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Normal and pathological erythropoiesis
Refractory anemias: the updated World Health Organization classification and novel molecular markers and targets used to grade and classify the disease
In the current WHO proposal (2017) the term refractory anemia has been removed and replaced by the term MDS with an additional explanatory appendix to define the number of lineage(s) involved with dysplasia (example: MDS with single lineage dysplasia).74-76 It is important to note that MDS with single lineage dysplasia can be sepa- rated into anemic, neutropenic and thrombocytopenic types. Table 3 shows the current WHO proposal to clas- sify MDS. Another important aspect is that only a few cytogenetic and molecular markers are used to define the subtype of MDS. For example, the 5q- syndrome is recog- nized as a separate entity by the WHO (MDS with isolat- ed 5q-) and is associated with particular sensitivity to lenalidomide. It has also been described that the SF3B1 mutation is highly indicative of the presence of ring sideroblasts.74-76 Therefore, this mutation, when present, serves as a diagnostic feature. In particular, MDS variants with ring sideroblasts can be diagnosed when ring sider- oblasts account for either ≥15% of all red cells (old defi- nition) or ≥5% in the presence of a SF3B1 mutation (new adjunct).74-76 For the morphologist, this definition implies that more red cells have to be counted in the iron stain (at least 100 red cells) to arrive at a correct diagnosis.52 This individualization might be of importance because patients with this disorder usually do not respond to ery- thropoietin but may benefit from specific treatment, such as a GDF11 inhibitor. Another relevant change in the cur- rent WHO classification (update 2017) relates to the defi- nition of erythroleukemia. Details are discussed below under the section ‘Red cell neoplasms’. Based on the changed definition, a new subset of poor-risk patients with MDS, formerly diagnosed as having erythroid leukemia or M6 acute myeloid leukemia (AML) according to the French-American-British classification, will require attention.74-76 In fact, these patients often behave like patients with AML, are usually resistant to cytoreductive agents and chemotherapy, and are characterized by pre- dominant erythropoiesis (>50% of bone marrow cells). The poor prognosis of these patients is also reflected by their poor-risk cytogenetics, often in the form of a com- plex karyotype. If possible, debulking with poly-
Table 3. Updated WHO classification of myelodysplastic syndromes, 2017.
chemotherapy (regimens used for AML) or hypomethy- lating agents should be considered, and in young and fit patients, intensive post-debulking therapy, preferably in the form of hematopoietic stem cell transplantation, (HSCT) is often recommended.77-79
Treatment of anemias: novel agents and concepts
During the workshop, standard treatments and novel therapeutic approaches for various forms of anemias were discussed. With regard to erythropoietin, standard indica- tions remain renal anemia and anemic patients with MDS in whom a relative erythropoietin deficiency has been documented and a response to erythropoietin is seen.80-84 For other similar indications, such as anemia with low endogenous erythropoietin levels accompanying myelo- mas, lymphomas or chronic leukemias, treatment with erythropoiesis-stimulating agents (ESA) may also be use- ful.85,86 Even in some form of ICUS (elderly ICUS-A patients) or anemia of chronic disease, the use of erythro- poietin may be justified.87,88 However, our faculty is of the opinion that in all these indications, ‘inadequate’ (insuffi- cient) production of erythropoietin should be documented before starting erythropoietin therapy. Moreover, we are of the opinion that erythropoietin therapy is no longer jus- tified for patients with solid tumors or other malignant disorders after chemotherapy (in certain malignancies tumor cells may express erythropoietin receptor) and should no longer be considered for patients with elevated endogenous erythropoietin levels (especially levels >500 U/L). However, there are other potential indications for erythropoietin and other ESA, such as trauma or certain neurological disorders.89-91 Although beneficial effects of erythropoietin for these indications have been document- ed, the mechanisms contributing to these beneficial effects have not been elucidated so far.
With regard to the type of erythropoietin preparation or erythropoietin-like ESA, no major differences in responses have been reported. In fact, several meta-analyses of patients with MDS and other indications have shown that short-acting and long-acting erythropoietin-based drugs all exert very similar effects.92-94 However, erythropoietin therapy should always be administered with caution, especially when hemoglobin levels rise. In fact, it has been described that hemoglobin levels above 12 g/dL can even be associated with complications and a poor outcome
Table 4. Overview of red cell neoplasms.
Neoplasm
Myelodysplastic syndrome with erythroid predominance
Pure erythroid leukemia
Polycythemia vera
Key Features / Criteria
Variant
MDS with single lineage dysplasia
MDS with ring sideroblasts
MDS with ring sideroblasts and single lineage dysplasia MDS with ring sideroblasts and multilineage dysplasia
MDS with multilineage dysplasia MDS with excess blasts
MDS with isolated del(5q)
MDS unclassifiable
Provisional entity: refractory cytopenia of childhood
Abbreviation
MDS-SLD
MDS-RS MDS-RS-SLD MDS-RS-MLD
MDS-MLD MDS-EB - MDS-U -
Bone marrow cell dysplasia >50% erythroid cells and myeloblasts <20%
Proerythroblasts ≥30% and
>80% of all BM cells are erythroid cells; myeloblasts <20%
JAK2 V617F or CALR mutations and myeloblasts <20% and WHO criteria for PV fulfilled
WHO: World Health Organization; BM: bone marrow: PV: polycythemia very; JAK2: janus kinase 2; CALR: calreticulin.
WHO: World Health Organization; MDS: myelodysplastic syndrome.
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