Acute myeloid leukaemiaC92.0, C92.5, C92.6, C92.7, C92.8, C92.9, C93.0

Acute myeloid leukemia (AML) is a neoplasm of myelopoiesis with variable involvement of myeloid cell lineages. Untreated AML leads to death in 50% of patients 5 months after the first symptoms (Southam CM et al 1951). It was only after the introduction of daunorubicin and cytarabine that complete remissions and long-term success were achieved (Crowther D et al 1970).The prognosis of AML has improved steadily since the 1970s. Prognosis of older patients over 70 to 75 years of age remains poor.

The improved understanding of the molecular pathogenesis of AML is reflected in the current WHO classification, which includes several balanced translocations or inversions as separate entities. inversions have been included as separate entities [t(15;17), t(8;21), inv(16), t(9;11), inv(3)/t(3;3), t(6;9), t(1;22)] as well as two molecularly defined entities (AML with NPM1 mutation and AML with CEBPA double mutation) and one provisional molecularly defined entity (RUNX1 mutation).

Another subgroup of AML is defined by genetic alterations. This is AML with myelodysplasia-associated cytogenetic alterations, which includes a whole range of unbalanced and balanced aberrations. Overall, based on this classification, well over 50% of patients with AML are now classifiable by cytogenetic and molecular genetic characteristics. Thus, the new classification offers a significant advance in objectivity and reproducibility compared to the previously used, predominantly morphological criteria of the FAB classification ((Haddad H et al. 2014).

Subgroup AML with Myelodysplasia Related Changes (MRC): An AML-MRC according to WHO is present with ≥20% myeloblasts in KM or PB if at least one of the following criteria is met:

• History of MDS or MDS/MPN.
• Myelodysplasia-associated cytogenetic alterations.
• Multilineage dysplasia in KM at initial AML diagnosis (≥ 50% dysplasia in ≥ 2 hematopoietic series) in the absence of genetic markers from the WHO entity "Acute Myeloid Leukemia with recurrent genetic aberrations".

The following cytogenetic alterations are considered myelodysplasia-associated according to WHO:

• Complex karyotype (defined as 3 or more chromosomal aberrations without concomitant presence of any of the genetic markers from the WHO entity "Acute Myeloid Leukemia with recurrent genetic aberrations".
• Unbalanced aberrations: -7 or del(7q); -5 or del(5q); i(17q) or t(17p); -13 or del(13q); del(11q); del(12p) or t(12p); idic(X)(q13)
• Balanced aberrations: t(11;16) (q23.3;p13.3); t(3;21)(q26.2;q22.1); t(1;3) (p36.3;q21.2); t(2;11)(p21;q23.3); t(5;12) (q32;p13.2); t(5;7)(q32;q11.2); t(5;17) (q32;p13.2); t(5;10)(q32;q21.2); t(3;5) (q25.3;q35.1)

Therapy-related myeloid neoplasia (tAML) subgroup

WHO defines any myeloid neoplasia that has occurred after prior cytotoxic therapy as therapy-associated (Arber DA et al. (2016).

The incidence is approximately 3.7 cases per 100,000 population per year and increases with age with age-specific incidences of over 100 cases per 100,000 population in patients over 70 years of age.

Origin is the pathological proliferation of clonal myeloid cells, mostly belonging to the highly proliferative progenitor pool (i.e. CD34+/CD38+) or more rarely to the stem cell pool (i.e. CD34+/CD38-). This proliferating clone overgrows the healthy bone marrow and leads to depletion of healthy hematopoiesis with the resulting clinical consequences:

• Granulocytopenia (infections, sepsis)
• Thrombocytopenia (bleeding)
• Anemia (dyspnea, reduced performance).

In contrast to chronic myeloid leukemia (CML), different cytogenetic aberrations are found in AML. Besides gene translocations such as the translocations t(8;21), t or the inversion inv (Creutzig U et al. 2010), numerical alterations such as:

• Trisomy 8
• monosomy 7

or

complex alterations with more than three recurrent chromosomal aberrations in one clone.

Modern molecular techniques (Next Generation Sequencing - NGS) have shown that the disease often consists of genetically different subclones (on average 5 recurrent alterations). The composition of the different clones can change over the course of the disease. The most common mutations are found in the genes:

• FLT3
• NPM1
• DNMT3A
• IDH1
• IDH2

Almost all patients have at least 1 mutation in one of 9 functional groups critical for transformation. These alterations can be divided into 9 classes:

1. activating mutations of signal transduction(FLT3,KIT,KRAS,NRAS et al.)
2. mutations of myeloid transcription factors(RUNX1,CEBPA and others)
3. Fusions of transcription factor genes (PML-RARA,MYH11-CBFB and others)
4. Mutations of chromatin modifiers (MLL-PTD, ASXL1 and others)
5. Mutations in the cohesin complex(SMC1 and others)
6. Spliceosome mutations
7. Mutations in tumor suppressor genes(TP53,WT1 et al.)
8. NPM1 mutations
9. Mutations in DNA methylation genes(TET1, TET2, IDH1, IDH2, DNMT3B, DNMT1, DNMT3A)

In addition to the dominant main clone, at least one other subclone is found in approximately 50% of patients; in individual patients, up to three additional leukemia clones may be present. This "clonal heterogeneity" is likely to have a role in treatment response or in the development of relapse (Papaemmanuil E et al. 2016).

Risk factors: Causative factors include exposure to radioactive radiation (according to Japanese data from survivors of the atomic bombs on Hiroshima and Nagasaki), benzenes, tobacco, petroleum products, ethylene oxides, herbicides, pesticides and paints. Cytostatic agents are among the most important causative agents, typically alkylating agents with onset of leukemia 4-6 years after application and aberrations on chromosomes 5 and/or 7, and topoisomerase II inhibitors (anthracyclines, anthraquinones, epipodophylotoxins) with onset of leukemia 1-3 years after exposure and often associated chromosomal aberrations of chromosome 11 band q23 but also of the balanced translocation t(1,17).

Further risks are: younger age at the time of diagnosis of the primary tumor, therapy with intercalating substances (anthracylines, anthraquinones) as well as topoisomerase II inhibitors are associated with a short latency period until the occurrence of secondary AML(Kayser S et al. 2011).

Further, a clear association between smoking and AML development has been documented. The risk of AML is increased by 40% in active smokers and by 25% in former smokers compared to non-smokers (p<0.001). It correlates with cigarette quantity and affects both sexes equally (Fircanis S et al 2014). It is not uncommon to be associated with myelodysplastic syndromes (MDS in history; MDS-typical morphology or cytogenetics (Weinberg OK et al. 2009).

Age-associated clonal hematopoiesis of undetermined potential (ARCH/CHIP) is a risk factor for the development of AML. Mutations in the following genes were found more frequently in CHIP (CHIP= clonal hematopoiesis of indeterminate potential) carriers who later developed AML than in CHIP carriers who did not develop AML: DNMT3A, TET2, SRSF2, ASXL1, TP53, U2AF1, JAK2, RUNX1 and IDH2.

The median age of adult patients is 72 years.

The clinical appearance of AML is determined by the increasing hematopoietic insufficiency due to blastic bone marrow infiltration. Often the symptoms are initially unspecific and in the further course prove to be the expression of anaemia (fatigue, reduced performance, pallor, etc.), neutropenia (in particular bacterial infections of the lungs, pharynx and skin as well as systemic mycoses) and thrombocytopenia (petechiae, ecchymoses, menorrhagia or epistaxis).

However, an increased bleeding tendency is also possible due to disseminated intravascular coagulation and hyperfibrinolysis. In the blood, leukocytosis is found in about 60% of patients, and leukemic blasts are found regardless of the leukocyte count. If leukocytosis exceeds 100,000/µl, there is a risk of leukostasis with hypoxia, pulmonary obstruction, retinal hemorrhage, and neurologic symptoms. Leukostasis represents a hematologic emergency and requires rapid lowering of the peripheral leukocyte count by chemotherapy and, in exceptional cases, by the combination of chemotherapy and leukapheresis.

More rarely, aleukemic courses with normal or even decreased leukocyte counts are observed. These are frequently found in secondary or therapy-associated AML and in older patients. In myelomonocytic/monoblastic differentiated AML, extramedullary manifestations such as skin infiltrates (see leukaemia cutis below), meningeosis leukaemica, gingival hyperplasia and infiltration of the spleen and liver are observed with above-average frequency.

Disease-defining is a blast percentage of ≥20% in peripheral blood or bone marrow, or evidence of the AML-defining genetic aberrations t(8;21)(q22;q22.1), RUNX1-RUNX1T1, inv(16)/t(16;16)(p13.1;1q22) CBFB-MYH11 or t(15;17)(q22;q12) PML-RARA (see WHO classification, Arber DA et al. 2016).

Medical history and physical examination findings.

Blood count and differential blood count

Bone marrow biopsy (mandatory for punctio sicca).

Immunophenotyping (CD33 on blasts, CD4, CD56, CD123 and TCL1 to differentiate a BPDCN).

Cytogenetics: FISH; if cytogenetic analysis is unsuccessful: detection of translocations such as RUNX1-RUNX1T1, CBFB-MYH11, KMT2A (MLL), and EVI1; or loss of chromosome 5q, 7q, or 17p.

Molecular genetics (detection of the following mutations):

• NPM1
• CEBPA
• RUNX1
• FLT3 (internal tandem duplications (ITD), mutant-wild type quotient)
• TKD (codon D835 and I836)
• IDH1
• IDH2
• TP53
• ASXL1

Molecular genetics (translocations)

• PML-RARA
• CBFB-MYH11
• RUNX1-RUNX1T1
• BCR-ABL1
• KMT2A (MLL) fusions
• DEK-NUP214
• GATA2 MECOM
• RBM15-MKL1

General condition (ECOG/WHO score)

Evaluation of comorbidities (e.g. HCT-CI Score)

Clinical chemistry, coagulation, urinalysis

Pregnancy test

Gene panel sequencing (in case of clinical consequences)

Gene panel sequencing (for clinical consequences)

HLA typing (of siblings, parents, children, if applicable) + CMV status (in patients suitable for allogeneic stem cell transplantation).

Other additional examinations:

Hepatitis and HIV serology

X-ray thorax

ECG

Cardiac echo

Lung function

Acute lymphoblastic leukemia: bone marrow cytochemistry (peroxidase or esterase positivity), immunophenotyping, cyto- and molecular genetics

Acute leukemia of unclear lineage: bone marrow cytochemistry (pox- or esterase positivity), immunophenotyping, cyto- and molecular genetics

Viral infections (e.g. parvovirus B19, EBV, CMV or HIV), virus detection (PCR, Ag or serological), lack of blast detection in PB or KM immunophenotyping.

Myelodysplastic syndromes: < 20% blasts in bone marrow and/or peripheral blood, cyto- and molecular genetics.

Vitamin B12/folic acid deficiency anemia: history, vitamin B12 and folic acid levels, KM morphology (megaloblasts).

Aplastic anemia: KM morphology (aplasia)Cytogenetics

Leukemic lymphomas: absent detection of myeloid blasts in PB or KM, immunophenotyping, soluble interleukin-2 receptor if applicable.

Myeloproliferative neoplasms: < 20% blasts in BM (exception: blast crisis of CML), often no anemia or thrombocytopenia, cytogenetics t(9;22), molecular genetics: BCR-ABL, JAK2 mutation, CALR mutation.

The therapy of AML should be carried out at a haematological-oncological centre and within the framework of a therapy study. Since the 1980s, several AML study groups and multicenter studies have been formed in Germany:

AML-CG: In case of morphological suspicion or cytogenetic (t(15;17)) or molecular biological (PML-RARA) evidence of acute promyelocytic leukemia (APL, FAB M3), therapy with all-trans-retinoic acid (ATRA) must be initiated immediately, followed by APL-specific cytostatic therapy. In general, intensive curative intent therapy for AML is divided into induction therapy with the goal of complete remission (CR) and post-remission therapy to maintain CR. The chance of achieving CR after intensive induction therapy is mainly determined by the genetic background of AML and less by the age of the patients. It is >80-90% in patients with favorable cyto- or molecular genetic aberration (including t(8;21), in(16), NPM1-mut, CEBPAdm) versus <30% in patients with unfavorable aberrations (including TP53 mutation, monosomal karyotype). Therefore, cyto- and molecular genetic findings are already indispensable in the selection of initial therapy.

First-line therapy:

Intensively treatable patients with curative therapy intention ("fit"). Patients with a biological age of up to 75 years and no or few comorbidities are assigned to this group.

In young patients with a desire to have children or who have not yet completed their family planning, the possibility of fertility-preserving measures should be considered, depending on the urgency of the therapy.

Induction therapy (patients for whom there is an immediate indication for therapy at initial diagnosis and the results of genetic diagnostics are not yet available).

Standard induction therapy (7+3 regimen) includes the combination of 3 days of anthracycline/anthracenedione (e.g. daunorubicin 60 mg/m², idarubicin 10-12 mg/m², or mitoxantrone 10-12 mg/m²) and 7 days of cytarabine (100-200 mg/m² continuous).

When classified into the following subgroups, an alternative induction regimen is recommended:

• Patients with CD33-positive core-binding factor AML (CBF-AML) and patients with CD33-positive NPM1 mutation in FLT3wt.
• Patients with FLT3 mutation
• Patients with AML-MRC and patients with therapy-associated AML (tAML) at FLT3wt
• Patients with CD33-positive intermediate-risk AML in FLT3wt
• Patients with CD33-positive core-binding factor AML (CBF-AML) and patients with CD33-positive NPM1 mutation at FLT3wt
• For patients in this subgroup, the addition of gemtuzumab ozogamicin (GO) to the first cycle of standard 7+3 induction therapy is recommended. Gemtuzumab ozogamicin (GO), a conjugate of CD33 antibody and cytotoxin calicheamicin was developed based on versch. Study results (Hills RK et al. 2014), was approved by the EMA in 2018 for primary therapy in combination with standard chemotherapy based on the ALFA-0701 trial. CD33 positivity is a prerequisite for use of this agent enshrined in the GO approval.
• Patients with FLT3 mutation
• Patients with FLT3-ITD or FLT3-TKD mutation should receive midostaurin from day 8-21 of induction therapy. According to data from a randomized placebo-controlled trial, midostaurin in combination with standard chemotherapy can significantly prolong both EFS, RFS and OS in FLT3-mutated AML patients up to 60 years of age (Thein MS et al. (2013). Note: Strong CYP3A4 inducers (e.g., carbamazepine, rifampicin, enzalutamide, phenytoin, St. John's wort) should not be given concomitantly because of the decrease in levels of midostaurin.
• Patients with AML-MRC and patients with therapy-associated AML (tAML).
• For this subgroup, the use of CPX-351 ((cytarabine and daunorubicin liposome) is approved as a replacement for the classic combination of cytarabine and anthracycline in induction therapy (Lancet JE et al. (2018) CPX-351. The included patients were aged between 60 - 75 and belonged to the following different subgroups.
• Prior MDS (47%) or CMML (7.5%).
• de novo AML with MDS karyotype (25%)
• tAML (20%)
• Patients with CD33-positive intermediate-risk AML at FLT3wt.
• For this group of patients, the meta-analysis on the effect of GO in combination with standard chemotherapy also demonstrated a survival benefit, with NPM1-mutated patients included in the intermediate-risk group.
• Patients not assigned to the above subgroups
• Patients who cannot be assigned to any of the above subgroups according to available specific diagnostics, or who require immediate initiation of therapy at initial diagnosis and the results of genetic diagnostics are not yet available, receive standard induction therapy.

Post-remission therapy:

Patients who achieve CR require consolidation therapy, otherwise rapid relapse of AML can be expected. Consolidation therapy can generally be given with high-dose cytarabine or allogeneic hematopoietic stem cell transplantation.

Patients with CD33-positive core-binding factor AML (CBF-AML) and patients with CD33-positive NPM1 mutation at FLT3wt.: The risk of relapse in these subgroups is comparatively low at 20-40%, so post-remission therapy with high-dose cytarabine results in a relatively high proportion of long-term remissions. Outside of trials, patients with cytogenetically favorable risk, i.e. t(8;21) or inv(16) should therefore receive chemoconsolidation with high-dose cytarabine (HDAC), as long-term remission can be achieved for them in this way with a high probability (Krönke J et al. 2011).

Patients with FLT3 mutation: For the patient group with FLT3 mutation and cytarabine-based chemoconsolidation should receive midostaurin from day 8-21 of consolidation therapy if midostaurin was used in induction. After completion of chemoconsolidation: midostaurin maintenance therapy for 12 cycles of 28 days each.Despite allogeneic stem cell transplantation, the risk of relapse is increased in FLT3-ITD AML. An antileukemic effect of sorafenib after allogeneic SCT is beeligible (Chappell G et al 2019).

Patients with AML-MRC and patients with therapy-associated AML (tAML): Patients with AML-MRC have a high risk of relapse, and therefore allogeneic stem cell transplantation is recommended as post-remission therapy in suitable patients in remission after CPX-351 with an available donor. In the absence of a transplant option, CPX-351 is also available for consolidation (Lancet JE et al (2018)

Patients with intermediate or unfavourable prognosis: Due to the relevant risk of relapse, allogeneic SCT is recommended as post-remission therapy for both subgroups if the patient is fit and a suitable donor is available (Appelbaum FR et al 2006).

In older fit patients without t(8;21) or inv(16) who have achieved CR after induction therapy, allogeneic SZT after dose-reduced conditioning should be pursued if possible (Ossenkoppele G et al.(2015), as long-term remissions of 30% can be achieved in this case.

Elderly patients ≥55 years of age with intermediate or unfavorable genetic risk with CR/CRi after intensive induction therapy with or without prior consolidation therapy, but who are not suitable for allogeneic stem cell transplantation can be treated with the oral azacitidine formulation CC-486 (Wei AH et al. (2020).

Elderly fit patients: patients with biological age > 65 years with absent or minor comorbidities: Parsi M et al (2021) Leukemia Cutis. 2021 Jul 21. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. PMID: 31082180.

To assess the optimal treatment strategy, newly diagnosed AML patients should present to an experienced treatment center. A decision should be made between more palliative therapy with cytoreductive outpatient chemotherapy or best supportive care (BSC). A small proportion of newly diagnosed patients may be so compromised by leukemia-related organ impairment (e.g., leukemic infiltration of the liver), neutropenic infectious complications, or B symptoms that intensive therapy is not possible or justifiable at initial diagnosis. Successful treatment of AML with HMA or LDAC, possibly in combination with venetoclax, may improve the condition such that SCT appears possible and can be successfully performed.

Recurrence therapy: In fit patients who are to be treated in recurrence with curative intention, allogeneic stem cell transplantation remains the only procedure with the possibility of long-term remission. If neither an HLA identical family donor nor an unrelated donor is available, alternative stem cell sources, especially HLA haploidentical transplants from familial donors, can also be used.

Second-generation type I FLT3 inhibitor gilteritinib for monotherapy of relapsed/refractory AML with FLT3 mutation opens up an additional third route to allogeneic SCT (Perl AE et al. (2019. Therefore, in patients with relapsed/refractory disease and FLT3 mutation, gilteritinib is recommended as first-line relapse therapy, even if the patient is suitable for intensive salvage therapy and allogeneic SCT is planned.

Supportive therapy: The prognosis of newly diagnosed AML patients has improved significantly over the last decades, especially in the younger patient population. Essential components of supportive therapy are infection prophylaxis and therapy of immunosuppressed and stem cell transplanted patients, transfusions, antiemesis and therapy of gastrointestinal complications.

Age and molecular or cytogenetic changes have the strongest influence on prognosis. With increasing age, the chance of achieving a complete remission decreases, while the risk of recurrence increases. In larger registries, 5-year survival rates were 60% in patients younger than 30 years, 43% in patients between 45 and 54 years, 23% between 55 and 64 years, and continued to decline at older ages (Juliusson G et al (2012).

Other risk factors include a high LDH and leukocyte count at initial diagnosis.

Acute promyelocytic leukemia (APL) occupies a special position, with a long-term survival rate of over 80%, the highest of all AML diseases, if the acute initial coagulation derailment and resulting life-threatening complications can be effectively managed.

Follow-up: During ongoing therapy, remission control is generally performed at the following time points:

two weeks after the start of induction I ( early puncture )

after the end of induction therapy with regenerated blood count

before the start of each consolidation therapy

at the end of post-remission therapy

Follow-up: AML patients should be followed up clinically and haematologically to detect relapse as early as possible. This requires regular clinical presentations, as well as blood count and bone marrow checks. In case of clinical suspicion of a relapse or abnormal blood count, a bone marrow examination must be performed. Since the majority of relapses occur within 18-24 months after achieving remission, blood count checks are recommended every 1-3 months within the first two years, then every 3-6 months for years 3-5.

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