Conference Abstracts - 2026 National Summit on Hematologic Cancers
Vol. 6, Issue Supplement 2, 2026 · S1-2
Germline Predisposition to Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-like Syndrome (IEC-HS) after CAR T Cell Therapy for Lymphoma and Myeloma
Anath Lionel, MD, PhD,Cao Cuong Le, PhD,Jianlong Liao, PhD,Federico Mario Aletti, MD,Faezeh Darbaniyan, PhD,Sushanth Gouni, MD,Xubin Li, PhD,Jared Henderson, PhD,Ajlan Al Zaki, MD, PhD,Aniruddha Mundhada, MBBS,Christen Dillard, MD,Sherif Seif, MD,David Berrios Nolasco, MSc,Amy Ayers, MSc,Misha Hawkins, MSN,Fateeha Furqan, MBBS,Ayushi Chauhan, MBBS,Hun Ju Lee, MD,Luis Fayad, MD,Ranjit Nair, MD,Luis Malpica, MD,Chijioke Nze, MD,Preetesh Jain, MD, PhD,Michael Wang, MD,Elizabeth Shpall, MD,Partow Kebriaei, MD,Dai Chihara, MD, PhD,Paolo Strati, MD,Jason Westin, MD,Christopher Flowers, MD, PhD,Sheeba Thomas, MD,Michelle Hildebrandt, PhD,Sairah Ahmed, MD,Swaminathan Iyer, MD,Mark Hamilton, MD, PhD,Krina Patel, MD,Linghua Wang, PhD,Michael Green, PhD,Sattva Neelapu, MD
Submission received: 2026-08-14 / Accepted: 2026-08-25 / Published: 2026-09-28
Abstract
Background
IEC-HS is a rare but potentially fatal adverse event following chimeric-antigen-receptor T-cell (CART) therapy. Clinically, IEC-HS resembles primary/familial hemophagocytic lymphohistiocytosis (HLH), which is caused by homozygous mutations in genes regulating cytotoxic and phagocytic immune cells. Here, we investigated germline predisposition to risk for IEC-HS in lymphoma and myeloma patients.
Methods
We performed whole-exome-sequencing on blood samples from 18 cases with IEC-HS (12 lymphoma/6 myeloma) and 59 controls (41 lymphoma/18 myeloma) without IEC-HS after standard-of-care CART therapy.
Results
The frequency of protein-truncating variants (PTVs) and pathogenic variants (as per ClinVar) in 587 genes associated with inherited disorders of the immune system was significantly more common in the cases vs. the controls (median 10/pt vs. 3/pt; p<0.001) and greater proportion of IEC-HS cases than controls (9/18 vs. 12/59; p<0.05) had such mutations affecting 51 genes implicated in primary HLH. The IEC-HS cases had nonsense mutations in UNC13D and HAVCR2, frameshift mutations causing premature truncation in UNC13D, CYBC1, STXBP2, WAS, LAMP1, NLRP3, ADA and CDC42, and a pathogenic missense variant in TNFRSF1A; none of these genes were altered in the controls. To elucidate potential mechanisms, UNC13D- and STXBP2-knockout (KO) CD19 CART were generated from healthy-donor-derived T-cells. In co-culture with B-cell lymphoma cell-lines, both KO CART showed impaired degranulation, reduced cytotoxicity, and markedly elevated IFN-γ, GM-CSF, and TNF-α production. In B-cell lymphoma xenografts, UNC13D-KO CART showed delayed tumor clearance and sustained elevation of serum pro-inflammatory cytokines. Consistent with this, significantly higher plasma IFN-γ and IL-18 was noted for 7 days post-infusion in IEC-HS pts versus controls, with concordant increases in downstream IFN-γ/IL-18-driven cytokines.
Conclusion
Heterozygous germline variants in primary HLH genes may predispose patients to IEC-HS after CART therapy, with CART activation triggering excessive IFN-γ and pro-inflammatory cytokine production. These findings improve understanding of IEC-HS pathophysiology, potentially guiding risk stratification, and improved prophylactic/therapeutic strategies.