Acute myeloid leukemias (AML) are a heterogeneous group of diseases. AML can either develop de novo, after previous cytotoxic and/or radiotherapy (t-AML), or secondarily from a pre-existing myeloproliferative disease or MDS (s-AML). The incidence of AML is 2.5 - 3.0 / 100,000 inhabitants per year. The median age is 65 years. In children under the age of 15, AML accounts for only about 15-20% of acute leukemias.
Classification of AML
The new AML WHO Classification 2017 divides AML into specific AML subgroups, first according to the patient's medical history (de novo, t-AML, s-AML) and then taking into account a large number of recurrent, balanced cytogenetic abnormalities (see Table 1). Overall, this means that 80% - 90% of patients with AML can now be classified by cytogenetic and/or molecular genetic markers.
AML WHO Classification 2017
(Arber DA et al. 2016, Swerdlow et al. 2017)
Acute myeloid leukemia (AML) and related neoplasms
AML with recurrent genetic abnormalities
AML with t(8;21)(q22;q22.1); RUNX1-RUNX1T1
AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
Acute promyelocytic leukaemia (APL) with PML-RARA
AML with t(9;11)(p21.3;q23.3); KMT2A-MLLT3
AML with t(6;9)(p23;q34.1); DEK-NUP214
AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM
AML (megakaryoblastic) with t(1;22)(p13.3;q13.3); RBM15-MKL1
AML with BCR-ABL1 (provisional entity)
AML with mutated NPM1
AML with biallelic mutation of CEBPA
AML with mutated RUNX1 (provisional entity)
AML with myelodysplasia-related changes
Therapy-related myeloid neoplasm
AML, not otherwise classified (NOS)
AML with minimal differentiation
AML without maturation
AML with maturation
Acute myelomonocytic leukemia
Acute monoblastic and monocyte leukemia
Pure erythroid leukemia
Acute megakaryoblastic leukemia
Acute basophilic leukemia
Acute panmyelosis with myelofibrosis
Myeloid proliferation associated with Down syndrome
- Transient abnormal myelopoiesis (TAM)
- Myeloid leukemia associated with Down syndrome
According to the WHO classification, a blast percentage of at least 20% in peripheral blood or bone marrow is required for the diagnosis of AML. In AML with t(8;21)(q22;q22.1), RUNX1-RUNX1T1 or inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 and acute promyelocytic leukemia (APL) with PML-RARA, the disease is classified as acute leukemia even if the blast count is below 20%.
blasts in blood or bone marrow define a AML
(Onkopedia guidelines AML)
AML - Diagnostics
AML: MRD (Measurable Residual Disease)
The determination of Measurable Residual Disease (formerly known as minimal residual disease) opens up new possibilities for certain AML subgroups in terms of prognosis and classification with regard to response to therapy. The search for suitable parameters is often difficult. The diversity of clones can be high, and preleukemic clones and subclones exist side by side. Over time, the composition of the clones may change, especially under the selection pressure of the therapy. Nevertheless, it has been shown very well that certain markers are suitable for prognostic assessment.
The determination of the mutation load of the marker NPM1 by means of quantitative polymerase chain reaction (qPCR) can, for example, be used very well to assess the risk of recurrence and give an indication as to which patient should be given an allogeneic stem cell transplantation or not due to MRD negativity. Patients with wild-type NPM1 and intermediate risk benefit from an MRD determination after induction therapy by flow cytometry, which also allows a prognosis of the risk of relapse. The determination of the transcription level of fusion proteins such as RUNX1-RUNX1T1 at specific points in time during therapy also allows an assessment of the risk of relapse. MRD negativity is a very favourable parameter for survival and a low risk of relapse (Freeman et al. 2019, Rücker et al. 2019, Schuurhuis et al. 2018).
Prognosis of AML
Karyotype and molecular genetic changes most important prognostic parameters
In addition to age, leukocyte count and general condition, the karyotype and molecular genetic changes are important prognostic parameters and have a major influence on the therapy strategy. Several studies have shown that especially patients with normal karyotype benefit from additional molecular genetic information regarding therapy choice and prognosis assessment (Döhner et al. 2010, 2015, 2017). Modern genetic prognosis systems combine molecular mutations and cytogenetics (Grimwade et al. 2016, Döhner et al. 2017).
The cytogenetic abnormalities and molecular genetic changes with prognostic relevance defined so far are listed in Tables 3 and 4.
Table 3: Risk distribution with independent prognostic relevance in younger AML patients (16 - 60 years)
(according to Grimwade et al. 2016)
|Risk category||Genetic abnormality|
t(15;17)(q24;q21) / PML-RARA
aberrations, which are not classified as favourable or adverse
abn(3q) except t(3;5)(q21~25;q31~35)/ NPM1-MLF1)
*only if none of the cyto- and molecular genetic abnormalities classified as favourable are present
Table 4: Risk classification according to ELN recommendation
(Döhner et al. 2017)
|Risk category||Genetic abnormality|
Mutated NPM1 and FLT3-ITDhigh
- three or more unrelated chromosome abnormalities in the absence of 1 of the WHO-designated recurring
# excluding core-binding-factor (CBF) AML
AML - Therapy
For a long time, all AML subtypes were treated with the same standard therapy 7+3 or similar protocols, which were specifically designed for fit patients with a biological age below 75 years. A fast start and intensive treatment was considered important, which consisted of induction therapy with the aim of complete remission (CR) and post-remission therapy to maintain CR. Allogeneic transplantation played a major role in this process. The response to therapy was very much determined by the genetic background of AML. For the first time, it was possible to introduce a specific therapy for acute promyelocytic leukemia with all-trans-retinoic acid (ATRA) (later also in combination with arsenic), which was specifically oriented on the genetics of AML. In recent years, the spectrum of targeted therapies has expanded for several other AML subgroups, relapsed patients and especially patients who did not seem suitable for intensive therapy due to comorbidities. The most accurate genetic characterization of AML is essential for the use of targeted therapies.
For clinically stable patients at the time of the initial diagnosis delay in the start of therapy due to the genetic analyses, which can take several days, does not lead to a worse response but rather to an improved long-term prognosis through the use of adapted therapies.
Today, according to the Onkopedia guidelines (status: 10/2019), patients with
CD33-positive Core Binding Factor AML (CBF-AML) and with CD33-positive NPM1 mutation in FLT3wt
AML-MRC and patients with therapy-associated AML (t-AML) at FLT3wt
CD33-positive intermediary risk-AML in FLT3wt
can be treated with an alternative induction scheme.
The B-cell lymphoma (BCL-2) inhibitor Venetoclax, in combination with hypomethylating agent (HMA) therapy, showed very good success in older patients with NPM1 mutant AML, who otherwise have a comparatively adverse prognosis compared to younger patients. Studies with a small cohort of older de novo AML patients with an intermediate or adverse risk profile after ELN also showed that venetoclax in combination with decitabine or azacidine is a very good alternative to standard therapy. CR rates of between 54% and 67% were shown, with a response being achieved as early as 1 to 2 cycles, mortality was only 3 to 6% and survival was significantly prolonged (DiNardo et al. 2019).
FLT3 inhibitors represent a new therapeutic option for patients with mutated FLT3. FLT3 inhibitors of class I (midostaurine) or II (gilteritinib, quizartinib) are used as first-line therapy as well as in recurrence. The FLT3 inhibitor midostaurine, together with conventional chemotherapy, has a positive effect on all risk groups grouped by ELN (Döhner et al. 2020). Studies have shown that second-generation FLT3 inhibitors in combination with the 7+3 regimen in refractory patients lead to improved CR rates (48% vs. 27%), longer survival (6.2 months vs. 4.7 months) and a higher probability of receiving a stem cell transplant. So far it is questionable whether these inhibitors also have a positive effect in maintenance therapy, although initial study results suggest that they do (DiNardo et al. 2020).
Older patients who do not respond to HMA in first-line therapy have had an adverse prognosis. This prognosis has been improved by the introduction of IDH antagonists (IDH1-ivosidenib and IDH2-enasidinib) for AML patients with IDH mutation. Response rates of 29% to 34% and a median survival of 9 months demonstrate the potency of these drugs. Of the patients who responded to an IDH antagonist, 50% were still alive after 18 months. In addition, 21% of the patients achieved deep remission of IDH1 (DiNardo et al. 2020).
Gemtuzumab ozogamicin (GO) is currently used together with the 7+3 regimen as first-line therapy for low and intermediate risk groups classified as ELN. The positive effect occurs mainly with mutations that affect cell signalling (FLT3-ITD, FLT3-TKD, NRAS) and correlate with high CD33 expression (Fournier et al. 2020).
For patients with secondary AML, therapy-associated AML or AML associated with MDS, Vyxeos (CPX-351) represents a new alternative. It consists of a fixed combination of daunorubicin and cytarabine in an optimal 5:1 ratio for the treatment and a liposomal formulation that leads to improved biological accessibility in the body. A group of patients in the intermediate and adverse risk group benefited in several studies in terms of response rate (58% in CR and 55% MRD<103), overall survival (5.95 vs. 9.56 months) and survival rate after two years (31% vs. 12%).
AML is defined by ≥20% blasts in peripheral blood and/or bone marrow. This differentiates AML from myelodysplastic syndromes. To confirm the diagnosis the following tests are recommended according to the current oncopedia guidelines for AML.
Diagnostic confirmation in case of suspected AML (Oncopedia-LL AML; 10/2019)
- Medical history and physical examination
- Blood count and differential blood count
- Bone marrow cytology and cytochemistry
- Bone marrow biopsy (absolutely necessary in case of punctio sicca)
- FISH (if the cytogenetic analysis is not successful: detection of translocations such as RUNX1-RUNX1T1, CBFB-MYH11, KMT2A and EVI1; or loss of chromosome 5q, 7q or 17p)
Molecular genetics (gene mutations)
FLT3 (internal tandem duplications (ITD), mutant wild type ratio)
FLT3-TKD (Codon D853 and I836)
Molecular genetics (gene fusions)