Introduction. The outcome of relapsed/refractory large B-cell lymphomas, not eligible or cured by high dose chemotherapy due to persistent disease, is very unsatisfactory. The introduction of anti-CD19 chimeric antigen receptor T cells (CAR-T) in this setting, showed impressive long-term results in registrative trials. Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are registered and reimbursed in Italy by Agenzia Italiana del Farmaco (AIFA) for the treatment of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma (PMBCL) patients after at least 2 lines, with an ECOG 0-1, and an age lower than 71 years. To evaluate in real-life the patients treated in Italy with CAR-T cells, the Italian Society of Hematology (SIE) designed an observational study.

Methods. The CART-SIE is an ongoing prospective and retrospective observational trial with the following aims: 1. consecutively register all DLBCL and PMBCL treated in the Italian authorized centers; 2. evaluate the intention to treat overall response rate (ORR, complete [CR] and partial response [PR]), duration of response (DOR), progression free survival (PFS) and overall survival (OS); 3. evaluate safety in terms of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) and long-term cytopenia; 4. compare the two different CAR-T products. Primary endpoint was to evaluate the overall response and survival at one year of the patients receiving CAR-T cells.

Results. Since March 2019 to June 2021, 208 patients were enrolled and leukapheresed; 191 patients were infused (92%); 17 were not due to rapidly progressive disease and worsening of clinical conditions (11), severe infection (4), persistent complete remission (1) and manufacturing failure (1). Clinical characteristics of the 191 infused patients were: median age 53 years (range 19-70), stage III/IV 127 (69%); median number of prior lines was 3 (2-12), including 58 (30%) with prior autologous stem cell transplantation. According to local pathology reports, 134 (70%) were DLBCL, 22 (12%) high-grade B-cell lymphoma (HGBCL) and 35 (18%) PMBCL. Bridging therapy was delivered to 177 (93%) patients: 45 (25%) radiotherapy, 115 (65%) systemic therapy (chemotherapy and/or immunotherapy), 17 (10%) combined therapy (radiotherapy + chemotherapy). All patients received Fludarabine-Cyclophosphamide as lymphodepletion regimen. Axi-cel was infused in 92 (48%), and tisa-cel in 99 (52%) patients. Median follow-up time for infused patients was 7.66 months (IQR: 4.14-14.74). All 191 patients were evaluable for response at 30-days after the infusion: 84 (44%) CR, 61 (32%) PR, with an ORR of 76%. Median DOR was not reached for CR and PR patients, but CR patients did better than PRs (p=0.04). In the whole series, 6 and 12-months PFS were 56% (95% CI:49-65) and 47% (95%CI:39-56); 6 and 12-months OS were 80% (95%CI:74-87); 71% (95%CI:63-80), respectively. The 6-months PFS and OS by histotype were: 52% (95% CI: 44-62) and 79% (95% CI: 72-87) for DLBCL, 57% (95% CI: 39-83) and 72% (95% CI: 54-97) for HGBCL, 73% (95% CI: 59-90) and 87% (95% CI: 76-99) for PMBCL. No outcome differences between axi-cel and tisa-cel were reported: 6-months PFS and OS were 58% (95% CI: 48-70) and 81% (95% CI: 73-91) vs. 55% (95% CI: 45-66) and 79% (95% CI: 70-88), respectively. Of note, tisa-cel was not used in PMBCL. Severe (grade 3-4) CRS was observed in only 9 (5%) patients, and severe ICANS in 15 (8%). One-hundred and eight (57%) patients received at least one dose of tocilizumab and 62 (33%) received steroids; 24 (13%) patients were admitted in intensive care unit. Cytopenia beyond 90 days was reported in 59 of 179 (33%) evaluable patients. At the time of the analysis, 43 (23%) patients had died, 39 due to lymphoma progression, 4 due to complications related to subsequent therapies.

Conclusions. In CART-SIE study, the outcome of patients treated with CAR-T was similar to those of the registrative trials. No differences across histotypes and commercial CAR-T products (axi-cel and tisa-cel) were observed. CRS and ICANS in real world are manageable with adequate risk management plan. Cytopenias are emerging problems in real-life setting.

Disclosures

Chiappella: Gilead Sciences: Other: lecture fee, advisory board; Roche: Other: lecture fee, advisory board; Takeda: Other: advisory board; Clinigen: Other: lecture fee, advisory board; Celgene Bristol Myers Squibb: Other: lecture fee, advisory board; Astrazeneca: Other: lecture fee; Janssen: Other: lecture fee, advisory board; Incyte: Other: lecture fee; Novartis: Other: lecture fee; Servier: Other: lecture fee. Santoro: Eli-Lilly: Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Speakers Bureau; Arqule: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Roche: Speakers Bureau; AbbVie: Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Sanofi: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Sandoz: Speakers Bureau; Eisai: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tisi: Incyte: Membership on an entity's Board of Directors or advisory committees; BWS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Perriello: Novartis: Other: Advisory Board. Corradini: AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Consultancy; AbbVie, ADC Theraputics, Amgen, Celgene, Daiichi Sankyo, Gilead/Kite, GSK, Incyte, Janssen, KyowaKirin, Nerviano Medical Science, Novartis, Roche, Sanofi, Takeda: Honoraria; KiowaKirin; Incyte; Daiichi Sankyo; Janssen; F. Hoffman-La Roche; Kite; Servier: Consultancy; Amgen; Takeda; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations; Novartis; Gilead; Celgene: Consultancy, Other: Travel and accommodations; BMS: Other: Travel and accommodation; Sanofi: Consultancy, Honoraria; Incyte: Consultancy; Novartis, Janssen, Celgene, BMS, Takeda, Gilead/Kite, Amgen, AbbVie: Other: travel and accomodations.

© 2021 by The American Society of Hematology
2021
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