Bispecific DART® as salvage therapy for primary induction failure and early relapse

Flotetuzumab is an investigational CD123 x CD3 bispecific DART® molecule currently in clinical development for patients with acute myeloid leukaemia (AML) and primary induction failure and early relapse, a population with poor prognosis and high unmet medical need. Flotetuzumab demonstrated encouraging activity in the presented phase 1/2 study [1].

Approximately 40% of patients with newly diagnosed AML either fail to achieve complete remission (CR) with intensive induction therapy or experience disease recurrence after a short remission (CR1 <6 months). While these patients are treated collectively with late relapse patients (CR1 >6 months), the probability of response for patients with primary induction failure and early relapse is particularly poor (~12%), with median expected overall survival (OS) approximately 3.5 months.

The low-affinity IL-3 receptor, CD123, is normally expressed on plasmacytoid dendritic cells, basophils, monocytes, and haematopoietic progenitor cells. CD123 is overexpressed on leukaemic stem cells in AML and other haematologic malignancies. Flotetuzumab co-engages T cells (anti-CD3) with CD123 as tumour-associated antigen. It is designed to redirect T cells to kill tumour cells and to recognise tumours independent of T-cell receptor specificity and presentation by the major histocompatibility complex [1].

Dr Ibrahim Aldoss (City of Hope Medical Center, California, USA) presented an update of the first-in-human study evaluating flotetuzumab in AML patients with primary induction failure and early relapse (NCT02152956). Primary induction failure was defined as being refractory to induction with ≥1 high-intensity cytarabine-based chemotherapy cycles, ≥2 but ≤4 BCL-2 inhibitor-based combinations, or gemtuzumab ozogamicin only. Early relapse was defined as relapse following CR1 <6 months. The phase 1 part of this study was completed and published recently [2]. The study is currently enrolling patients in the expansion cohort.

On flotetuzumab, 42.1% of patients achieved a CR, with over half of those subsequently receiving a stem cell transplant. Median duration of response was 3.1 months and appeared to be longer in patients with primary induction failure (15.2 months). With a median follow up time of 10.8 months, median overall survival (OS) was 4.5 months. OS was longer in patients with primary induction failure (15.9 months). In patients who responded, median OS was 7.7 months. Overall, 6- and 12-month survival rates were 41% and 24%, respectively.

Flotetuzumab treatment showed a manageable safety profile. Cytokine-release syndrome (CRS) was the most frequently reported treatment-related adverse event but was manageable. In addition, neurological toxicity was infrequent. A single patient experienced a grade 3 infusion-related reaction and CRS. Treatment was tolerable with a required minimum 8-day hospitalisation.

1. Aldoss I, et al. Flotetuzumab As Salvage Therapy for Primary Induction Failure and Early Relapse Acute Myeloid Leukemia. 62^nd ASH Annual Meeting, 5-8 December 2020. Abstract 331.
2. Uy GL, et al. Blood. 2020;blood.2020007732.

Posted on 18 February 202122 February 2021