[Erythropoietin: biochemical characteristics, biologic effects, indications and results of use in hematology].
Anahtar kelimeler
Öz
This review has two objects: a brief recapitulation of the biological background of erythropoietin (EPO), and a review of its clinical utilization in hematology. EPO, both in its naturally occurring and recombinant form (rH-EPO), is a single chain glycoprotein with an approximate molecular weight of 30.000 to 34.000 kD. Its heavy glycosilation is essential for its activity in vivo, since asialoEPO is readily cleared by the heptic asialoglycoprotein receptor. This impedes the recombinant molecule's synthesis in biologic cultures other than mammalian cells (Chinese hamster's ovary cells), and inevitably increases costs. If in vitro glycosilation of E. coli-derived rH-EPO could be achieved, the 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 however three published cases of pure red cell aplasia (PRCA) caused by immunization against autologous EPO. It is now established that in adults EPO is synthetized in renal peritubular interstitial cells, although some residual activity remains in the liver. Hypoxia results in a rapid induction of EPO expression, although the role of the oxygen sensor system is still debated. Cellular targets are notoriously erythroid progenitors and precursors (BFU-E, CFU-E, early and intermediate erythroblasts). The global erythropoietic activity resulted in various effects (proliferation, differentiation, survival), but most probably each single effect is integrated with and complementary of the others. The utilization of rH-EPO in hematologic diseases came much later than its dramatic success in renal anemia. A variety of tools useful for assessing the possible beneficial effects of rH-EPO in clinical hematology 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 with depressed but nonclonal erythropoiesis (chemotherapy, lymphoid malignancies such as multiple myeloma-MM and chronic lymphatic leukemia-CCL) and patients with at least partially clonal anemia, such as paroxysmal nocturnal hemoglobinuria (PNH), hemoglobinopaties, myelodysplastic syndromes (MDS) and others. Results in the first category of patients are, as expected, prompt and satisfactory with physiologic doses. Although therapeutic strategy for MM is moving fast to curative intents, the utilization of rH-EPO is indicated for the control of anemia in conservatively-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 of bone marrow transplantation there is an inadequate production of endogenous EPO in the allogeneic setting, and randomized studies have shown the benefits of rH-EPO in this situation. However, the most important results have been obtained in post-major-ABO incompatible PRCA, when the removal of the recipient's isohemagglutinins does not resolve 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-saving when an otherwise successful allogeneic transplant is at the risk of failure because of this relatively uncommon but severe immunohematologic complication.