Darbepoetin alfa effectively maintains hemoglobin concentrations at extended dose intervals relative to intravenous rHuEPO in Japanese dialysis patients

Darbepoetin alfa (KRN321) is a novel molecule that stimulates erythropoiesis by the same mechanism as endogenous erythropoietin. Due to its three-fold longer half-life and greater biological activity than recombinant human erythropoietin (rHuEPO), KRN321 maintains an effective hemoglobin (Hb) level at extended dose intervals compared with rHuEPO. In this multicenter, open-label study, 513 dialysis patients maintained on stable rHuEPO therapy were switched to KRN321 at extended dose intervals. Those receiving rHuEPO two (n = 144, 28.1%) or three times (n = 305, 59.5%) per week were switched to KRN321 once per week, and those receiving rHuEPO once per week (n = 64, 12.5%) were switched to KRN321 once every two weeks. The doses of KRN321 (10-120 microg) were titrated to maintain Hb concentrations at 10-13 g/dL and, if possible, within 11-12 g/dL for up to 52 weeks. If the Hb concentration remained between 10.5 and 12 g/dL, conversion of the dosing frequency from once per week to once every two weeks was allowed. Hemoglobin concentrations were maintained regardless of the dosing interval. The percentage of patients with Hb values within 11-12 g/dL was 23.6% at week 0, 41.3% at week 7, 46.1%-51.9% between weeks 11 and 22 and 45.6% at week 52. KRN321 was well tolerated and the safety profile was consistent with previous trials conducted for KRN321. KRN321, when administered at extended dose intervals, is well tolerated and effective Hb concentrations are attained in Japanese hemodialysis patients.     

Erythropoietin Administration May Potentiate Mobilization of Storage Iron in Patients on Oral Iron Chelation Therapy

Five, repeatedly transfused, patients with refractory anemia (RA) or RA with ringed sideroblast (RARS) subtypes of myelodysplastic syndrome (MDS), with serum ferritin (SF) levels of >2,000 μg/L, and one female with Hb E [β26(B8)Glu→Lys]/β⁰-thalassemia (thal) with an SF level of 1,760 μg/L, were treated with deferiprone (L1) at the dose of 4–6 g per day for at least 26 months. Beginning in the second month, all patients received recombinant human erythropoietin (rHuEPO) at the dose of 150 IU/kg thrice weekly, subcutaneously for 24 months. A significant increase in iron excretion after combined administration of L1 and rHuEPO compared to treatment with L1 as a single agent, was observed in all patients. The amount of excreted iron in urine ranged from 7.5 to almost 20 mg per day. In one patient, a response to rHuEPO resulted in transfusion independence and her SF decreased from 2086 to 879 μg/L. In four MDS patients, who remained dependent on red blood cell (RBC) transfusions, simultaneous administration of L1 and rHuEPO enabled the stabilization of SF levels, despite continuing iron load from the transfusions. Combined administration of rHuEPO and oral iron chelators may potentiate mobilization of storage iron and maintain iron balance in transfusion-dependent iron overloaded early MDS patients.     

Effect of early correction of anemia with erythropoietin on left ventricular mass in predialysis patients: a multi-center trial

Objective To assess the effects of early correction of anemia with recombinant human erythropoietin (rHuEPO) on the development and progression of left ventricular hypertrophy (LVH) in patients with mild-to-moderate chronic renal insufficiency (CRI) who are not on hemodialysis. Methods A total of 158 patients with serum creatinine from 147μmol/L to 400μmol/L were enrolled in this prospective, multicenter study. Eighty-six patients with hemoglobin (Hb)<110g/L received rHuEPO treatment with a target Hb of > 110g/L (Group A). Forty patients with comparable Hb concentration ( <110g/L) but did not receive rHuEPO (Group B) and 32 patients with Hb≥110g/L and without rHuEPO treatment (Group C) were served as controls. Left ventricular mass index (LVMI) was evaluated by echocardiography at baseline and every 3 months for 2 years. Results There was no difference in age, gender, etiology of renal failure, blood pressure and cardiovascular risk factors among the 3 groups. At baseline, the prevalence of LVH was 72.1 % in group A, 72.5% in group B and 59.4% in group C. LVMI was inversely correlated with Hb levels (r=0.70, P<0.01). During the 2-year period, the mean LVMI decreased from 142.6±25.7g/m2 to 132.4±18.5 g/m2 in group A, while increased significantly in both group B and group C. The mean Hb concentration increased from 93.8±14.6g/L to 111.2±10.3g/L(P<0.05) in group A, but tended to decrease in group B and group C. There was no significant change of the mean blood pressure, number of anti-hypertensive drugs and serum creatinine concentrations in all 3 groups. However, patients' serum creatinine doubled more often in group B and group C than in group A. Conclusions LVH was common in predialysis CRI patients and was associated with the severity of anemia. Early intervention with rHuEPO may reverse LVH in these patients.     

早期纠正贫血对慢性肾衰竭心血管病变影响的多中心临床研究

目的观察早期使用促红细胞生成素治疗贫血对透析前慢性肾衰竭(CRF)患者心血管病变的影响.方法采用多中心、前瞻性、对照临床研究.血肌酐(Scr)在147～400 μmol/L的CRF患者158例,按基线Hb水平分组.将Hb<110 g/L的患者分为2组,(1)治疗组86例,每周接受α-促红细胞生成素100～135 U/kg皮下注射;(2)对照Ⅰ组40例,未接受α-促红细胞生成素治疗;将Hb≥110 g/L的32例患者作为对照Ⅱ组,未接受α-促红细胞生成素治疗.行超声心动图检查,测左心室质量指数(LVMI)、血压等,随访时间2年.结果 3组患者基线临床资料(年龄、性别、原发病、营养状况、高血压的发生率、使用降压药物的种类和数量等)无明显差异(均P>0.05);治疗组、对照Ⅰ组、对照Ⅱ组患者左心室肥厚(LVH)的发生率分别为72.1%、72.5%、59.4%;LVMI与Hb水平呈负相关(r=-0.70, P<0.01),与Scr呈正相关(r=0.64, P<0.05).治疗24个月后,治疗组患者Hb水平较基线时明显上升(P<0.05),LVMI较基线时明显下降(P<0.05),LVH的发生率(55.8%)较治疗前降低16.3%,但平均动脉压、使用降压药物的数量与基线相比无明显差异.对照Ⅰ组与对照Ⅱ组患者Hb逐渐下降,LVMI明显增加,LVH发生率与基线相比明显增高(P<0.05).随访期间,Scr较基线增高1倍的患者比率,治疗组(3.4%)与对照Ⅰ组(15.0%)相比差异有统计学意义(P<0.05),而对照Ⅰ组与对照Ⅱ组(9.4%)相比无明显差异(P>0.05).结论轻中度CRF患者存在LVH,贫血是导致透析前CRF患者LVH的重要原因.用促红细胞生成素早期治疗贫血能使部分患者LVH逆转.透析前CRF患者用促红细胞生成素治疗并不加重高血压,并可能有助于延缓肾衰竭的进程.     

Erythropoietin administration may potentiate mobilization of storage iron in patients on oral iron chelation therapy

Five, repeatedly transfused, patients with refractory anemia (RA) or RA with ringed sideroblast (RARS) subtypes of myelodysplastic syndrome (MDS), with serum ferritin (SF) levels of > 2,000 microg/L, and one female with Hb E [beta26(B8)Glu --> Lys]/beta0-thalassemia (thal) with an SF level of 1,760 microg/ L, were treated with deferiprone (L1) at the dose of 4-6 g per day for at least 26 months. Beginning in the second month, all patients received recombinant human erythropoietin (rHuEPO) at the dose of 150 IU/kg thrice weekly, subcutaneously for 24 months. A significant increase in iron excretion after combined administration of L1 and rHuEPO compared to treatment with L1 as a single agent, was observed in all patients. The amount of excreted iron in urine ranged from 7.5 to almost 20 mg per day. In one patient, a response to rHuEPO resulted in transfusion independence and her SF decreased from 2086 to 879 microg/L. In four MDS patients, who remained dependent on red blood cell (RBC) transfusions, simultaneous administration of L1 and rHuEPO enabled the stabilization of SF levels, despite continuing iron load from the transfusions. Combined administration of rHuEPO and oral iron chelators may potentiate mobilization of storage iron and maintain iron balance in transfusion-dependent iron overloaded early MDS patients.     

Recombinant human erythropoietin in very elderly patients with myelodysplastic syndromes: results from a retrospective study

Myelodysplastic syndromes (MDS) are common in elderly patients. Recombinant human erythro-poietin (rHuEPO) has been widely used to treat anemia in lower risk MDS patients, but few data are known about rHuEPO treatment in the very elderly patient group. In order to investigate the role of rHuEPO treatment in terms of response, overall survival (OS), and toxicity in a very elderly MDS patient group, 93 MDS patients treated with rHuEPO when aged ≥80 years were selected among MDS cases enrolled in a retrospective multicenter study by the cooperative group Gruppo Romano Mielodisplasie (GROM) from Jan 2002 to Dec 2010. At baseline, median age was 82.7 (range 80–99.1) with a median hemoglobin (Hb) level of 9 g/dl (range 6–10.8). The initial dose of rHuEPO was standard (epoetin alpha 40,000 IU/week or epoetin beta 30,000 IU/week) in 59 (63.4 %) pa-tients or high in 34 (36.6 %) (epoetin alpha 80,000 IU/week) patients. We observed an erythroid response (ER) in 59 (63.4 %) patients. No thrombotic event was reported. Independent predictive factors for ER were low transfusion requirement before treatment (p?=?0.004), ferritin <200 ng/ml (p?=?0.017), Hb >8 g/dl (p?=?0.034), and a high-dose rHuEPO treatment (p?=?0.032). Median OS from rHuEPO start was 49.3 months (95 % CI 27.5–68.4) in responders versus 30.6 months (95 % CI 7.3–53.8) in resistant patients (p?=?0.185). In conclusion, rHuEPO treatment is safe and effective also in the very elderly MDS patients. However, further larger studies are warranted to evaluate if EPO treatment could be worthwhile in terms of quality of life and cost-efficacy in very old patients.     

Darbepoetin alfa (KRN321) administered intravenously once monthly maintains hemoglobin levels in peritoneal dialysis patients

Abstract: Darbepoetin alfa (KRN321) is a novel molecule that stimulates erythropoiesis by the same mechanism as endogenous erythropoietin. Due to its longer half‐life and greater biological activity than recombinant human erythropoietin (rHuEPO), KRN321 maintains an effective hemoglobin (Hb) level at extended dose intervals compared with rHuEPO. This multicenter, open‐label, single‐arm study of 72 patients with end stage renal failure on peritoneal dialysis (PD) evaluated the efficacy and safety of KRN321 administered intravenously with the dosing intervals extended to monthly. PD patients that were either rHuEPO‐naïve or rHuEPO‐receiving were enrolled. In rHuEPO‐naïve patients, the initial dose of KRN321 was 40 μg weekly by intravenous administration. For rHuEPO‐receiving patients, an initial regimen of fortnightly intravenous administration was given and the initial dose was based on the dose of rHuEPO used before switching to KRN321. After starting the study medication, the Hb concentration was maintained between 10.0 g/dL and 13.0 g/dL. In those patients whose Hb concentrations showed a stable time‐course, the dosing intervals of KRN321 were extended. The results suggest that it may be feasible to reduce the frequency of treatment to a monthly schedule, with an associated adjustment of dose, in most patients. Adverse events were observed in 67 of the 72 patients (93.1%, 267 events). Most of all the adverse events were reported in patients with chronic renal failure receiving conventional rHuEPO. No safety problems specific to KRN321 were noted. These results suggest that KRN321 could reduce of frequency of hospital visits for PD patients receiving erythropoietic therapy for renal anemia.     

Subcutaneous erythropoietin for treatment of refractory anemia in hematologic disorders. Results of a phase I/II clinical trial.

We have used recombinant human erythropoietin (rHuEPO) in a phase I/II clinical trial to evaluate its ability to reverse refractory anemia in hematologic disorders. rHuEPO was administered subcutaneously 5 days per week at escalating doses (50 to 150 U/kg per day). The aim of treatment was a hemoglobin (Hb) level greater than or equal to 10 g/dL without blood transfusion. Of 25 patients treated, 17 were evaluable, most of them with a regular need for transfusion. Eight of these had lymphoproliferative disorders (three cases of malignant lymphoma and five of monoclonal gammopathy) and were exposed to cytotoxic therapy. The other nine patients had hematopoietic stem cell disorders (four cases of myelodysplastic syndrome, three of idiopathic myelofibrosis, and two of chronic myelogenous leukemia). All patients with lymphoproliferative disorder had serum EPO levels inappropriately low for the degree of anemia, while patients with stem cell disorder showed variable values. Erythroid marrow activity was inadequate in all cases. Seven of eight patients with lymphoproliferative disorder responded to treatment maintaining Hb above 10 g/dL without transfusion. The median dose of rHuEPO required for correction of anemia was 75 U/kg. In four cases response was maintained with 50 U/kg, three times per week. There was no complete response among patients with hematopoietic stem cell disorder, although transfusion requirement was eliminated or reduced in four cases. Four patients developed functional iron deficiency during rHuEPO treatment and required iron supplementation to obtain response. Aggravation of splenomegaly was observed in two cases of myeloproliferative disorder. We conclude that: (1) subcutaneous administration of rHuEPO can be effective and safe in patients with lymphoproliferative disorder exposed to chemotherapy and showing inappropriate EPO response to anemia; (2) this is less likely in hematopoietic stem cell disorders, although favorable responses may be observed in occasional patients; and (3) functional iron deficiency as a cause of nonresponse to rHuEPO is frequent also in nonrenal anemia.     

Prediction of response to erythropoietin treatment in chronic anemia of cancer [see comments]

Chronic anemia of cancer can be corrected in approximately 50% of the cases by treatment with recombinant human erythropoietin (rHuEPO). Early prediction of responsiveness would avoid the emotional and financial burden of ineffective medical intervention. Eighty patients with chronic anemia of cancer undergoing treatment with rHuEPO (150 U/kg, 3 times per week by subcutaneous injection; after 6 weeks without response, 300 U/kg) participated in this study. Response was defined as a gain of at least 2 g/dL hemoglobin (Hb) within 12 weeks. Multivariate discriminant analysis and logistic regression analysis of response were performed on routine blood tests; serum levels of EPO, iron, ferritin, transferrin, and its receptor; World Health Organization (WHO) performance status; various cytokines; neopterin; stem cell factor; C- reactive protein; and alpha 1-antitrypsin. At baseline, none of these factors showed sufficient prognostic power. The following predictive algorithm was developed: (1) If after 2 weeks of therapy both the serum EPO level is > or = 100 mU/mL and Hb concentration has not increased by at least 0.5 g/dL, unresponsiveness of the patient is very likely (predictive power, 93%); otherwise, response may be predicted with an accuracy of 80%. (2) If both the serum level of EPO is less than 100 mU/mL and Hb concentration has increased by > or = 0.5 g/dL, response is highly probable (predictive power, 95%). (3) Alternatively, a serum ferritin level of > or = 400 ng/mL after 2 weeks of rHuEPO therapy strongly indicates unresponsiveness (predictive power, 88%), whereas a level less than 400 ng/mL suggests response in 3 of 4 patients.     

Treatment of myelodysplastic syndromes with retinoic acid and 1 alpha-hydroxy-vitamin D3 in combination with low-dose ara-C is not superior to ara-C alone. Results from a randomized study. The Scandinavian Myelodysplasia Group (SMG)

63 evaluable patients with myelodysplastic syndromes (MDS) and 15 with acute myelogenous leukemia (AML) were randomized between low-dose ara-C (arm A) and low dose ara-C in combination with 13-cis-retinoic acid (13-CRA) and 1 alpha-hydroxy-vitamin D3 (1 alpha D3) (arm B). 69 patients were evaluable and 18 (26.1%) responded to therapy. The addition of 13-CRA and 1 alpha D3 had no positive influence on survival of the patients, remission rates or duration of remissions. 12/27 patients in arm A and 6/29 patients in arm B progressed from MDS to AML during the course of the study (p = 0.0527). Arm B gave significantly more side-effects than arm A (p = 0.005). Therapeutic effects of 13-CRA and 1 alpha D3 on MDS is not supported by this study. However, an inhibiting effect on AML development in some MDS subgroups cannot be excluded.     

Recombinant human erythropoietin therapy after allogeneic hematopoietic cell transplantation with a nonmyeloablative conditioning regimen: low donor chimerism predicts for poor response

PURPOSE: After allogeneic hematopoietic stem cell transplantation with nonmyeloablative conditioning (NMHCT), many patients experience prolonged anemia and require red blood cell (RBC) transfusions. We enrolled 60 consecutive patients undergoing NMHCT in a phase II trial to determine the optimal utilization of recombinant human erythropoietin (rHuEPO) therapy in this setting. PATIENTS AND METHODS: The first 14 NMHCT recipients did not receive rHuEPO (control group). Nineteen patients were scheduled to start rHuEPO on day 0 (EPO group 2) and 27 patients on day 28 after the transplant (EPO group 1). RHuEPO was administered subcutaneously once weekly at a dose of 500 U/kg/wk with the aim of achieving hemoglobin (Hb) levels of 13 g/dL. The 3 groups were well balanced for major characteristics. RESULTS: During the first month (p < 0.0001) as well as days 30 to 100 (p < 0.0001) and days 100 to 180 (p < 0.0001), Hb values were higher in patients receiving rHuEPO compared to those not receiving it. However, transfusion requirements were significantly decreased only in the first month in EPO group 2 (p = 0.0169). T-cell chimerism above 60% on day 42 was the best predictor of Hb response (p < 0.0001) or Hb correction (p = 0.0217), but myeloid chimerism above 90% also predicted for Hb response (p = 0.0069). Hb response was also decreased in patients receiving CD8-depleted grafts and increased in the few patients not receiving TBI, but only in univariate analysis. CONCLUSIONS: Anemia after NMHCT is sensitive to rHuEPO therapy, but less so than after conventional allogeneic HCT. RHuEPO decreases transfusion requirements only in the first 30 days posttransplant. T-cell chimerism below 60% on day 42 impaired Hb response, suggesting possible inhibition of donor erythropoiesis by residual recipient lymphocytes. A prospective randomized trial should be performed with rHuEPO starting on the day of transplantation to assess its clinical benefit in terms of transfusion requirements and quality of life.     

Impacts of Recombinant Human Erythropoietin Treatment During Predialysis Periods on the Progression of Chronic Kidney Disease in a Large‐Scale Cohort Study (Co‐JET study)

The effect of recombinant human erythropoietin (rHuEPO) treatment on the progression of chronic kidney disease (CKD) has not been fully evaluated in Japan. We therefore retrospectively evaluated this in a sub‐cohort of a prospective multicenter study to investigate optimal hemoglobin (Hb) level of CKD patients on hemodialysis (HD) treated with rHuEPO; Japan Erythropoietin Treatment Study for Target Hb and Survival (JET study). Effect of rHuEPO treatment during predialysis period to delay initiation of HD was retrospectively assessed in 2434 patients from the JET study comparing groups with and without rHuEPO treatment. The assessment was done by Cox proportional hazards regression analysis and inverse probability‐weighted (IPW) analysis to adjust for time‐dependent confounders. The weights used in the IPW analysis were calculated using a logistic model that included baseline confounders and time‐dependent variables. During the predialysis period, 71.7% (1746 patients) were treated with rHuEPO (mean Hb level of 8.7 g/dL at initiation of rHuEPO treatment). Covariates significantly associated with initiation of rHuEPO treatment were Hb level, serum creatinine level, age, diabetes, cardiac insufficiency, and hypertension. The adjusted hazard ratio for time until HD initiation under rHuEPO treatment was 0.272 (95% CI, 0.223–0.331; P < 0.001) in the Cox analysis and 0.63 (95% CI, 0.53–0.76; P < 0.0001) in the IPW analysis. This retrospective study suggests that rHuEPO treatment during the predialysis period has preventive effects on the progression of CKD although further prospective investigation on the efficacy is needed.     

Myelodysplastic features in patients with long-term HIV infection and haemophilia

HIV-related bone marrow changes are consistent with myelodysplastic features (MDF). Their pathogenesis may differ from primary myelodysplastic syndromes (MDS) and is associated with various factors including the virus itself or the antiretroviral therapy. In order to evaluate the differences between HIV-related MDF and MDS, the morphological changes in peripheral blood and bone marrow, cytogenetic analysis and the response to anaemia treatment were studied in 158 HIV+ patients with haemophilia and the results were compared with those of 61 patients with primary MDS (31 with RA, 10 with RARS, 11 with RAEB, three with RAEB-t and six with CMML). The eligibility criteria for patients with MDS were primary MDS, Hb levels < 10 g dL(-1), and no significant organ disease. The peripheral blood and bone marrow examination revealed MDF in 44 HIV-infected haemophilic patients (27.8%). The median time from seroconversion was 12.5 years and the mean time under AZT therapy was 44.1 months. Nineteen of these patients (43.1%) had Hb levels < 10 g dL(-1), while neutropenia and thrombocytopenia were observed in 29.5% and 25%, respectively. Every patient of this study with Hb < 10 g dL(-1) received erythropoietin (Epo). There were statistically significant morphological alterations between HIV-related MDF and MDS: hypocellularity, plasmatocytosis and eosinophilia were more pronounced in HIV haemophiliacs with MDF, while dysplasia of erythroblasts, megakaryocytes and granulocytes was more frequent in MDS patients. No HIV haemophilic patient with MDF had more than 5% blasts in the bone marrow nor did any develop RAEB or acute leukaemia during the period of this study. The cytogenetic analysis was normal in HIV-infected patients with haemophilia whereas 42.6% of patients with MDS had an abnormal karyotype. Complete erythroid response was achieved with Epo administration in 84.2% of HIV+ haemophilic patients with anaemia compared to 19.7% of patients with MDS. These data suggest that bone marrow changes in long-term HIV patients have different characteristics from primary MDS and constitute the entity for which the name HIV-myelopathy has been proposed in the literature.     

Arterial hypertension in patients with chronic kidney insufficiency in hemodialysis with erythropoietin

The purpose of this study was to evaluate the effect of the partial correction of anaemia with recombinant human erythropoietin (rHuEPO) on the blood pressure (BP) of patients on chronic haemodialysis (HD). A group of 50 patients (26 men and 24 woman, mean age of 50 +/- 19.0 and range of 21 to 67) with basal levels of haemoglobin (Hb) less than or equal to 8 g/dl was evaluated before and during treatment with rHuEPO. Recombinant erythropoietin was started at 50 U/kh I.V. 3 times a week, immediately after each session of HD, for 4 weeks, and this dose was increased in steps of 25 U/kg until and Hb level of 12 g/dl or a maximum dose of 100 U/kg were reached. Before the administration of rHuEPO 33 patients (67.3%) were normotensives and 16 (32.6%) were hypertensives treated and well controlled. During the period of administration of rHuEPO 10 of the normotensives (30.3%) and 5 (31.3%) of the hypertensives patients showed an increase in the B.P. There was no correlation between the frequency of increase in B.P. and sex, age, length of time on HD and previous levels of B.P., but that frequency was higher in the patients with the lowest basal levels of haematocrit (Hct) and with the greatest increases in Hct (delta Hct). An immediate effect of I.V. administration of rHuE-PO on B.P. levels was not found. Finally we discuss the etiopathologic factors eventually responsible for the increase in BP and suggest some rules to be observed in the therapeutic use of rHuEPO.     

Evaluation of the effectiveness of treatment with erythropoietin on anemia, cognitive functioning and functions studied by comprehensive geriatric assessment in elderly cancer patients with anemia related to cancer chemotherapy

The primary aim of the present study was to examine the relationship of changes in hemoglobin levels following recombinant human erythropoietin (rHuEPO) treatment to changes in cognitive functioning studied by Mini Mental State Examination (MMSE) in elderly cancer patients undergoing chemotherapy treatment. The secondary aim was that to assess the relationship of changes in hemoglobin levels following rHuEPO treatment to changes in functions studied by Comprehensive Geriatic Assessment (CGA), such as Activity of Daily Living (ADL), Instrumental Activities of Daily Living (IADL), Geriatric Depression Scale (GDS) and the Mini Nutritional Assessment (MNA). To this end, hemoglobin levels and cognitive functioning were evaluated in a sample of cancer patients prior to the start of chemotherapy treatment and again after 4, 8 and 12 weeks of treatment with chemotherapy plus rHuEPO. Ten elderly patients (mean age 71.4 years) were enrolled. At baseline, enrolled patients had a mean Hb value of 10.3g/dl. After 4 weeks of rHuEPO treatment, Hb values increased significantly (p<0.0001), with a mean increase of 1.2g/dl (range: 0.2-2.1). Remarkably, 8 out of 10 (80%) showed an increase of Hb levels >or=1g/dl in comparison to baseline and therefore were considered responders. At baseline, four patients (40%) showed a moderate cognitive impairment, whilst six patients (60%) showed a normal cognitive function. After 4 weeks of rHuEPO treatment nine patients (90%) showed a significant improvement of cognitive functions in comparison to baseline (p<0.005): eight of them were responders also to rHuEPO in terms of correction of anemia. The Spearman's rank correlation test showed a statistical significant correlation between Hb increase and increase in cognitive functioning assessed by MMSE after 4 weeks (p=0.049), 8 weeks (p=0.044) and 12 weeks (p=0.031) of rHuEPO treatment. Therefore, the findings of this study provide support for the hypothesis that significant increases in hemoglobin over the course of chemotherapy supplemented with rHuEPO administration would be accompanied by significant improvement in cognitive performance over the same interval.     

Quality of life, physical function and MRI T2* in elderly low-risk MDS patients treated to a haemoglobin level of ≥120 g/L with darbepoetin alfa ± filgrastim or erythrocyte transfusions

Objective: Anaemia in low‐risk myelodysplastic syndromes (MDS) is associated with reduced quality of life (QoL). Response to treatment with erythropoietin ± granulocyte colony‐stimulating factor (G‐CSF) is associated with improved QoL, but whether transfusion therapy with higher haemoglobin (Hb) target levels has similar effects is unknown. The objective for this prospective phase II Nordic multicentre trial was to assess QoL, response rate and physical function in elderly anaemic MDS patients treated to a target Hb level of >120 g/L. Methods: Thirty‐six elderly patients with low‐ and intermediate‐1 risk MDS received darbepoetin (DA) 300 μg/wk, with the addition of G‐CSF if no response. If the Hb target was reached at 16 wk, treatment was maintained until week 26. Remaining patients were transfused to reach the target level for at least 8 wk. Results: Twenty‐seven patients completed the study. Response rate to DA ± G‐CSF was 67% in evaluable patients and 56% according to intention to treat. Eighteen patients reached the target Hb level according to protocol. QoL scores for fatigue, dyspnoea, constipation, and physical, role and social functioning improved significantly during study, with similar results for transfused and untransfused patients. Maintaining Hb >120 g/L did not confer a higher transfusion rate, once the target was reached. In two of fourteen patients, magnetic resonance imaging T2* indicated cardiac iron overload, however, without association with ferritin levels. Conclusions: In elderly anaemic MDS patients, an increment in haemoglobin is associated with improved QoL, whether induced by growth factor treatment or transfusion therapy.     

A population-based study of hemoglobin, race, and mortality in elderly persons

Background. Anemia is associated with increased mortality risk. The impact of mildly low hemoglobin concentration (Hb) on risk for mortality remains unclear, especially among blacks. We examined the racial differences between Hb and mortality. Methods. This was a population-based study conducted from 1993 through 2006, in a geographically defined community of Chicago, Illinois. A stratified, random sample of 1806 participants 65 years old or older and 50% black, who were participating in the Chicago Health Aging Project and underwent clinical evaluation. Mortality was ascertained using the National Death Index. Cox proportional hazard models were used to assess the independent relation of Hb to mortality risk. Results. The proportion of participants with anemia by World Health Organization (WHO) criteria (Hb < 13.0 g/dL for men and < 12.0 g/dL for women) was 39% among blacks, and 17% among whites. Blacks had lower mean Hb (12.6 +/- 1.5 g/dL) than did whites (13.5 +/- 1.5 g/dL). In multivariable analysis, anemia was associated with increased mortality risk in blacks (hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.43-2.53) and in whites (HR, 1.85; 95% CI, 1.32-2.59). Among blacks, Hb 0-0.9 g/dL below the anemia threshold is associated with increased mortality risk compared to Hb 0-0.9 g/dL above the anemia cutoff (HR, 1.84; 95% CI, 1.21-2.79), Hb 1.1-2.0 g/dL above the anemia cutoff (HR, 1.35; 95% CI, 0.88-2.05) and Hb 2.1-3.0 g/dL above the anemia cutoff (HR, 2.24; 95% CI, 1.12-4.47). The terms for interaction between black ethnicity/race and anemia suggested that blacks did not have a statistically significant difference in mortality risk compared to whites. Subgroup analyses of interaction terms suggested that Hb 0.1-1.0 g/dL above anemia cutoff group, blacks may have lower mortality risk compared to whites in the mildly low normal ranges of Hb (p =.02). Conclusion. Both anemia by WHO criteria and mild reductions in Hb were related to increased risk of mortality in older blacks and whites.     

Efficacy and safety of administration of oral iron chelator deferiprone in patients with early myelodysplastic syndrome

Forty-eight patients with early myelodysplastic syndrome (MDS) without excess of blasts, with average initial serum ferritin levels of 2739.5 μg/L (range 825-11287 μg/L), were treated with deferiprone (L1) in a daily dose of 40-90 mg/kg. Median duration of chelation treatment was 10.9 months (range 4-24 months). Chelation was effective (maintained or decreased iron stores) in 16 out of 22 patients (73%) with serum ferritin levels <2000 μg/L in contrast to only 12 out of 26 patients with serum ferritin levels >2000 μg/L. Combination of L1 with recombinant human erythropoietin (rHuEPO) (30-40 kU/week) resulted in effective chelation in five additional patients with serum ferritin levels >3000 μg/L. Incidence of adverse effects was comparable to that in thalassemic patients. Gastrointestinal symptoms represented the most frequent adverse effect of L1 therapy (37.5% of patients) that limited an effective escalation of the daily dose of the drug and led to discontinuation of the treatment for six patients. A decreased number of granulocytes was observed in five (13%) patients and agranulocytosis occurred in two patients (4%). Granulocyte counts were restored after cessation of L1 treatment and administration of granulocyte colony stimulating factor (G-CSF) in all but one patient. Administration of L1 in a daily dose of at least 75 mg/kg may represent an alternative approach in treatment of mild and moderate iron overload in MDS patients who cannot be treated with deferasirox (DFRA) or deferoxamine (DFO).     

2004 Japanese Society for Dialysis Therapy guidelines for renal anemia in chronic hemodialysis patients

The guideline committee of Japanese Society for Dialysis Therapy (JSDT), chaired by Professor F. Gejyo of Niigata University, now publishes an original Japanese guideline entitled 'Guidelines for Renal Anemia in Chronic Hemodialysis Patients'. It includes the re-evaluation of the usage of recombinant human erythropoietin (rHuEPO) with the medical and economical arguments regarding the prognosis and the quality of life of Japanese hemodialysis patients. This guideline consists of 7 sections. The first section comprises the general definition and the differential diagnosis of anemia. The hemoglobin (Hb) level of the Japanese population seemed to be low when compared with that of the European and American populations. The second section describes the target Hb level in hemodialysis patients. Multivariate analysis of the data that were collected from dialysis institutions throughout the country showed that an Hb level of 10-11 g/dL (Ht level 30-33%) at the first dialysis session in a week is the ideal range for chronic hemodialysis patients in terms of the 3-5 year survival rate. The supine position at blood sampling and the sampling timing at the first dialysis session in a week might affect the lower setting of target Hb hematocrit (Ht), compared to that of European and American guidelines. However, we particularly recommended that an Hb level of 11-12 g/dL (Ht level from 33 to 36%) at the first dialysis session in a week is desirable in relatively young patients. In the third section, the markers of iron deficiency are discussed. The Transferin saturation test (TSAT) and serum ferritin were emphasized as the standard markers. The routes of administration of rHuEPO and its dosages are written in the fourth section. The subcutaneous route was associated with the occurrence of secondary red cell aplasia due to anti-rHuEPO antibodies; however, secondary red cell aplasia was seldom observed in the venous injection. From this fact we recommend venous injection for chronic hemodialysis patients. We advocate an initial dosage of 1500 U three times per week. The fifth section deals with the factors refractory to treatment with rHuEPO. If the patient shows an inadequate response to the usage of 9000 U per week, this condition defines the inadequate response to rHuEPO in Japan. Blood transfusion must be avoided where possible. The reasons for this and the adverse effects are interpreted in section six. In the final section, the adverse effects of rHuEPO are listed. Among them, hypertension, thrombotic events and secondary red cell aplasia were emphasized as the major complications.     

Optimal and continuous anaemia control in a cohort of dialysis patients in Switzerland

Background

Guidelines for the management of anaemia in patients with chronic kidney disease (CKD) recommend a minimal haemoglobin (Hb) target of 11 g/dL. Recent surveys indicate that this requirement is not met in many patients in Europe. In most studies, Hb is only assessed over a short-term period. The aim of this study was to examine the control of anaemia over a continuous long-term period in Switzerland.

Methods

A prospective multi-centre observational study was conducted in dialysed patients treated with recombinant human epoetin (EPO) beta, over a one-year follow-up period, with monthly assessments of anaemia parameters.

Results

Three hundred and fifty patients from 27 centres, representing 14% of the dialysis population in Switzerland, were included. Mean Hb was 11.9 ± 1.0 g/dL, and remained stable over time. Eighty-five % of the patients achieved mean Hb ≥ 11 g/dL. Mean EPO dose was 155 ± 118 IU/kg/week, being delivered mostly by subcutaneous route (64–71%). Mean serum ferritin and transferrin saturation were 435 ± 253 μg/L and 30 ± 11%, respectively. At month 12, adequate iron stores were found in 72.5% of patients, whereas absolute and functional iron deficiencies were observed in only 5.1% and 17.8%, respectively. Multivariate analysis showed that diabetes unexpectedly influenced Hb towards higher levels (12.1 ± 0.9 g/dL; p = 0.02). One year survival was significantly higher in patients with Hb ≥ 11 g/dL than in those with Hb <11 g/dL (19.7% vs 7.3%, p = 0.006).

Conclusion

In comparison to European studies of reference, this survey shows a remarkable and continuous control of anaemia in Swiss dialysis centres. These results were reached through moderately high EPO doses, mostly given subcutaneously, and careful iron therapy management.