Venetoclax-based therapy can induce responses in approximately 70% of older previously untreated patients with acute myeloid leukemia (AML). However, upfront resistance as well as relapse following initial response demonstrates the need for a deeper understanding of resistance mechanisms. In the present study, we report that responses to venetoclax + azacitidine in patients with AML correlate closely with developmental stage, where phenotypically primitive AML is sensitive, but monocytic AML is more resistant. Mechanistically, resistant monocytic AML has a distinct transcriptomic profi le, loses expression of venetoclax target BCL2, and relies on MCL1 to mediate oxidative phosphorylation and survival. This differential sensitivity drives a selective process in patients which favors the outgrowth of monocytic subpopulations at relapse. Based on these fi ndings, we conclude that resistance to venetoclax + azacitidine can arise due to biological properties intrinsic to monocytic differentiation. We propose that optimal AML therapies should be designed so as to independently target AML subclones that may arise at differing stages of pathogenesis. SIGNIFICANCE: Identifying characteristics of patients who respond poorly to venetoclax-based therapy and devising alternative therapeutic strategies for such patients are important topics in AML. We show that venetoclax resistance can arise due to intrinsic molecular/metabolic properties of monocytic AML cells and that such properties can potentially be targeted with alternative strategies.
Key Points
Responses and survival with venetoclax for “real-world” AML patients were promising but inferior to those treated in a clinical trial. Compared with induction, response rates are as high as would be predicted and venetoclax patients had a lower than expected early death rate.
The use of natalizumab to treat multiple sclerosis (MS) has been associated with the development of progressive multifocal leukoencephalopathy (PML), with 242 PML cases reported as of May 3, 2012. Fortunately, rapid withdrawal of the drug and administration of plasma exchange has allowed survival in many of these patients, but a new problem, immune reconstitution inflammatory syndrome (IRIS), has emerged after drug withdrawal. This report provides an update on PML in natalizumab-treated patients and reviews what is currently known about PML-IRIS in this setting; autopsy findings from a well-studied patient are illustrated. This patient with relapsing-remitting MS had been treated for 4 years with natalizumab, with discontinuation of drug after diagnosis of PML by cerebrospinal fluid polymerase chain reaction testing. Disease was manifested by severe paraparesis and expressive aphasia, which progressed before and after the diagnosis of PML. Immune reconstitution inflammatory syndrome was diagnosed, comfort care was instituted, but demise did not occur until 9 months later. Autopsy showed ongoing severe PML-IRIS, with massive cavitary brain lesions containing abundant perivascular and parenchymal CD8-positive T-cell infiltrates. Bone marrow and spleen, but not brain, contained monoclonal T-cell populations by polymerase chain reaction-based gene rearrangement studies, indicating overstimulation of peripheral T cells; T-cell lymphoma was not identified by morphological or immunohistochemical criteria.
Venetoclax (ven) + azacitidine (aza) is the standard of care for newly-diagnosed acute myeloid leukemia (AML) patients who are not candidates for intensive chemotherapy (IC). Some patients who are IC candidates instead receive ven/aza. We retrospectively analyzed newly-diagnosed AML patients who received ven/aza (N=143) or IC (N=149), to compare outcomes and seek variables that could predict response to one or the other therapy, and ascertain whether treatment recommendations can be refined. The response rate for ven/aza was 76.9% and 70.5% for IC. The median overall survival (OS) for IC was 884 days compared to 483 for ven/aza (p=0.0020). A propensity-matched cohort was utilized to compare outcomes in the setting of equivalent baseline variables, and when matched for age, biological risk, and transplantation, the median OS was 705 days for IC and not reached for ven/aza (p=0.0667). Variables that favored response to ven/aza over IC included older age, secondary AML and RUNX1 mutations. AML M5 favored response to IC over ven/aza. In the propensity-matched cohort analyzing OS, older age, adverse risk and RUNX1 mutations favored ven/aza over IC, while intermediate risk favored IC over ven/aza. In conclusion, IC patients have improved OS compared to ven/aza. However, in a propensity-matched cohort of patients with equivalent baseline factors, there was a trend toward a favorable OS for ven/aza. Specific variables, such as reported here for the first time RUNX1 mutations, can be identified that favor ven/aza or IC, helping to guide treatment decisions for patients who may be eligible candidates for either therapy.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.