ERYTHROPOIETIN - BIOCHEMICAL PROFILES, BI OLOGICAL BACKGROUND, INDICATIONS AND THERAPEUTIC RESULTS IN HEMATOLOGY

This review has two objects: a brief recapitulation of the biological background of erythropoietin (EPO), and a review of its clinical utili zation in hematology. EPO, both in its naturally occurring and recombi nant form (rH-EPO), Is a single chain glycoprotein with an approximate molecular weight of 30.000 to 34.000 kD. Its heavy glycosilation is e ssential for its activity in vivo, since asialoEPO is readily cleared by the hepatic asialoglycoprotein receptor. This impedes the recombina nt molecule's synthesis in biologic cultures other than mammalian cell s (Chinese hamster's ovary cells), and inevitably increases costs. If in vitro glycosilation of E. coli-derived rH-EPO could be achieved, th e clinical utilization of the product would be considerably enhanced, most especially when very high doses are necessary, as discussed later . There is no antigenic diversity between natural and recombinant EPO, so that out of the enormous clinical experience only one single case of immunization has been recorded. Almost paradoxically there are howe ver three published cases of pure red cell aplasia (PRCA) caused by Im munization against autologous EPO. It is now established that in adult s EPO is synthetized in renal peritubular interstitial cells, although some residual activity remains in the river. Hypoxia results in a rap id induction of EPO expression, although the role of the oxygen sensor system is still debated. Cellular targets are notoriously erythroid p rogenitors and precursors (BFU-E, CFU-E, early and intermediate erythr oblasts). The global erythropoietic activity global resulted in variou s effects (proliferation, differentiation, survival), but most probabl y each single effect is integrated with and complementary of the other s. The utilization of rH-EPO in hematologic diseases came much later t han its dramatic success in renal anemia. A variety of tools useful fo r assessing the possible beneficial effects of rH-EPO in clinical hema tology has been proposed, among which a low level of endogenous EPO is a good predictor for therapeutic success. 'Hemopathic' anemia can be subdivided into three categories: patients with normal erythropoiesis due to inadequate EPO production (anemia of prematurity), patients wit h depressed but nonclonal erythropoiesis (chemotherapy, lymphoid malig nancies such as multiple myeloma-MM and chronic lymphatic leukemia-CCL ) and patients with at least partially clonal anemia, such as paroxysm al nocturnal hemoglobinuria(PNH), hemoglobinopaties, myelodysplastic s yndromes (MDS) and others. Results in the first category of patients a re, as expected, prompt and satisfactory with physiologic doses. Altho ugh therapeutic strategy for MM is moving fast to curative intents, th e utilization of rH-EPO is indicated for the control of anemia in cons ervatively-treated patients. In the third category the most important and controversial area is MDS. Significant erythropoietic results are generally obtained in about 20% of patients; however, the association with G-CSF has considerably enhanced the response rate. In the field o f bone marrow transplantation there is an inadequate production of end ogenous EPO in the allogeneic setting, and randomized studies have sho wn the benefits of rH-EPO in this situation. However, the most importa nt results have been and are obtained in post-major-ABO incompatible P RCA, when the removal of the recipient's isohemagglutinins does not re solve the anemia. High and very high doses of rH-EPO (even over 500 UI /kg/day for 2-4 weeks) may resolve this occasionally quite refractory condition. Although extremely expensive, this treatment may be life-sa ving when an otherwise successful allogeneic transplant is at the risk of failure because of this relatively uncommon but severe immunohemat ologic complication.