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CAR-T cells are modified T cells expressing a chimeric antigen receptor targeting a specific antigen. They have revolutionized the treatment of B cell malignancies (aggressive lymphomas, B-ALL), and this has raised hopes for application in many other pathologies (myeloma, AML, solid tumors, etc.). However, these therapies are associated with novel and specific toxicities (cytokine release syndrome and neurotoxicity). These complications, although mostly managed in a conventional hospitalization unit, can sometimes be life threatening, leading to admission of patients to the intensive care unit. Management relies mainly on anti-IL6R (tocilizumab) and corticosteroids. However, the optimal treatment regimen is still a matter of debate, and the management of the most severe forms is even less well codified. In addition to CRS and ICANS, infections, cytopenia and hypogammaglobulinemia are other frequent complications. This article reviews the mechanisms, risk factors, clinical presentation, and management of these toxicities.

Chimeric antigen receptors (CAR)-T cells are genetically engineered T-lymphocytes redirected with a predefined specificity to any target antigen, in a non-HLA restricted manner, therefore combining antibody-type specificity with effector T-cell function. This strategy was developed some thirty years ago, after extensive work established the key role of the immune system against cancer. The first-engineered T-cell with chimeric molecule was designed in 1993 by Israeli immunologist Zelig Eshhar. Since then, several modifications took place, including the addition of co-stimulatory domain, to further improve CAR-T cell anti-tumor potency. The first clinical application of CAR-T cell was done in Rotterdam in 2005 for metastatic renal cell carcinoma and simultaneously at the National Cancer Institute (NCI) for metastatic ovarian cancer. These pioneered studies failed to demonstrate a therapeutic benefit, but warning emerged concerning their safety of use. The real clinical success came with anti-CD19 CAR-T cells, used since 2009 by Steven Rosenberg at the NCI in a patient with refractory follicular lymphoma and in 2011 by Carl June and David Porter from the University of Pennsylvania in patients with chronic lymphocytic leukemia and B-cell acute lymphoblastic leukemia. From that time, large centers in North America have embarked in several early phase and pivotal trials that have demonstrated unprecedent response rate in heavily pretreated chemo refractory patient with B-cell malignancies. Theses clinical success have led to the approval of three anti-CD19 CAR-T cells products for the management of B-cell malignancies in the United States and in Europe as of December 2020.

International audience; The chimeric antigen receptor T-cells are a new class of anticancer treatment consisting in genetically modifying autologous or allogenic T-cells to make express a CAR directed against a membrane tumor antigen. In Europe, tisagenlecleucel (KymriahTM) has a marketing authorization for the treatment of relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia in children and young adults and of R/R diffuse large B-cell lymphoma (DLBCL). The marketing authorization for axicabtagene ciloleucel (YescartaTM) is the treatment of DLBCL and primary R/R mediastinal B-cell lymphoma. The two products are autologous T-cells directed against CD19. This collaborative work, part of a series of expert opinion-based work, aims to give practical advice to help centers in selection of patients for commercially available CAR T-cell treatment.

Context Tisagenlecleucel demonstrated durable responses and manageable safety in adult patients with r/r diffuse large B-cell lymphoma. Objective Determine the efficacy and safety of tisagenlecleucel in adult patients with r/r FL. Design ELARA (NCT03568461) is an international, multicenter, single-arm, phase 2 trial of tisagenlecleucel treatment. Patients or Other Participants Adult (≥18 years) patients with r/r FL (grades 1–3A) after ≥2 lines of therapy or whose disease relapsed after autologous stem cell transplant were eligible. As of September 28, 2020, 98 patients were enrolled. Interventions Bridging therapy was permitted, and disease status was reassessed prior to infusion. Patients received tisagenlecleucel (0.6–6×10 8 CAR+ viable T-cells) after lymphodepleting chemotherapy. Main Outcomes Measures Primary endpoint was complete response rate (CRR) by central review (Lugano 2014 criteria). Secondary endpoints included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and cellular kinetics. Results Ninety-seven patients received tisagenlecleucel (median follow-up, 10.6 months). Median age at study entry was 57 years (range, 29-73), 85% had stage III–IV disease, 60% had a FLIPI score ≥3, 65% had bulky disease, and 42% had LDH > upper limit of normal. Median number of prior therapies was 4 (range, 2–13); 78% of patients were refractory to their last treatment, and 60% progressed ≤2 years of initial anti-CD20-containing treatment. Among 94 patients evaluable for efficacy, CRR was 66% (95% CI, 56%–75%), and ORR was 86% (95% CI, 78%–92%). Estimated DOR (CR) and PFS rates at 6 months were 94% (95% CI, 82%–98%) and 76% (95% CI, 65%–84%), respectively. Of 97 patients evaluable for safety, 65% experienced grade ≥3 adverse events ≤8 weeks post-infusion, most commonly neutropenia (28%) and anemia (13%). Any-grade cytokine release syndrome (Lee scale) occurred in 49% of patients. Any-grade neurological events (per CTCAE v4.03) occurred in 9% of patients. Three patients died from disease progression. C(max) and AUC(0–28d) for tisagenlecleucel were similar between responders and nonresponders. C(max) was achieved at a median of 10 days in responders and 12.9 days in nonresponders. Conclusions Tisagenlecleucel demonstrated efficacy and a favorable safety profile in patients with r/r FL. The study was funded by Novartis.

Context Glofitamab, a T-cell-engaging, bispecific, full-length antibody, allows bivalent binding to CD20 (B-cells) and monovalent binding to CD3 (T-cells). In NP30179 (NCT03075696), an ongoing multicenter, phase I, dose-escalation and expansion study, glofitamab SUD, in addition to Gpt, allowed dose escalation ≤30 mg to maximize efficacy while mitigating cytokine release syndrome (CRS) (Hutchings et al. J Clin Oncol 2021). Objective To present updated efficacy data from glofitamab monotherapy SUD cohorts. Methods Gpt (1000 mg) was given 7 days pre-glofitamab initial dose. Intravenous glofitamab SUD was given on day (D) 1 and 8 of cycle (C) 1, then at target dose from C2D1 (2.5/10/16 mg or 2.5/10/30 mg); treatment continued for ≤12 cycles, every 21 days. Response rates were based on the Lugano criteria (Cheson et al. J Clin Oncol 2014). Results As of December 1, 2020, 52 pts received glofitamab SUD; 17 and 35 pts received 2.5/10/16 mg and 2.5/10/30 mg, respectively. Twenty-eight pts (53.8%) had aggressive NHL (aNHL) and 24 pts had indolent NHL (iNHL). Median age: 68 (44–85) years; median 3 (1–12) prior lines of therapy; 40 (76.9%) and 38 (73.1%) pts were refractory to their most recent and any prior CD20 therapy, respectively. Median follow-up duration: 6.3 months. Best overall response (OR) and complete metabolic response (CMR) rates for aNHL cohort: 64.3% and 57.1%, respectively. 4/5 pts (80%) with mantle cell lymphoma (2.5/10/16 mg, n=2; 2.5/10/30 mg, n=2) had CMR. For aNHL, 13/16 CMRs are ongoing, with 8 CMRs lasting >3 months. OR and CMR rates for pts with iNHL: 79.2% and 70.8%, respectively, with 14/17 CMRs ongoing and 10 CMRs lasting >3 months. As of August 3, 2020, common adverse events were CRS (63.5%), neutropenia (38.5%), and pyrexia (32.7%), with CRS mostly confined to C1. Grade (Gr) 1 and 2 CRS was reported in 18 (34.6%) and 12 (23%) pts, respectively; 3 pts had Gr 3 CRS; none had Gr 4/5 events (defined by ASTCT 2019 criteria). Conclusions Updated data for glofitamab monotherapy SUD show higher preliminary response rates than previously reported in pts with R/R NHL who have failed multiple lines of therapy. CRS was mostly manageable, low-grade, and confined to C1.

Introduction L’infusion de CAR T cells est un traitement innovant des hemopathies malignes B (lymphomes B diffus a grandes cellules [LBDGC], lymphomes indolents transformes [trL], leucemies aigues lymphoides B [LAL-B]). Une chimiotherapie lymphodepletive est suivie de l’infusion de cellules T genetiquement modifiees ciblant l’antigene CD19 via l’expression d’un recepteur antigenique chimerique. Les effets secondaires « off-target », le syndrome de relargage cytokinique (CRS) et la toxicite neurologique, sont traites par immunotherapie anti-IL6 et corticotherapie. La distinction entre CRS et sepsis est difficile, responsable d’une exposition anti-infectieuse importante. Materiels et methodes Etude prospective, monocentrique, observationnelle d’une suite consecutive de patients recevant des CAR T cells anti-CD19+ entre janvier 2017 et novembre 2019. Suivi clinique et bio-monitoring minimum de 3 mois et jusqu’a 12 mois post-infusion. Resultats Inclusion de 75 patients d’âge median de 55 ans [intervalle interquartile (IIQ) 44–64], de sex-ratio H/F de 1,7, traites pour un LBDGC (58,6 %, n = 44), un trL (22,6 %, n = 17), une LAL-B (2,6 %, n = 2) ou autre (16 %, n = 12), refractaires (n = 47, 62,7 %) ou en rechute (n = 28, 37,3 %) apres une mediane de 3 lignes [IIQ : 3–4] de traitement. Tous les patients avaient une prophylaxie par valaciclovir, 85,3 % (n = 64) par cotrimoxazole. Les complications post-infusion etaient l’aplasie (76 %, n = 57) d’une duree mediane de 10 jours [IIQ : 6–12], un CRS (82,6 %, n = 62), une toxicite neurologique (28 %, n = 21) necessitant un traitement par anti-IL6 (52 %, n = 39) ou corticoides (36 %, n = 27). Une colonisation urinaire et digestive etait presente respectivement dans 61,3 % (n = 46) et 38,6 % (n = 29) des cas, incluant 8 % (n = 6) et 22,6 % (n = 17) de bacteries multiresistantes. A j30, 28 (37,3 %) patients cumulaient 40 infections dont 35 % (n = 14) avant ou au jour de l’infusion, majoritairement bacteriennes (87,5 %, n = 35) dont 14 (40 %) bacteriemies et 9 (25,7 %) infections digestives a Clostridium difficile (n = 4, 11,4 %) et a Campylobacter spp (n = 4, 11,4 %). La survenue d’une infection n’etait pas statistiquement associee a l’occurrence d’un CRS (p = 0,75), a l’utilisation d’un anti-IL6 (p = 0,81) ou de dexamethasone (p = 0,21). A j90, 18 (24 %) patients cumulaient 24 infections a une mediane de 62 jours [IIQ : 44–84] post-infusion, majoritairement bacteriennes (58,3 %, n = 14). La survenue d’une infection n’etait statistiquement pas associee a l’occurrence d’un CRS (p = 0,16), a l’utilisation d’un anti-IL6 (p = 0,17) ou de dexamethasone (p = 0,12). A j180, 13 (17,3 %) patients cumulaient 17 infections, majoritairement bacteriennes (70,6 %, n = 12). La mediane de suivi etait de 150 jours [IIQ : 92–261]. La mortalite globale a j30, j90 et j180 etait de 1,4 % (n = 1), 10,6 % (n = 8), 24 % (n = 18) sans mortalite directe attribuable a une complication infectieuse. Conclusion Six mois post-CAR T cells, les complications infectieuses etaient surtout bacteriennes sans directe letalite associee.

Major progress in the understanding of diffuse large B-cell lymphoma (DLBCL) biology has been made in the last decade. Many specific compounds have now entered early phase clinical trials. However, further efforts are needed to find an accurate, fast, reproducible, and affordable technique to translate DLBCL subtype determination by gene expression profiles into clinical application. This article discusses the advantages and drawbacks of the currently available techniques of DLBCL subtype determination as well as important prognostic implications related to the cell of origin. Furthermore, the article provides a schematic description of how molecularly defined DLBCL subtypes could guide tailored therapy.

Summary Background Romidepsin is a histone deacetylase inhibitor approved in the USA for patients with recurrent or refractory peripheral T-cell lymphoma and has shown activity in this setting with mainly haematological and gastrointestinal toxicity. Although it has limited efficacy, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy is widely used for treatment of de-novo peripheral T-cell lymphoma. We aimed to assess the safety, tolerability, and activity of romidepsin combined with CHOP in patients with previously untreated disease. Methods We enrolled patients aged 18–80 years with histologically proven, previously untreated, peripheral T-cell lymphoma (Eastern Cooperative Oncology Group performance status ≤2) into a dose-escalation (phase 1b) and expansion (phase 2) study at nine Lymphoma Study Association centres in France. In the dose-escalation phase, we allocated consecutive blocks of three participants to receive eight 3 week cycles of CHOP (intravenous cyclophosphamide 750 mg/m 2 , doxorubicin 50 mg/m 2 , and vincristine 1·4 mg/m 2 [maximum 2 mg] on day 1 and oral prednisone 40 mg/m 2 on days 1–5) in association with varying doses of romidepsin. The starting dose was 10 mg/m 2 intravenously on days 1 and 8 of each cycle, and we used a 3 + 3 design. We assessed dose-limiting toxicities only during the first two cycles. The primary endpoint was to determine the recommended dose for the combination. For the phase 2 study, we aimed to increase the cohort of patients receiving the recommended dose to a total of 25 patients. Patients were assessed for safety outcomes at least twice per cycle according to the Common Terminology Criteria for Adverse Events, version 4.0. Safety analyses included all patients who received at least one dose of romidepsin and CHOP. This trial is registered at the European Clinical Trials Database (EudraCT), number 2010-020962-91 and ClinicalTrials.gov, number NCT01280526. Findings Between Jan 13, 2011, and May 21, 2013, we enrolled 37 patients (18 treated in phase 1b and 19 patients in phase 2). Three of six patients initially treated at 10 mg/m 2 had a dose-limiting toxicity. The dose-escalation committee decided to modify the study protocol to redefine dose-limiting toxicities with regard to haematological toxicity. Three patients were treated with 8 mg/m 2 of romidepsin, an additional three at 10 mg/m 2 (one dose-limiting toxicity), and six patients at 12 mg/m 2 (three dose-limiting toxicities). We chose romidepsin 12 mg/m 2 as the recommended dose for phase 2. Of the 37 patients treated, three had early cardiac events (two myocardial infarctions and one acute cardiac failure). No deaths were attributable to toxicity. 25 (68%) of 37 patients had at least one serious adverse event. Overall, the most frequent serious adverse events were febrile neutropenia (five [14%] of 37 patients), physical health deterioration (five [14%]), lung infection (four [11%]), and vomiting (three [8%]). 33 (89%) of patients had grade 3–4 neutropenia, and 29 (78%) had grade 3–4 thrombocytopenia. Interpretation Romidepsin can be combined with CHOP but this combination should now be tested in comparison to CHOP alone in a randomised trial. Funding Celgene.