Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, in patients with refractory or relapsed peripheral T-cell lymphoma (JACKPOT8 Part B): a single-arm, multinational, phase 2 study.

BACKGROUND: Golidocitinib, a selective JAK1 tyrosine-kinase inhibitor, has shown encouraging anti-tumour activity in heavily pre-treated patients with relapsed or refractory peripheral T-cell lymphoma in a phase 1 study (JACKPOT8 Part A). Here, we report the full analysis of a phase 2 study, in which we assessed the anti-tumour activity of golidocitinib in a large multinational cohort of patients. METHODS: We did a single-arm, multinational, phase 2 trial (JACKPOT8 Part B) in 49 centres in Australia, China, South Korea, and the USA. Eligible patients were adults (aged ≥18 years) with relapsed or refractory peripheral T-cell lymphoma who had received at least one previous line of systemic therapy and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were given oral golidocitinib 150 mg once daily until disease progression or other discontinuation criteria were met. The primary endpoint was the CT-based objective response rate, assessed by an independent review committee (IRC) per Lugano 2014 classification. The activity analysis set included all patients who received at least one dose and whose pathological diagnosis of peripheral T-cell lymphoma had been retrospectively confirmed by a central laboratory and who had at least one measurable lesion at baseline assessed by IRC. The safety analysis set included all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT04105010, and is closed to accrual and follow-up is ongoing. FINDINGS: Between Feb 26, 2021, and Oct 12, 2022, we assessed 161 patients for eligibility, of whom 104 (65%) were enrolled and received at least one dose of study drug; the activity analysis set included 88 (85%) patients (median age 58 years [IQR 51-67], 57 [65%] of 88 were male, 31 [35%] were female, and 83 [94%] were Asian). As of data cutoff (Aug 31, 2023; median follow-up was 13·3 months [IQR 4·9-18·4]), per IRC assessment, the objective response rate was 44·3% (95% CI 33·7-55·3; 39 of 88 patients, p<0·0001), with 21 (24%) patients having a complete response and 18 (20%) having a partial response. In the safety analysis set, 61 (59%) of 104 patients had grade 3-4 drug-related treatment-emergent adverse events. The most common grade 3-4 drug-related treatment-emergent adverse events were neutrophil count decreased (30 [29%]), white blood cell count decreased (27 [26%]), lymphocyte count decreased (22 [21%]), and platelet count decreased (21 [20%]), which were clinically manageable and reversible. 25 (24%) patients had treatment-related serious adverse events. Deaths due to treatment-emergent adverse events occurred in three (3%) patients: two (2%) due to pneumonia (one case with fungal infection [related to golidocitinib] and another one with COVID-19 infection) and one (1%) due to confusional state. INTERPRETATION: In this phase 2 study, golidocitinib showed a favourable benefit-risk profile in treating relapsed or refractory peripheral T-cell lymphoma. The results of this study warrant further randomised clinical studies to confirm activity and assess efficacy in this population. FUNDING: Dizal Pharmaceutical.

Bendamustine in the treatment of patients with indolent non-Hodgkin lymphoma refractory or relapse to rituximab treatment: An open-label, single-agent, multicenter study in China.

BACKGROUND: The optimal treatment strategy for refractory or relapse (R/R) indolent non-Hodgkin lymphoma (iNHL) has not been fully identified. This study aims to investigate the efficacy and tolerance of bendamustine hydrochloride developed in native Chinese corporation in the treatment of patients with R/R iNHL. METHODS: A total of 101 patients from 19 centers were enrolled in this study from July 2016 to February 2019. Bendamustine hydrochloride (120 mg/m2 ) was given on days 1 and 2 of each 21-day treatment cycle for six planned cycles or up to eight cycles if tolerated. Parameters of efficacy and safety were analyzed. RESULTS: The median age of the patients was 53.44 (range, 24.4-74.6) years old. A total of 56 (55.44%) patients completed at least six treatment cycles, and the relative dose intensity was 93.78%. The overall response rate was 72.28%, and the median duration of response was 15.84 months (95% confidence interval [CI], 13.77-27.48 months). Median progression-free survival was 16.52 months (95% CI, 14.72-23.41 months), and the median overall survival was not reached. Grade 3 or 4 hematologic toxicities included neutropenia (77.22%), thrombocytopenia (29.70%), and anemia (15.84%). The most frequent nonhematologic adverse events (any grade) included nausea, vomiting, fatigue, fever, decreased appetite, and weight loss. Seven patients died during the trial, and four cases may be related to the investigational drug. CONCLUSIONS: This study reveals that bendamustine hydrochloride is a feasible treatment option for the indolent B-cell non-Hodgkin lymphoma patient who has not remitted or relapsed after treatment with rituximab. All adverse events were predictable and manageable.

Tislelizumab with gemcitabine and oxaliplatin in patients with relapsed or refractory classic Hodgkin lymphoma: a multicenter phase II trial.

Although classic Hodgkin lymphoma (cHL) is highly curable with current treatment paradigms, therapy fails in 10-25% of patients. This prospective multicenter phase II study attempted to investigate the efficacy and safety of the combination of tislelizumab with gemcitabine and oxaliplatin (T-GemOx) in relapsed or refractory cHL. Participants received six to eight courses of gemcitabine (1 g/m2 on day 1) and oxaliplatin (100 mg/m2 on day 1) combined with tislelizumab (200 mg on day 2) at 21-day intervals, followed by tislelizumab maintenance (every 2 months for 2 years). The main outcome measure was the best complete remission rate. As of August 2022, a total of 30 patients had been consecutively enrolled and given induction therapy. The best overall response rate and complete remission rate were 100% (95% confidence interval [CI]: 88.4-100%) and 96.7% (95% CI: 82.8-99.9%), respectively. The median duration of follow-up after initiation of T-GemOx was 15.8 months. The 12-month progression-free survival rate without autologous stem cell transplant was 96% (95% CI: 74.8-99.4%). There were 122 adverse events recorded, of which 93.4% were grade 1 or 2. Thrombocytopenia (10%) and anemia (6.7%) were the most common grade 3 or 4 adverse events. Overall, T-GemOx demonstrated promising antitumor activity with manageable toxicities as a salvage treatment for relapsed or refractory cHL. A longer follow-up duration is required to determine whether maintenance therapy with tislelizumab rather than transplantation can be curative following such a highly active regimen. This trial was registered with the Chinese Clinical Trials Registry (http://www.chictr.org.cn) on June 1, 2020, identifier ChiCTR2000033441.

Orelabrutinib in relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma patients: Multi-center, single-arm, open-label, phase 2 study.

Orelabrutinib is a novel, small molecule, selective irreversible Bruton's tyrosine kinase inhibitor. The aim of this study was to evaluate the efficacy and safety in patients with refractory or relapsed chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). This is single-arm, multi-center, open-label, phase 2 study in 80 eligible Chinese patients, who were treated with monotherapy of orelabrutinib at 150 mg once daily. Overall response rate evaluated by an independent review committee was the primary endpoint, and secondary endpoints include progression-free survival, overall survival, and safety. Independent review committee assessed overall response rate was 92.5% (74/80); complete response 21.3% (17/80), partial response 60.0% (48/80), partial response with lymphocytosis 11.3% (9/80). At a 32.3-month median follow-up, the median progression-free survival had not been achieved, while the 30-month progression-free survival rate and overall survival rates were 70.9% (95% confidence interval [CI], 59.5-79.6) and 81.3% (95% CI, 70.8-88.2), respectively. Orelabrutinib also revealed substantial response in patients with high prognostic risks: overall response rates of patients carrying positive TP53 mutational status or del(17p), del(11q), as well as unmutated immunoglobulin heavy-chain variable region gene were 100%, 94.7%, and 93.9%, respectively. Most adverse events were in low grade, with 86.8% of AEs being Grade 1 or 2. Nearly 67% of patients were still receiving orelabrutinib after almost a 3-year follow-up. In conclusion, Orelabrutinib demonstrated compelling efficacy as well as safety profiles, with a noteworthy number of patients obtaining complete response in refractory or relapsed CLL/SLL.

Orelabrutinib for the treatment of relapsed or refractory marginal zone lymphoma: A phase 2, multicenter, open-label study.

Marginal zone lymphoma (MZL) is an indolent type of non-Hodgkin lymphoma that develops through pathological B cell receptor signaling. Orelabrutinib, a new-generation oral small molecule Bruton's tyrosine kinase inhibitor, was evaluated in relapsed/refractory (r/r) MZL patients. Previously treated r/r MZL patients received orelabrutinib 150 mg once daily in a phase 2, multicenter, single-arm study conducted in China. The primary endpoint was overall response rate (ORR) assessed by an Independent Review Committee (IRC) based on the Lugano 2014 classification. Other efficacy, safety, and pharmacokinetic profiles were evaluated as secondary outcome measures. A total of 111 patients were enrolled, of which 90 patients had MZL confirmed by central pathology review, who were mainly with extra-nodal MZL of mucosa-associated lymphoid tissue (MALT, 46.7%) and nodal MZL (35.6%). The majority had late-stage disease, with stage IV accounting for 75.6%. After a median follow-up duration of 24.3 months, the IRC-assessed ORR was 58.9% (95% confidence interval [CI], 48.0-69.2), with rates of complete response and partial response being 11.1% and 47.8%, respectively. The IRC-assessed median duration of response was 34.3 months, and the IRC-assessed median progression-free survival (PFS) was not reached with a 12-month PFS rate of 82.8% (95% CI, 72.6-89.5). The rate of overall survival at 12 months was 91.0% (95% CI, 82.8-95.4). Common all-grade treatment-related adverse events (TRAEs) included anemia (27.9%), neutrophil count decrease (23.4%), white blood cell count decrease (18.0%), platelet count decrease (17.1%), blood present in urine (16.2%), rash (14.4%), and upper respiratory tract infection (10.8%). Thirty-four patients (30.6%) experienced grade 3 or higher TRAEs. Serious TRAEs occurred in 18 patients (16.2%), of which pneumonia (5.4%) was the most common. Seven patients (6.3%) discontinued orelabrutinib due to TRAEs. Orelabrutinib demonstrated high response rates with durable disease remission and was well tolerated in Chinese patients with r/r MZL.

Improved Artificial Potential Field Algorithm Assisted by Multisource Data for AUV Path Planning.

With the development of ocean exploration technology, the exploration of the ocean has become a hot research field involving the use of autonomous underwater vehicles (AUVs). In complex underwater environments, the fast, safe, and smooth arrival of target points is key for AUVs to conduct underwater exploration missions. Most path-planning algorithms combine deep reinforcement learning (DRL) and path-planning algorithms to achieve obstacle avoidance and path shortening. In this paper, we propose a method to improve the local minimum in the artificial potential field (APF) to make AUVs out of the local minimum by constructing a traction force. The improved artificial potential field (IAPF) method is combined with DRL for path planning while optimizing the reward function in the DRL algorithm and using the generated path to optimize the future path. By comparing our results with the experimental data of various algorithms, we found that the proposed method has positive effects and advantages in path planning. It is an efficient and safe path-planning method with obvious potential in underwater navigation devices.

Three-dimensional morphology measurement of underwater objects based on the photoacoustic effect.

Complexities of the underwater environment can seriously affect many underwater detection means, especially the influence of light scattering by water. To solve this problem, a three-dimensional (3D) morphology measurement method is proposed based on the photoacoustic effect. In this method, a measurement object is irradiated with pulsed laser light to produce ultrasonic waves via the photoacoustic effect. A probe collects the ultrasonic signal and subsequent data processing can yield complete object detection. This approach can make full use of the advantages of high precision and good directivity of laser ranging and completely avoid the influence on the laser of backscattering from water. The results yield a displacement measurement accuracy of less than 0.5 mm and an average error of 3D reconstruction of 0.21 mm, demonstrating great application potential.

The "m6A writer" METTL3 and the "m6A reader" IGF2BP2 regulate cutaneous T-cell lymphomas progression via CDKN2A.

It has been established that Cutaneous T-Cell lymphomas (CTCL) are caused by the monoclonal proliferation of T lymphocytes in the skin. This heterogeneous group of diseases represents a significant source of distress to patients since the diagnosis and treatment are often challenging. As one of the most abundant internal modifications in mRNA in higher eukaryotes, N6-methyladenosine (m6A) is widely recognized to affect the development and progression of cancers. However, knowledge on the involvement of m6A in CTCL is still limited. In this work, we revealed the role of METTL3-mediated m6A modification in CTCL progression. ELISA, western blot, and qRT-PCR assays demonstrated that METTL3 was significantly downregulated in CTCL cells both in vivo and in vitro. CCK-8, EdU, flow cytometry, and transwell assays showed that the decline in METTL3 levels was responsible for CTCL cell proliferation and migration. Furthermore, using small interfering RNAs against METTL3 and the RIP assay, we showed that CDKN2A was a key regulator during this process in vitro and in vivo, and insufficient methylation modification blocked the interaction between CDKN2A and m6A reader IGF2BP2, resulting in mRNA degradation. To the best of our knowledge, this is the first study to depict the role of m6A in CTCL development and provide potential bio-targets for therapy.

Ixazomib-based frontline therapy in patients with newly diagnosed multiple myeloma in real-life practice showed comparable efficacy and safety profile with those reported in clinical trial: a multi-center study.

The induction therapy containing ixazomib, an oral proteasome inhibitor, has shown favorable efficacy and safety in clinical trials, but its experience in real-life remains limited. In routine practice, few patients received ixazomib-based induction therapy due to reasons including (1) patients' preference on oral regimens, (2) concerns on adverse events (AEs) of other intravenous/subcutaneous regimens, (3) requirements for less center visits, and (4) fears of COVID-19 and other infectious disease exposures. With the aim of assessing the real-life effectiveness and safety of ixazomib-based induction therapy, we performed this multi-center, observational study on 85 newly diagnosed multiple myeloma (NDMM) patients from 14 medical centers. Ixazomib-based regimens included ixazomib-lenalidomide-dexamethasone (IRd) in 44.7% of patients, ixazomib-dexamethasone (Id) in 29.4%, and Id plus another agent (doxorubicin, cyclophosphamide, thalidomide, or daratumumab) in 25.9%. Different ixazomib-based therapies were applied due to (1) financial burdens or limitations on local health insurance coverage, (2) concerns on treatment tolerance, and (3) drug accessibility issue. Ten patients received ixazomib maintenance. The median age was 67 years; 43.5% had ISS stage III disease; 48.2% had an Eastern Cooperative Oncology Group performance score ≥ 2; and 17.6% with high-risk cytogenetic abnormalities. Overall response rate for all 85 patients was 95.3%, including 65.9% very good partial response or better and 29.5% complete responses. The median time to response was 30 days. The response rate was similar across different ixazomib-based regimens. Median progression-free survival was not reached. Severe AEs (≥ grade 3) were reported in 29.4% of patients. No grade 3/4 peripheral neuropathy (PN) occurred. Patients received a median of 6 (range 1-20) cycles of ixazomib treatment; 56.6% remained on treatment at data cutoff; 15.3% discontinued treatment due to intolerable AEs. These results support that the ixazomib-based frontline therapy was highly effective with acceptable toxicity in routine practice and the ixazomib oral regimens could be good alternative options for NDMM patients.

Better outcomes of modified myeloablative conditioning without antithymocyte globulin versus myeloablative conditioning in cord blood transplantation for hematological malignancies: A retrospective (development) and a prospective (validation) study.

Cord blood transplantation (CBT) is an effective option for treating hematological malignancies, but graft failure (GF) remains the primary cause of therapy failure. Thus, based on myeloablative conditioning (MAC) of busulfan with cyclophosphamide (Bu/Cy) or total body irradiation with Cy (TBI/Cy), fludarabine (Flu) was added to Bu/Cy and cytarabine (CA) to TBI/Cy for a modified myeloablative conditioning (MMAC). To compare the prognosis of MMAC with MAC, we conducted a retrospective study including 58 patients who underwent CBT with MAC or MMAC from 2000 to 2011. Neutrophil and platelet engraftment rate, overall survival (OS) and disease free survival (DFS) were significantly higher in the MMAC group (adjusted hazard ratio [HR], 2.58, 2.43, 0.36 and 0.37; p < 0.01, p = 0.01, p = 0.02 and p = 0.02, separately). Nonrelapse mortality (NRM) was comparable (p = 0.183). To validate the outcomes noted in the MMAC group, we conducted a prospective single-arm clinical trial including 188 patients who underwent CBT with MMAC from 2011 to 2015. Engraftment rate, survival and NRM of the MMAC group in the prospective trail (MMAC-P) were similar to the MMAC group in the retrospective study (MMAC-R). This study is the first to demonstrate the superiority of MMAC to MAC in CBT for hematological malignancies.

European Group for Blood and Marrow Transplantation Risk Score Predicts the Outcome of Patients with Acute Leukemia Receiving Single Umbilical Cord Blood Transplantation.

The European Group for Blood and Marrow Transplantation (EBMT) risk score has been implemented as an important tool to predict patient outcomes after allogeneic hematopoietic stem cell transplantation. However, to our knowledge, this score has never been applied in cases of single umbilical cord blood transplantation (sUCBT). We retrospectively analyzed 207 consecutive patients with acute leukemia who received sUCBT at our center between February 2011 and December 2015. The probabilities of 3-year overall survival (OS) and leukemia-free survival (LFS) of the entire cohort were 65.0% and 59.8%, respectively, whereas the cumulative incidences of 3-year nonrelapse mortality (NRM) and relapse rate were 19.5% and 20.3%, respectively. In the univariate analysis, a higher EBMT risk score was associated with worse OS and LFS and higher NRM and relapse rate, ranging from 81.7%, 75.9%, 7.3%, and 15.3%, respectively, for patients with a score of 1 to 43.8%, 44.3%, 31.7%, and 23.9%, respectively, for patients with scores of 4 to 6. Hazard ratios of OS, LFS, and NRM all steadily increased for each additional score point. Importantly, the prognostic value of the EBMT risk score on OS, LFS, NRM, and relapse was maintained in the multivariate analysis. Moreover, considering the univariate analysis results of donor-recipient gender and mismatched allele-level HLA-A, -B, -C, and -DRB1 loci on patient outcomes and the fairly strong interaction between time from diagnosis to sUCBT and disease status, we developed a modified sUCBT-EBMT risk score by using degrees of 8-allele HLA match instead of donor type, donor-recipient gender combination, and time from diagnosis to sUCBT, and found that the modified score could also be used as a predictor for patient outcomes after sUCBT. The EBMT risk score is a good predictor of outcomes of patients with leukemia after sUCBT. The modified sUCBT-EBMT risk score can also be used as a pretransplant risk assessment, but this metric still requires further evaluation with a larger cohort.

[The curative efficacy of unrelated umbilical cord blood stem cells transplantation in intensified myeloablative conditioned patients with acute lymphoblastic leukemia].

OBJECTIVE: To retrospectively analyze the efficacy of unrelated umbilical cord blood transplantation (UCBT) with intensified myeloablative conditioning regimen in patients with acute lymphoblastic leukemia (ALL). METHODS: From September 2006 to December 2013, a total of 110 consecutive patients with ALL had received UCBT, including 79 male and 31 female patients with a median age of 14(2-51) years, a median weight of 45(12-100)kg. Sixty-one cases were in the first complete remission (CR), 30, 6 and 13 patients in the second, the third CR and advanced stages respectively. The conditioning regimen consisted of total body irradiation, cyclophosphamide and cytarabine (TBI/Cy/Ara-C) in 61 patients, busulfan, cyclophosphamide and fludarabine (BU/Cy/Flu) in 39 patients and BU/Cy/Ara-C in 10 patients. All patients received a combination of cyclosporine (CsA) and mycophenolate mofetil (MMF) for the prophylaxis of graft-versus-host disease (GVHD). RESULTS: The median amount of total nuclear cells(TNC) and CD34(+) cells were 3.90(1.97-13.50)×10(7)/kg and 2.07(0.40-5.56)×10(5)/kg. The cumulative incidence of sustained donor engraftment was 94.5% (95% CI 94.5%-94.6%) at a median of 18 days after transplantation (range, 12-37 days). The cumulative incidence of platelet recovery at 180 days after transplantation was 82.1% (95% CI 81.8%-82.4%) with a median time to recovery of 40 (range, 15-153) days. Incidences of grade Ⅱ~Ⅳ and Ⅲ~Ⅳ acute GVHD were 21.8% and 10.9% respectively. The cumulative incidence of chronic GVHD was 17.9%. During a median follow up period of 26 (range 6-94) months, the disease free survival (DFS) and overall survival (OS) rates at 3 years were 54.5% and 58.8%, respectively. The transplantation-related mortality (TRM) at 180 days after transplantation was 22.7%. The cumulative incidence of 3-year relapse rate was 18.3% (95% CI 17.9%-18.6%). CONCLUSIONS: UCBT with intensified myeloablative conditioning regimen not only improves the donor engraftment, but also shortens the interval of neutrophil and platelet recovery. It is a safe and effective option for children and adult ALL patients lack of matched related donors.

A prospective phase 2 study of combination epigenetic therapy against relapsed/refractory peripheral T cell lymphoma.

BACKGROUND: Peripheral T cell lymphomas (PTCLs) are prototypical epigenetic malignancies with invariably poor prognoses. Novel and effective therapeutic strategies are needed to improve clinical outcomes, particularly in relapsed/refractory patients. METHODS: We conducted a multicenter phase 2 study to evaluate the therapeutic efficacy of azacitidine and chidamide, alone or in combination with gemcitabine and oxaliplatin (GemOx), in patients with relapsed/refractory PTCLs (registration number: ChiCTR2000037232). The primary endpoint was the best overall response rate. FINDINGS: As of May 1st, 2024, thirty patients were evaluable for efficacy and toxicity. The best overall response rate was 53.3%, meeting its primary endpoint. Among the patients with angioimmunoblastic T cell lymphoma (AITL; N = 19), a numerically higher response rate was observed, regardless of whether chemotherapy was combined, compared to patients with non-AITL. After a median follow-up of 36.6 months, median progression-free survival and overall survival were 7.1 and 8.7 months, respectively. Patients with AITL who received combination chemotherapy (N = 12) achieved the most promising response rates (overall response rate, 91.7%; complete remission rate, 66.7%) and survival outcomes (median progression-free survival, 17.2 months; median overall survival, 38.8 months). The most common grade 3-4 toxicities were neutropenia (40.0%) and thrombocytopenia (30.0%). CONCLUSIONS: The combination of epigenetic therapy with GemOx was well tolerated and highly effective in patients with relapsed/refractory PTCLs. Patients with AITL, in particular, may benefit more from this combination treatment and should be the focus of future studies. FUNDING: This work was funded by the Natural Science Foundation of Jiangsu Province (BK20232039).

Unrelated cord blood transplantation for central nervous system relapse in high-risk childhood acute lymphoblastic leukemia.

Few clinical studies have investigated the role of unrelated cord blood transplantation (CBT) for central nervous system (CNS) relapse of childhood acute lymphoblastic leukemia (ALL) patients with high-risk factors. The aim of this report is to identify the potential benefits of unrelated CBT in high-risk childhood ALL with CNS relapse who has been treated on CNS-directed treatment strategies. Eleven childhood ALL patients with CNS relapse who underwent unrelated CBT enrolled in our study between 2001 and 2011, and all of the patients had features associated with poor outcomes, such as high white blood cells at diagnosis, ph + chromosome, or a history of bone marrow relapse. All transplants were performed with myeloablative-conditioning therapy (BU/cyclophosphamide (CY2) or total body irradiation/CY) plus highly CNS-active agents (carmustine or high-dose cytarabine). All patients achieved neutrophil engraftment and platelet engraftment. A total of nine patients (81.8 %) developed pre-engraftment syndrome at a median of 7 days, and three patients developed acute graft-vs-host disease at a median of 21 days. The median follow-up after CBT was 28.5 months. The probability of overall survival at 9 years was 63.6 %, and no patient experienced a CNS relapse. Our experience suggests that unrelated CBT appears to be an effective treatment option for CNS relapse of childhood ALL patients associated with poor outcome features.

Real-world data for lenalidomide maintenance in responding patients of diffuse large B-cell lymphoma.

BACKGROUND: Approximately 40% patients of diffuse large B-cell lymphoma (DLBCL) would develop disease recurrence/progression after first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) induction therapy, with highly poor prognosis. An effective strategy to prolong the survival of this patient population is the additional single-drug maintenance therapy. lenalidomide, an immunomodulatory drug with oral activity, has direct anti-tumor activity and indirect effects mediated by multiple immune cells in the tumor microenvironment, such as B, T, natural killer (NK), and dendritic cells. Combining its controllable toxicity, it is promising in long-term maintenance therapy. This study aims at evaluating the clinical effect of lenalidomide maintenance therapy in responding DLBCL patients with R-CHOP treatment. METHODS: This retrospective study was devised in DLBCL cases who obtained complete response (CR) or partial response (PR) following 6-8 cycles of R-CHOP treatment between January 1, 2015 and July 31, 2019. Patients (n = 141) included were respectively assigned to receive lenalidomide maintenance treatment (lenalidomide, n = 50) and drug-free maintenance treatment (control, n = 91) after CR/PR. lenalidomide was provided orally at 25 mg/day for 10 days, with a cycle of 21 days and a treatment course of 2 years. Progression-free survival (PFS) was taken as the primary outcome. RESULTS: Of the total 141 subjects, the median follow-up time was 30.9 months (range, 5.7-68.9 months). The 2-year PFS was 84% (95% CI: 74%-94%) in the lenalidomide group and 53% (95% CI: 43%-63%) in the control group. The median PFS of the lenalidomide group was not reached, and that of the control group was 42.9 months (HR = 0.32; 95% CI: 0.16-0.63; p = 0.001). No remarkable difference in overall survival (OS) between the two groups was indicated (HR = 0.42; 95% CI: 0.16-1.12; p = 0.08). Central nervous system (CNS) recurrence happened in 5 patients (5.5%) of the control group, while none of the patients with lenalidomide had CNS recurrence. Additionally, neutropenia and cutaneous reactions were the most common Grade 1-2 adverse reactions after lenalidomide treatment, and neutropenia was the most frequent Grade 3-4 adverse reaction. CONCLUSION: Two-year lenalidomide maintenance treatment can significantly prolong the PFS of DLBCL patients who obtained CR/PR to first-line R-CHOP treatment.

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.

Sugemalimab Monotherapy for Patients With Relapsed or Refractory Extranodal Natural Killer/T-Cell Lymphoma (GEMSTONE-201): Results From a Single-Arm, Multicenter, Phase II Study.

PURPOSE: Relapsed or refractory extranodal natural killer/T-cell lymphoma (R/R ENKTL) is a rare and aggressive type of non-Hodgkin lymphoma with limited treatment options. This phase II study evaluated the efficacy and safety of sugemalimab, an anti-PD-L1 monoclonal antibody, in R/R ENKTL. METHODS: Eligible patients received sugemalimab 1,200 mg intravenously once every 3 weeks for up to 24 months or until progression, death, or study withdrawal. The primary end point was objective response rate (ORR) assessed by an independent radiologic review committee. Key secondary end points included ORR assessed by the investigators, complete response rate, duration of response, and safety. RESULTS: At the data cutoff (February 23, 2022), 80 patients were enrolled and followed for a median of 18.7 months. At baseline, 54 (67.5%) had stage IV disease and 39 (48.8%) had received ≥2 lines of prior systemic therapy. Independent radiologic review committee-assessed ORR was 44.9% (95% CI, 33.6 to 56.6); 28 (35.9%) patients achieved a complete response and seven (9.0%) achieved a partial response, with a 12-month duration of response rate of 82.5% (95% CI, 62.0 to 92.6). Investigator-assessed ORR was 45.6% (95% CI, 34.3 to 57.2), and 24 (30.4%) patients achieved a complete response. Most treatment-emergent adverse events were grade 1-2 in severity, and grade ≥ 3 events were reported in 32 (40.0%) patients. CONCLUSION: Sugemalimab showed robust and durable antitumor activity in R/R ENKTL. Treatment was well tolerated with expected safety profile for this drug class.

Orelabrutinib for the treatment of relapsed or refractory MCL: a phase 1/2, open-label, multicenter, single-arm study.

Relapsed or refractory (r/r) mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with a poor prognosis. Bruton tyrosine kinase (BTK) is a mediator of B-cell receptor signaling and is associated with the development of B-cell lymphomas. Patients with r/r MCL were enrolled in this phase 1/2 study and treated with orelabrutinib, a novel, highly selective BTK inhibitor. The median number of prior regimens was 2 (range, 1-4). The median age was 62 years (range, 37-73 years). Eligible patients received oral orelabrutinib 150 mg once daily (n = 86) or 100 mg twice daily (n = 20) until disease progression or unacceptable toxicity. A dose of 150 mg once daily was chosen as the preferred recommended phase 2 dose. After a median follow-up duration of 23.8 months, the overall response rate was 81.1%, with 27.4% achieving a complete response and 53.8% achieving a partial response. The median duration of response and progression-free survival were 22.9 and 22.0 months, respectively. The median overall survival (OS) was not reached, and the rate of OS at 24 months was 74.3%. Adverse events (AEs) occurring in >20% of patients were thrombocytopenia (34.0%), upper respiratory tract infection (27.4%), and neutropenia (24.5%). Grade ≥3 AEs were infrequent and most commonly included thrombocytopenia (13.2%), neutropenia (8.5%), and anemia (7.5%). Three patients discontinued treatment because of treatment-related adverse events (TRAEs), but no fatal TRAEs were reported. Orelabrutinib showed substantial efficacy and was well tolerated in patients with r/r MCL. This trial was registered at www.clinicaltrials.gov as #NCT03494179.

A national, multicenter, retrospective study of Castleman disease in China implementing CDCN criteria.

Background: Castleman disease (CD) is a group of rare and heterogenous lymphoproliferative disorders including unicentric CD (UCD), human herpesvirus-8(HHV-8)-associated multicentric CD (HHV8-MCD), and HHV-8-negative/idiopathic multicentric CD (iMCD). Knowledge of CD mainly comes from case series or retrospective studies, but the inclusion criteria of these studies vary because the Castleman Disease Collaborative Network (CDCN) diagnostic criteria for iMCD and UCD were not available until 2017 and 2020, respectively. Further, these criteria and guidelines have not been systematically evaluated. Methods: In this national, multicenter, retrospective study implementing CDCN criteria, we enrolled 1634 CD patients (UCD, n = 903; MCD, n = 731) from 2000 to 2021 at 40 Chinese institutions to depict clinical features, treatment options, and prognostic factors of CD. Findings: Among UCD, there were 162 (17.9%) patients with an MCD-like inflammatory state. Among MCD, there were 12 HHV8-MCD patients and 719 HHV-8-negative MCD patients, which included 139 asymptomatic MCD (aMCD) and 580 iMCD meeting clinical criteria. Of 580 iMCD patients, 41 (7.1%) met iMCD-TAFRO criteria, the others were iMCD-NOS. iMCD-NOS were further divided into iMCD-IPL (n = 97) and iMCD-NOS without IPL (n = 442). Among iMCD patients with first-line treatment data, a trend from pulse combination chemotherapy toward continuous treatment was observed. Survival analysis revealed significant differences between subtypes and severe iMCD (HR = 3.747; 95% CI: 2.112-6.649, p < 0.001) had worse outcome. Interpretation: This study depicts a broad picture of CD, treatment options and survival information in China and validates the association between the CDCN's definition of severe iMCD and worse outcomes, requiring more intensive treatment. Fundings: Beijing Municipal Commission of Science and Technology, CAMS Innovation Fund and National High Level Hospital Clinical Research Funding.

(Bortezomib plus lenalidomide/thalidomide)- vs. (bortezomib or lenalidomide/thalidomide)-containing regimens as induction therapy in newly diagnosed multiple myeloma: a meta-analysis of randomized controlled trials.

The aim of the study was to perform a meta-analysis of the efficacy and safety of (bortezomib plus lenalidomide/thalidomide)- vs. (bortezomib or lenalidomide/thalidomide)-containing regimens as induction therapy in newly diagnosed multiple myeloma. We searched electronic and printed sources for relevant articles published. Inclusion criteria was as follows: randomized controlled trials (RCT) of (bortezomib plus lenalidomide/thalidomide) vs. (bortezomib or lenalidomide/thalidomide)-containing regimens as induction therapy in newly diagnosed multiple myeloma. Two reviewers independently assessed potentially eligible studies and extracted relevant data. We retrieved five RCT studies including a total of 1,200 patients. Using the random-effects model to pool the five RCT with a statistically significant heterogeneity (P = 0.03; X² = 10.69; df = 4; I² = 63%), the weighted risk ratios of a complete response (CR) for (bortezomib plus lenalidomide/thalidomide)-containing regimens was 1.81 (P = 0.005; 95% CI: 1.20-2.73). When we excluded the study by Cavo et al. (Lancet 376:2075-2085, 2010), the pooled risk ratio for CR was 1.59 (P < 0.0001, 95% CI: 1.29-1.96) with no statistically significant heterogeneity (P = 0.54; X² = 2.14; df = 3; I² = 0%) among four RCT under the fixed effects mode. The pooled odds ratio for the main grade III/IV adverse events (the peripheral neuropathy, thrombotic events, and infections) were 1.76 (P = 0.32; 95% CI: 0.58-5.31), 0.92 (P = 0.76, 95% CI: 0.52-1.61), and 1.05 (P = 0.82, 95% CI: 0.70-1.57), respectively. Our analysis showed (bortezomib plus lenalidomide/thalidomide)-containing regimens as induction treatment in newly diagnosed multiple myeloma improved CR but did not increase the risk of major adverse events (the peripheral neuropathy, thrombotic events, and infections).