Preliminary Results Show Flotetuzumab Well-Tolerated and Effective in Relapsed/Refractory AML and MDS

In early results from a phase I trial presented at the 2017 ASH Annual Meeting, researchers reported that the bispecific antibody flotetuzumab demonstrated anti-leukemic activity, with a manageable safety profile, in patients with relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS).

“One of the challenges in AML is finding the appropriate target,” study co-author Geoffrey Uy, MD, an associate professor at Washington University School of Medicine in St. Louis, Missouri, told ASH Clinical News. “In other cancers, such as B-cell malignancies, we have drugs and immunotherapies that target antigens that are present on the surface of these B lymphocytes. In AML, the problem is finding a marker on the surface of AML cells that is relatively specific for the leukemic blasts.”

Flotetuzumab is a bispecific antibody that targets both CD3 and CD123, which has been shown to be highly expressed on AML leukemic blasts and AML stem cells. Targeting these antigens allows “simultaneous binding of leukemic blasts to a patient’s own T cells and [for] those T cells to recognize and potentially kill those blasts,” Dr. Uy explained.

He shared findings from the initial dose-escalation phase of the study, which enrolled 45 patients (40 with AML and 5 with MDS) whose disease had failed to respond or relapsed after treatment with conventional cytotoxic chemotherapy. The median age of the entire cohort was 64 years (range not provided).

Participants were treated with flotetuzumab at varying doses (3-1,000 ng/kg/day) in 28-day cycles on one of two dosing schedules: four days on/three days off or seven days on. To mitigate cytokine release syndrome (CRS), patients received lead-in doses of flotetuzumab during week one of cycle one, followed by a target dose (300-1,000 ng/kg/day) on either of the dosing schedules. If clinically indicated, CRS was managed with steroid-sparing, anti-cytokine therapy.

At the time of data presentation, the maximum tolerated dose and schedule were identified as 500 ng/kg/day.

Toxicity has been manageable, the authors reported. Infusion-related reactions and CRS were the most common adverse events (AEs; n=34/45; 76%), and grade ≥3 flotetuzumab-related AEs were observed in 20 patients (44%).

“With any T-cell redirecting therapies, including bispecific antibodies and chimeric antigen receptor T cells, CRS is a potentially severe and dose-limiting toxicity,” Dr. Uy said. “We found that CRS could be managed with either temporary interruption of flotetuzumab or administering steroids or the interleukein-6 antibody tocilizumab.”

Of the 45 patients, 14 treated with 500 to 700 ng/kg/day have completed at least one cycle of treatment and received a post-treatment bone marrow biopsy. In eight of the 14 (57%), anti-leukemic activity was observed, including six who met International Working Group response criteria., for an overall response rate of 43 percent.

Two patients had stable disease and bone marrow blast reduction of 20 percent and 25 percent from baseline, respectively. Also, Dr. Uy added, “when we looked at patients who received doses above 500 nanograms, we saw about 40 to 50 percent of the patients having some evidence of anti-leukemic activity, with about 20 to 30 percent of the patients having measurable responses.”

While the results from this early-phase study will need to be confirmed in larger, randomized trials, they “support the role for this immune-activating agent in treating AML.” The study continues to enroll patients.

“The lack of response may be because certain patients do not express the tumor antigen on their leukemic cells, or because these tumors are able to evade the patient’s own immune system, so we are investigating whether checkpoint inhibitors can augment the effects of flotetuzumab,” he said. “Next, we are looking at ways to mitigate CRS risk, through better dose optimization, changing dosing schedules, or adding additional agents and different antibodies to different cytokines.”

The authors report financial relationships with MacroGenics, the manufacturer of flotetuzumab.


Uy GL, Godwin J, Rettig MP, et al. Preliminary results of a phase 1 study of flotetuzumab, a CD123 ´ CD3 bispecific Dart® protein, in patients with relapsed/refractory acute myeloid leukemia and myelodysplastic syndrome. Abstract #637. Presented at the 2017 American Society of Hematology Annual Meeting, December 11, 2017; Atlanta, GA.