Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) is a type of acute myeloid leukemia (AML). In detail, patients who develop AML from myelodysplastic syndrome (MDS) or a mixed MDS/myeloproliferative neoplasm, those who test positive for specific MDS-related cytogenetic abnormalities, and individuals with AML with multilineage dysplasia may be diagnosed with AML-MRC. The creation of this category mainly corresponds to the qualifying features' influence on the prognosis.
AML-MRC interferes with hematopoiesis and progressive bone marrow failure. Accordingly, patients usually present with symptoms of pancytopenia . On the one hand, anemia accounts for pallor, fatigue, and limited resistance to exercise . Physical activity may induce dyspnea, chest pain, palpitations, dizziness, and even syncopes. Patients suffering from symptomatic leukopenia are prone to infections and may present with recurrent infections of the skin, respiratory or gastrointestinal tract, among others. Fever is common, and microbiological analyses may reveal the involvement of opportunistic pathogens. Finally, thrombocytopenia predisposes to hemorrhages, which may aggravate anemia. Patients may report epistaxis, gum bleeding, hemoptysis, bloody stools or urine. More or less extensive subcutaneous hemorrhages may result from minor trauma.
The first step towards the diagnosis of AML-MRC comprises a thorough anamnesis and consideration of the patient's medical history. The prior diagnosis of MDS or mixed MDS/myeloproliferative neoplasm in a pancytopenic patient should raise suspicion as to a possible transformation to AML.
Subsequently, blood samples have to be obtained for complete blood counts with differentials. Pancytopenia is the most common, yet non-specific finding in AML-MRC patients. Any combination of anemia, leukopenia, and thrombocytopenia may also be found . Valuable hints at the underlying disorder may be gathered upon the examination of peripheral blood smears. If morphological dysplasia is recognized in >50% of the cells in at least 2 cell lines, multilineage dysplasia may be diagnosed. Even if the aforementioned threshold is not exceeded, dysplastic changes are recognized in most AML-MRC cases. The following features may be observed  :
Similar findings may be obtained by analyzing bone marrow specimens, which constitutes the following step in AML-MRC workup. Occasionally, dysplastic changes are more easily recognized in the bone marrow than in peripheral blood. In any case, immunohistochemical staining for myeloperoxidase expression or immunophenotyping of bone marrow blasts should be performed to confirm the involvement of the myeloid lineage. The presence of more than 20% leukemic blasts in peripheral blood or bone marrow specimens is required for the diagnosis of AML, which, in turn, is a prerequisite for the diagnosis of AML-MRC .
Furthermore, bone marrow cells should be analyzed regarding their cytogenetic and molecular features. These features may allow for the diagnosis of AML-MRC with specific MDS-related cytogenetic abnormalities, or call for the exclusion of the index case due to the presence of recurrent genetic abnormalities. In detail, the following genetic abnormalities are considered sufficient to diagnose AML-MRC when >20% of peripheral blood or bone marrow blasts are present and prior cytotoxic therapy (suggestive of therapy-related AML) has been excluded :
Additional abnormalities may be found but are not, by themselves, considered to be qualifying features for AML-MRC.
Chemotherapy is the mainstay of treatment. There are no specific guidelines regarding the management of AML-MRC, and patients are generally treated according to the recommendations for AML therapy. Treatment should be initiated as soon as the workup has been completed, with minimal delay. The standard for induction therapy comprises three days of an anthracycline like idarubicin and cytarabine  . Those who respond to this regimen may be considered for distinct post-remission strategies, such as intensive conventional chemotherapy, prolonged maintenance treatment, and high-dose therapy followed by autologous or allogeneic hematopoietic stem cell transplantation . The latter is associated with the lowest rates of relapse, and a Japanese study has provided evidence that hematopoietic stem cell transplantation may overcome the relatively poor prognosis of AML-MRC .
AML-MRC is associated with a worse outcome than AML, not otherwise specified . Slow progression has been reported for AML arising from previous MDS and rare cases of pediatric AML-MRC , but otherwise, median overall survival is less than a year . Those who are diagnosed with AML-MRC with unfavorable cytogenetics are said to have the poorest prognosis, and this category includes patients with a complex karyotype with 3 or more abnormalities as well as aberrations and losses of chromosomes 5 and 7 . The prognostic value of cytogenetic findings has repeatedly been questioned, though .
Despite the poor prognosis, complete remission may be achieved by chemotherapy in as much as 67% of patients, and similar results have been reported after hematopoietic stem cell transplantation  . However, complete remission does not necessarily predict long-term survival, as has been shown by Devillier and colleagues: Only about one-fourth of the aforementioned 67% of patients who remitted under intense chemotherapy remained alive after two years .
There is no single trigger of AML-MRC; multiple mutations are required to develop this disease. Indeed, intermediate stages on the way from physiological hematopoiesis to AML-MRC may manifest as distinct entities, such as MDS. Little is known about the initial or late events leading to severe anomalies in the differentiation and proliferation of hematopoietic stem cells, as observed in AML-MRC. Both endogenous and exogenous factors may contribute to this process.
On the one hand, patients may be genetically predisposed to MDS and/or AML. There are syndromic forms of inherited bone marrow failure, as observed in families affected by Fanconi anemia, dyskeratosis congenita, or Shwachman syndrome, and non-syndromic familial cases. The latter have been referred to as "pure familial MDS/AML" and have been related to mutations in genes CEBPA (familial AML with mutated CEBPA), GATA2 (susceptibility to MDS and AML), RUNX1 (familial platelet disorder with associated myeloid malignancy), and TERC and TERT (telomere biology diseases due to mutated TERC or TERT) .
On the other hand, damage to the hematopoietic stem cells may be caused by ionizing radiation or by chemical carcinogens such as cigarette smoke, herbicides, pesticides, benzene, and heavy metals. The administration of cytotoxic drugs like alkylating agents and topoisomerase II inhibitors may similarly contribute to leukemogenesis . These are the same factors assumed to be implicated in the pathogenesis of AML, not otherwise specified - little is truly known about the specific causes of AML-MRC.
Epidemiological data have to be interpreted in the context of changing definitions of AML with multilineage dysplasia and AML-MRC.
AML-MRC arises from multiple mutations that allow for the uncontrolled proliferation and abnormal maturation of degenerated hematopoietic stem cells . The preferential multiplication of leukemic cells interferes with physiological hematopoiesis, leading to bone marrow failure and pancytopenia. Accordingly, the disease is characterized by the clonal expansion of myeloid progenitors, so-called blasts, in the bone marrow and peripheral blood.
The spectrum of mutations underlying AML is broad; gene defects may affect any step in the differentiation and maturation process, rendering it a heterogeneous disease. Despite there being a considerable overlap between AML-MRC and AML, not otherwise specified, genetic studies revealed specific molecular patterns of AML-MRC . Relatively high frequencies of mutation were reported for genes ASXL1 and RUNX1, while anomalies in DNMT3A, FLT3, and NPM1 occurred at a lower rate. Mutations of ASXL1 and RUNX1 are non-specific and may alter transcription regulation.
In the aforecited study, no differences were found between the mutation profiles of primary and secondary, post-MDS AML-MRC. This may be suggestive of a common molecular pathway irrespective of any history of MDS. Alternatively, MRC-AML may derive from a previous chronic stage that may manifest as MDS or go unnoticed .
Few recommendations can be given to prevent the development of AML-MRC. In general, the exposure towards any physical or chemical stimulus that may interfere with hematopoiesis should be avoided or reduced to a minimum. Patients who are known to be predisposed to AML-MRC should be monitored carefully for transformation.
AML-MRC is a myeloproliferative disorder. According to the World Health Organization classification of myeloid neoplasms and acute leukemia, AML-MRC may be diagnosed if either of the following criteria is fulfilled   :
Thus, AML-MRC replaces and expands the former category of AML with multilineage dysplasia . This is owing to increasing awareness regarding the impact of a history of prior MDS, cytogenetic and molecular genetic features on the outcome. More recently, high-throughput whole genomic analyses have led to the discovery of other mutations and chromosomal aberrations that are likely to affect the prognosis, and these findings may be used as the basis of a further refinement of the classification system in the future .
Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) is a form of acute myeloid leukemia, i.e., it is a type of cancer that affects the bone marrow and peripheral blood.
Distinct types of blood cells, namely erythrocytes, leukocytes, and platelets, arise from hematopoietic stem cells in the bone marrow. If one of these stem cells starts to proliferate in an uncontrolled manner, degenerated cells take up a lot of room and thereby impede the generation of healthy, functional cells. Accordingly, the patient may develop anemia, leukocytopenia, and thrombocytopenia. These conditions manifest in:
These symptoms may be observed in patients suffering from distinct types of acute myeloid leukemia, and the distinction of AML-MRC requires further analyses. Blood and bone marrow samples are obtained to confirm the diagnosis of acute myeloid leukemia and to characterize those cells deriving from the degenerated stem cell. These cells are called "blasts". Furthermore, the examination of blood and bone marrow specimens may allow for the identification of dysplastic changes in several lineages of blood cells. Multilineage dysplasia is characteristic of myelodysplasia, but the latter may also be diagnosed on the basis of gene mutations and chromosomal aberrations. What's more, AML-MRC patients may have a history of myelodysplasia. This is another type of cancer; it may evoke symptoms similar to those described above or not cause clinical disease.
In sum, AML-MRC may be diagnosed upon the confirmation of acute myeloid leukemia if the patient has a medical history of myelodysplasia, if specific genetic abnormalities are detected, or if multilineage dysplasia is found. While some patients may be genetically predisposed to AML-MRC, the precise cause remains unknown in the majority of cases.