Page 34 - 2018_10-Haematologica-web

P. Valent et al.
compared to hemoglobin levels below 12 g/dL, especially in patients with chronic kidney disease.95 The target hemoglobin level should, therefore, be around 11 g/dL independently of the ESA applied, underlying disease, or age. For some indications, the use of additional drugs, together with erythropoietin/ESA, may be useful. For example, in patients with chronic kidney disease or chron- ic inflammation, addition of iron may lead to a more rapid correction of anemia.96-98 In MDS, the addition of granulo- cyte or granulocyte-macrophage colony-stimulating factor may work and increase the rate of responding patients.83,84 In other patients, low erythropoietin synthesis may be accompanied by other insufficiencies that need to be cor- rected, such as a lack of vitamin B12, iron deficiency or folate deficiency.
There are also other (in part novel) emerging agents that may be useful in patients with anemias. These drugs include, among others, hypoxia-inducible factor stabiliz- ing compounds, prolyl hydroxylase inhibitors, and activin/GDF11-trapping agents such as sotatercept or lus- patercept.97-105 The latter may even work in bone marrow failure syndromes. In addition, GDF11 blockers are able to counteract anemia in patients with b-thalassemia.42,101
However, in advanced bone marrow neoplasms, such as MDS, or in aplastic anemia, the effectiveness of broadly acting growth factors, ESA and other drugs (mentioned above) is limited. In these patients, the use of disease- modifying agents, such as demethylating agents and/or chemotherapy in MDS or immunosuppressive therapy in aplastic anemia may lead to an improvement or even cor- rection of the anemia. In low-risk MDS patients with iso- lated 5q-, lenalidomide therapy usually works well and often leads to transfusion independence or even to a cyto- genetic response. In patients with paroxysmal nocturnal hemoglobinuria the use of complement-targeting drugs has revolutionized the treatment of anemia. Finally, sever- al new agents are currently being tested in patients with hemolytic anemia, thalassemia, or anemia of chronic inflammation. A detailed description of these agents and of new treatment approaches is beyond the scope of this article - we refer the interested reader to the available lit- erature.
Red cell neoplasms
Red cell neoplasms: classification and criteria
Red cell neoplasms can be classified according to their etiology (de novo or secondary, i.e. following MDS or a mutagenic event), WHO criteria and the presence or absence of certain molecular markers. Erythroid neo- plasms include PV (JAK2-mutated or wild-type JAK2), MDS with a prominent erythroid compartment (previous- ly AML M6) and (pure) erythroid leukemia (Table 4). Based on the 2017 update of the WHO classification, ery- throid neoplasms have been reclassified.74,75,106 In the previ- ous definition provided by the French-American-British group and later by the WHO, a blast cell percentage of ≥20% in the non-erythroid compartment together with erythroid predominance (≥50% of nucleated bone mar- row cells) was indicative of AML (AML M6). In the 2017 update of the WHO classification, these cases are reclassi- fied as MDS (usually MDS with excess blasts) unless the total blast cell percentage (without subtracting erythroid cells) is ≥20%.74-76 In the case of a total blast cell percentage
of ≥20% and erythroid predominance, the final diagnosis is AML [AML not otherwise specified (NOS), acute ery- throid leukemia of erythroid/myeloid type] unless molec- ular or cytogenetic markers identify another AML sub- type.74-76 In those with >80% immature erythroid precur- sors, ≥30% proerythroblasts and a total blast cell percent- age <20%, the final diagnosis is acute erythroid leukemia (AML, pure erythroid type). In an updated revision, AML NOS, acute erythroid leukemia (erythroid/myeloid type) was replaced by AML NOS (erythroid subtype).106 Overall, the erythroid leukemias appear to comprise a heteroge- neous group of malignancies. For example, erythroid leukemias can occur as primary (de novo) leukemia or as a secondary form of leukemia, for instance, following MDS or MPN (Online Supplementary Table S1). In rare cases, even the blast phase of Philadelphia chromosome-positive chronic myeloid leukemia may have a clinical and patho- logical picture indistinguishable from that of ery- throleukemia (Online Supplementary Figure S2). It is also important to note that erythroleukemia can develop as an acute and rapidly progressive disease or a more chronic form of leukemia. The acute forms of erythroid leukemias represent a diagnostic challenge and may be overlooked. Rarely, acute erythroleukemia presents as a large-cell anaplastic neoplasm mimicking a histiocytic malignancy or even small-cell carcinoma; such cases can also easily be overlooked unless appropriate phenotypic studies with antibodies against glycophorin A/C or CD71 are conduct- ed (H-PH, unpublished observation). The chronic form of erythroleukemia must be distinguished from PV and reac- tive erythrocytosis (polyglobulia), for example, in cases with an erythropoietin-producing tumor.
The diagnostic criteria for PV have also changed. Whereas expression of the JAK2 V617F mutation is still considered a major criterion of PV the threshold levels of hemoglobin were changed: in the 2008 WHO definition, cut-offs were 16.5 g/dL for females and 18.5 g/dL for males, while in the 2017 revision, hemoglobin cut-offs were 16.0 g/dL for females and 16.5 g/dL for males.74,75 Although rather specific for MPN and often found in PV patients, CALR mutations are not yet regarded as diagnos- tic criteria of MPN/PV. A summary of erythroid neoplasms is provided in Table 4.
Molecular mechanisms regulating red cell neoplasms
In many instances, the molecular mechanisms underly- ing red cell expansion in MPN or erythroid leukemias remain unknown. In the classical MPN, including PV, the JAK2 point mutation V617F and CALR mutations are con- sidered to act as major disease drivers. One critical aspect is that these mutant forms initiate complex networks of signaling cascades that drive the affected cell and trigger growth factor independence. A detailed description of these networks is beyond the scope of this review. Some of the most important networks are shown in Online Supplementary Figure S1. The faculty also discussed novel preclinical models of red cell neoplasms. Based on recent molecular insights into the etiology of PV and erythroid leukemias, several mouse models have been established. In the field of PV/MPN these models are primarily based on the JAK2 mutation V617F and CALR mutations.107-110 Indeed, mice expressing a mutated and thus hyperactive Jak2 may develop a MPN-like condition over time.107-110 However, additional factors (mutations or signaling mole- cules) are required to convert the condition into a full-
1600
haematologica | 2018; 103(10)