Hemophagocytic Lymphohistiocytosis-like Syndrome after Anti-CD19 CAR T-Cells for B-Cell Lymphoma and B-Cell Acute Lymphoblastic Leukemia: A Lysa, Sfce and Graall Study from the Descar-T Registry

Introduction: CAR T-cell therapy has emerged as a key treatment for patients with relapsed/refractory B-cell malignancies but is associated with significant side-effects. While cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are the most notable and well characterized toxicities, data on Immune Effector Cell Hemophagocytic lymphohistiocytosis-like Syndrome (IEC-HS), a rare and life-threatening complication, are limited. Here, IEC-HS was investigated using real-world data from the DESCAR-T registry (NCT04328298).

Methods: A multicenter retrospective study has been conducted on patients with R/R B Non-Hodgkin Lymphoma (B-NHL) or R/R B-cell Acute Lymphoblastic Leukemia (B-ALL) who experienced IEC-HS. Clinical and biological characteristics of patients have been described as well as Overall Response Rate (ORR), Overall Survival (OS) and Non-Relapse Mortality (NRM). IEC-HS were characterized using ASTCT criteria (Hines et al, TCT 2023).

Results:

Among 2,176 treated patients included in DESCAR-T, 41 patients with hemophagocytic lymphohistiocytosis-like syndrome (HS) were identified. Among them, 7 patients were excluded, 3 because HS occurred at disease relapse and 4 patients for missing data, leaving a cohort of 34 patients for analysis: 12 B-ALL (prevalence 8.8%) and 22 B-NHL (prevalence 1.1%); 8 diffuse large B cell lymphoma, 9 transformed indolent B-NHL, 4 mantle cell lymphoma and one follicular lymphoma). Median age at infusion was 15 years (range 0-21) for B-ALL and 63 years (33-72) for B-NHL. Most patients had refractory or progressive disease before lymphodepletion (LD). All B-ALL patients received tisa-cel, while B-NHL patients received axi-cel (n = 12), tisa-cel (n = 6), or brexu-cel (n = 4).

HS diagnosis occurred after a median time of 7 days (IQR 5-16) after CAR T-cell infusion. Elevated LDH and ferritin, and low fibrinogen levels were the most prevalent markers for HS diagnosis: median ferritin 18,561 µg/L (IQR 11,904-49,802), LDH 738 UI/L (IQR 527-1612), and fibrinogen 0.9 g/L (IQR 1-1). Most patients (n = 28) had a high CAR-HEMATOTOX score ≥ 2 (B-NHL 77%; B-ALL 92%) before LD. Most patients (n = 32; 94%) experienced CRS prior to HS including 18 patients with grade ≥ 3 CRS (56%). At HS onset, CRS had resolved in 10 patients (31%) and was ongoing in 22 patients (68%). HS appeared to be exclusively related to CAR T-cell therapy in 53% (n = 18) with other factors such as infection (n = 6), early disease progression (n = 2), or ongoing grade ≥ 3 CRS (n = 3) were also present in the remaining cases. Data for other factors are missing for 6 patients. Grade ≥ 3 HS occurred in 15 patients (44%), with 10 patients (29%) experiencing grade 4. Severity is likely underestimated due to missing grade data (n = 8), as 22 patients (65%) required ICU hospitalization.

Among the 24 patients treated for IEC-HS (71%; 6 patients with missing data), 50% received 2 lines of treatment (n=12) and 21% received ≥ 3 lines (n=5), with corticosteroids (n = 20, 83%) and anakinra (n = 10, 42%) being the most used. Four patients were not treated due to grade 1 HS resolved without intervention. All anakinra-treated patients also received corticosteroids with an ORR/CR of 70%/40%. Corticosteroid monotherapy achieved an ORR/CR 80%/70%, likely in less severe patients. Seven patients received etoposide, with ORR/CR of 71%/14%. Half of the patients developed at least one infection after HS, of which 59% were bacterial (2 B-ALL; 8 B-NHL), 35% fungal (1 B-ALL; 5 B-NHL), 29% viral (0 B-ALL; 5 B-NHL) and 29% unknown (2 B-ALL; 3 B-NHL).

Among B-NHL patients, the best ORR/CR to CAR T-cells was 63.6%/50%, and the CR rate for ALL patients was 67%. One-year OS was 22% (95% CI 7-42) for B-NHL patients (median follow-up [mFU] 12.2 months) and 46% (95% CI 17-71) for B-ALL patients (mFU 19.6 months). Death occurred in 74% (9 B-ALL, 16 B-NHL) patients including progression (n = 17), infection (n = 4, 3 unidentified and 1 invasive aspergillosis), CAR-T cells toxicity complications (n = 2), stroke (n = 1) and unknown cause (n = 1). One-year NRM was 24.1% for B-NHL patients and 16.7% for B-ALL patients.

Conclusion: This large real-world study highlights that IEC-HS is a rare and life-threatening adverse event of CAR T-cells, with a high mortality rate of 74% though steroids and anakinra give a high but transient response rate. Analyses are ongoing to better characterize primary drivers of IEC-HS and improve management strategies.

Brisou:Kite-Gilead: Honoraria. Chauchet:abbvie: Consultancy; beignet: Consultancy. Di Blasi:Pfizer: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodation, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees; Abbvie: Speakers Bureau. Houot:Kite-Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead, Novartis, Bristol-Myers Squibb/Celgene, Incyte, Miltenyi, Roche, Abbvie: Consultancy; Kite/Gilead, Novartis, Incyte, Janssen, MSD, Takeda, Roche, Abbvie: Honoraria. Morschhauser:Servier: Consultancy; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead Sciences: 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; AstraZeneca: 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; Chugai: Honoraria; Eisai: Honoraria.