Baseline Serum Erythropoietin Levels Research Articles

Red Blood Cell Transfusion Dependence Is Associated with Greater Healthcare Resource Utilization, Higher Medical Cost, and Poorer Prognosis in Patients with Lower-Risk Myelodysplastic Syndromes: A 28-Year Retrospective Observation Study Result

Myelodysplastic syndromes (MDS) encompass a heterogeneous group of myeloid neoplasms characterized by cytopenia due to inefficient hematopoiesis, with a considerable risk of progression to acute myeloid leukemia (AML) or early mortality. In lower-risk MDS (LR-MDS) patients, anemia and its associated complications have been the focus of clinical attention. A significant portion of these patients eventually develop red blood cell transfusion dependence (RBC TD), which has been linked to a poorer prognosis. Given the limited efficacy of available treatments in reducing RBC TD, most patients face increased risks of chronic anemia and various complications. Moreover, RBC TD is known to be associated with reduced overall survival (OS) and leukemia-free survival (LFS). This study aimed to assess the impact of RBC TD on the socioeconomic burden and clinical prognosis of LR-MDS patients, utilizing an electronic medical records (EMR) database spanning nearly 30 years of MDS patient data. This retrospective observational study examined adult MDS patients (≥ 18 years of age) treated at Samsung Medical Center in the Republic of Korea. Eligible patients were diagnosed with MDS between Sep 1, 1994, to Apr 1, 2022 (index period), with the observation period spanning from Sep 1, 1994, to Sep 1, 2022. Baseline assessments included estimation of revised international prognostic scoring system (IPSS-R) scores, categorizing patients with very low, low or intermediate risks as lower-risk MDS (LR-MDS). TD was defined as the occurrence of any 16-week period with RBC transfusion of ≥ 2 units per 8 weeks, without consecutive 56-day period without transfusion. Healthcare resource utilization (HCRU), medical costs, and prognosis indicators including overall survival (OS) and AML-free survival (AFS) were analyzed and compared between patients who experiencing TD and those not (non-TD). Out of 831 MDS patients, 349 (42.0%) were classified as lower-risk at baseline. Among LR-MDS patients, 29.5% (103/349) experienced TD while 23.3% (194/831) experienced TD in the entire study population. The median age at diagnosis of MDS was 63 (ranging from 18 to 89), and 65.3% (543/831) were male. In LR-MDS patients, there were no significant differences in either baseline age (61 vs 63, P=0.16) or gender (71.8% vs 61.0% males, P=0.053) between TD and non-TD groups. However, TD group exhibited significantly higher median erythropoietin (EPO) level than non-TD group (290.5U/L vs. 112U/L, P<0.001) among LR-MDS patients with available baseline serum EPO levels (76 TD and 178 non-TD). Among the 76 TD LR-MDS patients with baseline serum EPO levels, 51 (67.1%) exhibited > 200U/L, which is considered a clinical threshold for erythropoiesis-stimulating agent (ESA) treatment. As shown in Table 1, RBC TD was consistently associated with greater HCRU and higher medical costs, especially in LR-MDS patients. TD LR-MDS patients had higher rates of outpatient department and emergency room visits (15676 vs. 8303 visits and 587 vs. 328 visits per 1000 person-years [PY], respectively), and increased hospitalizations (709 vs. 456 per 1000 PY), with longer hospital stays (13343 vs. 8272 days per 1000 PY). Furthermore, TD LR-MDS patients required over four-times of packed RBC units than non-TD patients (31107 vs. 7073 units per 1000 PY). Consequently, TD LR-MDS patients incurred higher total medical cost than their non-TD counterpart (13.5 million vs. 6.1 million USD per 1000 PY). Median OS (58.4 months vs. 103.1 months) and AFS (52.7 months vs. 102.7 months) were both significantly shorter in the TD group compared to the non-TD group among LR-MDS patients, while the differences in OS and AFS did not reach the level of significance in the entire study population (Table 1 and Figure 1). Notably, median OS after the first documented RBC TD event was 33.8 months (95% confidence interval: 24.7-58.5 months) in LR-MDS patients. The findings of this study indicate that RBC TD can be a strong predictor of increased HCRU and medical costs, as well as decreased OS and AFS over a 20-year period following the initial diagnosis of LR-MDS. Given that a majority of LR-MDS patients experiencing TD may not be eligible for ESA treatment due to elevated EPO levels exceeding 200U/L, and the use of cytotoxic agents is not usually recommended for these patients, these results highlight a substantial unmet need for alternative treatment options to address RBC TD in LR-MDS patients.

Effect of nonsurgical periodontal therapy and smoking status on hematological variables related to anemia of chronic disease in chronic periodontitis patient: a case-control study.

Background Chronic infectious, inflammatory, or neoplastic disorders are associated with anemia of chronic disease. Chronic inflammatory diseases such as periodontitis may contribute to masked anemia, especially in smokers. This study was aimed at verifying and comparing the efficacy of nonsurgical periodontal therapy (NSPT) for improving anemia among chronic periodontitis patients with and without the habit of smoking.Methods Thirty systemically healthy individuals with chronic periodontitis were divided into two groups of 15 each, smokers (group A) and nonsmokers (group B). The groups were compared based on hematological parameters such as serum erythropoietin (SE) and serum ferritin (SF) levels at baseline and 3 months after NSPT for anemia evaluation.Results The baseline SE levels in groups A and B were 11.84 and 15.19 mIU/mL (p=0.031), respectively; the corresponding levels at 3 months after NSPT were 13.00 and 17.74 mIU/mL (p=0.022). The baseline SF levels in groups A and B were 95.49 and 44.86 ng/mL (p=0.018), respectively; the corresponding levels at 3 months after NSPT were 77.06 and 39.05 ng/mL (p=0.009). Group B showed a significant increase and decrease in the SE and SF levels, respectively, at 3 months after NSPT (p=0.035 and p=0.039, respectively), whereas group A showed insignificant changes (p=0.253 and p=0.618, respectively).ConclusionNSPT led to an improvement in anemia among chronic periodontitis patients. However, the improvement is less in smokers compared to that in nonsmokers. Furthermore, SF and SE levels might serve as effective biomarkers for assessing anemia in smokers and nonsmokers with chronic periodontitis.

Management of MDS with Isolated Del(5q) Patients in the European MDS (EUMDS) Registry, a Unique Prospective Real-World Dataset

Management of MDS with Isolated Del(5q) Patients in the European MDS (EUMDS) Registry, a Unique Prospective Real-World Dataset

Efficacy and Safety of Darbepoetin Alfa (DA) in Patients with Myelodysplastic Syndromes (MDS): A Systematic Review and Meta-Analysis

Introduction: Erythropoiesis-stimulating agents (ESAs) have been used in treating anemic MDS patients to improve erythropoiesis and reduce the risk of red blood cell (RBC) transfusion. Two previous systematic reviews found that ESA use was efficacious, but these reviews focused on short-acting epoetin alfa (EA). Since then, the results of a number of prospective interventional trials of DA have been reported. We present an updated systematic review and meta-analysis to estimate the efficacy of DA in the treatment of MDS-related anemia.Methods: We conducted a systematic review of the medical literature to identify prospective interventional trials of DA in patients with MDS. The main inclusion-exclusion (IE) criteria were: that studies had to be prospective and interventional in nature; have at least 10 adult subjects with MDS reporting either World Health Organization (WHO), French-American-British (FAB) criteria, or International Prognostic Scoring System (IPSS) status; and report results for the pre-specified primary outcome (proportion of patients with erythroid response) or one of the secondary outcomes (which included major hemoglobin response, changes from baseline in hemoglobin levels, transfusion status, and quality of life (QoL) measures). We recorded and collated all reported adverse events. Two independent reviewers identified the studies and abstracted the information and a third reviewer adjudicated. Clinical and methodological heterogeneity across studies were evaluated with respect to the study population and participant selection method (e.g. MDS diagnosis, history of ESA use, baseline erythropoietin (EPO), hemoglobin, and creatinine levels, transfusion status, and other factors), the intervention (e.g. initial and maintenance ESA dose), and the endpoints of interest including the response criteria. Forest plots with formal testing using Cochran's Q-statistic was also used to assess the heterogeneity across the studies. We used random effects methodology to generate combined estimates when warranted by the data. Subgroup analyses and/or meta-regressions were conducted by dose level, ESA-naïve status, baseline EPO level, hemoglobin level, transfusion status, and other factors.Results: Ten studies (9 single-arm, 1 randomized controlled trial [RCT]) with a total of 647 patients were included in the systematic review, with response rates ranging from 38% to 72%, and the median duration of response varying from 5 to 12 months. The overall response rate for the nine studies that used IWG 2000 response criteria could not be evaluated because of heterogeneity. However, among studies that stratified response rates by baseline endogenous EPO levels, patients with EPO <100 IU/L had an overall response of 81% (95% confidence interval [CI]: 73-90%), and on average a 39% [95% CI: 22-56%] better response than patients with EPO >100 IU/L. Across the studies that reported response stratified by prior ESA use, ESA-naïve patients had a median response rate of 75% compared to 53% for patients previously treated with an ESA. Baseline mean hemoglobin was significantly associated with response (p=0.0204), with higher baseline levels associated with improved response. We also found that response tended to improve with dose (p=0.2; Figure 2): the estimated response for a mean initial dose of 150 μg once weekly (QW) was 57% (95% CI: 49-66%) compared to 64% (95% CI: 55-74%) for 300 μg QW. Baseline transfusion independence (6 studies), and low-risk IPSS status (2 studies) were reported to be significantly associated with better response in several studies. Treatment with DA tended to show an improvement in the quality of life (QoL) measures, transfusion rates, and hemoglobin levels, but the number of studies that reported these outcomes was small. Hypertension, thromboembolism, and progression to acute myeloid leukemia were respectively reported in 2%, 1%, and 1% of the patients.Conclusions: Published studies suggest that treatment with DA yielded high hemoglobin response (38-72%) in MDS patients with anemia. The response was strongest in patients with lower baseline serum EPO level, and ESA naïve patients. [Display omitted] [Display omitted] DisclosuresPark:Hospira: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Fenaux:Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Mehta:Amgen Inc.: Employment; Amgen Inc.: Equity Ownership. Callaghan:Amgen Inc.: Employment; Amgen Inc.: Equity Ownership. Kim:Amgen Inc.: Employment; Amgen Inc.: Equity Ownership. Tomita:Amgen Inc.: Employment; Amgen Inc.: Equity Ownership. Xu:Amgen Inc.: Employment; Amgen Inc.: Equity Ownership.

Serum Erythropoietin Level and Mortality in Kidney Transplant Recipients

Posttransplant anemia is frequently reported in kidney transplant recipients and is associated with worsened patient survival. Similar to high erythropoiesis-stimulating agent requirements, resistance to endogenous erythropoietin may be associated with worse clinical outcomes in patients with ESRD. We examined the association between serum erythropoietin levels and mortality among kidney transplant recipients. We collected sociodemographic, clinical, medical, and transplant history and laboratory data at baseline in 886 prevalent kidney transplant recipients (mean age 51 ± 13 [SD] years, 60% men, 21% diabetics). A solid-phase chemiluminescent immunometric assay was used to measure serum erythropoietin. Cox proportional hazards regression was used to model the association between baseline serum erythropoietin levels and all-cause mortality risk. During the median 39-month follow-up, 99 subjects died. The median serum erythropoietin level was 10.85 U/L and hemoglobin was 137 ± 16 g/L. Mortality rates were significantly higher in patients with higher erythropoietin levels (crude mortality rates in the highest to lowest erythropoietin tertiles were 51.7, 35.5, and 24.0 per 1000 patient-years, respectively [P = 0.008]). In unadjusted and also in adjusted Cox models each SD higher serum erythropoietin level significantly predicted all-cause mortality: HR(1SD increase) 1.22 and 1.28, respectively. In adjusted Cox models each SD higher serum erythropoietin/blood hemoglobin ratio also significantly predicted all-cause mortality: HR(1SD increase) 1.32. Serum erythropoietin predicted mortality in all analyzed subgroups. In this sample of prevalent kidney transplant recipients, higher serum erythropoietin levels were associated with increased mortality.

Treatment of Anemia with Darbepoetin Alfa in Patients with Low and Intermediate-1 Risk Myelodysplastic Syndromes. Results from the ARAMYS Study

Anemia is the main symptom in patients (pts) with myelodysplastic syndromes (MDS) which usually makes subjects with this pathology dependent on transfusions, resulting in a very limited quality of life. Darbepoetin alfa (DA) is a highly glycosylated erythropoiesis-stimulating agent (ESA) with a pharmacokinetic profile that includes a longer serum half-life and allows it to be administered less frequently than rHuEPO, thereby increasing patient convenience. This single-arm, open-label, multi-center, phase 2 study evaluated the efficacy and safety of DA in pts with low risk MDS. Eligible pts had low or intermediate-1 risk MDS [International Prognostic Scoring System (IPSS) criteria], anemia [Hemoglobin (Hb) 10 g/dL], FAB (French–American–British) classification of refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), or refractory anemia with excess blasts (RAEB) (with marrow blasts ≤ 10%), serum erythropoietin levels < 500 IU/L and transfusion requirements < 2 packed red blood cells cells/month over the preceding 2 months. Pts were evaluated for erythroid response after 8 weeks (wks) and 16 wks of treatment. Major erythroid response (MaR) was defined as an increase in Hb values ≥2 g/dl on baseline values and/or suppression of transfusion requirements. A minor erythroid response (MiR) was defined as a > 1 g/dL increase in Hb values but < 2 g/dl on baseline values or a reduction in transfusion requirements of at least 50%. DA treatment was initiated at a fixed dose of 300 mcg weekly (QW). For pts achieving a MaR at wk 8, DA could be administered at the same dose every two wks (Q2W). For pts who did not achieve a MaR by 8 weeks, filgrastim 300 mcg QW was added for an additional 8 wks. If at any time during the treatment period Hb values of > 12g/dL were obtained, DA was discontinued until Hb falls to values of < 11 g/dL. At this time, DA treatment was reintroduced with half of the previous dose (150 mcg). A number of 44 evaluable pts were included in the study. Median age 75, 8 years (range 41, 3–92, 4), 53, 5% male and 90,7% with ECOG Performance Status (0–1). FAB diagnoses were 30,2% RA, 62,8% RARS and 7% RAEB; divided into IPSS low (76,7%) and intermediate-1 (23,3%). Baseline mean (SD) Hb was 9,2 g/dL (0.8) and serum erythropoietin 122,1 IU/L (124,7).72,7% of the pts were transfusion independent. An erythroid response was achieved by 31 of 44 pts (70,5%) at wk 8 (43,2% MaR, 27,3% MiR, 29,5% no response) and by 30 of 43 pts (69,8%) at week 16 (51,2% MaR, 18,6% MiR, 30,2% no response). A total of 19 pts received filgrastim between wk 8 and 16. Erythroid response at wks 8 and 16 depending on the transfusion dependence were 68,8% (59,1% MaR and 40,9% MiR) and 71.0% (68,2% MaR and 31,8% MiR) in the transfusion independent group and 75.0% (66,7% MaR and 33,7% MiR) and 66,70% (87,5% MaR and 12,5% MiR) in the transfusion dependent group. Baseline serum erythropoietin levels were the only predictive factor of response found in the study population. DA was generally well tolerated. Three mild adverse events were considered related to DA (iron deficiency, flu syndrome and headache), one severe (iron deficiency) and one fatal (thromboembolic event). Results from this study indicate that a fixed dose of 300 mcg DA QW (+/− filgrastim) is an effective and well-tolerated treatment of anemic patients with low- and intermediate-1 risk MDS.

Erythropoiesis-stimulating agents in the treatment of anemia in myelodysplastic syndromes: a meta-analysis

The present meta-analysis was undertaken to (1) assess erythroid response rates in myelodysplastic syndromes (MDS) patients treated with epoetin alfa as a monotherapy, (2) gain further insights into predictors of response rates, and (3) compare the erythroid response rates observed with epoetin alfa and darbepoetin alfa. A systematic review of studies from 1990 to 2006 in MDS patients treated with epoetin alfa or darbepoetin alfa was performed and yielded 30 studies evaluating a total of 1,314 patients (epoetin alfa: 22 studies, 925 patients; darbepoetin alfa: eight studies, 389 patients). Pooled estimates of erythroid response rates, stratified by the International Working Group criteria (IWGc) and treatment group, were calculated using random-effects meta-analysis methods. Univariate meta-regression analyses were further conducted to identify study characteristics associated with erythroid response rate. The pooled estimate of erythroid response rate was significantly higher for epoetin alfa IWGc studies (57.6%) as compared to non-IWGc studies (31.6%; p < 0.001). Study factors predictive of higher response rate in the epoetin alfa IWGc studies included higher proportion of patients with RA/RARS (p < 0.001), lower mean baseline serum erythropoietin level (p = 0.007), and fixed dosing regimen (p < 0.001). There was no significant difference in the pooled erythroid response rates between the two agents (epoetin alfa: 57.6% vs. darbepoetin alfa: 59.4%; p = 0.828). The current study reported significantly higher erythroid response rates predominantly in the more recent studies that primarily utilized IWGc to define response. With the use of standardized patient selection and response evaluation methods, epoetin alfa and darbepoetin alfa yielded comparable erythroid response rates in MDS patients.

Erythroid response (ER) rates in myelodysplastic syndromes (MDS) patients treated with epoetin alfa (EPO): A meta-analysis using the International Working Group criteria (IWGc) for MDS response

6572 Background: Refractory anemia is a clinical hallmark of MDS. The most consistently used therapy for this anemia is EPO. Prior to the introduction of IWGc in 1997, ER rates varied substantially between studies. The present meta-analysis was undertaken to compare ER rates in studies of EPO-treated patients in MDS when defined by either IWGc or non-IWGc. Methods: A systematic review and data extraction of studies published from 1990–2005 in MDS patients treated with EPO was performed and yielded 21 studies evaluating a total of 895 patients. Pooled estimates of ER rates, stratified by IWGc, were calculated using random-effects meta-analysis methods, which incorporated both between- and within-study variations. Univariate meta-regression analyses were conducted to identify study characteristics that were significant determinants of ER rate. Results: Ten studies (604 patients) used the IWGc to define ER (overall, major, minor), while 11 studies (291 patients) used other definitions. Mean age for all patients was 70.6 years; 45% women. Mean baseline (BL) serum erythropoietin level and proportion of patients with refractory anemia or refractory anemia with ringed sideroblasts were comparable between studies; however, the proportion of transfusion-dependent patients at BL was lower in the IWG studies vs the non-IWG studies (36% vs. 84%, respectively, p&lt;.001). The pooled estimate of ER rate was significantly higher for the IWG studies compared to the non-IWG studies (50.5%, 95% CI: 38.6%-62.3% vs. 27.8%, 95% CI: 22.7%-32.8% respectively, p=.002). Among patients in the IWG studies who achieved an ER, 62% (188/305) achieved a major ER. Studies reporting mean BL serum erythropoietin level &lt;400mU/mL, &lt;65% of patients transfusion-dependent at BL and use of subcutaneous EPO were found to be associated with higher ER rates. Conclusions: This meta-analysis of MDS patients treated with EPO demonstrates significantly higher ER rates in studies utilizing IWGc. These findings may be due to more refined definitions of ER and MDS diagnostic criteria as well as improvement in the management of anemia. [Table: see text]

Epoetin alfa increases hemoglobin levels and improves quality of life in anemic geriatric cancer patients receiving chemotherapy

To evaluate epoetin alfa (EPO) treatment of anemia in geriatric cancer patients receiving chemotherapy, a retrospective subgroup analysis was conducted of anemic cancer patients > or =65 years of age from three 16-week community-based studies of thrice-weekly (TIW) or once-weekly (QW) EPO for chemotherapy-related anemia (CRA). Analyses were conducted on the overall geriatric population (> or =65 years) and by age subgroup (65-74, 75-84, and > or =85 years), and compared with younger patients (<65 years) for each individual study and for pooled data. Some 3,634 geriatric patients were compared with 3,467 younger patients. From baseline to final measurement, EPO therapy significantly increased Hb by 2.0 g/dl in patients > or =65 years and 1.9 g/dl in patients <65 years (P<0.0001) and reduced transfusion utilization in both groups (P<0.006). Both age groups also had significant improvements in quality of life (QOL), measured by the 100-mm Linear Analog Assessment Scale (LASA). In younger patients, mean LASA changes were significantly greater than those in geriatric patients (P<0.05); however, QOL improvements in both age groups were clinically meaningful. There were no significant differences across geriatric age subgroups or between TIW and QW regimens for Hb change or QOL improvement. Overall hematopoietic response rate to EPO was 65.4% for patients > or =65 years and 64.7% for patients <65 years. Predictors of greater hematopoietic response (based on a pooled analysis) included lower body weight, baseline Hb, and baseline serum erythropoietin levels; better tumor response; and history of EPO dose reduction and longer time on study. Anemic geriatric patients receiving EPO for CRA responded comparably to younger patients <65 years and should be treated similarly.

Baseline and early treatment factors are not clinically useful for predicting individual response to erythropoietin in anemic cancer patients.

Recombinant human erythropoietin (rHuEPO) is an effective treatment for anemia in patients with cancer, and recent studies show that over two-thirds of patients can be expected to respond with a large increase (>2 g/dl) in hemoglobin concentration. However, it would be helpful to identify likely responders and nonresponders before initiating treatment. Previous studies have suggested that high pretreatment endogenous erythropoietin levels are associated with a lower response to erythropoietin, especially in certain patient groups, such as patients with hematological malignancies, non-chemotherapy patients, or patients with myelodysplastic syndrome. Various algorithms have therefore been developed to predict patient response to rHuEPO using baseline serum erythropoietin levels and other baseline factors. We performed an analysis of data pooled from four randomized clinical trials of 604 patients with non-myeloid malignancies, examining the clinical usefulness of pretreatment and early treatment factors for predicting response to erythropoietin. The analysis confirms several other reports that the most predictive models combined pretreatment and early treatment factors, including change in hemoglobin at 4 weeks, but even these models did not increase sensitivity above 85% (total response in unselected patients was 68.1%), while specificity remained poor. We conclude that clinically useful prediction of response to erythropoietin is not possible using baseline or early response variables because of poor sensitivity and specificity of prediction compared with generally accepted clinical tests.

Effects of losartan or enalapril on hemoglobin, circulating erythropoietin, and insulin-like growth factor-1 in patients with and without posttransplant erythrocytosis.

Both angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists reduce hemoglobin (Hb) levels in patients with posttransplantation erythrocytosis (PTE). However, their effects in transplant recipients without PTE are not certain, and the mechanism by which they reduce Hb levels in patients with PTE remains unclear. This study evaluated the effects of losartan and enalapril on Hb levels in relation to serum erythropoietin (EPO) and insulin-like growth factor-1 (IGF-1) levels in 8 patients with PTE and 10 patients without PTE. All 18 patients were treated sequentially with 24 weeks of losartan therapy, followed by 24 weeks of enalapril therapy; the two treatment phases were separated by a washout period. Patients with PTE showed significantly greater baseline Hb and IGF-1 concentrations compared with patients without PTE before both losartan and enalapril treatments. Baseline serum EPO levels were similar for patients with and without PTE. Baseline Hb level correlated significantly with IGF-1 level (r = 0.517; P = 0.002), but not with EPO level. Treatment with enalapril, 5 mg, reduced Hb levels more markedly than treatment with losartan, 50 mg, in patients with PTE. In patients without PTE, enalapril, 5 mg, mildly reduced Hb levels, whereas losartan, 50 mg, had no significant Hb-lowering effect. The reduction in Hb levels with enalapril therapy in patients with PTE was associated with a significant reduction in circulating IGF-1 levels, but not EPO levels, whereas losartan reduced Hb levels with no significant change in circulating IGF-1 and EPO levels. In patients without PTE, no significant change was noted in serum EPO and IGF-1 levels with either treatment. The differential Hb-lowering effect with losartan and enalapril treatment in patients with and without PTE suggests that the pathogenesis for PTE is complex and heterogeneous. Different erythropoietic mechanisms may be involved in patients with and without PTE. Further large-scale study is needed to determine the exact interaction between the renin-angiotensin system and regulation of IGF-1 and EPO synthesis and define the exact mechanism by which losartan and enalapril reduce Hb levels.

Serum erythropoietin (EPO) levels correlate with survival and independently predict response to EPO treatment in patients with myelodysplastic syndromes.

Treatment with recombinant erythropoietin (EPO) can alleviate anaemia in patients with myelodysplastic syndromes (MDS). The present study, based on a long-term follow-up of 68 MDS patients (26RA, 16 RAS, 26 RAEB) treated with EPO alone, pinpoints pre-treatment variables associated with response induction, response duration and overall survival. Response, defined as an increase in haemoglobin >15gL1 or eliminated erythrocyte transfusion requirements, was observed in 22 of 66 (33%) evaluable patients. The median response duration was 15 (range 3-64+) months. Using univariate logistic regression models, responders displayed significantly lower baseline serum EPO levels (S-EPO), more often normal bone marrow blast cell content (RA/RAS vs. RAEB), normal cytogenetics and no need for erythrocyte transfusion. In a multiple logistic regression model, S-EPO (P=0.009), marrow blast content (P=0.031) and erythrocyte transfusion need (P=0.024) remained associated with response induction. The probability of response for a patient with S-EPO >50UL1, RA/RAS and no transfusion need was 0.79 (0.53-0.93, 95% CI). The median overall survival time from start of EPO treatment was 26 months, significantly longer for responders than for non-responders (49 vs. 18 months, P=0.018). Survival was also predicted by baseline S-EPO; patients with S-EPO >50UL1 (n=50) had a median survival of 17 months, as compared to 65 months for those with S-EPO >50UL1 (n=14, P=0.024). The international prognostic scoring system (IPSS) for MDS predicted survival (P=0.003) and progression to acute leukemia (P<0.001) but not response to EPO treatment. Furthermore, in a logistic regression model with S-EPO and IPSS, S-EPO (but not IPSS) was again a significant predictor for response (P=0.007). Our data facilitate the optimal selection of MDS patients suitable for EPO treatment and pinpoint S-EPO as a powerful predictor of response and overall survival in MDS.

Hemoglobin switching protocols in thalassemia. Experience with sodium phenylbutyrate and hydroxyurea.

Homozygous beta thalassemia affects thousands of people around the world. Current management of this condition includes regular transfusion of red cells, which leads to transfusional iron overload requiring chelation therapy: increasing hemoglobin levels while decreasing or eliminating iron overload is therefore a major therapeutic goal in the treatment of thalassemia. Bone marrow transplantation may achieve this goal, but it is not an option for most patients. This study reports on efforts to increase gamma-globin transcription and HbF production using sodium phenylbutyrate (SPB) and hydroxyurea (HU). It was found that 36% (4/11) of all patients or 50% (4/8) of non-transfused patients responded to SPB (increase in Hb levels of 1 g/dL). A positive correlation between baseline serum erythropoietin level and likelihood of response to SPB was observed. Since HU may also increase HbF production, evaluation of combination therapy with these drugs is underway and preliminary results are reported.

Recombinant Human Erythropoietin Treatment: Investigational New Drug Protocol for the Anemia of the Acquired Immunodeficiency Syndrome

Anemia associated with human immunodeficiency virus infection may be due to reduced erythropoiesis related to the disease itself or to concomitant medications (eg, zidovudine). Clinical studies have shown recombinant human erythropoietin (r-HuEPO) to be effective in correcting the anemia of zidovudine-treated patients infected with human immunodeficiency virus with baseline serum erythropoietin levels of 500 U/L or less. A treatment investigational new drug protocol that provided r-HuEPO to 1943 anemic patients with the acquired immunodeficiency syndrome was studied. Enrollment criteria included a clinical diagnosis of acquired immunodeficiency syndrome, serum erythropoietin level of 500 U/L or less, hematocrit less than 0.300, and age of 12 years or more. The initial r-HuEPO dosage was 4000 U subcutaneously for 6 days each week. On the basis of response, the r-HuEPO dosage could be increased sequentially to 8000 U subcutaneously for 6 days per week. This was an open-label multicenter treatment protocol. A total of 1943 patients were treated by 510 investigators. Efficacy evaluations were based on the effect of r-HuEPO on hematocrit levels and transfusion requirements relative to baseline. Adverse experiences that were considered by the investigator to be possibly related to r-HuEPO therapy were collected to assess safety. Therapy with r-HuEPO resulted in an increase in mean hematocrit from a baseline of 0.280 to 0.331 at week 12 and 0.338 at week 24. This increase was sustained throughout the course of the study to week 54. Overall, 40% of patients (769/1943) required at least one transfusion in the 6-week interval immediately preceding study entry (baseline). After 12 and 24 weeks of r-HuEPO treatment, corresponding percentages were 22% (311/1387) and 18% (119/650), respectively. Response to therapy, defined as an increase of 0.060 from baseline in hematocrit, with no transfusions within 28 days before achieving that hematocrit, was observed in 44% of patients. Adverse experiences not clearly related to acquired immunodeficiency syndrome were reported by 11% of patients. In a study population of 1943 anemic patients with acquired immunodeficiency syndrome treated with r-HuEPO, the hematocrit increased and blood transfusion requirements decreased. Therapy with r-HuEPO was well tolerated.

Influence of Thalassemia on the Response to Recombinant Human Erythropoietin in Dialysis Patients

Thalassemia is a common genetic disorder among the South Chinese. To see if thalassemia would adversely affect the erythrocyte response to recombinant human erythropoietin (rHuEPO, Epogen) in dialysis patients, the response to rHuEPO in 4 dialysis patients with thalassemic traits (thal-t) was compared with that of 4 control patients who were matched for age, sex, mode of dialysis and baseline hemoglobin levels over a 6-month period. Patients with thal-t showed a reduced erythrocyte response to rHuEPO compared to control dialysis patients as reflected by a reduced reticulocyte index, a slower rise in hemoglobin or hematocrit levels, requirement of a higher cumulated dose of rHuEPO to achieve a target hemoglobin of 10 g/dl and a higher maintenance dose of rHuEPO. A dialysis patient with hemoglobin H disease (HbHD) was also studied. He failed to respond to rHuEPO despite that the dose was increased to 250 U/kg/week. In contrast, his matched control dialysis patient, despite a lower baseline hemoglobin level (6.1 versus 8.8 g/dl), was able to reach a target hemoglobin level of 10 g/dl by 6 weeks and could be maintained at this level with 50 U/kg/week. The patient with HbHD had splenomegaly and a higher baseline serum erythropoietin level, reticulocyte count, serum bilirubin, serum ferritin and serum iron saturation than control patients and patients with thal-t. It was concluded that thal-t reduces the erythrocyte response to rHuEPO in dialysis patients and that in the presence of active hemolysis and enhanced endogenous erythropoietin secretion, dialysis patients with HbHD are resistant to treatment with rHuEPO.

Effects of recombinant human erythropoietin in infants with the anemia of prematurity: A pilot study

In an attempt to stimulate endogenous erythrocyte production and thereby provide an alternative to erythrocyte transfusions, we administered recombinant human erythropoietin (rHuEpo) in doses of 75 to 300 units/kg/wk to seven infants with the anemia of prematurity. Treatment was started between 21 and 33 days of life, maintained for 4 weeks, and was well tolerated. All the patients had low baseline serum erythropoietin levels. After rHuEpo therapy, the number of reticulocytes increased from a mean baseline count of 75 x 10(9)/L to 95, 141, and 165 x 10(9)/L on days 7, 10, and 14 of therapy, respectively. Correction or stabilization of the anemia was observed in six of seven patients, whose estimated total erythrocyte volume increased by 49% during therapy (vs a predicted increment of 18% in the absence of rHuEpo). In one patient, however, the hematocrit declined during the treatment, and in three of the responders a secondary fall in hematocrit was noted either during therapy or after its discontinuation. Serum iron and ferritin levels rapidly decreased after the initiation of rHuEpo therapy, and in most patients transient early thrombocytosis and late neutropenia were observed. These data suggest that rHuEpo may correct or stabilize the anemia of prematurity. Its effects, however, may be limited by a variety of factors, among which iron availability probably plays an important role. Controlled studies will be needed to confirm these preliminary observations.