Darbepoetin Alfa for the Treatment of Anemic Patients with Low- and Intermediate-1-Risk Myelodysplastic Syndromes
Darbepoetin Alfa for the Treatment of Anemic Patients with Low- and Intermediate-1-Risk Myelodysplastic Syndromes
Abstract & Commentary
By Stuart M. Lichtman, MD, FACP, Associate Attending, Memorial Sloan-Kettering Cancer Center, Commack, NY. Dr. Lichtman reports no financial relationship to this field of study.
Synopsis: In a clinical trial of darbepoetin alfa for patients with low or intermediate risk myelodysplasia, the drug was well tolerated and resulted in improved hemoglobin levels and quality of life in a substantial proportion of patients.
Source: Stasi R, et al. Darbepoetin alfa for the treatment of anemic patients with low- and intermediate-1-risk myelodysplastic syndromes. Ann Oncol. 2005;16:1921-1927.
The current management of myelodysplastic syndromes (MDS) involves an individualized care plan for each patient. The International Prognostic Scoring System (IPSS) has become an indispensable tool in the identification of treatment goals.1 Many of the patients are elderly with non-hematological comorbidities, and often limit therapeutic options. Therefore, many patients receive supportive care only irrespective of their IPSS risk group. In low- and intermediate-1-risk MDS, anemia is often the major or only clinical problem; and red cell transfusion is the mainstay of therapy. Recombinant human erythropoietin (rhEPO) has been consistently used to relieve anemia and reduce transfusion requirements in these patients. The overall response rate to rhEPO is ~20%, but it can be as high as 60% in a subset of low-risk MDS, particularly those with a diagnosis of refractory anemia, no transfusions prior to rhEPO therapy, and low serum levels of endogenous EPO.2
Darbepoetin alfa (DA) is an erythropoietic agent with greater sialic acid content, an approximately 3-fold longer terminal half-life, and greater biological activity than rhEPO—allowing less-frequent administration with a similar efficacy and safety profile and increased biological activity. Recent clinical trials have demonstrated the efficacy of this erythropoietic agent in the treatment of cancer-related anemia.3,4 In this phase II study, Stasi and colleagues evaluated the impact of DA therapy on hemoglobin levels, transfusion requirements, and changes in quality of life (QoL) in anemic patients with previously untreated low- and intermediate-1-risk MDS.
Commentary
Fifty-three patients with low- and intermediate-1-risk MDS according to the IPSS were included in this study after they had signed an institutional review board-approved informed consent. There were 30 men and the group had a median age of 70 years. MDS cases are reported according the World Health Organization classification. The classifications for this study are:
- refractory anemia (RA) 31 patients;
- refractory anemia with ringed sideroblasts (RARS), 1 patient;
- refractory cytopenia with multilineage dysplasia (RCMD), 10 patients;
- refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS), 1 patient;
- refractory anemia with excess blasts-1 (RAEB-1), 8 patients.4
Median time from diagnosis to initiation of DA therapy was 16 months (range, 9-21). At enrollment, 46 patients were transfusion dependent, with a median of 2 U (range, 1-5) of packed red blood cell (RBC) transfusions per month for 3 months before the study. Transfusions were usually given when the hemoglobin concentration was < 8 g/dL.
Therapy consisted of a 24-week schedule of DA administered subcutaneously once a week. DA treatment was initiated at 150 µg fixed dose and was increased to 300 µg fixed dose if after 12 weeks there was no or suboptimal erythroid response. If responders achieved hemoglobin levels > 13 g/dL, the DA doses had to be adjusted to maintain their hemoglobin levels between 11 and 13 g/dL. Treatment extended beyond 24 weeks, individually tailored, was given to patients with a continued response. Treatment was discontinued at the patient’s request, if patients developed severe diseases other than MDS, and if severe side-effects or transformation to AREB-2 or acute myelogenous leukemia occurred. Responses were categorized according to the criteria developed by the International Working Group. In particular, a major response (MaR) for the erythroid lineage was considered a rise in untransfused hemoglobin concentrations of at least 2 g/dL or a 100% decrease in RBC transfusion requirements during the treatment period. A minor response (MiR) was defined as an increase in untransfused hemoglobin values of 1-2 g/dL or a > 50% decrease in RBC transfusion requirements. No response was defined as a response less than a MiR. All responses were evaluated at the end of the 24 weeks of DA therapy.
According to defined response criteria, on week 24 of treatment the erythroid response rate was 45%. Changes in blood cell counts, transfusion requirements, and laboratory parameters before and after treatment in responders are detailed in Table 2 of the article. The response was MaR in 21 patients, MiR in 3, and absent in 29. All but one of the patients who attained a major hematological improvement exhibited an optimal response at the dose of 150 g, with responses occurring by the eighth week of treatment. All 3 cases with a MiR showed a hematological improvement only after being challenged with DA at 300 mg, and in 2 of them the response was based solely on a decrease in transfusion requirements. By the end of the study, the scores for the 3 Linear Analog Scale Assessment (LASA) domains showed a statistically significant improvement. There was a notable difference in mean LASA change scores between hemoglobin responders and non-responders. Prediction of response was also analyzed. In univariate analysis the variables that significantly differed between the 2 groups were serum levels of endogenous EPO and transfusion requirements. Twenty-one of 28 patients with serum levels of EPO < 200 mIU/mL achieved a response, as compared with 3 of 25 patients with higher levels (P < 0.001). Six patients who had a transfusion requirement > 4 U per month did not respond to DA therapy, as compared with 18 of 47 patients with lower transfusion requirements. It should also be noted that only one of the 8 patients with RAEB-1 had a response to treatment. In multivariate analysis, only serum EPO levels retained its predictive value.
In the present study, administration of DA to anemic patients with low- and intermediate-1-risk MDS resulted in an overall erythroid response rate of 45%. With a median follow-up of 9.4 months, 17 of 24 responders maintained their response. All but one of the patients who attained an MaR exhibited an optimal response at the starting dose of 150 g/week, corresponding approximately to the weekly global dose of rhEPO (30,000 U, usually fractionated in 10,000 U 3 times a week). In this series all responses obtained with the starting dose of DA occurred by the eighth week of treatment. Dose escalation (300 g/week) resulted in only a small proportion of patients obtaining a MiR, and one patient improving the response from MiR to MaR. The authors concluded that the results indicate that DA is an active, safe, and well tolerated treatment for anemia in a substantial proportion of patients with low- and intermediate-1-risk MDS, and has a positive impact on the patients’ QoL.
References
1. Greenberg P, et al. International Scoring System for Evaluating Prognosis in Myelodysplastic Syndromes. Blood. 1997;89:2079-2088; Erratum in: Blood. 1998;91:1100.
2. A randomized double-blind placebo-controlled study with subcutaneous recombinant human erythropoietin in patients with low-risk myelodysplastic syndromes. Italian Cooperative Study Group for rHuEpo in Myelodysplastic Syndromes. Br J Haematol. 1998;103:1070-1074.
3. Stasi R, et al. Darbepoetin Alfa for the Treatment of Anemic Patients with Low- and Intermediate-1-Risk Myelodysplastic Syndromes. Ann Oncol. 2005;16:1921-1927.
4. Vardiman JW, et al. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002;100:2292-2302.
In a clinical trial of darbepoetin alfa for patients with low or intermediate risk myelodysplasia, the drug was well tolerated and resulted in improved hemoglobin levels and quality of life in a substantial proportion of patients.Subscribe Now for Access
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