PI3K inhibitor idelalisib enhances the anti-tumor effects of CDK4/6 inhibitor palbociclib via PLK1 in B-cell lymphoma.

Relapsed or refractory diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) patients still faced with poor survival, representing an unmet clinical need. In-depth research into the disease's pathogenesis and the development of targeted treatment strategies are urgently needed. Here, we conducted a comprehensive bioinformatic analysis of gene mutation and expression using data from our center and public databases. Cell cycle-related genes especially for CDKN2A/B-CDK4/6/CCND1 machinery altered frequently in DLBCL and MCL. Clinically, high CDK4 and CDK6 expression were correlated with poor prognosis of DLBCL and MCL patients. Furthermore, we also validated the pharmacological efficacy of CDK4/6 inhibitor palbociclib and its synergy effect with PI3K inhibitor idelalisib utilizing in vitro cell lines and in vivo cell-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models. Our results provided sufficient pre-clinical evidence to support the potential combination of palbociclib and idelalisib for DLBCL and MCL patients.

Germline variants of DNA repair and immune genes in lymphoma from lymphoma-cancer families.

The genetic predisposition to lymphoma is not fully understood. We identified 13 lymphoma-cancer families (2011-2021), in which 27 individuals developed lymphomas and 26 individuals had cancers. Notably, male is the predominant gender in lymphoma patients, whereas female is the predominant gender in cancer patients (p = .019; OR = 4.72, 95% CI, 1.30-14.33). We collected samples from 18 lymphoma patients, and detected germline variants through exome sequencing. We found that germline protein truncating variants (PTVs) were enriched in DNA repair and immune genes. Totally, we identified 31 heterozygous germline mutations (including 12 PTVs) of 25 DNA repair genes and 19 heterozygous germline variants (including 7 PTVs) of 14 immune genes. PTVs of ATM and PNKP were found in two families, respectively. We performed whole genome sequencing of diffuse large B cell lymphomas (DLBCLs), translocations at IGH locus and activation of oncogenes (BCL6 and MYC) were verified, and homologous recombination deficiency was detected. In DLBCLs with germline PTVs of ATM, deletion and insertion in CD58 were further revealed. Thus, in lymphoma-cancer families, we identified germline defects of both DNA repair and immune genes in lymphoma patients.

Camrelizumab plus gemcitabine and oxaliplatin for relapsed or refractory classical Hodgkin lymphoma: a phase II trial.

BACKGROUND: Classical Hodgkin lymphoma (cHL) is a highly curable disease, while novel therapy is needed for refractory or relapsed (R/R) patients. This phase II trial aimed to evaluate the role of camrelizumab plus gemcitabine and oxaliplatin (GEMOX) in R/R cHL patients. METHODS: Transplant-eligible patients with R/R cHL were enrolled and received two 14-day cycles of camrelizumab 200 mg intravenously (IV) and two 28-day cycles of camrelizumab 200 mg IV, gemcitabine 1000 mg/m2 IV, and oxaliplatin 100 mg/m2 IV on days 1 and 15. Patients with partial response (PR) or stable disease received an additional cycle of combination therapy. Those who achieved complete response (CR) or PR proceeded to autologous stem cell transplantation (ASCT). The primary endpoint was the CR rate at the end of protocol therapy before ASCT. RESULTS: Forty-two patients were enrolled. At the end of protocol therapy, the objective response rate and CR rate were 94.9% (37/39) and 69.2% (27/39) in the evaluable set, and 88.1% (37/42) and 64.3% (27/42) in the full analysis set, respectively. Twenty-nine patients (69.0%) proceeded to ASCT, and 4 of 5 patients with PR achieved CR after ASCT. After a median follow-up of 20.7 months, the 12-month progression-free survival rate was 96.6% and the 12-month overall survival rate was 100%. Grade 3 or higher treatment emergent adverse events occurred in 28.6% of patients (12/42), mainly hematological toxicity. CONCLUSIONS: Camrelizumab combined with GEMOX constitutes an effective salvage therapy for R/R cHL, proving to be relatively well-tolerated and facilitating ASCT in most patients, thus promoting sustained remission. TRIAL REGISTRATION: ClinicalTrials.gov NCT04239170. Registered on January 1, 2020.

Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD.

Functional loss of TDP-43, an RNA binding protein genetically and pathologically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leads to the inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote the degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. Here, we show that mRNA transcripts harboring cryptic exons generated de novo proteins in TDP-43-depleted human iPSC-derived neurons in vitro, and de novo peptides were found in cerebrospinal fluid (CSF) samples from patients with ALS or FTD. Using coordinated transcriptomic and proteomic studies of TDP-43-depleted human iPSC-derived neurons, we identified 65 peptides that mapped to 12 cryptic exons. Cryptic exons identified in TDP-43-depleted human iPSC-derived neurons were predictive of cryptic exons expressed in postmortem brain tissue from patients with TDP-43 proteinopathy. These cryptic exons produced transcript variants that generated de novo proteins. We found that the inclusion of cryptic peptide sequences in proteins altered their interactions with other proteins, thereby likely altering their function. Last, we showed that 18 de novo peptides across 13 genes were present in CSF samples from patients with ALS/FTD spectrum disorders. The demonstration of cryptic exon translation suggests new mechanisms for ALS/FTD pathophysiology downstream of TDP-43 dysfunction and may provide a potential strategy to assay TDP-43 function in patient CSF.

Management and clinical outcomes of follicular lymphoma across continuous lines of treatments: a retrospective analysis in China.

Background: Follicular lymphoma (FL) is characterized by an incurable course that frequently necessitates multiple lines of treatment. While a range of new approaches have broadened therapeutic options for patients in later lines, data regarding treatment patterns and outcomes of Chinese patients with relapsed/refractory(R/R) FL was scarcely reported. Methods: This retrospective single-center study included patients diagnosed with FL grades 1-3a at our institution between January 2002 and December 2019. Endpoints of interest were analyzed according to lines and types of interventions. The endpoints mainly included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: The study enrolled 566 biopsy-proven patients. Among them, 544 patients initiated the first line of treatment, followed by 240 initiating the second line, 146 initiating the third line, 88 initiating the fourth line, 47 initiating the fifth line, and 28 initiating the sixth line. In terms of treatment patterns, anti-CD20 chemotherapy was a major modality in the first and second lines. However, for patients in the third line and subsequent lines, treatment approaches were diverse, and participation in clinical trials for new medications was common, which correlated with a survival benefit. The study also revealed that clinical indicators (such as ORR, PFS, and OS) gradually decreased with each subsequent line of treatment. The ORR at the first line was 86.6%, but decreased to 48.6% at the third line and 40.4% at the sixth line, respectively. Similarly, median OS and PFS decreased to 88.8 and 7.1 months at the third line and further reduced to 21.7 and 2.8 months at the sixth line, respectively. A total of 133 patients developed progression within 24 months from the initiation of first line anti-CD20 chemotherapy (POD24), and these patients exhibited poorer response rates and outcomes in subsequent lines of therapycompared to the non-POD24 group. Conclusion: This study revealed the clinical routine practices and prognosis of R/R FL patients within the Chinese population. It underscored the unmet need for optimal strategies to improve survival and also served as a benchmark for future trials.

Antitumor activity and safety of camrelizumab combined with apatinib in patients with relapsed or refractory peripheral T-cell lymphoma: An open-label, multicenter, phase II study.

Introduction: The treatment for relapsed/refractory peripheral T-cell lymphoma (r/r PTCL) is suboptimal. This open-label, multicenter, single-arm study aimed to investigate the antitumor activity and safety of camrelizumab (a PD-1 blockade) plus apatinib (an antiangiogenic agent) for patients with r/r PTCL. Methods: Eligible patients with r/r PTCL were enrolled and received camrelizumab 200 mg intravenously every 2 weeks and apatinib 500 or 250 mg orally once daily, 4 weeks as a cycle. The primary endpoint was overall response rate (ORR). Results: A total of 20 patients were enrolled and received study medications in the study, with a median number of prior treatment line of 3 (range 1-6). At the cutoff date of March 4, 2022, the median follow-up was 27.2 months (range: 0.5-39.9), and three patients remained on treatment. Six patients had early discontinuation without tumor response evaluation. For all patients, the ORR was 30% (6/20) (95% confidence interval [CI], 11.9% to 54.3%), with two patients (10%) achieving complete response. The median progression-free survival (PFS) and median overall survival for all patients were 5.6 months (95% CI, 1.8 to not reached) and 16.7 months (95% CI, 2.8 to not reached), respectively. Patients with PD-L1 expression ≥50% (3 patients) had a numerically higher ORR and longer median PFS than those with PD-L1 expression < 50% (5 patients). The most commonly reported grade 3 or higher adverse events were hyperlipidemia (15%), hypokalemia (15%) and anemia (15%). No treatment-related deaths occurred. Discussion: In this study, PD-1 inhibitors plus low-dose antiangiogenic drugs presented preliminary antitumor activity and manageable toxicity in patients with r/r PTCL.

Clinical characteristics and outcomes of follicular lymphoma patients with extranodal involvement: analysis of a series of 1090 cases in China.

BACKGROUND: Follicular lymphoma (FL) is the most common indolent B cell lymphoma in the world. The clinical features of extranodal involvement in FL were never extensively described. METHODS: We enrolled 1090 patients diagnosed as newly diagnosed FL at ten medical institutions in China from 2000 to 2020 and conducted this analysis and retrospectively explored clinical characteristics and outcomes of FL patients with extranodal involvement. RESULTS: 400 (36.7%) patients with newly diagnosed FL had no extranodal involvement, 388 (35.6%) patients had one site of extranodal involvement, and 302 (27.7%) had two or more sites of involvement. Patients with >1 extranodal site had significantly worse PFS (p<0.001), as well as OS (p=0.010). The most common site of extranodal involvements was bone marrow (33%), followed by spleen (27.7%) and intestine (6.7%). In patients with extranodal involvement, multivariate Cox analysis found that male patients (p=0.016), poor performance status (p=0.035), increased LDH (p<0.001) and pancreas involvement (p<0.001) was associated with poor PFS, while the latter three factors were also associated with poor OS. Compared to patients with one site of extranodal involvement, patients with >1 site involvement (p=0.012) had 2.04-fold risk to develop POD24. In addition, multivariate Cox analysis found that the usage of rituximab was not associated with better PFS (p=0.787) or OS (p=0.191). CONCLUSIONS: Our cohort is large enough to have statistical significance in FL patients with extranodal involvement. Male sex, increased LDH, poor performance status, >1 extranodal site, as well as pancreas involvement indicated useful prognostic factors in the clinical setting.

Differences in clinical characteristics and outcomes between patients with grade 3a and grades 1-2 follicular lymphoma: a real-world multicenter study.

BACKGROUND: The difference between clinical characteristics and outcomes between follicular lymphoma grade 1-2 (FL1-2) and FL3a defined pathologically remains unclear, resulting in uncertainty how to treat FL3a. However, it may be crucial for clinicians to discriminate grade 3a and grade 1-2 for predicting prognosis and thus making treatment decisions. METHODS: We compared 1403 patients with FL1-2 and 765 patients with FL3a diagnosed between January 2000 and December 2020 from fifteen centers nationwide in China to describe differences in clinical characteristics and outcomes. RESULTS: Compared with FL1-2 patients, FL3a subgroup had a higher percentage of elderly patients (P = 0.003), and relatively more FL3a patients presented with increased levels of LDH (P < 0.0001) and higher Ki-67 indexs greater than 30% (P < 0.001). More FL3a patients were treated with CHOP ± R (P < 0.0001), and fewer were treated with the watchful-waiting approach (P < 0.0001). The results showed a higher incidence of relapse among FL3a patients, in which more patients underwent histological transformation (HT) when compared to FL1-2 (P = 0.003). 1470 (76.2%) patients of the entire cohort received R-CHOP therapy; survival analysis revealed that FL3a patients had a worse progression-free survival (PFS) rate than FL1-2 patients. Survival of FL3a patients with respect to FLIPI showed an inferior PFS in the intermediate and high-risk groups than FL1-2 patients. FL3a patients had a much worse prognosis than FL1-2 with or without progression of disease within 24 months (POD24). FL3a patients had higher likelihood of lymphoma-related death (LRD, P < 0.05), whereas the rates for non-LRD were comparable. CONCLUSION: In conclusion, this study demonstrates a marked difference in clinical features and outcomes in FL3a patients compared with FL1-2 patients. The results highlight the need for applying therapeutic approaches distinct from FL1-2 when treating FL3a patients.

Efficacy and safety of relmacabtagene autoleucel, an anti-CD19 chimeric antigen receptor T cell, in relapsed/refractory B-cell non-Hodgkin's lymphoma: 2-year results of a phase 1 trial.

This study reported 2-year efficacy and safety of relma-cel in Chinese patients with relapsed/refractory (R/R) B-cell non-Hodgkin's lymphoma (B-NHL). In this phase 1 dose-escalating trial, patients received lymphodepleting chemotherapy for 3 days, followed by relma-cel as a single infusion in escalating dose levels (25 × 106, 50 × 106, 100 × 106, and 150 × 106 CAR-T cells). The endpoints included best objective response rate (ORR), best complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. A total of 23 patients were enrolled, including 60.9% with diffuse large B-cell lymphoma and 26.1% with follicular lymphoma. Twenty patients were evaluable for efficacy, and the best ORR was 85.0% and the best CRR was 75.0%. With a median follow-up of 24.2 months, 6 patients died and 2 had progressive disease, the median DOR, PFS, and OS were all not reached. The 2-year PFS and OS rates were 60.0% and 70.0%, respectively. Any grade and grade ≥ 2 cytokine release syndrome occurred in 18.2% and 13.6% of patients, respectively. Only 1(4.5%) patient had grade 3 CRS lasting 13 days, which was resolved by tocilizumab. No grade ≥ 2 neurotoxicity events or treatment-related deaths occurred. Patients with R/R B-NHL treated with relma-cel achieved durable response with favorable safety profile.

The Serum- and Glucocorticoid-Inducible Kinase 1 (SGK1) as a Novel Therapeutic Target in Mantle Cell Lymphoma.

INTRODUCTION: Mantle cell lymphoma (MCL) is an aggressive and incurable B-cell-derived malignant disease. MCL is treated using general chemotherapy; however, disease progression and relapse are common; thus, the development of novel therapeutic targets for treatment of MCL is urgently required. Serum- and glucocorticoid-inducible kinase 1 (SGK1) is involved in various cellular activities, and its dysregulation contributes to the pathogenesis of multiple types of cancer. However, little is known regarding its functional roles and associated molecular mechanisms in MCL. METHODS: SGK1 inhibition mediated by either shRNA or treatment with SGK1 inhibitor (GSK650394) was conducted in MCL cell lines. Western blotting analysis was performed to figure out the expression of related proteins. MCL-cell-derived xenograft models were constructed to evaluate the anti-tumor effects of SGK1 inhibition or/and Bruton's tyrosine kinase (BTK) inhibition in vivo. RESULTS: In this study, it was shown that inhibition of SGK1 significantly reduced cell proliferation, invasion and migration, increased apoptosis and blocked cell cycle progression in MCL cells. Furthermore, SGK1 inhibition significantly reduced the activation of ERK, AKT/mTOR, JAK2/STAT3 and the NF-κB signaling pathways. Using MCL-cell-derived xenograft mice models, SGK1 inhibition decreased tumor cell proliferation and tumor growth. Importantly, SGK1 overexpression significantly promoted xenograft tumor growth. Moreover, simultaneous inhibition of SGK1 and Bruton tyrosine kinase (BTK) resulted in synergistic anti-tumor effects on MCL both in vitro and in vivo. CONCLUSION: SGK1 may be a novel candidate therapeutic target and simultaneous inhibition of SGK1 and BTK may be a promising therapeutic strategy for MCL patients. Further pre-clinical and even clinical studies of SGK1 inhibitor or combination with BTK inhibitor are essential.

Signatures of glial activity can be detected in the CSF proteome.

Single-cell transcriptomics has revealed specific glial activation states associated with the pathogenesis of neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. While these findings may eventually lead to new therapeutic opportunities, little is known about how these glial responses are reflected by biomarker changes in bodily fluids. Such knowledge, however, appears crucial for patient stratification, as well as monitoring disease progression and treatment responses in clinical trials. Here, we took advantage of well-described mouse models of ß-amyloidosis and α-synucleinopathy to explore cerebrospinal fluid (CSF) proteome changes related to their respective proteopathic lesions. Nontargeted liquid chromatography-mass spectrometry revealed that the majority of proteins that undergo age-related changes in CSF of either mouse model were linked to microglia and astrocytes. Specifically, we identified a panel of more than 20 glial-derived proteins that were increased in CSF of aged ß-amyloid precursor protein- and α-synuclein-transgenic mice and largely overlap with previously described disease-associated glial genes identified by single-cell transcriptomics. Our results also show that enhanced shedding is responsible for the increase of several of the identified glial CSF proteins as exemplified for TREM2. Notably, the vast majority of these proteins can also be quantified in human CSF and reveal changes in Alzheimer's disease cohorts. The finding that cellular transcriptome changes translate into corresponding changes of CSF proteins is of clinical relevance, supporting efforts to identify fluid biomarkers that reflect the various functional states of glial responses in cerebral proteopathies, such as Alzheimer's and Parkinson's disease.

Anti-CD47 immunotherapy in combination with BCL-2 inhibitor to enhance anti-tumor activity in B-cell lymphoma.

CD47 expressed on cancer cells enables macrophage immune evasion. Blocking CD47 using anti-CD47 monoclonal antibodies (mAbs) is a promising strategy. The anti-CD47 mAb TJC4 has anti-tumor activity but lacks hematological toxicity. Venetoclax, a B-cell lymphoma 2 (BCL-2) inhibitor for B-cell malignancy, induces phosphatidylserine (PS) extracellular exposure, representing an "eat-me" signal for macrophages. The present study aimed to explore whether TJC4-Venetoclax combined therapy exerts synergistic anti-cancer properties in B-cell lymphoma. In vitro, flow cytometry and microscopy assessed whether TJC4 monotherapy or combination treatment could promote macrophage-mediated phagocytosis of tumor cells. Induced PS exposure on the cell membrane was measured using flow cytometry with Annexin V-FITC staining. In vivo, Venetoclax and TJC4's synergistic anti-tumor effects were evaluated. B cell lymphoma cell lines express high levels of CD47 and patients with diffuse large B cell lymphoma expressing CD47 have a worse clinical prognosis. TJC4 eliminates tumor cells via macrophage-mediated phagocytosis. In vitro and in vivo, the TJC4-Venetoclax combination increased phagocytosis significantly compared with either agent alone, showing synergistic phagocytosis, and displayed synergistic anti-cancer properties in B-cell lymphoma. Our results support the TJC4-Venetoclax combination as a promising therapy, and suppressing BCL-2 and CD47 simultaneously could represent a novel therapeutic paradigm for B-cell lymphoma.

A durable 4-1BB-based CD19 CAR-T cell for treatment of relapsed or refractory non-Hodgkin lymphoma.

Objective: Previous studies reported that 4-1BB-based CD19 chimeric antigen receptor (CAR)-T cells were more beneficial for the clinical outcomes than CD28-based CAR-T cells, especially the lower incidence rate of severe adverse events. However, the median progression-free survival (mPFS) of 4-1BB-based product Kymriah was shorter than that of CD28-based Yescarta (2.9 monthsvs. 5.9 months), suggesting that Kymriah was limited in the long-term efficacy. Thus, a safe and durable 4-1BB-based CD19 CAR-T needs to be developed. Methods: We designed a CD19-targeted CAR-T (named as IM19) which consisted of an FMC63 scFv, 4-1BB and CD3ζ intracellular domain and was manufactured into a memory T-enriched formulation. A phase I/II clinical trial was launched to evaluate the clinical outcomes of IM19 in relapsed or refractory (r/r) B cell non-Hodgkin lymphoma (B-NHL). Dose-escalation investigation (at a dose of 5×105/kg, 1×106/kg and 3×106/kg) was performed in 22 r/r B-NHL patients. All patients received a single infusion of IM19 after 3-day conditional regimen. Results: At month 3, the overall response rate (ORR) was 59.1%, the complete response rate (CRR) was 50.0%. The mPFS was 6 months and the 1-year overall survival rate was 77.8%. Cytokine release syndrome (CRS) occurred in 13 patients (59.1%), with 54.5% of grade 1-2 CRS. Only one patient (4.5%) experienced grade 3 CRS and grade 3 neurotoxicity. Conclusions: These results demonstrated the safety and durable efficacy of a 4-1BB-based CD19 CAR-T, IM19, which is promising for further development and clinical investigation.

A phase I pharmacokinetic study of copanlisib in Chinese patients with relapsed indolent non-Hodgkin lymphoma.

PURPOSE: Copanlisib, a pan-PI3K inhibitor, has previously shown clinical efficacy and a tolerable safety profile in patients with indolent non-Hodgkin lymphoma. However, the pharmacokinetics, safety, tolerability, and efficacy of copanlisib in Chinese patients have not been reported. METHODS: This was a single-arm, open-label, phase I study of copanlisib in Chinese patients with relapsed or refractory indolent non-Hodgkin lymphoma (iNHL). Patients received a single intravenous 60 mg infusion of copanlisib over 1 h on days 1, 8, and 15 of a 28-day cycle, with 1 week of rest. Safety was monitored throughout the study, and plasma copanlisib levels were measured for pharmacokinetic analysis. Tumor response was determined by independent central radiologic review. RESULTS: Sixteen patients were enrolled and 13 were treated with 60 mg of copanlisib for a median of 15.0 weeks. With a Cmax of 566 µg/L and a AUC (0-24) of 1880 µg·h/L following single intravenous infusion, the pharmacokinetic parameters of copanlisib were consistent with that in previous studies, and no accumulation in plasma was observed. Treatment-emergent adverse events were reported for all 13 patients, the most common of which were hyperglycemia (100.0%), hypertension (76.9%), decreased neutrophil count (76.9%), and decreased white blood cell count (69.2%). Seven out of 12 evaluated patients achieved partial response, resulting in an overall response rate of 58.3% CONCLUSIONS: Copanlisib was well tolerated in Chinese patients with relapsed or refractory iNHL at the dose of 60 mg and demonstrated encouraging disease control, thus warranting further clinical investigation. CLINICAL TRIAL REGISTRATION NUMBER: NCT03498430 (April 13, 2018).

Conditional Survival and Annual Hazard Estimates of Classical Hodgkin Lymphoma.

BACKGROUND: In the present study, we have tried to understand how the level of risk and survival probability changes over time for patients with classical Hodgkin's lymphoma by employing conditional survival and annual hazard as dynamic estimates of prognosis and survival. METHODS: This retrospective study reviewed the clinical data of patients with newly diagnosed classical Hodgkin's lymphoma admitted to Peking University Cancer Hospital between January 1, 2008, and December 31, 2017. Conditional survival and annual hazard rate were defined as the survival probability and yearly event rate, respectively, assuming that patients have survived for a defined time. RESULTS: A total of 384 patients were included (median age, 32 years; range, 6-77 years), of which 218 (56.8%) patients had early-stage disease. The median follow-up time was 41.3 months. The 5-year conditional overall survival (COS) rates remained favorable and showed an increase from 89% at treatment to 94% at year 5, while the 5-year conditional failure-free survival (CFFS) rate increased from 70% at treatment to 96% at year 5. The annual hazard of failure decreased from over 15% at diagnosis to less than 5% after 3 years. Early-stage patients had constantly lower annual estimates for hazard of death (range, 0-3.0%) and failure (range, 0-14.3%). However, the hazard of failure in advanced-stage patients decreased from 24.2% at diagnosis to below 8% after 3 years, whereas the hazard of death was always at relatively low levels. Patients with a high IPS risk score (≥3) had significantly lower COS and CFFS during the first 4 years. Patients who received the BEACOPP regimen had better 5-year COS and 5-year CFFS than those who received the ABVD regimen. CONCLUSION: The survival probability increased and hazard of failure decreased over time.

Phase 1 clinical trial of the PI3Kδ inhibitor YY-20394 in patients with B-cell hematological malignancies.

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 .

Clinical features and outcomes of 1845 patients with follicular lymphoma: a real-world multicenter experience in China.

Clinical features and outcomes of FL patients in Chinese population are limited, thus promoting us to perform this analysis on a large cohort of 1845 patients with FL enrolled from nine medical centers nationwide in China. In this cohort, the median age of patients at diagnosis was 53 years, which was comparable to that reported previously for Chinese FL patients (49-51 years) but younger than that for Western FL patients (60-65 years). In contrast with Western patients, Chinese FL patients more likely involved extranodal sites but less frequently infiltrated bone marrow. Other clinical characteristics were comparable between two populations. In this study, 91% of patients were managed with chemotherapy, yielding 72% and 46% of overall-response rate and complete remission. After median 55-month follow-up, 5-year progressive-free and overall survival were 61% and 89%, respectively. Both were analogous to those reported in prior Chinese and Western studies. Consistent with published data, addition of rituximab into both induction (Ri) and maintenance (Rm) treatment led to the most favorable outcomes. Interestingly, Ri only had better outcomes than Rm only. Notably, 7% of patients experienced histologic transformation (HT) and correlated with poor survival. Of the transformed FL cases, 3% and 4% of HT events occurred prior to or post-treatment, respectively. Importantly, the latter displayed worse outcomes than the former. Altogether, this study provides real-world information of the largest cohort of FL patients so far in China, which might lay a foundation for clinical investigation of Chinese FL in future.

Distribution of chimeric antigen receptor-modified T cells against CD19 in B-cell malignancies.

BACKGROUND: The unprecedented efficacy of chimeric antigen receptor T (CAR-T) cell immunotherapy of CD19+ B-cell malignancies has opened a new and useful way for the treatment of malignant tumors. Nonetheless, there are still formidable challenges in the field of CAR-T cell therapy, such as the biodistribution of CAR-T cells in vivo. METHODS: NALM-6, a human B-cell acute lymphoblastic leukemia (B-ALL) cell line, was used as target cells. CAR-T cells were injected into a mice model with or without target cells. Then we measured the distribution of CAR-T cells in mice. In addition, an exploratory clinical trial was conducted in 13 r/r B-cell non-Hodgkin lymphoma (B-NHL) patients, who received CAR-T cell infusion. The dynamic changes in patient blood parameters over time after infusion were detected by qPCR and flow cytometry. RESULTS: CAR-T cells still proliferated over time after being infused into the mice without target cells within 2 weeks. However, CAR-T cells did not increase significantly in the presence of target cells within 2 weeks after infusion, but expanded at week 6. In the clinical trial, we found that CAR-T cells peaked at 7-21 days after infusion and lasted for 420 days in peripheral blood of patients. Simultaneously, mild side effects were observed, which could be effectively controlled within 2 months in these patients. CONCLUSIONS: CAR-T cells can expand themselves with or without target cells in mice, and persist for a long time in NHL patients without serious side effects. TRIAL REGISTRATION: The registration date of the clinical trial is May 17, 2018 and the trial registration numbers is NCT03528421 .

Chemotherapy with a Pegylated Liposomal Doxorubicin-Containing Regimen in Newly Diagnosed Hodgkin Lymphoma Patients.

Anthracycline-related cardiotoxicity is an important dose-limiting toxicity for Hodgkin lymphoma (HL) treatment. This study aimed to assess the efficacy and safety of pegylated liposomal doxorubicin (PLD) for HL treatment. Patients with newly diagnosed HL treated with at least two cycles of PLD-containing chemotherapy were retrospectively analyzed. The dosing and scheduling of the PLD-containing regimen (the PBVD regimen) were as follows: PLD 25 mg/m2, vincristine 1.4 mg/m2 (maximum dose of 2 mg), bleomycin 10 mg/m2, and dacarbazine 375 mg/m2 at days l and 15, repeated every 28 days. Forty-six HL patients were analyzed. The median age was 41.5 years (range 12-77 years), with a male/female ratio of 0.9:1. Fourteen (30%) patients had an Eastern Cooperative Oncology Group (ECOG) performance status score > 1, and 32 (70%) had a history of cardiovascular disease (CVD) or related risk factors. The median chemotherapy cycle number with the PBVD regimen was 6 (range, 2-8). The overall response rate (ORR) was 91% for the whole cohort; 35 (76%) patients achieved complete remission (CR), and 7 (15%) achieved partial remission. The efficacy of the PBVD regimen was similar in patients with or without CVD or related risk factors (ORR 93% vs. 91%, P = 1.00; CR 86% vs. 72%, P = 0.46). With a median follow-up of 28.5 months, the 3-year progression-free survival (PFS) and overall survival (OS) rates were 70% and 82%, respectively, for the whole cohort. The differences in the PFS and OS rates between the groups with or without CVD or related risk factors were not significant. Cardiotoxicity was observed in 6 (13%) patients. All adverse events were grades 1-2. The PBVD regimen is an effective chemotherapy option with tolerable toxicity, and it could be a substitute in HL patients who cannot be treated with conventional doxorubicin, especially those with CVD or related risk factors.

Autologous hematopoietic stem cell transplantation with inadequate stem cell dose in patients with non-Hodgkin lymphoma.

Little is known regarding the outcome of lymphoma patients undergoing autologous hematopoietic stem cell transplantation (AHSCT) using inadequate hematopoietic stem cell (HSC) doses. Fifty-six patients were enrolled in the study, and the cohort was subdivided into two groups according to the infusion dose: < 1 × 106/kg (poor HSC group) and 1-2 × 106/kg (unfavorable HSC group). Compared with the unfavorable group, the poor HSC group had a longer median time to neutrophil (13 vs. 11 days, p = .007) and platelet engraftment (17 vs. 13 days, p = .024). CD34+ cell infusion dose of < 1 × 106/kg was the only risk factor for neutrophil and platelet engraftment. The expected 3-year progression-free survival and overall survival rates for the whole cohort were 53% and 66%, and no statistical difference was observed between two groups. In conclusion, inadequate HSC infusion dose did not negatively impact AHSCT patient survival but significantly prolonged the time to hematopoietic engraftment.