HLH Is a Possible New CAR T-Cell–Associated Toxicity in Young Patients

Take-aways:

• In a phase I trial, approximately one-third of patients with relapsed/refractory CD22-positive leukemia or lymphoma who received CAR T-cell products developed carHLH.
• CarHLH occurring in those with CRS associated with higher CAR T-cell expansion and persistence.
• Investigators suggest carHLH is a CRS variant requiring more research to understand its pathophysiology and subsequent treatment approach.

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A study published in Blood has characterized hemophagocytic lymphohistiocytosis (HLH)–like manifestations as a cytokine release syndrome (CRS) variant in young people with leukemia and lymphoma who received CD22-targeting chimeric antigen receptor (CAR) T-cell therapy.

“To date there have only been case reports of HLH-like toxicities in the setting of CAR T cells,” corresponding study author Nirali N. Shah, MD, MHSc, from the National Cancer Institute’s Center for Cancer Research, told Blood Cancers Today. “Our experience and systematic approach, which aligns both clinical manifestation and cytokine profiling and provides insights into this toxicity profile, is a first step towards thinking about the implications of CAR T-cell–associated HLH (carHLH) as a CAR T-cell toxicity.”

Outcomes for CAR T-cell therapy are in large part contingent on toxicity mitigation, explained Dr. Shah. “Our study highlights the need to conceptualize carHLH as a CRS variant that warrants a more systematic approach to understand this pathophysiology, and subsequent treatment approach to improve outcomes from patients who experience carHLH.”

This retrospective analysis looked at patient and CAR T-cell product characteristics from a phase I trial of CAR T-cells in 59 patients with relapsed/refractory CD22-positive leukemia or lymphoma. Only those patients who were considered evaluable for toxicity were included in the retrospective analysis.

Approximately 88% of patients (n, 52) developed CRS. In addition, 36% of patients developed carHLH manifestations, with CRS preceding these manifestations in all cases. Twenty-one of the 52 patients with CRS also had carHLH.

Looking at patient characteristics, those with carHLH were slightly older than those without carHLH (median age, 17 and 13 years, respectively). A slightly larger proportion of patients without carHLH had previously undergone stem cell transplantation (74.2% vs. 61.9%) and had received prior CAR T-cell therapy (64.5% vs. 52.4%). The median time to CRS onset after infusion was 8 days in the group without carHLH and 7.5 days in the group with carHLH.

In the group of patients with CRS, clinical features of carHLH included coagulopathy, elevated lactate dehydrogenase, hepatic transaminitis, hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, hyperbilirubinemia, occasionally hemophagocytosis, and severe neutropenia.

The development of carHLH was associated with pre-infusion NK-cell lymphopenia as well as a higher bone marrow T/NK-cell ratio, which the investigators noted was amplified with CAR T-cell expansion. Specifically, a relative NK-cell lymphopenia was more profound in patients with carHLH at peak CAR expansion. The investigators wrote that NK-cell lymphopenia remained at day 28 and converged “with the relative predominance of both CD8 and CAR T-cells at days 14 and 28.”

The investigators added that “carHLH was further characterized by persistent elevation of HLH-associated inflammatory cytokines, which contrasted with declining levels in those without carHLH.”

A limitation of this study included its retrospective nature. Dr. Shah added that this analysis only reviewed CD22-targeting CAR T-cell therapy, so the findings may not be applicable to CAR T cells with alternative targets, such as CD19. “Nonetheless, the clinical manifestations of carHLH are also being seen with CD19 targeting,” she said. “Thus, using this experience to further explore the pathophysiology, identify which patients are experiencing carHLH, and determine who would benefit from a specific approach to treatment of carHLH represent critical next steps.”

Disclosures: This research was supported by the National Institutes of Health. The study authors reported no relevant conflicts of interest.

Reference

Lichtenstein DA, Schischlik F, Shao L, et al. Characterization of HLH-like manifestations as a CRS variant in patients receiving CD22 CAR T-cells. Blood. 2021 Sep 15; blood.2021011898.