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Abstract HLX01 (HanliKang®) is a rituximab biosimilar that showed bioequivalence to reference rituximab in untreated CD20-positive diffuse large B-cell lymphoma (DLBCL) in the phase 3 HLX01-NHL03 study. Here, we report the 5-year follow-up results from the open-label extension part. Patients were randomised to either rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or HLX01 plus CHOP (H-CHOP) every 21 days for up to six cycles. The primary efficacy endpoint was overall survival (OS), and secondary efficacy endpoint was progression-free survival (PFS). Of the 407 patients enrolled in HLX01-NHL03, 316 patients (H-CHOP = 157; R-CHOP = 159) were included in the 5-year follow-up for a median duration of 65.1 (range, 2.2–76.5) months. 96.5% of the patients had an International Prognostic Index (IPI) of 1 or 2, and 17.7% had bone marrow involvement. The 5-year OS rates were 81.0% (95% CI: 74.9–87.5%) and 75.4% (95% CI: 68.9–82.6%)( HR: 0.75, 95% CI 0.47–1.20; p = 0.23) while 5-year PFS rates were 77.7% (95% CI: 71.4–84.6%) and 73.0% (95% CI: 66.3–80.3%) (HR: 0.84, 95% CI 0.54–1.30; p = 0.43) in the H-CHOP and R-CHOP groups, respectively. Treatment outcomes did not differ between groups regardless of IPI score and were consistent with the primary analysis. H-CHOP and R-CHOP provided no significant difference in 5-year OS or PFS in previously untreated patients with low or low-intermediate risk DLBCL.

Abstract Background To explore the effects of monitoring measurable residual disease and post‐remission treatment selection on the clinical outcomes of B‐cell acute lymphoblastic leukemia (B‐ALL) in adults. Methods Between September 2010 and January 2022, adult patients with B‐ALL who received combination chemotherapy, with or without allogeneic hematopoietic stem cell transplantation (allo‐HSCT), were included in the retrospective study, which was approved by the Ethics Committee and the observation of Declaration of Helsinki conditions. Results One hundred and forty‐three B‐ALL patients achieved complete remission (CR) were included in the study, of whom 94 patients (65.7%) received allo‐HSCT in first complete remission (CR1). Multivariate analysis showed that the most powerful factors affecting OS were transplantation (hazard ratio [HR] = 0.540, p = 0.037) and sustained measurable residue disease (MRD) negativity (HR = 0.508, p = 0.037). The subgroup analysis showed that the prognosis of the allo‐HSCT group was better than that of the chemotherapy group, regardless of whether MRD was negative or positive after two courses of consolidation therapy. After consolidation therapy, the prognosis of patients with positive MRD remained significantly better in the allo‐HSCT group than in the chemotherapy group. However, no significant difference was observed in the prognosis between the allo‐HSCT and chemotherapy groups with negative MRD after consolidation therapy. Conclusions B‐ALL patients who achieve sustained MRD negativity during consolidation therapy have excellent long‐term outcomes even without allo‐HSCT. Allo‐HSCT is associated with a significant benefit in terms of OS and DFS for patients who were with positive MRD during consolidation therapy.

Abstract Genetic heterogeneity poses a great challenge to the understanding and management of acute myeloid leukemia (AML). Knowledge of the IKZF1 mutation in AML specifically is extremely limited. In a previous work, we described the distribution pattern of IKZF1 mutation in AML, but its clinical impact has remained undefined due to the limited number of cases. Herein, we attempt to answer this question in one relatively large cohort covering 522 newly diagnosed AML patients. A total of 26 IKZF1 mutations were found in 20 AML patients (20/522, 3.83%). This condition has a young median age of onset of morbidity (P = 0.032). The baseline characteristics of IKZF1-mutated and wild-type patients were comparable. IKZF1 mutation showed significant co-occurrences with CEBPA (P 0.20) showed relatively short overall survival period (P = 0.012), and it was an independent factor for the increased risk of death (hazard ratio, 6.101; 95% CI 2.278–16.335; P = 0.0003). In subgroup analysis, our results showed that IKZF1 mutation conferred poor therapeutic response and prognosis for SF3B1-mutated AML (P = 0.0017). We believe this work improves our knowledge of IKZF1 mutation.

Burkitt lymphoma or leukemia (BL) is a highly aggressive non-Hodgkin lymphoma. Older age (over 60 years old) and the presence of high-risk factors (such as abdominal mass, high levels of the serum lactic dehydrogenase, Ann Arbor stage II-IV and so on) usually predict a poorer outcome. Chimeric antigen receptor T cells (CART) have achieved remarkable success in the treatment of B-cell leukemia and lymphoma. Here, for the first time, we report a 61-year-old, high-risk BL patient with autologous stem cell transplantation (ASCT) bridging therapy prior to CART as consolidation therapy. Our findings demonstrate that the combination of ASCT and CART for BL is safe and feasible.

Hematotoxicity is the most common long-term adverse event after chimeric antigen receptor T cell (CAR-T) therapy. Here, a total of 71 patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) or large B-cell lymphoma (LBCL) were used to develop an early hematotoxicity predictive model and verify the accuracy of this model. The incidences of early hematotoxicity at 3 month following CAR-T infusion in B-ALL and LBCL were 45.5% and 38.5%, respectively. Multivariate analyses revealed that the severity of cytokine release syndrome (CRS) was an independent risk factor affecting early hematotoxicity. The analysis between the peak cytokine levels and early hematotoxicity suggested that tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP) were closely associated with early hematotoxicity. Then, an early predictive model of hematotoxicity was constructed based on the peak contents of TNF-α and CRP. This model could diagnose early hematotoxicity with positive predictive values of 87.7% and 85.0% in training and validation cohorts, respectively. Lastly, we constructed the nomogram for clinical practice to predict the risk of early hematotoxicity, which performed well compared with the observed probability. This early predictive model is instrumental in the risk stratification of CAR-T recipients with hematotoxicity and early intervention for high-risk patients.

Abstract Background Consolidative allogeneic hematopoietic stem cell transplantation is a controversial option for patients with relapsed/refractory acute lymphoblastic leukemia after chimeric antigen receptor T cell (CAR-T) therapy. We performed a multicenter retrospective study to assess whether patients can benefit from haploidentical hematopoietic stem cell transplantation after CAR-T therapy. Methods A total of 122 patients after CAR-T therapy were enrolled, including 67 patients without subsequent transplantation (non-transplant group) and 55 patients with subsequent haploidentical hematopoietic stem cell transplantation (transplant group). Long-term outcome was assessed, as was its association with baseline patient characteristics. Results Compared with the non-transplant group, transplantation recipients had a higher 2-year overall survival (OS; 77.0% versus 36.4%; P < 0.001) and leukemia-free survival (LFS; 65.6% versus 32.8%; P < 0.001). Multivariate analysis showed that minimal residual disease (MRD) positivity at transplantation is an independent factor associated with poor LFS (P = 0.005), OS (P = 0.035), and high cumulative incidence rate of relapse (P = 0.045). Pre-transplant MRD-negative recipients (MRD− group) had a lower cumulative incidence of relapse (17.3%) than those in the non-transplant group (67.2%; P < 0.001) and pre-transplant MRD-positive recipients (MRD+ group) (65.8%; P = 0.006). The cumulative incidence of relapse in MRD+ and non-transplant groups did not differ significantly (P = 0.139). The 2-year LFS in the non-transplant, MRD+, and MRD− groups was 32.8%, 27.6%, and 76.1%, respectively. The MRD− group had a higher LFS than the non-transplantation group (P < 0.001) and MRD+ group (P = 0.007), whereas the LFS in the MRD+ and non-transplant groups did not differ significantly (P = 0.305). The 2-year OS of the MRD− group was higher than that of the non-transplant group (83.3% versus 36.4%; P < 0.001) but did not differ from that of the MRD+ group (83.3% versus 62.7%; P = 0.069). The OS in the non-transplant and MRD+ groups did not differ significantly (P = 0.231). Conclusion Haploidentical hematopoietic stem cell transplantation with pre-transplant MRD negativity after CAR-T therapy could greatly improve LFS and OS in patients with relapsed/refractory acute lymphoblastic leukemia. Trial registration The study was registered in the Chinese clinical trial registry ( ChiCTR1900023957 ).

Abstract Rituximab in combination with chemotherapy has shown efficacy in patients with diffuse large B-cell lymphoma (DLBCL) for more than 15 years. HLX01 was developed as the rituximab biosimilar following a stepwise approach to demonstrate biosimilarity in analytical, pre-clinical, and clinical investigations to reference rituximab. With demonstrated pharmacokinetic similarity, a phase 3 multi-center, randomized, parallel, double-blind study (HLX01-NHL03) was subsequently conducted to compare efficacy and safety between HLX01 plus cyclophosphamide, doxorubicin, vincristine, and prednisone (H-CHOP) and reference rituximab plus CHOP (R-CHOP) in a total of 407 treatment-naïve, CD20-positive DLBCL patients aged 18–80 years. The primary efficacy endpoint was best overall response rate (ORR) within six cycles of treatment in the per-protocol set (PPS). Secondary endpoints included 1-year efficacy outcomes, safety, and immunogenicity profile. The results showed difference in ORRs [H-CHOP 94.1%; R-CHOP 92.8%] between two treatment groups was 1.4% (95% confidence interval [CI], − 3.59 to 6.32, p = 0.608) which falls within the pre-defined equivalence margin of ± 12%. The safety profile was comparable between the treatment groups, with a similar overall incidence of treatment-emergent adverse events (H-CHOP 99.5%, R-CHOP 99.0%, p = 1.000) and serious adverse events (H-CHOP 34.0%, R-CHOP 32.5%, p = 0.752). This study established bioequivalence in efficacy and safety between HLX01 and reference rituximab. The trial was registered at http://www.chinadrugtrials.org.cn on 26 August 2015 [#CTR20150583].

SAMHD1 (sterile alpha motif domain and histidine-aspartate domain-containing protein 1) is a deoxynucleoside triphosphate triphosphohydrolase regulating innate immune and modulating DNA damage signaling. It plays an important role in the development of some tumors. SAMHD1 was also reported as a barrier to cytarabine, a common chemotherapy drug for mantle cell lymphoma (MCL), and as a biomarker of grim prognosis for acute myelocytic leukemia (AML) patients. However, SAMHD1 expression and function in MCL have not been well-defined. In the present study, we evaluated SAMHD1 expression by immunohistochemistry and its gene structure by Sanger sequencing in MCL. Our results showed that SAMHD1 was positive in 36 (62.1%) patients. Importantly, SAMHD1-positive patients were associated with lower chemotherapy response rate (p = 0.023) and shorter overall survival (p = 0.039) than SAMHD1-negative cases. These results suggest that SAMHD1 is an adverse biomarker for MCL patients, which is due to the high expression of SAMHD1 and rapid cell proliferation. These findings were confirmed in an in vitro study using the siRNA technique. Silencing the SAMHD1 gene in the MCL cell line Jeko-1 significantly decreased cell proliferation and increased cell apoptosis. The MCL cell line with SAMHD1 knockdown showed lower Ki-67 proliferation index, higher caspase-3, and higher sensitivity to cytarabine. Furthermore, for the first time, four previously unreported missense mutations (S302Y, Y432C, E449G, and R451H) in exon 8 and exon 12 of the SAMHD1 gene were discovered by sequencing. The mutations had not been found to corelate with SAMHD1 protein expression detected by immunohistochemistry. The biological functions of this mutated SAMHD1 remain to be investigated.

Junctional adhesion molecule-like protein (JAML), a newly discovered junctional adhesion molecule (JAM), mediates the adhesion and migration processes of various immune cells and endothelial/epithelial cells, ultimately regulating inflammation reaction. However, its role in tumors remains to be determined. The expression of JAML was examined in gastric cancer (GC) and peritumoral tissues from 63 patients. The relationship between JAML expression and clinical characteristics was also observed. In vitro, GC cell migration and proliferation were assessed by wound healing assay, transwell migration assay and EdU incorporation assay. Immunohistochemical staining results showed that JAML expression level was higher in GC tissues than in peritumoral tissues. High expression of JAML in cancer tissues was associated with worse cell differentiation, local lymph node involvement, deep infiltration, and advanced stage. In vitro, we found that JAML silencing inhibited GC cell migration and proliferation, while JAML overexpression promoted GC cell migration and proliferation, partially via p38 signaling. Taken together, our study revealed a critical role for JAML to promote GC cell migration and proliferation. JAML might be a novel diagnostic biomarker and therapeutic target for GC.

Abstract The efficacy and safety of chidamide, a new subtype-selective histone deacetylase (HDAC) inhibitor, have been demonstrated in a pivotal phase II clinical trial, and chidamide has been approved by the China Food and Drug Administration (CFDA) as a treatment for relapsed or refractory peripheral T cell lymphoma (PTCL). This study sought to further evaluate the real-world utilization of chidamide in 383 relapsed or refractory PTCL patients from April 2015 to February 2016 in mainland China. For patients receiving chidamide monotherapy (n = 256), the overall response rate (ORR) and disease control rate (DCR) were 39.06 and 64.45%, respectively. The ORR and DCR were 51.18 and 74.02%, respectively, for patients receiving chidamide combined with chemotherapy (n = 127). For patients receiving chidamide monotherapy and chidamide combined with chemotherapy, the median progression-free survival (PFS) was 129 (95% CI 82 to 194) days for the monotherapy group and 152 (95% CI 93 to 201) days for the combined therapy group (P = 0.3266). Most adverse events (AEs) were of grade 1 to 2. AEs of grade 3 or higher that occurred in ≥5% of patients receiving chidamide monotherapy included thrombocytopenia (10.2%) and neutropenia (6.2%). For patients receiving chidamide combined with chemotherapy, grade 3 to 4 AEs that occurred in ≥5% of patients included thrombocytopenia (18.1%), neutropenia (12.6%), anemia (7.1%), and fatigue (5.5%). This large real-world study demonstrates that chidamide has a favorable efficacy and an acceptable safety profile for refractory and relapsed PTCL patients. Chidamide combined with chemotherapy may be a new treatment choice for refractory and relapsed PTCL patients but requires further investigation.