Picking from the Red Book of the CHS: What's New in This Year's Recommendations for Diagnosis and Treatment of AML?
In recent years, there have been significant advances in the diagnosis and therapy of acute myeloid leukemia (AML). High-quality laboratory diagnostics (molecular genetics, cytogenetics, and flow cytometry) are absolutely essential, and monitoring measurable residual disease is becoming increasingly important. The range of treatment options is also beginning to expand. The content of the latest 'Recommendations for the Diagnosis and Treatment of Acute Myeloid Leukemia (AML),' which are part of this year's updated 'Red Book' of the Czech Hematology Society ČLS JEP (CHS), is primarily based on the 2022 European Leukemia Network (ELN) guidelines and offers, among other things, an updated disease classification and risk stratification, as well as an overview of current treatment options for both intensive and non-intensive regimens.
New Classification of AML
The 2023 recommendations completely remove some AML subunits and focus on others. The diagnostic condition of at least 20% blasts in bone marrow or peripheral blood still applies, except for the AML subunit with recurrent genetic aberrations, where the criterion is the presence of at least 10% blasts in bone marrow or peripheral blood. However, there is an exception to this as well—BCR::ABL1 translocation, where the 20% blast condition still applies.
A specific unit is then MDS/AML, which is used in cases of finding 10–19% blasts in bone marrow or peripheral blood without the presence of recurrent genetic aberrations. Biologically and prognostically, this unit lies between myelodysplastic syndrome and acute myeloid leukemia.
The classification of AML now looks as follows:
- AML with recurrent genetic aberrations
- AML with TP53 mutation
- AML with mutations associated with myelodysplasia
- AML with cytogenetic abnormalities associated with myelodysplasia
- AML not otherwise specified
- MDS/AML
The classification thus removed separate units of AML related to prior therapy, AML with dysplastic changes, and AML with germline predispositions. They are now only diagnostic attributes behind the main AML unit.
According to WHO 2022, AML without defining genetic or cytogenetic aberrations can be further classified based on morphology.
Risk Assessment
There have been changes in risk stratification as well:
- AML with myelodysplastic mutations and with myelodysplastic cytogenetic abnormalities fall into the high-risk group. The exception is a non-frameshift mutation in the bZIP region of the CEPBA gene, which belongs to the low-risk group.
- FLT3-ITD moves to the intermediate-risk group regardless of allele ratio.
- With the accumulation of new knowledge, new cytogenetic abnormalities have been added to the high-risk group.
- The last change is the definition of a complex karyotype, which now excludes hyperdiploid karyotype with ≥ 3 trisomies or polysomies without structural abnormalities.
Evaluation of Treatment Response
In terms of evaluating the treatment response, there has been a development in the definition of MRD—referred to as measurable residual disease. Negative MRD no longer means complete eradication of the disease but a reduction of residual disease below a defined threshold. The most common methods to determine MRD include multiparametric flow cytometry and quantitative polymerase chain reaction (qPCR).
According to the ELN 2022 recommendations, MRD determination is appropriate when the result can influence the treatment plan. However, due to the uniqueness of each AML patient, the choice of timing and frequency of MRD determination remains a highly individual matter in clinical practice.
A New Standard in Non-Intensive AML Therapy
Treatment options for AML continue to expand, and one of its new standards is now venetoclax in combination with the hypomethylating agent azacitidine. This combination is relevant for non-intensive therapy, primarily aimed at prolonging progression-free survival (PFS) and overall survival (OS), or it can be used in vulnerable patients as a bridge to allogeneic transplantation.
Venetoclax belongs to the family of Bcl-2 inhibitors. It is administered either in the mentioned combination with azacitidine at a dose of 400 mg/day, where it significantly improved clinical response compared to monotherapy, or—in the case of the inability to use hypomethylating agents—in an alternative regimen with low-dose cytarabine.
With the azacitidine + venetoclax regimen, it is essential to keep in mind that during the first cycle, the dose is gradually escalated over 3 days to prevent tumor lysis syndrome (TLS). Similarly, in managing the therapy, it is necessary to consider the significant drug interactions of venetoclax, particularly with strong CYP3A4 inhibitors.
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Source: Mrkvová Z., Horňák T., Jindra P. et al. Chapter 3: Recommendations for the Diagnosis and Treatment of Acute Myeloid Leukemia (AML) (excluding APL). In: Red Book. Treatment Guidelines in Hematology 2023. Czech Hematology Society ČLS JEP, March 20, 2023. Available at: www.hematology.cz/wp-content/uploads/2023/03/03-Akutni_myeloidni_leukemie-verze-01-2023.pdf
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