Learning more about monocytic resistance to venetoclax is a new direction toward improving outcomes for patients with acute myeloid leukemia.
Morphological classification systems have fallen from favor in the field of acute myeloid leukemia (AML). But with the possibility that venetoclax (Venclexta)-based regimens are less effective in patients with monocytic AML, do we need to resuscitate the French American British (FAB) morphological classification system? The topic will be explored in “Is Acute Myeloid Leukemia With Monocytic Features a Separate Entity?” on Wednesday, September 6, 2023 at 3:49 pm.
AML with monocytic features is a distinct subtype of AML; this was formally recognized in 1976 with the advent of the FAB classification system, which used morphology to categorize AML subgroups.1 Before the availability of cytogenetic or molecular testing, morphology was 1 of the only ways to distinguish AML subtypes. Classification systems, however, are clinically useful only if they identify groups that have differences with respect to prognosis or treatment. It is for this reason that the FAB system was largely replaced by classification systems that were more biologically driven, and in recent years, pathologic grouping of AML by morphology is not commonly done. There can be no argument that AML with monocytic features is a distinct entity; the important question for clinicians is whether the identification of this AML subtype would change the treatment one would otherwise prescribe.
The FAB recognized 2 AML subtypes that had monocytic features. Myelomonocytic leukemia, M4, was described as having both granulocytic and monocytic differentiation present in varying proportions, with 20% of the nucleated cells in the bone marrow being made up of promonocytes and monocytes. Monocytic leukemia, M5, could be poorly differentiated (monoblastic), with large blasts, or differentiated, with monoblasts, promonocytes, and monocytes all detected.1 Clinically, these subtypes were known to often progress from an antecedent chronic myelomonocytic leukemia (but could also arise de novo) and often had extramedullary presentations or relapses. Hyperleukocytosis was noted to be common, as was disseminated intravascular coagulation; while not necessarily less responsive to therapy, outcomes were believed to be suboptimal because of treatment-related toxicity and extramedullary relapses.2,3 However, no differences in treatment recommendations, beyond potential consideration for diagnostic lumbar punctures, were made for these monocytic subtypes, and while retained in more “biologically relevant” classification systems as AML not otherwise specified,4 the morphological characteristics of monocytic AML were not frequently noted in pathology reports or discussed.
Therefore, there is no denying the fact that AML with monocytic features is a distinct AML subgroup; whether it is a clinically relevant subgroup is the important question. I would argue that it was minimally relevant, for the above reasons, for as long as the standard-of-care therapy for AML patients was intensive induction chemotherapy. With the advent of a novel therapy with a distinct mechanism, the BCL-2 inhibitor venetoclax, the relevance of this subtype has become clear.
An ex vivo drug screening method first suggested venetoclax might be less effective for leukemia cells with increased monocytic differentiation.5 Subsequently it was confirmed, in a multivariate analysis of risk factors for resistance to venetoclax, that FAB M5 was the only significant variable among those analyzed.6 Out of 100 patients with a new AML diagnosis who received venetoclax and azacitidine, 62% (8/13) with FAB M5 were refractory, compared with 8% (7/87) of patients who are non–FAB M5. In addition, this work showed that select patients who responded and then relapsed did so with enrichment in the monocytic population, present at diagnosis but expanded at relapse.6 Other groups have subsequently validated or provided complimentary data to support these findings.7-9
Understanding the mechanism for venetoclax resistance in FAB M5 AML is a priority. BCL-2 dependence in AML with monocytic differentiation is significantly lower than more primitive AML subsets; interestingly, in AML with monocytic differentiation, MCL-1 expression is higher, providing a potential therapeutic target for these patients.6 Forthcoming data suggest monocytic populations with a leukemia stem cell (LSC) component are resistant to venetoclax, while monocytic populations without an LSC component are sensitive (according to unpublished data.
Other recent abstracts have suggested no such resistance of monocytic populations to venetoclax; however, they group M4 and M5 together. In our experience, resistance to venetoclax appears to be an M5 phenomenon.6 Mechanistic reasons for this are unclear but may be related to the presence or absence of a viable LSC population. Finally, in data presented at the European Hematology Association 2023 Congress, there was a suggestion that the morphological phenotype plus particular genomic mutations may be a better predictor of response to venetoclax than morphology alone. More data will be required to refine the understanding of how this subtype might differ with respect to response to venetoclax.
AML with monocytic features is a distinct AML subtype. With the approval and widespread use of venetoclax and a suggestion that this subtype is resistant to this therapy, it has become a clinically relevant AML subtype. Recognition of this is important because clinical trials should be designed to overcome this resistance with specific therapies that hold promise to improve outcomes for patients with AML and monocytic features. Some potential strategies to successfully do this would be to target MCL1, monocytic markers like LILRB4, or perhaps RAR alpha overexpression with tamibarotene. Regardless, learning more about monocytic resistance to venetoclax is a new direction toward improving outcomes in AML patients.
Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol. 1976;33(4):451-458. doi:10.1111/j.1365-2141.1976.tb03563.x
Tobelem G, Jacquillat C, Chastang C, et al. Acute monoblastic leukemia: a clinical and biologic study of 74 cases. Blood. 1980;55(1):71-76.
Odom LF, Lampkin BC, Tannous R, Buckley JD, Hammond GD. Acute monoblastic leukemia: a unique subtype--a review from the Childrens Cancer Study Group. Leuk Res. 1990;14(1):1-10. doi:10.1016/0145-2126(90)90140-5
Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2405. doi:10.1182/blood-2016-03-643544
Kuusanmäki H, Leppä AM, Pölönen P, et al. Phenotype-based drug screening reveals association between venetoclax response and differentiation stage in acute myeloid leukemia. Haematologica. 2020;105(3):708-720. doi:10.3324/haematol.2018.214882
Pei S, Pollyea DA, Gustafson A, et al. Monocytic subclones confer resistance to venetoclax-based therapy in patients with acute myeloid leukemia. Cancer Discov. 2020;10(4):536-551. doi:10.1158/2159-8290.CD-19-0710
Zhang H, Nakauchi Y, Köhnke T, et al. Integrated analysis of patient samples identifies biomarkers for venetoclax efficacy and combination strategies in acute myeloid leukemia. Nat Cancer. 2020;1(8):826-839. doi:10.1038/s43018-020-0103-x
Romine KA, Nechiporuk T, Bottomly D, et al. Monocytic differentiation and AHR signaling as primary nodes of BET inhibitor response in acute myeloid leukemia. Blood Cancer Discov. 2021;2(5):518-531. doi:10.1158/2643-3230.BCD-21-0012
White BS, Khan SA, Mason MJ, et al. Bayesian multi-source regression and monocyte-associated gene expression predict BCL-2 inhibitor resistance in acute myeloid leukemia. NPJ Precis Oncol. 2021;5(1):71. doi:10.1038/s41698-021-00209-9