تسجيل الدخول

تسجيل

Biology of Relapsed/Refractory Acute Myeloid Leukemia

المؤلف:  Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.

المصدر:  Hematology : Basic Principles and Practice

الجزء والصفحة:  8th E , P949

2026-10-13

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Treatment failure is the most important cause of mortality in AML. This includes cases that relapse after achieving remission and cases that are refractory to initial therapy. Chemotherapy, targeted therapy, and immunotherapy impose different therapeutic bottlenecks and are associated with different mechanisms of resistance.

Allogeneic stem cell transplantation exerts its principal antileukemic effect by providing cell-mediated immunity against AML cells (“graft-versus-leukemia”). Therefore it is not surprising that the major mechanisms that have been identified in AML patients who relapse after transplant involve adaptations that allow AML cells to evade immune attack. These include loss of mismatched HLA alleles by somatic recombination after haploidentical transplant and downregulation of class II antigens after matched allogeneic transplant.

Resistance to conventional cytotoxic chemotherapy has been associated with mutations in sensors and effectors of the DNA damage response (e.g., TP53) and a metabolic state that is not sufficiently “primed” towards apoptosis in response to DNA damage (e.g. BCL-2 dependence). Using peptides to probe the status of the mitochondrial apoptotic pathway, retrospective studies have demonstrated that cells from AML patients who were refractory to remission induction had a lower level of priming for apoptosis. Finally, cytotoxic chemotherapy is often successful in removing the bulk AML population but leaves behind a residual population capable of seeding relapse (see Leukemia Stem Cells, earlier) with intrinsic properties (including quiescence and expression of drug efflux pumps) that render cells less sensitive to chemotherapy.

Small molecules that target key driver mutations (e.g., FLT3, IDH1/2) have emerged as important therapeutic tools in AML. Predictably, escape from the selective pressure induced by these agents is frequently associated with mutations in the drug target or pathway. With IDH inhibitors, resistance may be conferred by a second site mutation in the drug target (in cis or in trans) or by emergence of a subclone harboring a mutation in the other isoform (e.g., IDH1 mutations emerging after treatment of IDH2-mutant AML with an IDH2 inhibitor). Resistance to FLT3 inhibitors may be caused by mutations in the ATP binding pocket that affects drug binding or by nonmutational processes affecting parallel survival pathways. Finally, acquisition of RAS pathway mutations appears to be a relatively common nonspecific escape mechanism that has been associated with resistance to multiple targeted agents.