Expert Perspective:
Professor Tariq Mughal
Professor Mughal, how do you view the current treatment landscape for patients with acute myeloid leukemia (AML)?
In AML, treatment has two sequential objectives: first, to achieve complete remission, and second, to prevent relapse. For patients considered fit for intensive therapy, remission induction typically consists of one to two cycles of intensive chemotherapy, followed by post-remission (consolidation) therapy to reduce the risk of relapse and maximize the chance of cure.
Despite major advances in our understanding of AML biology and genomics, the standard intensive induction regimen has changed little in more than 50 years and remains associated with substantial toxicity. Consolidation typically involves further intensive chemotherapy or allogeneic stem cell transplantation.
For a patient, transplantation offers the best chance of long-term disease control, but it also carries serious risks, including transplant-related mortality and graft-versus-host disease. Several targeted agents have been incorporated into induction therapy, but their benefits have largely been confined to selected patient subgroups. Only around 50% of patients achieve long-term disease control, and the proportion is considerably lower in those with high-risk disease.
For patients considered unfit for intensive therapy, outcomes have improved markedly with hypomethylating agents (HMA) combined with venetoclax. These approaches are now also being evaluated in patients who would otherwise be candidates for intensive therapy.
There is still a major unmet need for more effective and less toxic treatment options. Given the limitations and risks of transplantation, there is growing interest in immunotherapeutic approaches, such as vididencel, in patients who achieve complete remission following induction.
And what are your thoughts on the treatment of patients with chronic myeloid leukemia (CML) beyond tyrosine kinase inhibitors (TKIs)?
The introduction of imatinib, the first tyrosine kinase inhibitor (TKI), into the treatment of CML in 2001 marked a dramatic paradigm shift, not only in CML but in cancer treatment more broadly, from largely untargeted therapies toward precision medicine based on the genetic features of cancer. Imatinib established the foundation of modern CML therapy, achieving durable disease control and greatly improving long-term survival. Second- and third-generation TKIs further improved on imatinib, particularly in the speed and depth of molecular responses. More recently, a new generation of allosteric TKIs has shown further improvements in efficacy.
Most patients, however, still require lifelong TKI therapy, with the potential for cumulative treatment-related adverse effects that can affect quality of life. Consequently, treatment-free remission (TFR) has emerged as an important therapeutic goal for patients who achieve a sustained deep molecular response. Clinical studies have demonstrated that TFR is both feasible and safe in appropriately selected patients. Even so, only around 50% of patients who attempt treatment discontinuation remain in sustained TFR, and long-term relapse remains a concern.
Further strategies are therefore being explored to improve the likelihood of durable TFR and long-term clinical outcomes. This is particularly important because approximately one-third of patients who start TKI therapy fail to achieve an optimal response, for a variety of reasons including intolerance and drug resistance.
What role could vididencel play in the treatment of AML and CML?
Vididencel is an investigational therapy in clinical development. It is intended to stimulate the patient’s immune system against residual disease following conventional first-line therapy. It is designed to harness some of the immune response against leukemia cells that contributes to the success of allogeneic stem cell transplantation, but in a safer and less burdensome way.
In AML, the goal is to suppress residual disease and reduce the risk of relapse. In CML, the objectives are twofold: to help more patients achieve deeper, sustained molecular responses to TKIs, increasing the likelihood of treatment-free remission (TFR), and to support durable TFR after TKI discontinuation.
The clinical and translational data generated to date demonstrate immune activation alongside an encouraging safety and tolerability profile. We believe vididencel has the potential to become an important component of future treatment strategies for patients with AML and CML.