Page 35 - 2018_10-Haematologica-web

Normal and pathological erythropoiesis
blown malignancy. These additional anomalies are indeed found in patients with MPN/PV or secondary AML and are, therefore, of clinical significance.111-116 They include mutations in TP53 and in various driver genes.112-116 Several of these changes lead to hyperactive signaling in clinically relevant pro-oncogenic signaling networks. For example, molecular changes that lead to an increased production and accumulation of tyrosine-phosphorylated STAT5 (a critical JAK2-downstream transcription factor) can trans- form an indolent MPN-like condition into a highly fatal disease with major thromboembolism in mice (RM and PV, unpublished observation).
In contrast to PV and other MPN, very little is known about the molecular mechanisms underlying the evolu- tion and progression of erythroid-rich MDS and erythroid leukemia. In fact, despite a growing list of mutations associated with erythroid leukemia, their role in the initi- ation and/or maintenance of the erythroid phenotype remains largely unknown.115-118 Whereas earlier studies showed that particular viruses, such as the avian ery- throblastosis virus and Friend spleen focus-forming virus, can induce neoplasms resembling erythroid leukemia in various animal models, no evidence of a viral etiology for the human disease has been identified so far. All in all, the faculty concluded that more research is needed to deci- pher molecular players and targets in these highly fatal neoplasms.
Therapy of red cell neoplasms
Despite novel treatment options, early and advanced erythroid neoplasms are still regarded as incurable malig- nancies. Most PV patients can be managed quite well with phlebotomy. If phlebotomy alone is not sufficient to bring erythrocyte counts under control (target hemat- ocrit: <45%) or thromboembolic events occur, additional cytoreductive therapy is recommended. Depending on age, risk factors, and expected adverse side effects, inter- feron-α or hydroxyurea can be prescribed. In highly symptomatic cases, ruxolitinib may be considered. For patients whose disease transforms into secondary AML, poly-chemotherapy or, in some cases, hypomethylating agents, plus HSCT should be considered. The same holds true for patients with advanced MDS and prominent ery- thropoiesis (previously AML M6) and cases with full- blown erythroid leukemia (fulfilling 2017 WHO criteria).77,78 In these patients, hypomethylating agents (5-
azacytidine or decitabine) or polychemotherapy (AML regimens) should be considered for debulking prior to HSCT.
Unfortunately, however, HSCT can only be offered to a restricted group of young and fit patients. In all patients, the risk of HSCT-related mortality and morbidity must be weighed against the potential benefit. The probability of long-term disease-free survival after HSCT is probably in the same range as that seen in secondary AML following MDS. In some of these patients, hypomethylating agents may exert clinically meaningful anti-neoplastic effects.79 Especially in older patients or those who cannot tolerate intensive chemotherapy, treatment with hypomethylating agents is often recommended as first-line therapy. Hypomethylating agents can also be considered for patients who are refractory to or relapse after poly- chemotherapy. When hypomethylating agents fail and the patient is fit, polychemotherapy or experimental drugs should be considered. Hydroxyurea is the palliative drug of choice in multi-resistant patients and those who are old and refuse intensive or experimental therapy.
Concluding remarks
Red cell production, survival and turnover in health and disease, and mechanisms regulating these processes, have attracted the attention of physicians and scientists in the past five decades and many different mechanisms and molecules involved in the regulation of red cell production and survival have been discovered. In addition, a number of molecular and immunological markers and targets have been identified in red cells and their progenitors. Several of these novel antigens may serve as diagnostic markers or as therapeutic targets. Resulting new diagnostic strategies and novel treatment concepts should advance the field and lead to more precise diagnosis, better therapies and improved prognosis in reactive and clonal erythroid disor- ders.
Acknowledgments
We would like to thank Heidi A. Neubauer, Julia Neusiedler- Nicolas, Sophia-Marie Rammler and Emir Hadzijusufovic for their excellent technical assistance. This study was supported by the Austrian Science Fonds, SFB grants F4701-B20, F4704- B20, F4705-B20 and F4706-B20.
References
1. Palis J. Primitive and definitive erythro- poiesis in mammals. Front Physiol. 2014;5:3.
2. Hattangadi SM, Wong P, Zhang L, Flygare J, Lodish HF. From stem cell to red cell: regula- tion of erythropoiesis at multiple levels by multiple proteins, RNAs, and chromatin modifications. Blood. 2011;118(24):6258-
6268.
3. Kuhrt D, Wojchowski DM. Emerging EPO
and EPO receptor regulators and signal
transducers. Blood. 2015;125(23):3536-3541.
4. Liang R, Ghaffari S. Advances in under- standing the mechanisms of erythropoiesis
in homeostasis and disease. Br J Haematol.
2016;174(5):661-673.
5. Oburoglu L, Romano M, Taylor N, Kinet S.
9. Stauder R, Valent P, Theurl I. Anemia at older age: etiologies, clinical implications and management. Blood. 2018;131(5):505-
Metabolic regulation of hematopoietic stem 514.
cell commitment and erythroid differentia- tion. Curr Opin Hematol. 2016;23(3):198- 205.
6. Carmel R. Anemia and aging: an overview of clinical, diagnostic and biological issues. Blood Rev. 2001;15(1):9-18.
7. Steensma DP, Tefferi A. Anemia in the elder- ly: how should we define it, when does it matter, and what can be done? Mayo Clin Proc. 2007;82(8):958-966.
8. Halawi R, Moukhadder H, Taher A. Anemia in the elderly: a consequence of aging? Expert Rev Hematol. 2017;10(4):327-335.
10. Guidi GC, Lechi Santonastaso C. Advancements in anemias related to chronic conditions. Clin Chem Lab Med. 2010;48(9): 1217-1226.
11. Valent P. Low blood counts: immune medi- ated, idiopathic, or myelodysplasia. Hematology Am Soc Hematol Educ Program. 2012;2012:485-491.
12. Guillaud C, Loustau V, Michel M. Hemolytic anemia in adults: main causes and diagnostic procedures. Expert Rev Hematol. 2012;5(2): 229-241.
13. Camaschella C, Nai A. Ineffective erythro-
haematologica | 2018; 103(10)
1601