S141 EXABS-248-NQ-AML Next Questions: Acute Myeloid Leukemia Farhad Ravandi, MD1,* 1Department of Leukemia, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA *Corresponding author: fravandi@mdanderson.org Keywords Acute myeloid leukemia Further insights into the biology of leukemogenesis in acute myeloid leukemia (AML) and the understanding of the molecular events and drivers of the disease is translating into the development of a number of effective agents with approval of ten new drugs/ combinations over the past four years. Further preclinical research is likely to lead to other molecularly targeted agents and this may progressively diminish our historical reliance on DNA interactive cytotoxic chemotherapy for the management of patients with AML. These insights into the biology are also transformational to our classification systems and allowing better prognostication of patients. Although AML continues to be a highly fatal disease, particularly in the older and less fit population with significant comorbid conditions, the introduction of venetoclax into the therapeutic armamentarium has significantly improved the outcomes. This is particularly evident in this population who once had a truly dismal prognosis when using traditional chemotherapy strategies. Development of other molecularly targeted agents including FLT3 and IDH inhibitors has also significantly improved the prognosis in patients with respective molecular aberrations in the relapse setting. More importantly, further development and incorporation of these agents in the frontline regimens is likely to increase the proportion of patients achieving and maintaining complete remission for longer durations. It is reasonable to believe that, as we develop more effective and potent, target-specific agents, our dependence on cytotoxic chemotherapy, with its associated toxicities, will diminish with time. The combination of venetoclax with the hypomethylating agents, decitabine and azacytidine, which is already a major component of therapy in the older adults, may be improved upon with the addition of third agents such as FLT3 inhibitors, IDH inhibitors and others such as drugs targeting menin or mutant TP53. Development of such highly potent strategies may eventually obviate the need for cytarabine and anthracycline chemotherapy, even in the younger population, similar to what we witnessed with the introduction of all-trans retinoic acid plus arsenic trioxide in acute promyelocytic leukemia (APL). As we develop potent regimens, capable of achieving high quality remissions, the reliance on sensitive assays to detect measurable disease (MRD) that can determine which patients are more likely to relapse, will likely increase. Although MRD monitoring using different assays such as multiparameter flow cytometry or molecular methods has already demonstrated great utility in predicting relapse risk using the traditional cytarabine based regimens, MRD assessment is likely to be as important in patients who receive less intensive but potent venetoclax based regimens. Available data suggests that eradication of MRD can be the goal of therapy in all subsets of AML with quantifiable surrogate markers. Agents capable of eliminating MRD including molecularly targeted agents and immune based strategies are already under investigation and may develop further as we better understand the mechanisms of relapse with clonal selection and clonal evolution. Allogeneic hematopoietic stem cell transplant has long been the most potent strategy to eliminate residual leukemia after initial induction and consolidation therapy, particularly in the more resistant subsets of AML and has only been limited by its potential toxicity and limited donor availability. Allogeneic stem cell transplant has demonstrated the importance of immune-based strategies in combating cancer and a number of such immunebased treatments are being actively explored. Antibodies including immunotoxins and bispecific molecules have demonstrated significant activity in early trials in AML. Further development of effective and less toxic cellular therapy may also further increase our armamentarium in managing patients with AML.
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