Novel Antibody-Based Therapies Emerge for AML

February 27, 2017

A handful of novel antibody-based therapies may soon emerge for the treatment of acute myeloid leukemia, according to a presentation at the 21st Annual International Congress on Hematologic Malignancies.

A handful of novel antibody-based therapies may soon emerge for the treatment of acute myeloid leukemia (AML), according to a presentation at the 21st Annual International Congress on Hematologic Malignancies: Focus on Leukemias, Lymphomas and Myeloma, held February 23–25 in Sunny Isles, Fla.

“AML is a highly heterogeneous disease, with poor outcomes, particularly among older patients. Conventional therapies have largely remained unchanged for decades. Improvements in outcomes are mainly related to advances in supportive care. Novel and effective diagnostic, prognostic, and therapeutic approaches are desperately needed,” said Amir T. Fathi, MD, director of the Leukemia Program at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School.

An emerging focus is on novel antibody-based treatments in AML, naked or bound to cytotoxic agents or radioisotopes, which carry the payload to the cell surface of the leukemic cell. An initial antibody-based therapy targeting CD33 was lintuzumab. This naked antibody was associated with modest efficacy, given as monotherapy or when combined with conventional leukemia treatments, Fathi said.

Gemtuzumab ozogamicin, an antibody-drug conjugate (ADC) targeting CD33, has demonstrated survival benefit in certain AML populations, but the incidence of hepatic sinusoidal obstruction syndrome, as well as controversies regarding dosing and schedule, have limited its pervasive use, said Fathi. The drug was voluntarily withdrawn in the United States, but has remained under study globally in recent years.

Vadastuximab talirine, another ADC, is now being extensively studied in clinical trials. This drug has demonstrated anti-leukemic activity as monotherapy in an ongoing phase I trial, clearing the marrow of blasts of a large proportion of treated patients with advanced AML.

Intriguingly, the combination of vadastuximab talirine with hypomethylating agents (HMA), commonly used gentle therapies among older patients, was well-tolerated with a high composite rate of remission as frontline therapy. “A lower dose of ADC in combination with gentle forms of treatment such as HMAs may in time be an option for older or less robust AML patients who are not eligible for aggressive induction chemotherapy,” said Fathi.

Among the 49 evaluable patients in this combination cohort, the composite rate of remission was 73%, which is much higher than expected with an HMA alone, he said. One-third of treatments were delayed due to adverse events, mainly cytopenias seen during AML therapy. The 30-day mortality and 60-day mortality rates were low (2% and 8%, respectively).

“After treatment with this combination, those who achieved remissions, and particularly those with no molecular evidence of minimal residual disease, lived longer,” said Fathi. Larger studies are necessary to confirm these initial, highly promising findings, and a large phase III, placebo-controlled trial comparing vadastuximab talirine plus HMA versus HMA alone is now accruing.

Additional targets and modalities of antibody-based approaches are also under vigorous study and may expand therapeutic options for patients, he said. In addition to CD33, these include CD123, CLL1, and CD47.

“We are thinking outside the box to find ways to promote cytotoxic treatment in a targeted fashion, to deliver a payload of cytotoxic agent directly to the cancer itself and limit toxicity to the patient. We need fresh ideas and the most effective anti-leukemic approaches that minimize risk to patients,” said Fathi.