2022 Chinese expert consensus and guidelines on clinical management of toxicity in anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma

Adoptive cellular immunotherapy with chimeric antigen receptor(CAR)T cells has emerged as a novel modality for treating relapsed and/or refractory B-cell non-Hodgkin lymphoma(B-NHL).With increasing approval of CAR T-cell products and advances in CAR T cell therapy,CAR T cells are expected to be used in a growing number of cases.However,CAR T-cell-associated toxicities can be severe or even fatal,thus compromising the survival benefit from this therapy.Standardizing and studying the clinical management of these toxicities are imperative.In contrast to other hematological malignancies,such as acute lymphoblastic leukemia and multiple myeloma,anti-CD19 CAR T-cell-associated toxicities in B-NHL have several distinctive features,most notably local cytokine-release syndrome(CRS).However,previously published guidelines have provided few specific recommendations for the grading and management of toxicities associated with CAR T-cell treatment for B-NHL.Consequently,we developed this consensus for the prevention,recognition,and management of these toxicities,on the basis of published literature regarding the management of anti-CD19 CAR T-cell-associated toxicities and the clinical experience of multiple Chinese institutions.This consensus refines a grading system and classification of CRS in B-NHL and corresponding measures for CRS management,and delineates comprehensive principles and exploratory recommendations for managing anti-CD19 CAR T-cell-associated toxicities in addition to CRS.

Prognostic value of interim ^(18)F-FDG PET/CT in diffuse large B-cell lymphoma

Objective： Diffuse 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. Methods： Thirty-two patients with DLBCL underwent baseline, interim and post-treatment lSF-FDG PET/CT scans. Imaging results were analyzed for the survival of patients via software SPSS 13.0, retrospectively. Results： Thirty-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 SUVmax CUt-Off value of 2.5 （P=0.039）. No significant differences were found in the 2-year PFS rates if SUVm, cut-offvalues were set as 2.0 and 3.0, respectively （P=0.360; P=0.113）. Conclusions： Interim PET/CT could predict the prognosis of DLBCL patients with the SUVmax cut-off value of 2.5, but more clinical data should be concluded to confirm this conclusion.

Prognostic value of pre-and post-transplantation 18F-fluorodeoxyglucose positron emission tomography results in non-Hodgkin lymphoma patients receiving autologous stem cell transplantation

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. lSF-fluorodeoxyglueose （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 cutoffvalue 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.

Prognostic value of ^(18)F-fluorodeoxyglucose positron emission tomography using Deauville criteria in diffuse large B cell lymphoma treated with autologous hematopoietic stem cell transplantation

Objective: High-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.18 F-fluorodeoxyglucose(18 F-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 18 FFDG PET/CT pre-and post-HSCT in predicting outcomes of patients with DLBCL.Methods: DLBCL patients who had PET/CT scan before and after HSCT were included. PET results were interpreted based upon Deauville criteria. The prognostic value of 18 F-FDG PET/CT in auto-HSCT was evaluated.Results: Eighty-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 firstline 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).Conclusions: PET 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.

PEG-asparaginase in BFM-90 regimen improves outcomes in adults with newly diagnosed lymphoblastic lymphoma

Objective： Although L-asparaginase（L-ASP） is a standard treatment for lymphoblastic lymphoma（LBL）,hypersensitivity reactions by some patients limit its application. Polyethylene glycol-conjugated asparaginase（PEGASP） 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-90regimen（PEG-ASP-BFM-90） for adult LBL.Methods： Between June 2012 and July 2015, we treated 30 adult patients with newly diagnosed LBL, using PEGASP-BFM-90 in a prospective, multicenter and single-arm clinical study at 5 participating institutions in China.Results： All 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 and36.7%（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.Conclusions： Our 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 therapyrelated 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.

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 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.Methods:We designed a CD19-targeted CAR-T(named as IM19)which consisted of an FMC63 scFv,4-1BB and CD3ζintracellular 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 5×10^(5)/kg,1×10^(6)/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.