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

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.

Dual Targeting of Multiple Myeloma Stem Cells and Myeloid-Derived Suppressor Cells for Treatment of Chemotherapy-Resistant Multiple Myeloma

“…IL-6 is one of the driving pro-inflammatory cytokines that contribute CRS and its pulmonary, cardiovascular, renal, and neurologic complications ( 60 , 64 – 71 ). Cytokine profiling in patients who developed CRS after APVO436 infusion indicates that the predominant cytokine in this inflammatory cytokine response is IL-6, which agrees with our current knowledge regarding CRS that occurs in the context of BsAB therapy ( 20 , 60 , 64 – 71 , 75 ). Within 1-2 days following the first dose of APVO436, the mean serum IL-6 concentration in these patients who developed CRS was elevated 145-fold over baseline (755 vs 5.2) and at the end of one week it was still elevated 83-fold over baseline.…”

“…Gender, race, age, absolute lymphocyte count or percentage of lymphocytes in peripheral blood did not predict neurotoxicity. Neurotoxicity occurred in 3 patients who also experienced CRS and in 2 patients who did not develop CRS ( 75 ). Conversely, of 10 patients who developed CRS, 7 did not experience any neurotoxicity ( 75 ).…”

“…Neurotoxicity occurred in 3 patients who also experienced CRS and in 2 patients who did not develop CRS ( 75 ). Conversely, of 10 patients who developed CRS, 7 did not experience any neurotoxicity ( 75 ).…”

Post-hoc Analysis of Pharmacodynamics and Single-Agent Activity of CD3xCD123 Bispecific Antibody APVO436 in Relapsed/Refractory AML and MDS Resistant to HMA or Venetoclax Plus HMA

“…The primary study was a multi-institutional Phase 1B clinical dose-escalation trial of APVO436 in patients with relapsed/refractory AML and higher-risk myelodysplastic syndrome (MDS) (ClinicalTrials.gov identifier: NCT03647800). APVO436 exhibited a promising tolerability and manageable treatment-emergent AEs ( 28 , 29 ). The weekly target dose levels for cohorts 2–10 were 1 mcg for Cohort 2, 3 mcg for Cohort 3, 9 mcg for Cohort 4, 18 mcg for Cohort 6A, 12 mcg for Cohort 6B, 24 mcg for Cohort 7, 36 mcg for Cohort 8, 48 mcg for Cohort 9, and 60 mcg for Cohort 10 ( 28 ).…”

“…APVO436 showed promising tolerability and single-agent activity in relapsed or refractory (R/R) AML and MDS ( 28 , 29 ). The primary purpose of this post-hoc analysis was to evaluate the therapeutic and pharmacodynamic effects of APVO436 in 14 R/R AML/MDS patients who had failed treatment with HMA or venetoclax plus HMA prior to being enrolled in the APVO436 Phase 1 study.…”