Early Studies Reveal Efficacy, Safety Concerns With Vadastuximab Talirine in Patients With Acute Myeloid Leukemia

Early studies of vadastuximab talirine (33A) in patients with acute myeloid leukemia (AML) have shown preliminary efficacy, whether the drug has been used as monotherapy or in combination with other treatments. However, recently reported deaths in several phase I trials, and hepatotoxicity, have prompted the U.S. Food and Drug Administration (FDA) to place the trials on clinical hold.

According to Anjali Advani, MD, of the Department of Hematologic Oncology and Blood Disorders at the Taussig Cancer Institute at the Cleveland Clinic in Ohio, who presented results at the 2016 ASH Annual meeting, the appeal of 33A is that it targets CD33 – a cell-surface antigen expressed in approximately 90 percent of patients with AML.

“Once the drug is internalized into the leukemia cells, the dimer attaches to the DNA within the leukemia cell and basically leads to cell death,” Dr. Advani told ASH Clinical News. “This drug may be a little better than some of the other previous drugs because it has this stable linker, [which suggests that] it doesn’t have much off-target toxicity.”

Dr. Advani presented results from a phase I study of 33A as a monotherapy in older patients with treatment-naïve CD33-positive AML.1 Twenty-seven patients (median age = 74 years; range = 67-89 years) received 33A administered intravenously at 40 mcg/kg (the recommended dose from the dose-escalation portion of the study) every three weeks for up to two treatment cycles. If patients achieved complete remission (CR) or CR with incomplete blood count recovery (CRi), they received low-dose maintenance with 33A. All patients had AML and an Eastern Cooperative Oncology Group performance status of 0-1, and were either ineligible for or declined conventional treatment with induction and consolidation.

Researchers found that most adverse events (AEs) associated with 33A were “manageable.” The most common grade ≥3 AEs were thrombocytopenia (44%), febrile neutropenia (41%), and anemia (33%).

Of the 26 patients who were evaluable for efficacy, 14 (54%) achieved either CR (n=6) or CRi (n=8), while five patients (19%) achieved a morphologic leukemia-free state. However, Dr. Advani noted that the remissions were short-lived. “I think [33A] is active as a single agent, but to achieve longer relapse-free and overall survival, it probably needs to be combined with [another] therapy,” she told ASH Clinical News. “We need to sort out the best way to do that.”

Amir T. Fathi, MD, of Massachusetts General Hospital in Boston, and co-authors investigated 33A in combination with hypomethylating agents in a phase I study of patients with previously untreated CD33-positive AML who had declined intensive therapy.2 Patients (median age = 75 years; range = 60-87 years) received 33A at a dose of 10 mcg/kg every four weeks; 33A was given on the last day of a five-day regimen of a hypomethylating agent (HMA) (either azacitidine or decitabine).

The authors concluded that the combination was “well tolerated with no identified pattern of off-target toxicity.” No dose-limiting toxicities or infusion reactions were reported, and grade ≥3 AEs (reported in ≥15% of patients) included thrombocytopenia (55%), anemia (43%), febrile neutropenia (43%), neutropenia (38%), pneumonia (19%), and leukopenia (17%). No grade 4 or 5 bleeding events were observed. Rates of 30- and 60-day mortality were 2 percent and 8 percent, respectively, with no treatment-related deaths reported.

Forty-nine patients were evaluable for efficacy: 36 patients (73%) achieved either CR (n=21) or CRi (n=15). Remissions were achieved after a median of two treatment cycles (range = 1-4 cycles). Most patients with poor-risk disease achieved remission, including those with antecedent myelodysplasia, adverse cytogenetics, FLT3/ITD mutation, and age ≥75 years, the authors noted.

“Activity with the combination appears markedly improved when compared with the historic experience of HMA monotherapy in this patient population,” the authors concluded. “The CR/CRi rate of 73 percent in this setting is particularly encouraging.”


  1. Bixby DL, Stein AS, Fathi AT, et al. Vadastuximab talirine monotherapy in older patients with treatment-naive CD33-positive acute myeloid leukemia (AML). Abstract #590. Presented at the 2016 ASH Annual Meeting, December 5, 2016; San Diego, California.
  2. Fathi AT, Erba HP, Lancet JE, et al. Vadastuximab talirine plus hypomethylating agents: a well-tolerated regimen with high remission rate in frontline older patients with acute myeloid leukemia. Abstract #591. Presented at the 2016 ASH Annual Meeting, December 5, 2016; San Diego, California.