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Purpose: To investigate the efficacy and safety of the novel orally active PI3Kδ inhibitor in relapsed and/or refractory patients with follicular lymphoma (FL) who had received at least two prior systemic treatments. Patients and Methods: Histologically confirmed relapsed and/or refractory patients with FL with disease progression after receiving second-line or greater systemic therapy were enrolled. Linperlisib was administered at 80 mg every day, orally in a 28-day cycle until disease progression or intolerable toxicity occurred. The primary outcome for the study was the objective response rate (ORR), with secondary outcomes including the duration of response (DOR), progression-free survival (PFS), overall survival (OS), disease control rate, and drug safety profile. Results: Of 114 screened relapsed and/or refractory patients with FL, 84 were enrolled in the full analysis set (FAS). The ORR of the 84 FAS patients was 79.8% [95% confidence interval (CI), 69.6–87.8, 67 patients], with 13 patients (15.5%) achieving a complete response and 54 patients (64.3%) with a partial response. The median DOR was 12.3 months (95% CI, 9.3–15.9). The median PFS was 13.4 months (95% CI, 11.1–16.7). The 12-month OS rate was 91.4% (95% CI, 82.7–95.8) and a median OS not reached by 42 months. The most frequent (>3%) treatment-related adverse events Grade ≥3 were infectious pneumonia (19.0%), neutropenia (15.5%), decreased lymphocyte count (4.8%), decreased leukocyte count (4.8%), increased lipase (3.6%), decreased platelet count (3.6%), hypertriglyceridemia (3.6%), and interstitial lung disease (3.6%). Conclusions: Linperlisib demonstrated compelling clinical activity and manageable tolerability for relapsed and/or refractory patients with FL who had received at least two prior systemic therapies.

List of participating hospitals for the clinical trial NCT04370405

Subgroup analysis of (A) ORR, (B) DOR and (C) PFS confirmed by investigator

We sought to investigate the nature and incidence of bloodstream infection complications and to identify the risk factors of central catheter-related bloodstream infections (CRBSI).During the study period, 291 consecutive patients with hematological malignancies who underwent PICC placement were retrospectively enrolled. We analyzed the covariates that were specified a priori for their association with CRBSI through multivariate Cox proportional hazards regression models. The association between each predictor and the related outcome was expressed using hazard ratios (HRs) with corresponding 95% confidence intervals (CIs).Of 391 peripherally inserted central catheter (PICCs) were inserted in 291 patients for a total of 63,714 catheter days during 7 years, with an infection rate of 0.71/1,000 catheter days. Among the patients with hematological malignancies, those with acute leukemia were prone to CRBSI. Having previous bloodstream infection (BSI) (HR 18.139; 95% CI, 8.19-40.174; P.0001), the number of PICCs insertions (HR 4.695; 95% CI, 1.842-11.967; P = .001) (twice), (HR 6.794; 95% CI, 1.909-24.181; P = .003) (≥3 times) were significantly associated with CRBSI. Not accompanied by chronic comorbidities (HR 0.34; 95% CI, 0.131-0.887; P = .028) and longer duration of PICC use (days) (HR 0.997; 95% CI, 0.994-0.999; P = .008) might be protective factors preventing CRBSI.Our finding suggests that previous BSI and a higher number of PICC insertions are associated with an increased risk of CRBSI. A lack of chronic comorbidities may help prevent CRBSI.

Atypical chronic myeloid leukemia (aCML) BCR-ABL1 negative is a rare myelodysplastic syndromes/myeloproliferative neoplasm (MDS/MPN) for which no standard treatment currently exists. The advent of next-generation sequencing has allowed our understanding of the molecular pathogenesis of aCML to be expanded and has made it possible for clinicians to more accurately differentiate aCML from similar MDS/MPN overlap syndrome and MPN counterparts, as MPN-associated driver mutations in JAK2, CALR, or MPL are typically absent in aCML. A 55-year old male with main complaints of weight loss and fatigue for more than half a year and night sweats for more than 2 months was admitted to our hospital. Further examination revealed increased white blood cells, splenomegaly, and grade 1 bone marrow fibrosis with JAK2 V617F, which supported a preliminary diagnosis of pre-primary marrow fibrosis. However, in addition to JAK2 V617F (51.00%), next-generation sequencing also detected SETBP1 D868N (46.00%), ASXL1 G645fs (36.09%), and SRSF2 P95_R102del (33.56%) mutations. According to the 2016 World Health Organization diagnostic criteria, the patient was ultimately diagnosed with rare aCML with concomitant JAK2 V617F and SETBP1 mutations. The patient received targeted therapy of ruxolitinib for 5 months and subsequently an additional four courses of combined hypomethylating therapy. The patient exhibited an optimal response, with decreased spleen volume by approximately 35% after therapy and improved symptom scores after therapy. In diagnosing primary bone marrow fibrosis, attention should be paid to the identification of MDS/MPN. In addition to basic cell morphology, mutational analysis using next-generation sequencing plays an increasingly important role in the differential diagnosis. aCML with concomitant JAK2 V617F and SETBP1 mutations has been rarely reported, and targeted therapy for mutated JAK2 may benefit patients, especially those not suitable recipients of hematopoietic stem cell transplants.

Introduction Diffuse large B cell lymphoma (DLBCL) is an aggressive hematological malignancy where patients rapidly progress on standard therapies. In relapsed/refractory (r/r) DLBCL, there is an urgent need for safe and effective therapies, especially being feasible to combine with other treatment regimens. The gemcitabine (GEM) oxaliplatin (OX) chemotherapy regimen is a standard treatment option with modest side effects providing an opportunity for potential combination with novel agents. The PI3Kδ selective inhibitor linperlisib is a structurally distinct oral agent previously demonstrated to be clinically efficacious with a favorable safety profile in follicular lymphoma and peripheral T cell lymphoma trials. Methods This Phase1b/2 trial (NCT04500561) initiated in December 2019. As of July 22, 2021, there were 39 r/r DLBCL patients (pts) enrolled at 6 clinical sites in China. All DLBCL subtypes were represented, and pts had a median of 2 prior systemic therapies, including 1 pt with prior stem cell transplant. Pts were dosed in a 21-day cycle with linperlisib 80 mg QD orally combined with 6 cycles of GEMOX (Gemcitabine 1000 mg/m 2, IV on day 1, Q3W, and Oxaliplatin 1000 mg/m 2 IV on day2, Q3W], followed by linperlisib alone until disease progression, intolerable toxicity, or withdrawal. Safety was evaluated according to NCI-CTCAE v5.0. Efficacy evaluation was conducted every 2 cycles by IWG 2007 criteria. Results In this Phase 1b study of linperlisib + GEMOX in r/r DLBCL, as of July 22, 2021, there were 35 evaluable pts. Two pts discontinued from study due to SAEs occurred at C1D16 and C1D15, and 2pts discontinued from the study due to withdrawing consent at C1D8 and C2D7, there were no post baseline imaging assessment for these patients.The r/r DLBCL pts were BCL-6 (+) (80%, 28 pts), BCL-6 (-) (11.4%, 4 pts), or unknown (8.6%, 3 pts); C-MYC (+) (80%, 28 pts), C-MYC (-) (2.8%, 1 pt), or unknown (17.1%, 6 pts), indicative of aggressive lymphomas. Most pts (74%,29pts) had received R-CHOP as a first line treatment, with later lines of R-EPOCH, R-ICE, lenolinamide, CAR-T, PD-1, and other regimens, with a median of 2 lines of prior systemic therapy. The overall response rate was 60% (21/35 pts) with 5 pts achieving a Complete Response (CR, 14%) and 16 pts with Partial Response (PR, 46%)(Figure 1). In addition, 4 pts had Stable Disease (SD, 11 %), with a 71% Disease Control Rate (DCR). The median time to response was 36 days. As of the data cutoff date, the median Progression Free Survival was 193 days and the median Duration of Response was not reached, and 17 evaluable pts (48.6%) remained on study. Ten pts received linperlisib monotherapy for at least 1 cycle after completing 6 cycles of linperlisib + GEMOX combination therapy, and 2 pts were continuing linperlisib monotherapy treatment for >9 months after enrolling. Linperlisib in combination with GEMOX was well-tolerated. All 39 pts experienced at least 1 Treatment Related Adverse Event (TRAE), of which the majority were Grade 1 or 2 (83.9%). The most common TRAEs (>10% all grades) were neutropenia (72%), leukopenia (62%),thrombocytopenia (56%), anaemia (51%), lymphopenia (15%), ALT increased (41%), ASP increased(54%), hyperamylasemia (23%), hypokalaemia (21%), nausea(31%), vomiting(23%), diarrhea(33%), and anaesthesia(13%).The most frequent ≥Grade 3 TRAE (>5%) were neutropenia (46.2%), thrombocytopenia (35.9%), leukopenia (25.6%), lymphopenia (7.7%). SAEs were reported in 14 pts, including 3 thrombocytopenia, 2 diarrhea, and one case of leukopenia, neutropenia, febrile neutropenia, fever, death NOS, cachexia, pleural effusion, cancer pain, hypotension, vomiting, laryngopharyngitis, pneumonitis, lung infection or skin infection. One pt had dose reduction to 60mg/day due to AE, 2 pts discontinued treatment due to a TRAE. The AEs observed were consistent with that in previous linperlisib monotherapy trials in FL, PTCL and lymphomas. Conclusions The combination of linperlisib and GEMOX treatment was well tolerated with a manageable AE profile, and led to a promising ORR in a difficult-to-treat r/r DLBCL. The preliminary data suggest that linperlisib + GEMOX is a safe and active combination. A Phase2 study of linperlisib in combination with GEMOX in r/r DLBCL is currently ongoing. Further, multiple combination treatments are planned as important avenues for future development of linperlisib. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

In this paper, we consider the probabilistic approach in adaptive state estimation for discrete-time linear stochastic time-varying systems with unknown inputs. When lack knowledge of noise, we regard the system state, unknown inputs and time-varying noise parameters as hidden variables with conjugate priors, and use variational Bayes method to side-step the complicated Bayesian inference. The proposed algorithm is based on optimal two-stage Kalman filtering technique that enables us to obtain marginal posterior distributions of hidden variables. A numerical example is provided to demonstrate the state estimation performance of proposed algorithm.

With economic and cultural globalization, the trend of globalization of higher education becomes inevitable. Using the concept of competitiveness, the authors established a principal component analysis (PCA) model to examine disciplinary competitiveness in stomatology of various higher education institutions worldwide. A total of forty-four universities entered the final list according to these calculations. Possible reasons for their selection were explored and explained at macro and micro levels. The authors further accessed various sources of data and summarized several suggestions for enhancing disciplinary competitiveness for other universities in pursuit of promoting their position in the global spectrum.