Venetoclax is an oral selective BCL2 inhibitor, which can restore apoptotic activation in leukemia cells that are dependent on this dysregulated pathway, and in combination with azacitidine (Aza/Ven), is an approved and common frontline therapy for patients with acute myeloid leukemia (AML). The treatment of AML has been revolutionized by the addition of this two-drug regimen (Aza/Ven) and the incorporation of disease genetics (mutation status) in initial treatment selection. Tolerability and efficacy with this two-drug regimen have increased access to remission-inducing therapy to patients with advanced age (>75 years) and even consideration in younger populations with adverse risk (poor) disease genetics where risks of intensive chemotherapies may outweigh the benefit.
Though responses are high with over two-thirds of patients achieving initial remission on Aza/Ven therapy, depth (what is the rate of measurable residual disease (MRD) clearance?) and duration (how long is the remission?) are two challenges that have emerged. Persistence of leftover disease (MRD) leads to increased rates of disease recurrence (relapse) and shorter remissions. Furthermore, experience with Aza/Ven has made it more evident which genetic disease groups benefit less, leading us to ask whether we can build upon this two-drug platform to extend the benefit of this therapy to others without increasing unnecessary toxicity. Therapies targeting selective mutations or surface antigens have emerged and represent new opportunities.
At Dana-Farber, clinical investigators in the Adult Leukemia Program are testing novel three-drug regimens or triplets for safety (tolerability and toxicity) and efficacy (improved responses) with a precision medicine approach. As a national-effort led by the National Cancer Institute (NCI) MyeloMATCH (Myeloid Malignancies Molecular Analysis for Therapy Choice), tiers of therapies are being offered at different stages of an AML patient’s treatment journey from diagnosis, induction, post-remission, transplant or MRD (NCT05564390; Dana-Farber 24-730). This includes promising clinical trials with azacitidine, venetoclax, and gilteritinib (a pill) for older patients with mutations in FLT3 (NCT06317649; Dana-Farber 25-152). We also have a clinical trial for patients with mutations in IDH1 which includes treatment with azacitidine, venetoclax, and ivosidenib (a pill) (NCT03471260; Dana-Farber 19-443).
CD123 is potentially expressed in >80% of patients with AML and thus represents a relevant target. From compelling preclinical and preliminary data generated from the lab of Andrew Lane, MD, PhD, and at Dana-Farber (Lane AA et al., Blood Advances, 2024 Feb 13;8(3):591-602), we are launching a multi-site phase 1/2 clinical trial supported by the Break Through Cancer foundation for patients with AML that is CD123+ and has MRD positivity (NCT07148180; Dana-Farber 25-330). Based on encouraging safety and preliminary response data from a Dana-Farber-led phase 1 trial, our goal is to add tagraxofusp, which is a CD123-targeted immunotoxin conjugated to diphtheria toxin, to Aza/Ven to deepen and lengthen responses. Achieving MRD negativity has been associated with prolonged survival in AML.
Additional studies that we are excited to launch include a randomized control trial with combination azacitidine/venetoclax with bleximenib (a pill) versus combination azacitidine/venetoclax with placebo in patients with mutations in NPM1 or KMT2A-rearranged disease (CAMELOT-2, NCT06852222). This work extends from the pivotal preclinical data arising from the lab of Scott Armstrong, MD, PhD, demonstrating inhibition of the menin complex as a therapeutic vulnerability. Further, in a global phase 2 study we are testing the safety and efficacy of azacitidine, venetoclax, and tagraxofusp in patients with newly diagnosed CD123+ AML (TRILLIUM, NCT06456463; Dana-Farber 24-479).
With more tools and treatments available than ever before, the treatment of AML has become more tailored to individual patients and indicates better outcomes are within reach.