Early Metabolic Response and Tmtv Are Key Predictors of Control of Relapse/Refractory Follicular Lymphoma Treated with CAR-T Cells : Preliminary Results from the French Descar-T Registry

Background :

Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma. Despite initial responsiveness to conventional therapies, 10 to 20% of patients will experience early relapse or refractory (R/R) disease whereas the other will ultimately experience relapse. CD19-directed CAR-T cell therapies have emerged as promising options in relapse/refractory FL. Identifying early predictors of effectiveness is crucial to indicate appropriate treatment, especially when the treatment is potentially toxic and/or costly.

We aim to evaluate the metabolic predictive factors on clinical outcomes after CAR-T therapy in R/R FL patients from the French DESCAR-T registry.

Methods:

Patients with relapsed/refractory (R/R) FL from the DESCAR-T registry, treated with either tisagenlecleucel (tisa-cel) or axicabtagene ciloleucel (axi-cel), and with Fluorodeoxyglucose Positron Emission Tomography and Computed Tomography (FDG-PET/CT) before CAR T-cells infusion (Pre-CAR T) and 1, 3, 6, and 12 months after infusion, available for central review, were included. At each visit, Total Metabolic Tumor Volume (TMTV) and SUVmax of the tumor were measured. Deauville score (DS) and response according to 2014 Lugano classification were registered. PFS was defined as the time between CAR T-cell infusion and progression or death during follow-up.

A logistic regression modeling was conducted to evaluate the probability of being in progressive disease at M3. Cutoff for predicted value was estimated using the ROC curve. A Kaplan-Meier survival analysis was then conducted to compare survival of identified groups from the logistic regression model.

Results :

FDG-PET/CT were available for central review for 83 R/R FL patients (69 treated with tisa-cel and 14 with axi-cel), predominantly male (71.1%), with a mean age of 62 years. Most patients (81.7%) had advanced-stage disease (Ann Arbor stage III-IV). Median follow-up since CAR-T cells infusion was 11.8 months and best overall response rate was 71.1% with 24 patients experiencing progression or relapse. Death rate was 6% (5 patients), preventing overall survival analysis.

At 1 month (M1), 71 patients (85.5%) had a complete metabolic response (CMR, DS1-3), while 12 patients (14.5%) had a DS4-5. By 3 months (M3), 56 (78.9%) of the initial responders (DS1-3 at M1) maintained their response, while 15 (21.1%) progressed. One patient with DS4 at M1 showed a CMR at M3.

Regarding metabolic response at M1, DS1-3 was significantly associated with better PFS than DS4-5 (median 23.2 vs 2.1 months ; p<0.0001). Survival estimates showed 92% PFS for patients with a DS1-3 at M3 whereas those with a DS4-5 at M3 had a PFS of 25% (p < 0.0001).

According to the logistic regression analysis, significant predictors of progression at M3 included the combination of the DS at M1 and pre-CAR-T TMTV, allowing to distinguish three populations: 1) patients with DS4-5 at M1 (12 patients) showing a low median PFS of 3.1 months (95% CI: 2.6-4.8), 2) patients with DS1-3 at M1 and Pre-CAR-T TMTV > 300 mL (17 patients) with an intermediate median PFS of 8.8 months (95% CI: 4.8-NA), and 3) patients with DS1-3 at M1 and Pre-CAR-T TMTV ≤ 300 mL (52 patients) with a high median PFS of 24.2 months (95% CI: 24.2-NA; p<0.001).

Conclusion

Early metabolic response at M1 and pre-CAR-T TMTV predict control of R/R FL after CAR-T cell therapy. The combination of DS at M1 and pre-CAR-T TMTV allows to early stratify risk of relapse after CAR T-cell emphasizing the value of PET imaging for guiding therapeutic approaches of R/R FL patients.

Ysebaert:AbbVie, AstraZeneca, Janssen, Roche, Beigene, BMS/Celgene, Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Research Funding. Bachy:Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Other: Personal Fees, Research Funding; AbbVie, Roche, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; Novartis: Honoraria, Other: Personal Fees; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; ADC Therapeutics: Honoraria; Pfizer: Honoraria, Other: Personal Fees; Kite, a Gilead Company: Consultancy, Honoraria, Other: Personal Fees. Morschhauser:Epizyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genmab: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Honoraria, Other: Payment for Expert Testimony, Honoraria for Scientific Lectures; Chugai: Honoraria; Eisai: Honoraria; Kite/Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy. Houot:Kite-Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead, Novartis, Incyte, Janssen, MSD, Takeda, Roche, Abbvie: Honoraria; Kite/Gilead, Novartis, Bristol-Myers Squibb/Celgene, Incyte, Miltenyi, Roche, Abbvie: Consultancy. Cartron:Novartis: Honoraria; Beigene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; MedXcell: Consultancy; Takeda: Honoraria; Gilead: Honoraria; MAbQi: Consultancy; BMS: Consultancy, Honoraria; Roche, BMS, AbbVie, Ownards therapeutics, MAbQi, MedXcell, BeiGene: Consultancy; Roche: Consultancy, Honoraria; Janssen: Honoraria; Roche, BMS, Gilead, Novartis, Takeda, Beigen, Janssen, AbbVie: Honoraria; Ownards therapeutics: Consultancy. Thieblemont:Amgen: Honoraria; Incyte: Honoraria; Sanofi: Honoraria; ADC Therapeutics: Honoraria; AstraZeneca: Honoraria; Novartis: Consultancy, Honoraria; Cellectis: Honoraria; Janssen: Consultancy, Honoraria; Bayer: Honoraria; Roche: Honoraria, Research Funding; BeiGene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb/Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria, Research Funding; University of Paris: Current Employment, Ended employment in the past 24 months; Regeneron: Consultancy, Honoraria. Rossi:Janssen: Other: Travel accommodation; Abbvie: Other: Travel accommodation. Hermine:AB Science: Consultancy, Current equity holder in publicly-traded company, Patents & Royalties, Research Funding; Inatherys: Consultancy, Current equity holder in publicly-traded company, Patents & Royalties, Research Funding; BMS: Research Funding; Alexion: Research Funding; Roche: Research Funding; MSD Avenir: Research Funding.