**3. Vadastuximab talirine**

Vadastuximab talirine (SGN-CD33A) is a novel anti-CD33 mAb conjugated to 2 molecules of pyrrolobenzodiazepine (PBD). After internalization vadastuximab where transported to the lysosomes where the PBD dimer is released via proteolytic cleavage of the linker, crosslinking DNAand leading to apoptosis. Vadastuximab is highly stable in circulation with relatively less off-target toxicity compared to GO [129]. In a dose-escalation phase 1 study 27 treatment naive patients with CD33 positive AML and median age of 74 years were treated with vadastuximab talirine. Of the 26 efficacy evaluable treatment naive patients, 6 patients achieved CR, 8 patients CRi, and 5 patients achieved a morphologic leukemia-free state [130]. In another phase 1 trial of vadastuximab talirine as monotherapy in patients with CD33-positive AML a total of 131 patients, median age, 73 years were enrolled. The CR + CRi rate was 28%, 50% of patients who responded achieved minimal residual disease negativity. Most AEs were consistent with myelosuppression, nonhematological included fatigue, nausea, and diarrhea [131]. Also vadastuximab talirine was added to a 7 + 3 induction therapy in a phase 1b study in 42 patients with a median age of 45.5 years. The CR/CRi rate was 78%. Twenty-three of 31 (74%) patients attaining CR or CRi achieved MRD negative status. No 30-day mortality or significant hepatotoxicity was observed [132]. Fathi et al. combined vadastuximab talirine with hypomethylating agents in patients with CD33-positive AML. Among 53 patients treated, the median age was 75 years. The CR + CRi rate was 70% and 51% of remissions with minimal residual disease-negative status by flow cytometry. The majority of adverse events were a result of myelosuppression, with some causing therapy delays [133]. A phase III trial (CASCADE, NCT02785900) comparing HMA with or without SGN-CD33A in elderly patients with newly diagnosed AML was terminated because of due to safety reasons, specifically a higher rate of deaths, including fatal infections, in the SGN33A arm versus the control arm.
