Risk, Characteristics and Biomarkers of Cytokine Release Syndrome in Patients with Relapsed/Refractory AML or MDS Treated with CD3xCD123 Bispecific Antibody APVO436

Fatih M Uckun, Justin Watts, Alice S Mims, Prapti Patel, Eunice Wang, Paul J Shami, Elizabeth Cull, Cynthia Lee, Christopher R Cogle, Tara L Lin, Fatih M Uckun, Justin Watts, Alice S Mims, Prapti Patel, Eunice Wang, Paul J Shami, Elizabeth Cull, Cynthia Lee, Christopher R Cogle, Tara L Lin

Abstract

We evaluate the risk, characteristics and biomarkers of treatment-emergent cytokine release syndrome (CRS) in patients with relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who received APVO436 during the dose-escalation phase of a Phase 1B study (ClinicalTrials.gov, identifier: NCT03647800). Of four patients who developed Grade ≥ 3 CRS, two received steroid prophylaxis. The dose level, gender, race, obesity, or baseline hematologic parameters in peripheral blood did not predict the risk of CRS. Patients with a higher leukemia burden as determined by a higher total WBC, higher percentage of blasts in bone marrow, or higher percentage of blasts in peripheral blood (by hematopathology or immunophenotyping) did not have a higher incidence of CRS. There was an age difference between patients who did versus patients who did not develop CRS (72.9 ± 1.6 years (Median 73.5 years) vs. 63.3 ± 2.3 years (Median: 65.0 years), which was borderline significant (p = 0.04). Premedication with steroids did not eliminate the risk of CRS. Cytokine profiling in patients who developed CRS after APVO436 infusion indicates that the predominant cytokine in this inflammatory cytokine response was IL-6. APVO436-associated CRS was generally manageable with tocilizumab with or without dexamethasone. Notably, the development of CRS after APVO436 therapy did not appear to be associated with a response. The prolonged stabilization of disease, partial remissions and complete remissions were achieved in both patients who experienced CRS, as well as patients who did not experience CRS after APVO436 infusions.

Keywords: AML; APVO436; CD123; T-cells; bispecific antibody; clinical study; leukemia.

Conflict of interest statement

T.L.L., A.S.M., P.P., P.J.S., E.C., C.R.C., E.W., and J.W. and their institutions received research funding in the form of investigative site awards from Aptevo Therapeutics for conducting the study. F.M.U. and C.L. received compensation from Aptevo Therapeutics as consultants. No other conflicts are reported.

Figures

Figure 1
Figure 1
Serum cytokine levels of patients who developed CRS after APVO436. The MSD U-PLEX assay platform was used for measurement of serum levels of the proinflammatory cytokines IL-5, IL-6, IL-10 and TNF-α by electrochemiluminescence in serum samples from a select group of 4 primary AML patients who experienced Grade 2–4 CRS. Serum samples obtained pretreatment and at multiple timepoints after initiation of APVO436 treatment were used to understand the longitudinal changes in serum cytokine levels. The results are also presented in Table S6. See text for detailed discussion of the results. (A) Serum IL-6 levels (B) Serum IL-10 levels (C) Serum TNFα levels (D) Serum MCP-1 levels.
Figure 2
Figure 2
Survival outcome of AML/MDS patients according to development of CRS in the course of their APVO436 therapy. Depicted are the overall survival curves of the 10 patients who developed CRS and 36 patients who did not. See also Table 2.

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