Nd

EPO <500 U/L

EPO, recombinant erythropoietin; G-CSF, recombinant granulocyte colony-stimulating factor; GM-CSF, recombinant granulocyte-macrophage colony-stimulating factor; PRBC, packed red blood cell transfusions; RA, refractory anemia; RARS, refractory anemia with ringed sideroblasts; Hgb, hemoglobin (g/DL); ND, not determined.

EPO, recombinant erythropoietin; G-CSF, recombinant granulocyte colony-stimulating factor; GM-CSF, recombinant granulocyte-macrophage colony-stimulating factor; PRBC, packed red blood cell transfusions; RA, refractory anemia; RARS, refractory anemia with ringed sideroblasts; Hgb, hemoglobin (g/DL); ND, not determined.

needed to grow BFU-E and CFU-E from MDS bone marrows,12 and inappropriately low serum-erythropoi-etin levels are seen in only approximately one third of patients with MDS1314; perhaps these features account for the low clinical response rates seen. In the only randomized, placebo-controlled, phase III rHuEPO trial, 87 MDS patients with a Hgb <9.0 g/dL were treated with rHuEPO at a dose of 150 U/kg/day for 8 weeks. An overall response rate of 36.8% was detected.15 Patients with RA or refractory anemia with ringed sideroblasts (RARS) were the most responsive, and nontransfused patients fared better than those that had been transfused. Although rHuEPO can improve hematocrit levels in relatively low-risk patients with low erythropoi-etin levels and low transfusion requirements, its impact on survival and QOL is not well characterized. Also, most patients in these clinic trials received rHuEPO three or more times per week. This frequent self-injection schedule may be too cumbersome or uncomfortable for most patients, and it is unknown whether similar results can be achieved in a routine outpatient setting.

rHuEPO is well tolerated in patients with anemia, and although some cases of pure red cell aplasia have been associated with rHuEPO, these episodes appeared to be related to packaging and storage problems with a specific rHuEPO formulation (used primarily in Europe) that may have increased the immunogenicity of the drug.16 As transfusion therapy can be associated with short-term and long-term complications, the use of rHuEPO in responding anemic MDS patients has major advantages over transfusion therapy.

Granulocyte colony-stimulating factor (G-CSF) (and Granulocyte-macrophage colony-stimulating factor (GM-CSF) to a lesser extent) increase peripheral blood neutrophil counts in MDS patients,17 but neither has proven beneficial for long-term use. The lack of clinical benefit for G-CSF was demonstrated in a randomized clinical trial, which showed that prophylactic G-CSF did not decrease the incidence of infections or improve survival compared to standard supportive care.18 A randomized trial of GM-CSF likewise showed no significant benefit.19 Nonetheless, MDS patients may benefit from the short-term use of G-CSF, particularly during an infection-prone period (e.g., periopera-tively), during the transient neutropenia which follows induction chemotherapy, or in the setting of antibiotic-resistant infection. As G-CSF and GM-CSF can rarely exacerbate thrombocytopenia,18 20 these agents should be used with caution in severely thrombocy-topenic patients.

In vivo and in vitro synergy on erythropoiesis has been demonstsrated for rHuEPO and G-CSF. Erythroid response rates of 38-50% have been reported when these agents are combined2122 and responses have been lost and restored with the withdrawal and reinitiation of G-CSF, supporting their synergism.23 Having RARS (where the response rate is 50%)21'23'24 or low pretreatment erythropoietin levels (<500 U/L) and PRBC transfusion dependence of less than 2 units/ month is predictive of an erythroid response to combined rHuEPO/G-CSF.25 A randomized trial comparing G-CSF plus rHuEPO to supportive care showed that despite improvements in hematocrit and transfusion requirements, QOL parameters did not significantly improve, although the study showing this was likely underpowered to detect QOL differences.26 No change in survival has been reported with this treatment; thus, its use should still be largely investigational. Because of its toxicity and low response rate, the combination of GM-CSF and rHuEPO is not recommended for MDS patients.27

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