Chin J Cancer Res

ObjectivePrevious 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 months vs. 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.MethodsWe 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.ResultsAt 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.ConclusionsThese 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.

ObjectiveAlthough L-asparaginase (L-ASP) is a standard treatment for lymphoblastic lymphoma (LBL), hypersensitivity reactions by some patients limit its application. Polyethylene glycol-conjugated asparaginase (PEG-ASP) has a lower immunogenicity and is a standard treatment in all pediatric acute lymphoblastic leukemia (ALL). In this study, we investigated the efficacy and toxicity of PEG-ASP instead of L-ASP as used in the BFM-90 regimen (PEG-ASP-BFM-90) for adult LBL.MethodsBetween June 2012 and July 2015, we treated 30 adult patients with newly diagnosed LBL, using PEG-ASP-BFM-90 in a prospective, multicenter and single-arm clinical study at 5 participating institutions in China.ResultsAll the 30 patients, including 19 males and 11 females with a median age of 30 (range: 18−62) years, completed 128 times of the PEG-ASP, with the median of 4 (range: 2−6) times. Patients did not receive radiotherapy at this time. The overall response rate was 86.7% (26/30), with 50.0% (15/30) complete response and 36.7% (11/30) partial response. The 3-year overall survival was 46.0% [95% confidence interval (95% CI), 28.2%−64.8%], and the 3-year progression-free survival was 43.0% (95% CI, 25.7%−62.0%). Major adverse events were myelosuppression, reduced fibrinogen, liver dysfunction and digestive tract toxicities. No allergic reaction and no treatment-related mortality or severe complications were recorded.ConclusionsOur clinical data and observed outcomes indicate that 1 dose of PEG-ASP can replace multiple doses of native L-ASP in BFM-90, with predominantly grade 3−4 neutropenia for adult LBL, and no therapy-related deaths. The effect is similar to previous reports of PEG-ASP-containing regimens for adult ALL. Major advantages include less serious allergic reactions, 2−3 weeks of action duration, and convenience for patients and physicians.

Objective High-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT) is the standard of care in the upfront or relapsed/refractory setting in some patients with non-Hodgkin lymphoma (NHL). However, a proportion of patients do not respond to ASCT. ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) has been widely used for staging, response evaluation, and prognosis prediction. Here, we investigated the prognostic role of PET/CT in NHL patients before and after ASCT. Methods A retrospective study was conducted at Peking University Cancer Hospital. All NHL patients who underwent ASCT between March 2010 and July 2016 were identified. Patients who had PET/CT scan before and after ASCT were included. Deauville criteria (5-point scale) were used to interpret PET scans. Univariate and multivariate survival analyses were performed using Cox regression. The predictive value of PET scanning was estimated by comparing the area under the receiver operating characteristic (ROC) curve. Results In total, 79 patients were enrolled in this study. In univariate analysis, pre- and post-ASCT PET result was identified as prognostic factors for 3-year progression-free survival (PFS) and overall survival (OS). Patients with negative pre-ASCT PET result demonstrated significantly better PFS (84.2% vs. 54.2%) and OS (89.2% vs. 63.6%) than patients with positive pre-ASCT PET result. PFS (91.6% vs. 25.3%) and OS (96.5% vs. 36.8%) were also significantly different between patients with negative and positive post-ASCT PET result. Multivariate analysis also showed a significant association between survival and post-ASCT PET result. ROC analysis revealed that the predictive value of post-ASCT PET result was superior to that of pre-ASCT PET result alone. Combined pre- and post-ASCT PET result is better for predicting outcomes in patients with NHL receiving transplantation. Deauville criteria score >3 was identified as the best cutoff value for post-ASCT PET. Conclusions Post-ASCT PET result was more important than pre-ASCT PET result in predicting outcomes for NHL patients who underwent ASCT. The prognostic significance can be improved when combining pre-ASCT PET result with post-ASCT PET result. Deauville criteria can be used for interpreting PET scans in this scenario.

ObjectiveHigh-dose chemotherapy (HDC) followed by autologous hematopoietic stem cell transplantation (auto-HSCT) plays an important role in improving outcomes of diffuse large B cell lymphoma (DLBCL) patients. ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET)/computed tomography (CT) has been widely accepted in response assessment and prediction of prognosis in DLBCL. Here, we report the value of ¹⁸F-FDG PET/CT pre- and post-HSCT in predicting outcomes of patients with DLBCL.MethodsDLBCL patients who had PET/CT scan before and after HSCT were included. PET results were interpreted based upon Deauville criteria. The prognostic value of ¹⁸F-FDG PET/CT in auto-HSCT was evaluated.ResultsEighty-four patients were enrolled. In univariate analysis, pre- and post-HSCT PET findings were correlated with 3-year progression-free survival (PFS) [hazard ratio (HR)=4.391, P=0.001; HR=7.607, P<0.001] and overall survival (OS) (HR=4.792, P=0.008; HR=26.138, P<0.001). Patients receiving upfront auto-HSCT after first-line treatment had better outcomes than relapsed/refractory DLBCL patients (3-year PFS, P<0.001; 3-year OS, P<0.001). In the relapsed/refractory patients, pre- and post-HSCT PET findings were also associated with 3-year PFS (P=0.003 vs. P<0.001) and OS (P=0.027 vs. P<0.001). A significant correlation was observed between clinical response to chemotherapy before auto-HSCT and outcomes of patients in the entire cohort (3-year PFS, P<0.001; 3-year OS, P<0.001) and in the subgroup of 21 patients with positive pre-HSCT PET (3-year PFS, P=0.084; 3-year OS, P=0.240). A significant association between survival and post-HSCT PET findings was observed in multivariate analysis (HR=5.168, P<0.001).ConclusionsPET results before and after HSCT are useful prognostic factors for DLBCL patients receiving HSCT. Patients who responded to chemotherapy, even those with positive pre-HSCT PET, are appropriate candidates for auto-HSCT.

ObjectiveDiffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease. The prognostic factor currently used is not accurate enough to predict the outcomes of patients with DLBCL. The prognostic significance of interim PET/CT in DLBCL remains controversial. The aim of this study is to determine the predictive value of interim ¹⁸F-FDG PET/CT after first-line treatment in patients with DLBCL.MethodsThirty-two patients with DLBCL underwent baseline, interim and post-treatment ¹⁸F-FDG PET/CT scans. Imaging results were analyzed for the survival of patients via software SPSS 13.0, retrospectively.ResultsThirty-one of the 32 patients were treated with R-CHOP regimen, and interim ¹⁸F-FDG PET/CT of 24 patients was performed after 2 cycles of treatment. After a median follow-up period of 16.7 months, the 2-year progression-free survival (PFS) rates were significantly different between the groups above and below SUV_max cut-off value of 2.5 (P=0.039). No significant differences were found in the 2-year PFS rates if SUV_max cut-off values were set as 2.0 and 3.0, respectively (P=0.360; P=0.113).ConclusionsInterim PET/CT could predict the prognosis of DLBCL patients with the SUV_max cut-off value of 2.5, but more clinical data should be concluded to confirm this conclusion.Key WordsFludeoxyglucose F18; lymphoma; large cell; diffuse; prognosis; standard utility value

ObjectiveTo explore the application of genetic abnormalities in the diagnosis of angioimmunoblastic T-cell lymphoma (AITL) and the reliable pathological prognostic factors.MethodsThis study included 53 AITL cases, which were reviewed for morphological patterns, immunophenotypes, presence of Hodgkin and Reed-Sternberg (HRS)-like cells, and co-occurrence of B cell proliferation. The Epstein-Barr virus (EBV)-positive cells in tissues were counted, and cases were classified into “EBV encoded RNA (EBER) high-density” group if >50/HPF. Targeted exome sequencing was performed.ResultsMutation data can assist AITL diagnosis: 1) with considerable HRS-like cells (20 cases): RHOA mutated in 14 cases (IDH2 co-mutated in 3 cases, 4 cases with rare RHOA mutation), TET2 was mutated in 5 cases (1 case co-mutated with DNMT3A), and DNMT3A mutated in 1 case; 2) accompanied with B cell lymphoma (7 cases): RHOA mutated in 4 cases (1 case had IDH2 mutation), TET2 mutated in 2 cases and DNMT3A mutated in 1 case; 3) mimic peripheral T cell lymphoma, not otherwise specified (5 cases): RHOA mutated in 2 cases (IDH2 co-mutated in 1 case), TET2 mutated in 3 cases, and DNMT3A mutated in 1 case; 4) pattern 1 (1 case), RHOA and TET2 co-mutated. Besides RHOA^G17V (30/35), rare variant included RHOA^K18N, RHOA^R68H, RHOA^C83Y, RHOA^D120G and RHOA^G17del, IDH2^R172 co-mutated with IDH2^M397V in one case. There were recurrent mutations of FAT3, PCLO and PIEZO1 and genes of epigenetic remodeling, T-cell activation, APC and PI3K/AKT pathway. EBER high-density independently indicated adverse overall survival and progression-free survival (P=0.046 and P=0.008, Kaplan-Meier/log-rank).ConclusionsOver half AITL cases might be confused in diagnosis for certain conditions without mutation data. Targeted exome sequencing with a comprehensive panel is crucial to detect both hot-spot and rare mutation variants for RHOA and IDH2 and other recurrent mutated genes in addition to TET2 and DNMT3A. EBER high-density independently indicated adverse survival.

The incidence of primary gastrointestinal lymphomas (PGILs) has been increasing. The clinical presentation and treatment of PGIL are distinct from those of nodular lymphomas. Symptoms include abdominal pain, abdominal mass, changes in bowel habits, obstruction, and bleeding. Less life-threatening gastrointestinal bleeding occurs after chemotherapy and few reports have focused on the bleeding of PGILs. We report a case of severe gastrointestinal bleeding caused by low-dose chemotherapy, which was dramatically improved by rituximab monotherapy treatment. The prevention and treatment of gastrointestinal bleeding in PGIL should be given much attention.