resistance of 15.99 Ω sq-1 (conductivity of 2.5 × 103 S m-1) and a printed film thickness of 25 µm. The unique "sandwich" structure of the working electrode (WE) printed with this ink enhances its electrical conductivity, leading to high sensitivity, selectivity, and stability, with almost no water film generated between the WE and the ion-selective membrane (ISM), strong ion selectivity, long-term stability, and anti-interference. The lower detection limit of the sensor for Na+ is 0.16 mM with a slope of 75.72 mV per decade. To validate the sensor's usability, we analyzed three sweat samples collected during physical activity, with Na+ concentrations within the typical range for human sweat (51 ± 4 mM, 39 ± 5 mM, and 46 ± 2 mM).

A comprehensive analysis of coagulopathy during anti-B cell maturation antigen chimeric antigen receptor-T therapy in multiple myeloma, a retrospective study based on LEGEND-2.

Chimeric antigen receptor (CAR)-reprogrammed T cell therapy is a novel and powerful treatment against hematological malignancies. Cytokine release syndrome (CRS) and other potentially life-threatening toxicities are known side effects which need appropriate management and supportive care. Coagulopathy is a common and severe CAR-T-related adverse event, while a comprehensive profile of coagulopathy in patients with multiple myeloma (MM) undergoing CAR-T cell therapy has not been reported. Therefore, we performed a comprehensive analysis of coagulopathy in 51 patients with r/r MM given anti-B cell maturation antigen CAR-T cell therapy. We found that 49% of patients had coagulation disorders, and 29% of patients experienced disseminated intravascular coagulation (DIC). Severe CRS, abnormal liver function and higher tumor burden were risk factors for the CAR-T-related coagulopathy. We found that the serum IL-6 level and alanine aminotransferase level were potential indicators for CAR-T-related DIC. Furthermore, we found that coagulation disorders occurred within 1 month after CAR-T cell infusion, mainly between days 10 and 13, which was 2-5 days later than the beginning of CRS and simultaneous with the beginning of abnormal liver function and the peak of CRS. In addition, although patients with coagulation dysfunction had a trend for better outcomes and prognosis, no statistical significance was found. In conclusion, our research provided a comprehensive understanding of CAR-T-related coagulopathy in MM. Upon timely and standardized treatment, coagulopathy was manageable in most cases.

Synthesis of hierarchical Cd-Ni-MOF micro/nanostructures and derived Cd-Ni-MOF/CdS/NiS hybrid photocatalysts for efficient photocatalytic hydrogen evolution.

Hierarchical micro/nanostructures assembled from nanorods and nanosheets have become promising candidates for photocatalysis. In this work, a series of hierarchical Cd-Ni-MOF micro/nanostructures, assembled from nanosheets and nanorods, were fabricated via a two-step solvothermal process involving the partial replacement of Ni2+ with Cd2+ in the Ni-MOF-74 structure. Different morphologies were obtained by considering different volume ratios of DMF and ethanol as the solvent during synthesis. Hierarchical Cd-Ni-MOF-T/CdS/NiS hybrid micro/nanostructures were synthesized by Ni2+ and Cd2+ exchange of Cd-Ni-MOFs with S2-. The as-prepared samples, which were composed of thin nanosheets alone, exhibited the best photocatalytic H2 evolution rate of about 40.08 mmol g-1 h-1. The p-n junction between CdS and NiS was found to be beneficial for the migration of photogenerated electrons from the conduction band (CB) of NiS to the CB of CdS. The heterojunction between CdS and Cd-Ni-MOF-T further promoted the transfer of an electron from the CB of CdS to the CB of Cd-Ni-MOF-T. Thus, this study demonstrated that hierarchical Cd-Ni-MOF-T/CdS/NiS architectures have a large specific surface area, leading to significantly improved photocatalytic activity.

TAFRO syndrome was effectively treated with an inexpensive novel scheme: A case report.

A man diagnosed as TAFRO syndrome was successfully responded to a novel immunosuppressive regimen containing methylprednisolone and mycophenolate mofetil. Blood cells firstly recovered, followed by the general situation and complete recover 1 month later, highlighting the danger of TAFRO syndrome and the importance of immunosuppressive agents in reversing pathological course.

Clinical research on RSV prevention in children and pregnant women: progress and perspectives.

Respiratory syncytial virus (RSV) is a significant causative agent of bronchitis and pneumonia in infants and children. The identification and structural analysis of the surface fusion glycoprotein of RSV represents a pivotal advancement in the development of RSV prevention. This review provides a comprehensive summary of RSV monoclonal antibody (mAb) and vaccine clinical trials registered on ClinicalTrials.gov, emphasizing on the classification, name, target, phase, clinical outcomes, and safety data of RSV vaccination in newborns, infants and children. We also discuss the characteristics of the types of RSV vaccines for maternal immunity and summarize the current clinical research progress of RSV vaccination in pregnant women and their protective efficacy in infants. This review will provide new ideas for the development of RSV prevention for children in the future.

Five-year remission without disease progression in a patient with relapsed/refractory multiple myeloma with extramedullary disease treated with LCAR-B38M chimeric antigen receptor T cells in the LEGEND-2 study: a case report.

BACKGROUND: Multiple myeloma remains incurable despite treatment advancements over the last 20 years. LCAR-B38M Cells in Treating Relapsed/Refractory Multiple Myeloma was a phase 1, first-in-human, investigator-initiated study in relapsed/refractory multiple myeloma conducted at four sites in China. The study used LCAR-B38M chimeric antigen receptor-T cells expressing two B-cell maturation antigen-targeting single-domain antibodies designed to confer avidity, and a CD3ζ signaling domain with a 4-1BB costimulatory domain to optimize T-cell activation and proliferation. This chimeric antigen receptor construct is identical to ciltacabtagene autoleucel. In the LEGEND-2 study (n = 57, Xi'an site), overall response rate was 88%; median (95% CI) progression-free survival and overall survival were 19.9 (9.6-31.0) and 36.1 (26.4-not evaluable) months, respectively; and median follow-up was 25 months. This case study reports on a patient with relapsed/refractory multiple myeloma (λ light chain type) who was treated with LCAR-B38M chimeric antigen receptor T cells in the LEGEND-2 study (Xi'an site); he had received five prior lines of treatment and had extensive extramedullary lesions. CASE PRESENTATION: The patient, a 56-year-old Asian male, received cyclophosphamide (500 mg daily × 3 days) as lymphodepletion therapy and a total dose of 0.5 × 106 chimeric antigen receptor + T cells/kg split into three infusions (days 1, 24, and 84 from June to August 2016). He experienced grade 2 cytokine release syndrome after the first infusion; all symptoms resolved with treatment. No cytokine release syndrome occurred following the second and third infusions. His λ light chain levels decreased and normalized 20 days after the first infusion, and extramedullary lesions were healed as of January 2018. He has sustained remission for 5 years and received no other multiple myeloma treatments after LCAR-B38M chimeric antigen receptor T cell infusion. As of 30 October 2020, the patient is still progression-free and has maintained minimal residual disease-negative (10-4) complete response status for 52 months. CONCLUSIONS: This case provides support that treatment with LCAR-B38M chimeric antigen receptor T cells can result in long-term disease remission of 5 or more years without disease progression in a heavily pretreated patient with extensive extramedullary disease and no other treatment options.

Isorhapontigenin prevents ß­amyloid­associated cognitive impairments through activation of the PI3K/AKT/GSK­3ß pathway.

Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease that is the most common cause of dementia in the elderly. Aß1­42 is significantly associated with memory deficits and it can increase the level of acetylcholine, promote the activity of acetylcholinesterase (AChE), and cause cognitive dysfunction. Isorhapontigenin (ISO) is a stilbene derivative that has antioxidant, anti­tumor, and anti­inflammatory effects. However, it is still unclear whether ISO can affect ß­amyloid­associated cognitive impairments. In this study, we found that ISO improved cognitive dysfunction induced by Aß1­42 in rats. It inhibited the Aß­induced activation of M1 microglia and reduced the release of inflammatory cytokines. It alleviated amyloid beta­induced oxidative stress and led to an overall improvement in AD symptoms. Cellularly, we found that ISO alleviated Aß­induced inflammation and oxidative stress by activating the PI3K/AKT/GSK­3ß pathway and ultimately improved cognitive dysfunction in AD rats.

Erratum: KLF10 inhibits cell growth by regulating PTTG1 in multiple myeloma under the regulation of microRNA-106b-5p: Erratum.

[This corrects the article DOI: 10.7150/ijbs.45999.].

Four-year follow-up of LCAR-B38M in relapsed or refractory multiple myeloma: a phase 1, single-arm, open-label, multicenter study in China (LEGEND-2).

BACKGROUND: LCAR-B38M is a chimeric antigen receptor T cell product with two binding domains targeting B cell maturation antigen. Our previous reports showed a remarkable efficacy of LCAR-B38M in patients with relapsed/refractory multiple myeloma (RRMM) at a median follow-up of 2 years. Here, we report long-term safety and efficacy data from a median follow-up of 4 years. METHODS: LEGEND-2 was a phase 1, single-arm, open-label study conducted in four registered sites in China. Seventy-four participants with RRMM received LCAR-B38M treatment. Lymphodepletion was performed using cyclophosphamide or cyclophosphamide plus fludarabine. LCAR-B38M, at a median dose of 0.513 × 106 cells/kg, was intravenously administered either in three split infusions or in a single infusion. The primary objective was the safety of LCAR-B38M, and the secondary objective was efficacy. RESULTS: As of May 25, 2021, the median follow-up was 47.8 months. All patients experienced ≥ 1 adverse events (AEs). Grade ≥ 3 AEs were observed in 45/74 (60.8%) patients. Cytokine release syndrome (CRS) occurred in 68/74 (91.9%) cases; 7 (9.5%) had grade ≥ 3 CRS. One patient experienced grade 1 central nervous system toxicity. The overall response rate was 87.8%. Fifty-four out of 74 (73.0%) patients achieved complete response. The median progression-free survival was 18.0 months, and the median overall survival for all patients was not reached. The median duration of response was 23.3 months. Four patients experienced viral infection more than 6 months post-infusion, and four patients developed second primary non-hematological malignancies at a median time of 11.5 months post-CAR-T cell transfer. CONCLUSIONS: The 4-year follow-up data of LCAR-B38M therapy demonstrated a favorable long-term safety profile and a durable response in patients with RRMM. Trial registration Clinicaltrials.gov NCT03090659 (retrospectively registered on March 27, 2017); ChiCTR-ONH-17012285.

CCCTC-binding factor transcriptionally regulates Galectin-7 and activates the JNK/STAT3 axis to aggravate bronchial epithelial cell injury.

OBJECTIVE: Studies have shown that the expression of CCCTC-binding factor (CTCF) is significantly upregulated in the airway epithelial cells of asthmatic patients, suggesting that CTCF may play an important role in the progression of asthma. MATERIAL/METHODS: Human bronchial epithelial cells BEAS-2B were stimulated with transforming growth factor-ß1 (TGF-ß1) at a concentration of 10 ng/ml, and CTCF overexpression plasmid and CTCF small interfering RNA were transfected into the cells. The proliferation, apoptosis, inflammatory factor secretion, and airway remodeling marker protein expression of injured cells were detected. We bidirectionally regulated Galectin-7 expression in TGF-ß1-induced BEAS-2B cells and overexpress CTCF, while interfering with Galectin-7 to further explore the regulatory effect of CTCF on Galectin-7. We introduced SP600125, a c-Jun N-terminal kinase c-Jun (JNK) pathway inhibitor, to investigate whether CTCF affects asthma progression through the JNK pathway. RESULTS: The expression of CTCF in BEAS-2B cells induced by TGF-ß1 was significantly upregulated, interfering with CTCF expression promoted cell proliferation, inhibited apoptosis, reduced inflammatory factors secretion, and decreased the expression of airway remodeling marker protein. Luciferase reporter gene analysis and chromatin immunoprecipitation verified that CTCF directly bound to Galectin-7 promoter. The effect of Galectin-7 on cells is consistent with the effect of CTCF on cells. The regulatory effect of CTCF on injured cells was indeed mediated by activation of the JNK/STAT3 axis. CONCLUSIONS: CTCF transcriptionally regulated Galectin-7 and activated JNK/STAT3 axis to aggravate bronchial epithelial cell injury.

Effect of Temperature Field and Stress Field of Different Crack Behavior on Twins and Dislocations under Mg Alloy Rolling.

Aiming at the problem of the poor plasticity of magnesium alloy leading to serious edge cracks in the rolling process, this paper conducts a systematic study on the crack suppression mechanism of rolling under different thickness reductions. Using restricted rolling and conventional rolling, comparing the microstructure evolution of the plate after rolling, and combining the information of the simulated temperature field and stress field of the plates, the behavior of twins and dislocations under different thickness reductions is explained, and the influence of serious damage caused by single-pass hot rolling of magnesium alloy is explored. The compressive stress fields along with the transverse and normal directions under restricted rolling cause the compression twins to mature into secondary twins under rolling with small thickness reduction and induce a large number of tensile twins when the thickness reduction amount is increased. The multiple slips activated by the higher temperature field at the edge of the small thickness reduction amount cause dislocations to be distributed inside and outside the twins, while the edge with large thickness reduction can activate more slip due to the high-temperature field resulting from friction, resulting in the twin be destroyed.

Determining the Preferred Orientation of Silver-Plating via X-ray Diffraction Profile.

Determining the preferred orientation of plating film is of practical importance. In this work, the Rietveld method and quantitative texture analysis (RM+QTA) are used to analyze the preferred orientation of plating silver film with XRD profile, whose <311> axial texture can be completely described by a set of exponential harmonics index, extracted from a single XRD profile, C41,1(0.609), C61,1(0.278), C81,1(-0.970). The constructed pole figures with the index of the exponential harmonic are following those measured by the multi-axis diffractometer. The method using exponential harmonic index can be extended to characterize the plating by electroplating in a quantitative harmonic description. In addition, a new dimension involving crystallite shape and size is considered in characterizing the preferred orientation.

Identification and functional study of novel oligonucleotides: CpG Seq 13 and CpG Seq 19.

Aim: This study explored new immunoadjuvants with stronger immune activity to enhance therapeutic effects against leukemia. Materials & methods: Whole blood and bone marrow of acute myeloid leukemia (AML) patients and healthy volunteers were collected. Isolated mononuclear cells were treated with two newly designed CpG oligodeoxynucleotides, CpG sequence 13 and 19, and known CpG oligodeoxynucleotides and analyzed via flow cytometry. Results: CpG Seq 13 and 19 possess strong immune activation and enhance the proliferation, degranulation and cytotoxicity of T cells. They also inhibit AML cell proliferation. When CpG Seq 13/19 are combined with anti-OX40 antibodies, the cytotoxicity of T cells on AML cells are further enhanced. Conclusion: CpG Seq 13 and 19 are strong immune adjuvant candidates for AML treatment.

Identification of HLA-A*0201-restricted CTL Epitopes for MLAA-34-specific Immunotherapy for Acute Monocytic Leukemia.

Our previous research has shown that monocytic leukemia-associated antigen-34 (MLAA-34) was a novel antiapoptotic molecule with unique expression in acute monocytic leukemia (M5), making it an ideal target for T-cell-based immunotherapy. Here, we sought to identify HLA-A*0201-restricted cytotoxic T-lymphocyte (CTL) epitope of MLAA-34 by reverse immunology. In all, 10 HLA-A*0201 restricted epitopes of MLAA-34 were predicted by bioinformatics. MLAA-34324-332, MLAA-34293-301, and MLAA-34236-244 showed the strongest HLA-A*0201-binding affinity. The percentages of HLA-A*0201-MLAA-34236-244 tetramer+ CD8+ T cells in MLAA-34236-244-induced CTLs were raised apparently. Enzyme-linked immunospot showed that MLAA-34236-244 and MLAA-34324-332-specific CTLs produced a higher amount of interferon-γ. MLAA-34236-244-induced CTLs presented a stronger cytotoxic effect on THP-1 cells (HLA-A*0201+MLAA-34+) at various effector to target ratios. MLAA-34236-244 peptide vaccine could inhibit the tumor growth and improve mean survival time of leukemia-bearing human peripheral blood lymphocyte reconstituting severe combined immunodeficient mice. Mice immunized with MLAA-34236-244 vaccine had increased percentages of MLAA-34236-244 tetramer+ CD8+ T cells in the spleen after each round of immunization. High-purity CD8+ and CD4+ T cells were sorted by Dynabeads as effector cells. The killing activity of CD8+ T cells was higher than that of CD4+ T cells. CTLs derived from the MLAA-34 peptide vaccine group were significantly higher than other therapeutic groups and showed specific cytotoxicity to THP-1 cells. Increased interferon-γ and interleukin (IL)-2 and decreased IL-10 and IL-4 were seen in the MLAA-34236-244 peptide vaccine group. MLAA-34236-244 peptide (ILDRHNFAI) is an effective HLA-A*0201-restricted CTL epitope and that it may serve as a promising strategy in designing antigen-specific immunotherapy against MLAA-34-positive acute monocytic leukemia.

Effects of CpG oligodeoxynucleotides on the differentiation of Treg/Th17 cells.

AIM: The balance between Th17 cells and T regulatory (Treg) cells has emerged as a prominent factor in regulating cancer development. However, the effect of CpG oligodeoxynucleotides (ODNs) on the differentiation of Treg/Th17 cells has not been well studied. We sought here to explore the function of CpG ODNs in the differentiation of Tregs and Th17 cells in vitro and in vivo. METHODS: Mouse spleen cells were cultured with anti-CD3 monoclonal antibodies in vitro. Tregs and Th17 cell differentiation was induced by transforming growth factor (TGF)-ß and interleukin (IL)-2, or TGF-ß, IL-6, and IL-23, respectively. Then cells were treated with two CpG ODNs, CpG 1982, or CpG 1826. FBL-3-inoculated C57Bl/6 mice were treated with CpG 1826, tumor vaccine, or combination of CpG 1826 and tumor vaccine. After treatment, spleen cells and serum were isolated, and Tregs/Th17 cells were detected by flow cytometry. The expression of forkhead box P3 (Foxp3), retinoid-related orphan receptor gamma-t (RORγt), IL-10, and IL-17 mRNA was measured by real-time PCR, and protein levels were measured by Western blot and enzyme-linked immunosorbent assay. RESULTS: The frequency of Treg cells increased significantly (p < 0.05) in the FBL-3-inoculated leukemia mouse model compared with control mice, whereas the frequency of Th17 cells did not change. Median survival of mice after treatment with CpG 1826 and tumor vaccine was significantly prolonged compared with that of control mice (p < 0.05). The frequency of induced Treg cells decreased after treatment with CpG 1826, whereas the frequency of Th17 cells induced by cytokines in vitro and in the murine leukemia model increased following treatment with CpG 1826. Furthermore, after treatment with CpG 1826, the mRNA and protein levels of Foxp3 and IL-10 decreased significantly both in vitro and in vivo (p < 0.05), whereas those of RORγt and IL-17 increased significantly (p < 0.05). CONCLUSION: CpG 1826 may inhibit the differentiation of Treg cells induced by cytokines, promote the differentiation of Th17 cells in vitro and in murine leukemia models, and prolong the median survival of mice with leukemia.

Flumatinib versus Imatinib for Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia: A Phase III, Randomized, Open-label, Multi-center FESTnd Study.

PURPOSE: Flumatinib has been shown to be a more potent inhibitor of BCR-ABL1 tyrosine kinase than imatinib. We evaluated the efficacy and safety of flumatinib versus imatinib, for first-line treatment of chronic phase Philadelphia chromosome-positive chronic myeloid leukemia (CML-CP). PATIENTS AND METHODS: In this study, 394 patients were randomized 1:1 to flumatinib 600 mg once daily (n = 196) or imatinib 400 mg once daily (n = 198) groups. RESULTS: The rate of major molecular response (MMR) at 6 months (primary endpoint) was significantly higher with flumatinib than with imatinib (33.7% vs. 18.3%; P = 0.0006), as was the rate of MMR at 12 months (52.6% vs. 39.6%; P = 0.0102). At 3 months, the rate of early molecular response (EMR) was significantly higher in patients receiving flumatinib than in those receiving imatinib (82.1% vs. 53.3%; P < 0.0001). Compared with patients receiving imatinib, more patients receiving flumatinib achieved molecular remission 4 (MR4) at 6, 9, and 12 months (8.7% vs. 3.6%, P = 0.0358; 16.8% vs. 5.1%, P = 0.0002; and 23.0% vs. 11.7%, P = 0.0034, respectively). No patients had progression to accelerated phase or blast crisis in the flumatinib arm versus 4 patients in the imatinib arm by 12 months. Adverse events of edema, pain in extremities, rash, neutropenia, anemia, and hypophosphatemia were more frequent in imatinib arm, whereas diarrhea and alanine transaminase elevation were more frequent in flumatinib arm. CONCLUSIONS: Patients receiving flumatinib achieved significantly higher rates of responses, and faster and deeper responses compared with those receiving imatinib, indicating that flumatinib can be an effective first-line treatment for CML-CP. This trial was registered at www.clinicaltrials.gov as NCT02204644.See related commentary by Müller, p. 3.