Summary
Updated results from a phase I/II dose-expansion study of flotetuzumab, an investigational, bispecific CD123 x CD3 DART molecule in patients with primary induction failure and early relapsed acute myeloid leukemia (AML) were presented in an oral session at the 2019 ASH Annual Meeting (Abstract 733).
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Original Article
Primary Induction Failure & Early Relapsed Acute Myeloid Leukemia
Oncology Times
Updated results from a phase I/II dose-expansion study of flotetuzumab, an investigational, bispecific CD123 x CD3 DART molecule in patients with primary induction failure and early relapsed acute myeloid leukemia (AML) were presented in an oral session at the 2019 ASH Annual Meeting (Abstract 733).
“Patients with AML who have failed primary induction therapy or relapsed early after an initial response represent a significant unmet medical need. A remission rate of 32 percent observed in the ongoing study of flotetuzumab in this extremely challenging patient population is noteworthy,” said Geoffrey Uy, MD, Associate Professor, Department of Medicine, Division of Oncology at the Washington University School of Medicine in St. Louis. “Importantly, by implementing a lead-in dosing schedule for flotetuzumab, as well as early intervention with tocilizumab in this study, we were able to mitigate cytokine release syndrome, known to be associated with T-cell engagers.”
In the phase I/II (NCT02152956) open-label, dose-expansion study, 30 patients classified as primary induction failure or early relapsed AML who had received a median of four prior therapies were treated with flotetuzumab at the recommended phase II dose (RP2D) of 500 ng/kg/day by continuous infusion. Data were reported as of the cut-off date of November 1, 2019. The study is currently ongoing with additional patients being enrolled.
Responses, including complete remission (CR), CRh (CR with partial hematological recovery), and CRi (CR with incomplete hematological improvement) per a modified International Working Group (IWG) Response Criteria for AML, are summarized in the table below. Four responders received allogeneic hematopoietic stem cell transplantation as consolidation therapy and remain in remission after 6 to 21 months.
| Responders (N) |
ITT Population (N = 30) |
Evaluable Patients |
|
| CR | 5 | 16.6% | 17.9% |
| CR + CRh | 8 | 26.7% | 28.6% |
| CR + CRh + CRi | 9 | 30.0% | 32.1% |
The most common treatment-related adverse event (TRAE) was infusion-related reaction/cytokine release syndrome (IRR/CRS) that occurred in all (30/30) patients. However, most CRS events observed were of short duration and mild to moderate (grade 1 or 2) in severity, with only one grade 3 event reported in one patient.
A separate oral presentation described translational research that showed an inflammatory (IFN-γ-related) gene expression signature in a subset of patients with AML that correlated with a lack of response to induction chemotherapy (Abstract 460). Furthermore, the same gene signature was associated with patients more likely to respond to flotetuzumab, supporting the mechanism being exploited by this molecule. In addition, AML patients with an immune-infiltrated tumor micro-environment show high expression of immune checkpoint molecules, including PD-L1, which provides a scientific rationale for combining flotetuzumab with checkpoint blockade as a potential mechanism for enhanced anti-leukemic activity. Researchers have initiated a study combining flotetuzumab with MGA012, an anti-PD-1 antibody, given the strong preclinical and translational data that indicate the combination may enhance CD123-directed T-cell killing.