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2355 Macrophage Activation Syndrome-like Manifestations (MAS-L) Following BCMA-Directed CAR T-Cells in Multiple Myeloma

Program: Oral and Poster Abstracts
Session: 704. Immunotherapies: Poster II
Hematology Disease Topics & Pathways:
Biological, Therapies, CAR-Ts
Sunday, December 6, 2020, 7:00 AM-3:30 PM

Vanessa E Kennedy, MD1, Christopher Wong2*, Chiung-Yu Huang, PhD3*, Jeffrey L. Wolf, MD4, Thomas Martin, MD5, Nina Shah, MD6 and Sandy W. Wong, MD7

1University of California- San Francisco, San Francisco, CA
2School of Medicine, Touro University California, Vallejo, CA
3University of California, San Francisco, San Francisco
4University of California, San Francisco, San Francisco, CA
5University of California, San Francisco, CA
6Associate Professor of Medicine, University of California San Francisco, San Francisco, CA
7Division of Hematology and Oncology, University of California, San Francisco, San Francisco, CA

Chimeric antigen receptor (CAR) T-cells can induce a rapid disease response but are frequently associated with immunologic toxicities. In addition to cytokine release syndrome (CRS), macrophage activation syndrome-like manifestations (MAS-L), characterized by uncontrolled immune activation, have been described (Shah et al, 2020). Traditional MAS definitions are challenging to apply in patients receiving CAR T cells, due to overlapping signs and symptoms with lymphodepletion and CRS. Therefore, we sought to develop novel criteria to characterize MAS-L following CAR T cells and used these criteria to identify risk factors for developing MAS-L.

We conducted a retrospective review of 55 patients who received B cell maturation antigen-directed CAR T cells for multiple myeloma from 11/1/17 – 5/1/20. Based on the labs readily available in our patient population, we defined MAS-L using the following criteria: 1) rate of ferritin rise ³ 100 mg/L/hour within a 24 hour period and 2) minimum fibrinogen < 150 mg/dL or maximum LDH > 2 times the upper limit of normal. In developing these simplified criteria, we considered multiple laboratory markers of inflammation (ferritin, LDH, soluble interleukin receptor-2, natural killer cell activity) and end organ damage. Infection was defined as any culture positivity, febrile neutropenia, or clinical suspicion such that a new antimicrobial was started in the 30 days prior to CAR T cells. Wilcoxon rank-sums and Fisher’s exact test were used to compare continuous and categorical variables, respectively. Overall (OS) and progression-free survival (PFS) were compared using log-rank tests.

Of the 55 patients, 12 (21.8%) met the above criteria for MAS-L with similar disease trajectories. Following CAR T cells, all 12 patients first developed CRS, characterized by an elevated C-reactive protein (CRP) and administration of tocilizumab, and subsequently developed MAS-L, characterized by decrease in fibrinogen and rapid rise of ferritin and LDH (Figure 1).

Compared to the 45 patients who did not develop MAS-L, patients with MAS-L had similar baseline patient and disease characteristics (Table 1); however, a significantly higher proportion of patients with MAS-L had an infection prior to receiving CAR T cells (75% vs 9.3%, p < 0.001.) Patients with MAS-L also had higher peak ferritin (median 20,707 vs 573 ug/L, p < 0.001), D-dimer (14,000 vs 3,010 ng/mL, p < 0.001), aspartate aminotransferase (AST; 153 vs 48 U/L:, p < 0.001) and a trend towards higher alanine aminotransferase (ALT; 76 vs 50 U/L, p = 0.08). In contrast, patients with MAS-L had a lower peak C-reactive protein (CRP; 29.8 vs 60 mg/L, p = 0.03).

Compared to patients who did not develop MAS-L, a similar proportion of MAS-L patients developed any CRS (100% vs 84%, p = 0.33) and ³ grade 2 CRS (50% vs 50%, p = 1). Neurotoxicity was more common in patients with MAS-L (42% vs 14%, p = 0.05). A greater proportion of patients with MAS-L received tocilizumab (100% vs 70%, p = 0.05), systemic steroids (92% vs 27%, p < 0.001), and anakinra (83% vs 2.3%, p < 0.001). Anakinra was given per clinician discretion and not per study protocol.

Following CAR T cell therapy, patients with MAS-L had longer hospitalizations (21 vs 19 days, p = 0.009) and a greater proportion required ICU-level care (27% vs 2%, p = 0.02). OS and PFS between the two groups were similar (p = 0.15 and 0.63, respectively), with a 1-year OS of 65.2% vs 90.6% and PFS of 35.4% vs 54.7% for patients with vs without MAS-L, respectively.

In univariate logistic regression of baseline patient factors, disease characteristics, and ferritin, CRP, and D-dimer prior to receiving CAR T cells, only a history of documented infection in the 30 days prior to CAR T cells predicted MAS-L development (Hazard Ratio 29.2, 95% CI 5.54 – 154, p < 0.001).

In this analysis, we developed novel criteria for defining MAS-L following CAR T cell therapy and used these criteria to define the unique laboratory profile and clinical trajectory of patients with MAS-L. We also identify pre-existing infection as a strong risk factor for MAS-L development. Although patients with MAS-L frequently require prolonged monitoring, this immunologic toxicity can be mitigated with steroids, anakinra, and supportive care, and patients ultimately have similar survival compared to patients without MAS-L. Larger studies are needed to prospectively validate these novel criteria.

Disclosures: Wolf: Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Martin: Sanofi, Amgen, Seattle Genetics, JNJ - Janssen: Research Funding; Legend Biotech: Consultancy. Shah: BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding; GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy. Wong: Fortis: Research Funding; Roche: Research Funding; Janssen: Research Funding; Amgen: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; Bristol Myers Squibb: Research Funding.

*signifies non-member of ASH