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YY-20394, an oral phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor, was investigated in a first-in-human study of patients with relapsed or refractory B-cell malignancies. During dose escalation, 25 patients received 20–200 mg of YY-20394 daily. The primary outcome measures were tolerability and dose-limiting toxicity (DLT). The secondary outcomes were pharmacokinetic parameters, progression-free survival (PFS) and the objective response rate (ORR). Since no patients experienced DLT, the maximum tolerated dose (MTD) was not reached. The majority (≥ 5%) of drug-related adverse events were ≥ grade III, being neutropenia (44.0%), pneumonia (16.0%), hyperuricemia (12.0%), lymphocythemia (8.0%), leukopenia (8.0%) and pneumonitis (8.0%). The overall ORR was 64.0% (95% confidence interval (CI): 45.2, 82.8%) including 5 patients with complete remission (CR), 11 with partial remission (PR), 2 with stable disease (SD) and 7 with progressive disease (PD), while the disease control rate (DCR) was 72.0% (95% CI: 54.4, 89.6%). The ORR of 10 patients with follicular lymphoma was 90%. The median PFS time was 255 days. One PR patient with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who received 40 mg q.d. had a durable response of around 36 months. The median PFS time of 10 patients with follicular lymphoma was 300 days. A recommended phase 2 dose of 80 mg q.d. was established. Considering that YY-20394 was well-tolerated with promising preliminary efficacy, further development is warranted. Trial registration clinicaltrials.gov, NCT03757000, retrospectively registered, November 28, 2018, https://clinicaltrials.gov/ct2/show/NCT03757000?term=NCT03757000&draw=2&rank=1. [ABSTRACT FROM AUTHOR]

Primary central nervous system lymphoma (PCNSL) is a type of central nervous system restricted non-Hodgkin lymphoma, whose histopathological diagnosis is majorly large B cell lymphoma. To provide specific, evidence-based recommendations for medical professionals and to promote more standardized, effective and safe treatment for patients with PCNSL, a panel of experts from the Chinese Neurosurgical Society of the Chinese Medical Association and the Society of Hematological Malignancies of the Chinese Anti-Cancer Association jointly developed an evidence-based consensus. After comprehensively searching literature and conducting systematic reviews, two rounds of Delphi were conducted to reach consensus on the recommendations as follows: The histopathological specimens of PCNSL patients should be obtained as safely and comprehensively as possible by multimodal tomography-guided biopsy or minimally invasive surgery. Corticosteroids should be withdrawn from, or not be administered to, patients with suspected PCNSL before biopsy if the patient's status permits. MRI (enhanced and DWI) should be performed for diagnosing and evaluating PCNSL patients where whole-body PET-CT be used at necessary time points. Mini-mental status examination can be used to assess cognitive function in the clinical management. Newly diagnosed PCNSL patients should be treated with combined high-dose methotrexate-based regimen and can be treated with a rituximab-inclusive regimen at induction therapy. Autologous stem cell transplantation can be used as a consolidation therapy. Refractory or relapsed PCNSL patients can be treated with ibrutinib with or without high-dose chemotherapy as re-induction therapy. Stereotactic radiosurgery can be used for PCNSL patients with a limited recurrent lesion who were refractory to chemotherapy and have previously received whole-brain radiotherapy. Patients with suspected primary vitreoretinal lymphoma (PVRL) should be diagnosed by vitreous biopsy. PVRL or PCNSL patients with concurrent VRL can be treated with combined systemic and local therapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The accurate information about lymphoma burden at national and provincial levels remains unknown in China. Methods: Following the general analytical strategy used in GBD 2016, the age-, sex-, and province-specific incidence, mortality, and prevalence of lymphoma in China were analyzed. Trends in the incidence, mortality, prevalence, and disability-adjusted life years (DALYs) due to Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL) were assessed from 2006 to 2016. Results: It was estimated that there were 75,400 new cases and 40,500 deaths of lymphoma in 2016 in China, of which 6900 new cases and 2900 deaths were due to HL, while 68,500 new cases and 37,600 deaths were due to NHL. The age-standardized incidence rate (ASIR), mortality rate (ASMR), and prevalence rate (ASPR) per 100,000 were 0.46, 0.19, and 1.75 for HL, and 4.29, 2.45, and 14.9 for NHL, respectively. An upward trend with age in incidence and mortality was observed. Males had higher incidence and mortality rates than females in all age groups. Sociodemographic index had a correlation with the ASIR (r = 0.75), ASMR (r = − 0.74), ASPR (r = 0.84), and age-standardized DALYs (r = − 0.75) of HL, as well as with the ASIR (r = 0.80), ASPR (r = 0.83), and age-standardized DALYs (r = − 0.33) of NHL. From 2006 to 2016, the age-standardized DALYs of HL decreased significantly, while the age-standardized DALYs of NHL increased from 2006 to 2013 and remained stable from 2013 to 2016. Conclusions: The burden of lymphoma in China showed unexpected patterns varied by sex, age, and provinces, with an increased trend of NHL and a decreased trend of HL from 2006 to 2016. [ABSTRACT FROM AUTHOR]

Background: There is a dearth of accurate information about patterns of mortality of lymphoid neoplasms and temporal trends in China. In this nationwide mortality study, we aimed to assess the mortality of lymphoma and myeloma in 2017 and the changes in the trend from 2004 to 2016. Methods: Death certificate data obtained from the Chinese Center for Disease Control and Prevention's disease surveillance points system (CDC-DSP) and population data from the National Bureau of Statistics of China were used in this study. We described the mortality of lymphoma and myeloma in 2017 by age group, sex, residence, and region and evaluated the temporal trend from 2004 to 2016 using joinpoint regression. Results: An estimated 52,000 deaths associated with lymphoma and myeloma occurred in 2017. The age-standardized mortality rate China (ASMRC) and age-standardized mortality rate worldwide (ASMRW) per 100,000 were 3.74 and 2.60, respectively. Males had higher ASMRC than females (4.54 vs. 2.91 per 100,000). The ASMRC in urban areas was significantly higher than that in rural areas (4.35 vs. 3.47 per 100,000). The age-specific mortality rate showed an upward trend with age and reached a maximum in the age group of over 85 years. In terms of regional variation, Eastern China had the highest mortality rate (3.43/100,000), followed by Central China (3.10/100,000) and Western China (3.02/100,000). The mortality rates of lymphoma and myeloma increased annually by 4.5% during the period 2004–2016, with a significant rapid upward trend in rural areas since 2007. Conclusions: The mortality of lymphoma and myeloma increased in China from 2004 to 2017. The rapid increase in disease burden in rural areas highlights new challenges for disease prevention and control strategies. [ABSTRACT FROM AUTHOR]

Background: The precise mechanism of action for rituximab (R) is not fully elucidated. Besides antibody-dependent cellular cytotoxicity (ADCC), complements may also play an important role in the clinical response to rituximabbased therapy in diffuse large B cell lymphoma (DLBCL). The purpose of this study was to explore the relationship between C1qA[276] polymorphism and the clinical response to standard frontline treatment with R-CHOP in DLBCL patients. Methods: Genotyping for C1qA[276A/G] was done in 164 patients with DLBCL. 129 patients treated with R-CHOP as frontline therapy (R ≥ 4 cycles) were assessable for the efficacy. Results: Patients with homozygous A were found to have a higher overall response rate than those with heterozygous or homozygous G alleles (97.3% vs. 83.7%,P = 0.068). The complete response rate in patients with homozygous A was statistically higher than that in AG and GG allele carriers (89.2% vs. 51.1%,P = 0.0001). The overall survival of patients with homozygous A was longer than that of the G allele carriers (676 days vs. 497 days, P = 0.023). Multivariate Cox regression analysis showed that C1qA A/A allele was an independent favorable prognostic factor for DLBCL patients treated with R-CHOP as first-line therapy. Conclusion: These results suggest that C1qA polymorphism may be a biomarker to predict response to R-CHOP as frontline therapy for DLBCL patients. [ABSTRACT FROM AUTHOR]

Background: Mantle cell lymphoma (MCL) is an incurable B cell-derived malignant tumor with a median overall survival of 4–5 years. Mer tyrosine kinase (MerTK) has been reported to be aberrantly expressed in leukemia, melanoma, and gastric cancer, and plays a pivotal role in the process of oncogenesis. This study assessed the role of MerTK in MCL for the first time. Methods: Immunohistochemistry and western blot were performed to figure out expression of MerTK in MCL. MerTK inhibition by either shRNA or treatment with UNC2250 (a MerTK-selective small molecular inhibitor) was conducted in MCL cell lines. MCL-cell-derived xenograft models were established to evaluate the anti-tumor effects of UNC2250 in vivo. Results: MerTK was ectopically expressed in four of six MCL cell lines. Sixty-five of 132 (48.9%) MCL patients showed positive expression of MerTK. MerTK inhibition by either shRNA or treatment with UNC2250 decreased activation of downstream AKT and p38, inhibited proliferation and invasion in MCL cells, and sensitized MCL cells to treatment with vincristine in vitro and doxorubicin in vitro and in vivo. UNC2250 induced G2/M phase arrest and prompted apoptosis in MCL cells, accompanied by increased expression of Bax, cleaved caspase 3 and poly (ADP-ribose) polymerase, and decreased expression of Bcl-2, Mcl-1 and Bcl-xL. Moreover, UNC2250 delayed disease progression in MCL-cell-derived xenograft models. Conclusions: Our data prove that ectopic MerTK may be a novel therapeutic target in MCL, and further pre-clinical or even clinical studies of UNC2250 or new MerTK inhibitors are essential and of great significance. [ABSTRACT FROM AUTHOR]