A phase 1 trial of vadastuximab talirine combined with hypomethylating agents in patients with CD33-positive AML

Abstract

Treatment of acute myeloid leukemia (AML) among the elderly is challenging because of intolerance of intensive therapy and therapy-resistant biology. Hypomethylating agents (HMAs) are commonly used, with suboptimal outcomes. Vadastuximab talirine is a CD33-directed antibody conjugated to pyrrolobenzodiazepine (PBD) dimers. Preclinically, HMAs followed by vadastuximab talirine produced upregulated CD33 expression, increased DNA incorporation by PBD, and enhanced cytotoxicity. A combination cohort in a phase 1 study (NCT01902329) assessed safety, tolerability, and activity of vadastuximab talirine with HMAs. Those eligible had Eastern Cooperative Oncology Group status 0 to 1 and previously untreated CD33-positive AML, and declined intensive therapy. Vadastuximab talirine was administered intravenously at 10 μg/kg on last day of HMA (azacitidine or decitabine) infusion in 4-week cycles. Among 53 patients treated, the median age was 75 years. Patients had adverse (38%) or intermediate (62%) cytogenetic risk. Median treatment duration was 19.3 weeks. No dose-limiting toxicities were reported. The majority of adverse events were a result of myelosuppression, with some causing therapy delays. Thirty- and 60-day mortality rates were 2% and 8%, respectively. The composite remission rate (complete remission [CR] and CR with incomplete blood count recovery) was 70%. Fifty-one percent of remissions were minimal residual disease-negative by flow cytometry. Similarly high remission rates were observed in patients with secondary AML, aged at least 75 years, and with adverse cytogenetic risk. Median relapse-free survival and overall survival were 7.7 and 11.3 months, respectively. Compared with historical data for HMA monotherapy, the combination of vadastuximab talirine with HMAs produced a high remission rate, but was accompanied by increased hematologic toxicity.

Low-intensity regimens versus standard-intensity induction strategies in acute myeloid leukemia

“…This was the case with SGN-CD33A, a monoclonal antibody directed towards CD33 conjugated with a DNA-crosslinking pyrrolobenzodiazepine dimer. 55 A phase I trial found that the combination of CD33A with azacitidine yielded responses in 70% of patients with the majority of them achieving Minimal residual Disease (MRD) negativity, 56 but the phase III CASCADE trial comparing vadastuximab and HMAs with HMAs alone was put on hold due to excessive toxicity. Similarly, volasertib, a small molecule inhibitor of Polo-like kinase I that induces cell cycle arrest and apoptosis, in combination with LDAC demonstrated enhanced overall response rates (31% versus 13.3%, respectively), prolonged EFS (5.6 months versus 2.3 months, respectively), and OS (8 months versus 5.2 months, respectively) compared with LDAC alone.…”

Prevention of relapse after allogeneic stem cell transplantation in acute myeloid leukemia: Updates and challenges

“…Vadastuximab talirine (SGN‐CD33A) is a CD33‐directed antibody conjugated to pyrrolobenzodiazepine (PBD) dimers. Addition of vadastuximab talirine to HMAs induced remission, but at the cost of increased myelosuppression and nonhematologic AEs like fatigue, nausea, and diarrhea . The phase III CASCADE trial evaluated vadastuximab talirine in combination with the HMAs vs HMA alone in older patients with newly diagnosed AML, but was terminated early due to increased deaths due to veno‐occlusive disease (VOD) (NCT02785900).…”

Energy metabolism and drug response in myeloid leukaemic stem cells

“…CD44 is the receptor for hyaluronic acid, for which inhibition prevented engraftment of CML and AML cells in vivo (Jin et al, 2006). Similar pre-clinical studies have been performed targeting other cell surface molecules, including VCAM-1 (Jacamo et al, 2014) and CD33 (Fathi et al, 2018). Indeed, several groups have reasoned that targeting the microenvironment could help eradicate myeloid LSCs, which includes treatment with the CXCR4 antagonist, plerixafor (AMD3100), and strategies targeting the IL-3 receptor alpha chain, CD123 (Tables I, SI).…”