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Latest Research on Anemia
   
BJOG. 2008 Apr;115(5):595-601.
Outcome of anaemic monochorionic single survivors following early intrauterine rescue transfusion in cases of feto-fetal transfusion syndrome.
Quarello E, Stirnemann J, Nassar M, Nasr B, Bernard JP, Leleu-Huard F, Ville Y.
Department of Obstetrics and Gynecology, Centre Hospitalier Intercommunal de Poissy, Poissy, France. e.quarello@orange.fr <e.quarello@orange.fr>

OBJECTIVE: To evaluate the outcome of severely anaemic monochorionic (MC) twins surviving the death of their co-twin following early intrauterine rescue transfusion in cases of feto-fetal transfusion syndrome (FFTS). STUDY DESIGN: We reviewed all MC pregnancies complicated with FFTS following primary management, in which a single intrauterine fetal death (IUFD) was diagnosed with certainty within 24 hours between January 1999 and December 2006. We included MC survivors who presented ultrasound or Doppler features of fetal anaemia following the death of their co-twin. Intrauterine transfusion (IUT) was given to all survivors who were anaemic. RESULTS: Nineteen MC twin pregnancies presented a single intrauterine death (IUD) associated with an anaemic co-twin. Median gestational age at IUD was 23 [20-28] weeks. The median interval between IUD and IUT was 12 [8-24] hours. There were 58% (11/19) healthy survivors. Perinatal death rate was 26% (5/19) including 16% (3/19) intrauterine and 10% (2/19) neonatal deaths. Abnormal prenatal cerebral findings developed in 21% (4/19) cases, always within 1 month after the death of the co-twin. Considering occlusive techniques and other management separately, there were 64% (7/11) and 50% (4/8) healthy survivors, respectively, and perinatal death occurred in 36% (4/11) and 12.5% (1/8) of fetuses, respectively. Prenatal fetal cerebral lesions developed in 9% (1/11) of cases following occlusive techniques and in 37.5% (3/8) of fetuses when managed differently. The median gestational age at delivery in the survivors was 31 [25-38] weeks. CONCLUSION: In cases of FFTS with single anaemic survivors, early IUT could be offered following extensive counselling and close follow up.

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Eur J Cancer. 2008 Mar 14 [Epub ahead of print]
Prevention of anaemia by early intervention with once weekly epoetin alfa during chemotherapy.
Schouwink JH, Codrington H, Sleeboom HP, Kerkhofs LG, Wormhoudt LW.
Medisch Spectrum Twente, Department of Pulmonology, Haaksbergerstraat 55, 7513 ER Enschede, The Netherlands.

This study compared the effects of early intervention with standard use of epoetin alfa on haemoglobin (Hb) levels and transfusion requirements in cancer patients receiving chemotherapy. Patients with Hb>10 and 12g/dL were randomised 1:1 to epoetin alfa (40,000 IU, subcutaneously, once weekly), initiated within 7d of the start of the first on-study chemotherapy cycle (defined as early intervention) versus epoetin alfa when Hb10g/dL (defined as standard therapy). Increases in Hb values were significantly higher with early intervention compared to standard therapy from week 6 to 10 (P0.05) and approached significance at week 15/16 (P=0.0531). Although the percentage of patients receiving blood transfusions was similar in both groups, the amount of blood transfused was almost twice as high in the standard epoetin alfa group (n.s.). Early intervention with epoetin alfa was well tolerated and overall survival did not differ significantly between groups. Initiation of epoetin alfa at the onset of chemotherapy and Hb<12g/dL improves Hb levels significantly versus standard therapy.

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Am J Health Syst Pharm. 2008 Mar 15;65(6):540-6.
Erythropoietic agents for anemia of critical illness.
Shermock KM, Horn E, Rice TL.
Center for Pharmaceutical Outcomes and Policy, Allegheny General Hospital, Pittsburgh, PA, USA.

PURPOSE: Evidence regarding the cost-effective use of and benefits associated with epoetin alfa in treating anemia of critically ill patients is assessed. SUMMARY: Anemia of critical illness is a leading cause of inadequate oxygen delivery that affects almost all patients in the intensive care unit setting after day 3. Red blood cell transfusions are commonly used to correct anemia of critical illness, but they are also associated with risks including hemolytic reactions and viral transmission. The latest evidence suggests that when a strict transfusion protocol is implemented, epoetin alfa does not decrease the transfusion requirements of critically ill patients. In the absence of a strict transfusion protocol, an average of 5.1 doses of epoetin, at a cost of $2154, is required to avoid one transfusion. Evidence is accumulating that epoetin may reduce mortality rates in trauma patients. However, important questions remain regarding the magnitude and mechanism of the potential benefit and if the benefit outweighs the risk of thromboembolism. Therefore, the reduction in transfusion-related adverse events is the only clinical outcome benefit that is well-supported by current evidence. However, the known risk of transfusion-related adverse events is low; approximately 29,000 patients would need to be treated to avoid a serious transfusion-related event. Treating these patients would cost over $25 million, and it would take over 100 years to prevent one serious event in a unit admitting 20 epoetin-eligible patients per month. CONCLUSION: Published data suggest a prohibitive cost associated with epoetin alfa use in critically ill patients given that the only well-supported clinical benefit of this treatment is the avoidance of transfusion-related adverse events. Continued research is necessary to clarify if there is a net clinical benefit of epoetin use (especially in trauma patients) and to develop optimal blood management strategies.

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Br J Haematol. 2008 Mar 3 [Epub ahead of print]
Rituximab in the treatment of autoimmune haematological disorders.
Garvey B.
St Michael’s Hospital, University of Toronto, Toronto, ON, Canada.

Current treatment regimens for haematological autoimmune diseases are relatively non-selective and are often associated with considerable toxicity. Recently, it has become clear that B cells play a key role in both the development and perpetuation of autoimmunity, suggesting that B-cell depletion could be a valuable treatment approach for patients with autoimmune diseases. This article reviews data supporting the use of rituximab - an anti-CD20 monoclonal antibody that specifically depletes B cells - in four key autoimmune haematological disorders: idiopathic thrombocytopenic purpura (ITP); autoimmune haemolytic anaemia (AIHA); acquired haemophilia; and thrombotic thrombocytopenic purpura (TTP). Although treatment of ITP, AIHA, acquired haemophilia and TTP with rituximab is still relatively uncommon, results from case series and small phase II trials indicate that patients of all ages can respond to rituximab, irrespective of the number or type of prior treatments that they h
ave received. Moreover, patients with these diseases receiving rituximab experienced predominantly mild adverse events, with only a few serious adverse events reported. These data suggest that rituximab provides an effective and well-tolerated alternative treatment option for patients with ITP, AIHA, acquired haemophilia and TTP, many of whom have limited treatment choices.

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J Oncol Pharm Pract. 2008 Mar;14(1):5-22.
Parenteral iron with erythropoiesis-stimulating agents for chemotherapy-induced anemia.
Shord SS, Hamilton JM Jr, Cuellar S.
University of Illinois College of Pharmacy, University of Illinois Medical Center at Chicago. sshord@uic.edu.

Purpose. To discuss the clinical issues we addressed in the development of our institutional guidelines regarding the assessment of iron stores for cancer- and treatment-related anemia and the administration of parenteral iron with erythropoiesis-stimulating agents (ESAs). DATA SOURCE: : Studies published from January 1995 to August 2007 were identified by computer searches of Medline and hand searching of bibliographies of the articles identified via the computer searches. The current clinical practice guidelines were identified by computer searches of the web sites for national professional organizations that represent health care professionals who treat patients with cancer. RESULTS: of data analysis. Hematopoietic responses demonstrate that epoetin alfa and darbepoetin alfa provide similar outcomes for patients with chemotherapy-induced anemia (CIA); however, up to 50% of patients receiving these agents fail to adequately respond. Functional iron deficiency defined as a state of iron-restricted erythropoiesis is likely the primary contributor to the lack of response. Hematopoietic responses following ESA therapy with parenteral iron are substantially higher compared to response with no or oral iron. CONCLUSIONS: Iron stores should be assessed in all patients with cancer- or treatment-related anemia and parenteral iron should be administered to patients receiving ESA therapy to improve hematopoietic response. A unique algorithm that summarizes our institutional guidelines to assess iron stores and administer parenteral iron with ESA therapy in patients with CIA is included.

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J Clin Oncol. 2008 Feb 1;26(4):592-8.
Effect of once-weekly epoetin beta on survival in patients with metastatic breast cancer receiving anthracycline- and/or taxane-based chemotherapy: results of the Breast Cancer-Anemia and the Value of Erythropoietin (BRAVE) study.
Aapro M, Leonard RC, Barnadas A, Marangolo M, Untch M, Malamos N, Mayordomo J, Reichert D, Pedrini JL, Ukarma L, Scherhag A, Burger HU.
Institut Multidisciplinaire d'Oncologie, Clinique de Genolier, 1 route du Muids, Genolier, Switzerland. maapro@genolier.net

PURPOSE: The Breast Cancer-Anemia and the Value of Erythropoietin (BRAVE) study evaluated whether epoetin beta would improve survival in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: BRAVE was an open-label, randomized, multicenter study in patients with MBC treated with anthracycline- and/or taxane-based chemotherapy. Patients (hemoglobin [Hb] < 12.9 g/dL) were randomly assigned (1:1) to epoetin beta 30,000 U subcutaneously once weekly or control for 24 weeks. The primary efficacy variable was overall survival. Secondary efficacy outcomes included progression-free survival, transfusion- and severe anemia-free survival, Hb response, safety, and quality of life (QoL). RESULTS: After 18 months of follow-up, 62 (27%) of 231 patients survived with epoetin beta therapy and 63 (27%) of 232 with control. No difference was detected in overall survival (hazard ratio [HR] = 1.07; 95% CI, 0.87 to 1.33, P = .522) or progression-free survival (HR = 1.07; 95% CI, 0.89 to 1.30, P = .448). There was a statistically significant benefit on transfusion- and severe anemia-free survival compared with control (HR = 0.59; P = .0097). Median Hb level increased with epoetin beta (11.7 g/dL at baseline to 13.3 g/dL at 24 weeks) but did not change with control (11.5 v 11.4 g/dL). Patients receiving epoetin beta experienced more thromboembolic events (TEEs) compared with controls (13% v 6%; P = .012) with no difference in serious TEEs (4% v 3%). Epoetin beta did not significantly improve QoL in this study where patients had a high baseline Hb value. CONCLUSION: In patients with MBC receiving chemotherapy and initial Hb less than 12.9 g/dL, epoetin beta increased Hb. No difference was detected in overall survival. Because of its superiority design, this study cannot, however, exclude clinically important differences in survival with absolute certainty.

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Br J Haematol. 2008 Feb 26 [Epub ahead of print]
Outcome of unrelated donor stem cell transplantation for children with severe aplastic anemia.
Perez-Albuerne ED, Eapen M, Klein J, Gross TJ, Lipton JM, Baker KS, Woolfrey A, Kamani N.
Division of Stem Cell Transplantation and Immunology, Children’s National Medical Center, Washington, DC, USA.

For children with severe aplastic anemia (SAA) who fail immunosuppressive therapy and lack a human leucocyte antigen (HLA)-matched sibling donor, unrelated donors provide a source of hematopoietic stem cells. Data from 195 children with acquired SAA who underwent unrelated donor transplantation between 1989 and 2003 were analyzed. Neutrophil recovery (86% at day-28) was higher with total body irradiation-containing conditioning regimen and in younger recipients (aged </=16 years) receiving grafts from older donors (aged >40 years). Recovery was lower after mismatched transplants and transplantations prior to 1997. Mortality rates were higher after mismatched transplants, in recipients with a poor performance score, and when the interval between diagnosis and transplantation was longer than 4 years. When restricted to donor-recipient pairs with allele-level HLA typing (8-loci; n = 118), mortality rates were also higher after mismatched transplants and older recipients receivin
g grafts from older donors; 5-year probabilities of overall survival after HLA-A, -B, -C, -DRB1 matched and mismatched transplants adjusted for donor and recipient age were 57% and 39%, respectively (P = 0.008). The data suggest that unrelated donor transplantation is an acceptable alternative for children; early referral for transplantation and identification of an HLA-matched (allele-level) donor offers the best outcome.

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Clin Ther. 2008 Jan;30(1):206-18.
Use of darbepoetin alfa and epoetin alfa in clinical practice in patients with cancer-related anemia.
Berger A, Edelsberg J, Kallich J, Oster G.
Policy Analysis Inc. (PAI), Brookline, Massachusetts, USA.

Background: Patients with cancer may receive erythropoiesis-stimulating agents (ESAs), including darbepoetin alfa (DA) or epoetin alfa (EA), to treat cancer-related anemia (CRA). DA and EA differ, however, with respect to their assumed duration of effect and thus their approved frequency of dosing, complicating direct comparison of their doses and costs. Objective: The objective of this study was to examine, from the perspective of a third-party payer, patterns of use and costs of DA and EA in patients with CRA, using episode-based methodology to account for differences in assumed duration of effect and frequency of dosing with these products. Methods: Using a large US health insurance claims database, we identified all patients with cancer who received ESAs between January 1, 2005, and June 30, 2005 (study period). For each such patient, we identified all unique episodes of care (EOCs) with DA or EA, and then compared mean weekly dose and cost of ESA therapy within these EOCs, which were calculated using the ratio of total dose received and total cost of ESA therapy, respectively, to total EOC duration; only the first EOC for each patient was considered. EOCs were assumed to begin on the date of first ESA admin-istration within the study period, and end on the date of final ESA administration (within the episode) plus an assumed duration of effect based on the ESA received and corresponding dose. We also estimated the ratio of mean weekly dose of EA (in units) to mean weekly dose of DA (in micrograms) (EA/DA weekly dose ratio). Multivariate regression was used to control for differences in baseline characteristics of EA and DA patients. Results: We identified a total of 1226 patients with complete EOCs with ESAs (EA, 381; DA, 845). DA patients were more likely to have had evidence of receipt of chemotherapy (54% vs 47% for EA; P = 0.02); they also had more comorbidities (mean Charlson comorbidity scores, 4.3 and 3.9, respectively; P < 0.01). Estimated mean (95% CI) weekly dose within EOCs was 97 mug (94-99) for DA, and 43,184 U (40,181-46,589) for EA; EA/DA weekly dose ratio was 445:1. Adjustment for differences in patient characteristics yielded a slightly lower ratio (403:1). Results were sen-sitive to the exclusion of EOCs consisting of a single administration of ESA therapy and/or the addition of an assumed duration of effect to the final ESA dose administered. Conclusions: Cost comparisons of DA and EA are sensitive to the assumed duration of effect added to the final dose of ESA therapy, especially for EOCs with relatively few administrations.

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Biol Blood Marrow Transplant. 2008 Jan;14(1):43-9. Epub 2007 Dec 3.
Long-term outcome after bone marrow transplantation for aplastic anemia using cyclophosphamide and total lymphoid irradiation as conditioning regimen.
Inamoto Y, Suzuki R, Kuwatsuka Y, Yasuda T, Takahashi T, Tsujimura A, Sugimoto K, Oba T, Terakura S, Atsuta Y, Murata M, Ito M, Kodera Y, Miyamura K.
Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan. yinamoto@js3.so-net.ne.jp

We retrospectively studied 49 patients in a single institute to evaluate the long-term outcome of total lymphoid irradiation (TLI) conditioning for allogeneic stem cell transplantation (allo-SCT) to treat aplastic anemia (AA). Most of the patients had received transfusions and had undergone previous treatment, with 33 receiving related transplants and 16 receiving unrelated transplants. Conditioning consisted of cyclophosphamide (Cy; 200 mg/kg) plus TLI (750 cGy) for related transplantation and Cy plus total body irradiation (TBI; 500 cGy) and TLI (500 cGy) for unrelated transplantation. Antithymocyte globulin (ATG) was added for 6 of the unrelated transplantations. Graft-versus-host-disease (GVHD) prophylaxis consisted mainly of cyclosporine (CSA) and methotrexate (MTX). Graft failure developed in 2 patients (4.1%). With a median follow-up of 7 years, overall survival (OS) was 81% and was not statistically significantly different between the patients receiving related transplants and those receiving unrelated transplants. In multivariate analyses, a history of previous treatment with ATG was the sole factor associated with a worse survival rate, and the interval from diagnosis to treatment was not prognostic. The incidence of acute (grade II to IV) GVHD (aGVHD) was 23%, and that of chronic GVHD (cGVHD) was 29%. Female-to-male transplantation was the sole factor associated with chronic GVHD. B cell lymphoproliferative disorder developed only after the ATG-containing conditioning. No other secondary malignancies developed after long-term follow-up. Our findings suggest that TLI conditioning is feasible and effective for patients with AA.

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Diabetes Obes Metab. 2007 Dec 17 [Epub ahead of print]
Anaemia in diabetic renal failure: is there a role for early erythropoietin treatment in preventing cardiovascular mortality?
Abaterusso C, Pertica N, Lupo A, Ortalda V, Gambaro G.
Division of Nephrology, Department of Biomedical and Surgical Sciences, University Hospital of Verona, Verona, Italy.

The mortality rate in diabetics with chronic kidney disease (CKD) is seven times higher than end-stage renal disease mainly because of cardiac causes. Anaemia may have a relevant role in the pathogenesis of cardiovascular (CV) disease in CKD. Anaemia occurs at an earlier stage of CKD in diabetic individuals than in those with other causes of CKD. Observational findings support the unfavourable influence of anaemia on mortality in CKD patients, and the combination of anaemia and CKD in diabetics identifies a group with a particularly high mortality risk. While the effect of erythropoietin on these patients' quality of life is known, its impact on mortality and CV risk is uncertain. The recent Anaemia Correction in Diabetes (ACORD) trial in diabetic CKD patients, which targeted haemoglobin levels of 13-15 mg/dl, disclosed no statistically significant favourable or adverse effects on mortality or morbidity over the 2-year follow-up, while other studies endeavouring to nearly normalize haemoglobin have reportedly proved risky. Even if anaemia is causally involved, the pathogenesis of CV disease in diabetics with CKD is so complex that addressing just one factor (anaemia) may not suffice to prevent CV risk, and normalizing haemoglobin levels may even be harmful.

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Minerva Chir. 2007 Dec;62(6):431-5.
Preoperative anaemia does not affect the early postoperative outcome in patients with lung cancer.
Anile M, Venuta F, Diso D, Vitolo D, Longo F, De Giacomo T, Francioni F, Liparulo V, Ricella C, Ruberto F, Coloni GF.
Department of Thoracic Surgery, University of Rome La Sapienza, Rome, Italy m.anile@virgilio.it.

AIM: Several prognostic factors like age, gender, histology, stage, type of operation, associated disorders and administration of induction therapy have been evaluated to assess the risk of postoperative complications and outcome in patients with resectable lung cancer. Anemia is a frequent condition in this subset of patients being estimated up to 50%. The aim of this retrospective study was to evaluate the effect of preoperative anemia on early outcome after lung cancer resection.\METHODS: One-hundred thirty nine consecutive patients undergoing surgery for non small cell lung cancer were retrospectively considered. The mean age was 64.8+/-11.6 years. No patient received blood transfusions or administration of erythropoetin preoperatively. Overall, we performed 96 lobectomies, 14 pneumonectomies, 2 bilobectomies and 27 atypical resections. A subset of 27 patients (19.4%) (group I) had a preoperative value of Hb less than 12 g/dl (10.4+/-1.9 g/dL). Seven patients of them were stage IA (26%), 9 stage IB (33.3%), 2 stage IIA (7.4%), 6 stage IIB (22.2%), 2 stage IIIA (7.4%) and 1 stage IIIB (3.7%). Age, gender, stage, type of operation, induction chemotherapy, comorbidities were evaluated by univariate analysis comparing patients with and without preoperative anaemia. The two groups were homogenous regarding demographic characteristics. RESULTS: Three patients (11.1%) in group I and 2 (1.8%) in group II required blood transfusions after surgery (P=0.01); 4 of them received pneumonectomy (P<0.0001). The overall morbidity was 17.9% (25/139); the most frequent complication was persistent air leakage, followed by retention of secretions. No statistically significant difference was observed between the 2 groups about early mortality (1 patient-3.7% in group I and 2 patients-1.8% in group II) and postoperative complications (5 patients-18.5% in group I and 20 patients-17.9% in group II).\Conclusion: Preoperative anaemia is not a risk factor for an increased rate of postoperative complications and should not be considered a contraindication to surgery.

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South Med J. 2007 Dec;100(12):1200-7.
Clinical considerations and practical recommendations for the primary care practitioner in the management of anemia of chronic kidney disease.
Basile JN.
Ralph H. Johnson VA Medical Center and the Medical University of South Carolina, Charleston, South Carolina 29401, USA. Jan.Basile@med.va.gov

Anemia is prevalent in patients with chronic kidney disease (CKD) and is a risk factor for poor disease outcome. Anemia acts as a risk multiplier, significantly increasing the risk of death in anemic versus nonanemic CKD patients with similar comorbidities. Erythropoiesis-stimulating agents (ESA) are a mainstay for the treatment of anemia in renal patients on dialysis, but recent data suggests that earlier treatment of anemia in CKD may delay the onset of end-stage renal disease (ESRD) and decrease mortality. Nonetheless, anemia of CKD is under-recognized and undertreated during the period before initiation of dialysis, when anemia correction may have the greatest impact on disease outcome. This report describes anemia in CKD and its association with diabetes, cardiovascular disease, and poor disease outcome, and offers suggestions for the recognition and treatment of anemia of CKD in the primary care setting.

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Clin J Am Soc Nephrol. 2007 Dec 12 [Epub ahead of print]
Novel Erythropoiesis-Stimulating Agents: A New Era in Anemia Management.
Macdougall IC.
Department of Renal Medicine, King’s College Hospital, London, United Kingdom.

Nearly two decades ago, recombinant human erythropoietin transformed the management of chronic kidney disease anemia by allowing a more sustained increase in hemoglobin than was possible by intermittent blood transfusion. The treatment was highly effective, but because of the fairly short half-life of the molecule at approximately 6 to 8 h, injections usually had to be administered two to three times weekly. A second-generation erythropoietin analogue, darbepoetin alfa, was then created, with a longer elimination half-life in vivo that translated into less frequent dosing, usually once weekly or once every 2 wk. More recently, another erythropoietin-related molecule has been produced called Continuous Erythropoietin Receptor Activator with an even greater half-life, and other molecules are in development or are being licensed, including biosimilar epoetin products and Hematide. The latter is a synthetic peptide-based erythropoietin receptor agonist that, interestingly, has no structural homology with erythropoietin, and yet is still able to activate the erythropoietin receptor and stimulate erythropoiesis. The search goes on for orally active antianemic therapies, and several strategies are being investigated, although none is imminently available. This article reviews the latest progress with these novel erythropoietic agents in this new era in anemia management.

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Vox Sang. 2007 Dec 7 [Epub ahead of print]
Efficacy and safety of intravenous iron therapy as an alternative/adjunct to allogeneic blood transfusion.
Muñoz M, Breymann C, García-Erce JA, Gómez-Ramírez S, Comin J, Bisbe E.
Transfusion Medicine, School of Medicine, University of Málaga, Málaga, Spain.

Anaemia is a common condition among patients admitted to hospital medicosurgical departments, as well as in critically ill patients. Anaemia is more frequently due to absolute iron deficiency (e.g. chronic blood loss) or functional iron deficiency (e.g. chronic inflammatory states), with other causes being less frequent. In addition, preoperative anaemia is one of the major predictive factors for perioperative blood transfusion. In surgical patients, postoperative anaemia is mainly caused by perioperative blood loss, and it might be aggravated by inflammation-induced inhibition of erythropoietin and functional iron deficiency (a condition that cannot be corrected by the administration of oral iron). All these mechanisms may be involved in the anaemia of the critically ill. Intravenous iron administration seems to be safe, as very few severe side-effects were observed, and may result in hastened recovery from anaemia and lower transfusion requirements. However, it is noteworthy that many of the recommendations given for intravenous iron treatment are not supported by a high level of evidence and this must be borne in mind when making decisions regarding its application to a particular patient. Nonetheless, this also indicates the need for further large, randomized controlled trials on the safety and efficacy of intravenous iron for the treatment of anaemia in different clinical settings.

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Blood Rev. 2007 Dec 6 [Epub ahead of print]
Supportive care, growth factors, and new therapies in myelodysplastic syndromes.
Hellström-Lindberg E, Malcovati L.
Karolinska Institutet, Department of Medicine, Division of Hematology, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden.

Treatment of myelodysplastic syndromes (MDS) has evolved to encompass a broad spectrum of therapies aiming to inhibit apoptosis, promote hemopoiesis, and reduce proliferation of clonal immature cells. A small but expanding cohort of patients with MDS may be cured, but for the majority the aim of treatment is to prolong survival and to improve quality of life. Patients with low-risk MDS mainly suffer from the effects of severe anemia and an important therapeutic goal is to maintain acceptable hemoglobin levels by optimal transfusion regimens or by erythropoietin+/-granulocyte-colony-stimulating factor, which normalizes hemoglobin levels or abolish transfusion need in around 40% of patients. Lenalidomide has emerged as a drug of choice for patients with low-risk MDS and a 5q deletion, leading to complete erythroid response and cytogenetic remission in 2/3 of patients. A small cohort of younger patients may show excellent responses to anti-thymocyte globulin. Patients with more advanced disease may respond to treatment with the hypomethylating agents azacytidine and decitabine, who both have been shown to prolong time to leukemic transformation / death in MDS. In addition, there are several new agents under clinical investigation targeted to potential mechanisms of disease and progression in MDS. New therapeutic drug include inhibitors of angiogenesis, histone deacetylation, tyrosine kinases and farnesylation, as well as drugs interacting with apoptotic mechanisms. The role of these, alone and in combination with more established therapies will be discussed.

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Mayo Clin Proc. 2007 Aug;82(8):958-66.
Anemia in the elderly: how should we define it, when does it matter, and what can be done?
Steensma DP, Tefferi A.
Division of Hematology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (steensma.david@mayo.edu).

Anemia signifies an underlying disease and is associated with poor clinical outcomes. In elderly patients, in whom anemia has a high prevalence (greater than 10 percent), neither the hemoglobin threshold for concern nor the identity of the anemia-causing disease is easily established. This is an important shortfall, because even mild anemia can compromise patient well-being and survival, regardless of the underlying cause. This review discusses definitions of "normal" hemoglobin levels in adults, common causes of anemia in people aged 65 years and older (eg, nutritional deficiency, renal insufficiency, inflammatory disorders, and myelodysplastic syndrome), and potential consequences of anemia in elderly patients (eg, poorer cognitive status, increased frailty, and an elevated risk of hospitalization and of complications during hospitalization). We also outline a practical initial diagnostic approach that helps determine appropriate treatment, and we weigh therapeutic options in light of new safety concerns regarding erythropoiesis-stimulating agents.

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Obstet Gynecol. 2007 Aug;110(2):267-278.
Intravenous Ferric Carboxymaltose Compared With Oral Iron in the Treatment of Postpartum Anemia: A Randomized Controlled Trial.
Van Wyck DB, Martens MG, Seid MH, Baker JB, Mangione A.
University of Arizona College of Medicine, Tucson, Arizona; University of Oklahoma Health Sciences Center, Tulsa, Oklahoma; Lyndhurst Gynecologic Associates, Winston-Salem, North Carolina; Windmark Women Care Specialists, Idaho Falls, Idaho; and American Regent, Inc, Norristown, Pennsylvania.

OBJECTIVE: To estimate efficacy of rapid, large-dose intravenous (IV) administration of ferric carboxymaltose compared with oral iron therapy in anemic postpartum women. METHODS: In a randomized, controlled trial, we assigned anemic women (hemoglobin [Hb] less than or equal to 10 g/dL) within 10 days postpartum to receive either IV ferric carboxymaltose (less than or equal to1,000 mg over 15 minutes, repeated weekly to achieve a total calculated replacement dose) or ferrous sulfate (FeSO(4)) 325 mg orally thrice daily for 6 weeks. RESULTS: One hundred seventy-four patients received 350 IV doses of ferric carboxymaltose (mean total dose 1,403.1 mg) in 3, 2, or 1 injection (10.9%, 79.3%, or 9.8% of patients, respectively); 178 received FeSO(4). Patients assigned to IV ferric carboxymaltose compared with those assigned to oral iron achieved a Hb rise greater than or equal to 2.0 g/dL earlier (7.0 compared with 14.0 days, P<.001), were more likely to achieve a Hb rise greater than or equal to 3.0 g/dL at any time (86.3% compared with 60.4%, P<.001), and were more likely to achieve a Hb greater than 12.0 g/dL (90.5% compared with 68.6%, P<.001). A similar proportion of patients achieved a Hb rise greater than or equal to 2.0 g/dL (96.4% compared with 94.1%, IV compared with oral, P=.443). There were no serious adverse drug reactions. CONCLUSION: Large-dose IV ferric carboxymaltose administration is a new iron agent that is effective for the treatment of postpartum anemia. When compared with oral ferrous sulfate, IV ferric carboxymaltose is better tolerated, prompts a more rapid Hb response, and corrects anemia more reliably. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00396292 LEVEL OF EVIDENCE: I.

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Future Oncol. 2007 Aug;3(4):397-403.
Erythropoiesis-stimulating agents versus RBC transfusion in MDS: comparison of long-term outcomes.
Mundle SD.
OrthoBiotech Clinical Affairs LLC, Bridgewater, NJ, USA and, Rush University Medical Center, 743 Knoch Knolls Road, Naperville, IL 60565, USA. suneelmundle@hotmail.com.

Impaired erythropoiesis and refractory anemia are clinical hallmarks of the myelodysplastic syndromes (MDS). As the disease evolves, a steady decline in hemoglobin in these disorders invariably results in dependence on packed red blood cell (PRBC) transfusion. Such chronic transfusion dependence has been associated with iron overload causing cardio-hepatic toxicity and alloimmunization, and can result in reduced survival in these patients. The use of hematopoietic growth factors, particularly erythropoiesis-stimulating agents (ESAs), has been reported to reduce the need for PRBC transfusion, raise hemoglobin and improve quality of life, at least in patients responding to such a therapy. Importantly, the clinical benefits of ESA are well balanced, with an apparently favorable safety profile in MDS, thus providing an eminent therapeutic option to delay or avoid transfusion dependence in these patients. The present report provides a detailed comparative profile of long-term PRBC transfusions and the balance of clinical benefits versus risks associated with ESA therapy for MDS.

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Anticancer Res. 2007 Jul-Aug;27(4A):1745-57.
Preclinical and clinical effects of erythropoietin in the management of anaemia in patients with non-small cell lung cancer.
Dempke W.
TTG Bochum, Universitaetsstrasse 142, D-44799 Bochum, Germany. wolfram.dempke@bms.com

The myelosuppressive toxicities of chemotherapy are one of the principle reasons for the overall failure of some agents to have a meaningful impact on responses and survival in cancer, and anaemia is a common side-effect of almost all cytostatic drugs used clinically. As regulators of haematopoietic homeostasis, cytokines mediate cellular proliferation, differentiation and survival. Among the various growth factors currently available, erythropoietin (EPO) is the principle factor responsible for the regulation of red blood cell production during steady-state conditions and for accelerating recovery following cytostatic bone marrow depletion. Many studies have provided evidence that EPO is able to correct and to prevent anaemia in approximately 64% of cancer patients with subsequent reduction of blood transfusion requirement. Among the prognostic factors for survival in patients with advanced non-small cell lung cancers (NSCLC), anaemia is associated with reduced response rates and quality of life, and a poorer prognosis. Recently, some studies suggest a possible relationship between increased haemoglobin levels and survival in NSCLC patients. Furthermore, there is evidence that NSCLC patients with high haemoglobin levels have a better outcome after radio- or chemotherapy. Although the highest rate of transfusion-dependent patients (34%) has been observed in patients suffering from NSCLC, there are no universally accepted guidelines addressing the most effective methods of monitoring NSCLC patients for anaemia. Thus, further randomized, controlled trials are needed to evaluate the effect of any therapeutic intervention against anaemia on survival and disease control in patients with NSCLC.

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Int J Gynecol Cancer. 2007 Jul 21; [Epub ahead of print]
Effects of anemia correction with epoetin beta in patients receiving radiochemotherapy for advanced cervical cancer.
Strauss HG, Haensgen G, Dunst J, Hayward CR, Burger HU, Scherhag A, Koelbl H.
Departments of Gynecology and Radiotherapy, Martin Luther University Halle-Wittenberg, Halle, Germany.

Patients with cervical cancer frequently suffer from anemia. This two-stage, adaptive-design study investigated the effect of anemia correction with epoetin beta on treatment outcomes. Patients with stage IIB-IVA cervical cancer received radiochemotherapy (RCT) and were randomized to epoetin 150 IU/kg three times weekly (n = 34) or standard care (control; n = 40) for up to 12 weeks. Primary end point for stage 1 aimed to establish a correlation between anemia correction and treatment failure (no complete response or relapsing within 6 months after RCT initiation) as a proof of concept before moving into stage 2. Secondary end points included progression/relapse-free survival, overall survival, response to RCT, hemoglobin (Hb) response, and safety. Median baseline Hb was 11.4 and 11.6 g/dL in epoetin and control groups, respectively. At treatment end point, median Hb increased by 1.3 g/dL with epoetin, but decreased by 0.7 g/dL in the control group (P < 0.0001). No significant correlation between Hb increase and treatment failure was demonstrated. There were no significant differences between epoetin and control groups in progression/relapse-free survival (29.4% vs 32.5% patients with events; P = 0.96), overall survival (23.5% vs 12.5% patients with events; P = 0.22) or overall complete response (53% vs 58%; P = 0.86). Adverse events were well matched between groups. This study shows that epoetin beta rapidly, effectively, and safely increases Hb levels in patients with cervical cancer receiving RCT. No positive correlation of Hb increase and improvement in clinical outcomes could be demonstrated.

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Nephrol Dial Transplant. 2007 Jul 27; [Epub ahead of print]
Epoetin delta in the management of renal anaemia: results of a 6-month study.
Martin KJ; on behalf of the Epoetin Delta 3001 Study Group.
Division of Nephrology, Saint Louis University, St Louis, MO, USA.

BACKGROUND: Epoetin delta is an epoetin that, unlike existing agents, is produced in a human cell line. The present study investigated the efficacy and tolerability of intravenous (i.v.) epoetin delta compared with i.v. epoetin alfa. METHODS: This was a 6-month, multicentre, randomized, double-blind trial in haemodialysis patients previously receiving epoetin alfa. Haematological parameters were assessed, and adverse events monitored. Equivalent efficacy was defined as a difference in mean haemoglobin between the two agents over weeks 12-24 of </= 1 g/dl with a 90% confidence interval (CI) within the range -1 to 1 g/dl. RESULTS: In total, 560 patients received epoetin delta while 192 received epoetin alfa, and 76.8% and 79.7% of patients, respectively, completed the study. Both agents showed similar efficacy in controlling anaemia: the point estimate for the difference in mean haemoglobin over weeks 12-24 was 0.01 g/dl (90% CI, -0.13, 0.15 g/dl), confirming equivalence. Adverse events were those expected in dialysis patients. Events possibly related to treatment occurred in 9.2% of patients receiving epoetin delta and 8.4% receiving epoetin alfa. Serious adverse events (SAEs) occurred in 33.0% and 26.7% of patients in the epoetin delta and epoetin alfa groups, respectively. Six patients in the epoetin delta group experienced an SAE considered possibly related to treatment (mostly access-related clotting), compared with no patient in the epoetin delta group. None of these SAEs were life threatening. CONCLUSIONS: Epoetin delta was shown to have an equivalent efficacy and safety profile to epoetin alfa in this 6-month study.

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Acta Obstet Gynecol Scand. 2007;86(8):957-62.
Erythropoietin and intravenous iron therapy in postpartum anaemia.
Wågström E, Akesson A, Van Rooijen M, Larson B, Bremme K.
Department of Obstetrics and Gynecology, South Stockholm General Hospital, Stockholm, Sweden.

Background. We assessed whether recombinant human erythropoietin (rhEPO) enhances a rise in haemoglobin concentration in postpartum anaemia compared to intravenous iron alone. Design. Some 60 patients with haemoglobin values</=80 g/l were randomized within 72 h after parturition into 3 different treatment groups. All 3 groups were given a total dose of 450 mg intravenous iron sucrose. In addition, 2 groups were given 20,000 or 40,000 U of total rhEPO. All treatments were given on 2 occasions with an interval of 3 days (day 0 and 3). Results. Haemoglobin increased significantly in all 3 groups over time (p<0.001), and there were no differences between the different treatment groups on any day of evaluation (p=0.59). The total mean increment in haemoglobin in all subjects was 18 g/l after 1 week, and 28 g/l after 2 weeks. Conclusion. In comparison to intravenous iron alone, the addition of rhEPO did not further increase haemoglobin concentration in women with postpartum anaemia.

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Best Pract Res Clin Anaesthesiol. 2007 Jun;21(2):221-39.
Alternatives to allogeneic blood transfusions.
Pape A, Habler O.
Clinic of Anoesthesiology, Intensive Care Medicine and Pain Management, J. W. Goethe University Hospital Frankfurt am Main, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany. a.pape@em.uni-frankfurt.de

Inherent risks and increasing costs of allogeneic transfusions underline the socioeconomic relevance of safe and effective alternatives to banked blood. The safety limits of a restrictive transfusion policy are given by a patient's individual tolerance of acute normovolaemic anaemia. latrogenic attempts to increase tolerance of anaemia are helpful in avoiding premature blood transfusions while at the same time maintaining adequate tissue oxygenation. Autologous transfusion techniques include preoperative autologous blood donation (PAD), acute normovolaemic haemodilution (ANH), and intraoperative cell salvage (ICS). The efficacy of PAD and ANH can be augmented by supplemental iron and/or erythropoietin. PAD is only cost-effective when based on a meticulous donation/transfusion plan calculated for the individual patient, and still carries the risk of mistransfusion (clerical error). In contrast, ANH has almost no risks and is more cost-effective. A significant reduction in allogeneic blood transfusions can also be achieved by ICS. Currently, some controversy regarding contraindications of ICS needs to be resolved. Artificial oxygen carriers based on perfluorocarbon (PFC) or haemoglobin (haemoglobin-based oxygen carriers, HBOCs) are attractive alternatives to allogeneic red blood cells. Nevertheless, to date no artificial oxygen carrier is available for routine clinical use, and further studies are needed to show the safety and efficacy of these substances.

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Curr Opin Nephrol Hypertens. 2007 May;16(3):267-271.
The treatment of anemia in chronic kidney disease: understandings in 2006.
Levin A.
Division of Nephrology, University of British Columbia, St Paul's Hospital, Vancouver, British Columbia, Canada.

PURPOSE OF REVIEW: Anemia is a well recognized complication of chronic kidney disease and is associated with significant morbidity. It is important for clinical care to identify appropriate treatments and targets for hemoglobin. This review describes current understandings of the treatment of anemia using the most recent published articles. RECENT FINDINGS: Numerous studies, including observational and randomized control trials, of varying sizes and using both surrogate and hard outcomes have been published. On balance, there is little to support normalization of hemoglobin in the chronic kidney disease population. While some studies have described harm, there are some issues related to overinterpretation based on study trial reporting. The treatment of anemia can be successfully achieved with the use of oral or intravenous iron and erythropoiten-stimulating agents. Caution should be exercised when treating those with significant cardiovascular morbidity, and those who require very high doses of erythropoiten-stimulating agents to achieve normal hemoglobin. SUMMARY: Large observational population-based studies continue to demonstrate the association of low hemoglobin with adverse outcomes, and randomized control trials fail to show a benefit of normalized hemoglobin. Anemia therapy does improve quality of life. In the current era of aggressive chronic kidney disease management, it does not appear that anemia therapy attenuates left ventricular growth or changes cardiovascular outcomes.

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Acta Anaesthesiol Scand. 2007 May;51(5):565-569.
Transfusion of red blood cells: no impact on length of hospital stay in moderately anaemic parturients.
Palo R, Ahonen J, Salo H, Salmenpera M, Krusius T, Maki T.
Hospital District of Helsinki and Uusimaa, Department of Anaesthesia and Intensive Care, Helsinki University Hospital, Helsinki, Finland.

Background: In a search for information to improve decision making on red blood cell (RBC) transfusion, we examined the impact of RBC transfusion on the length of hospital stay for delivery in moderately anaemic women (haemoglobin, 7-10 g/dl). Methods: This was a retrospective, observational study covering 2 years (2002 and 2003), and included major blood-transfusing hospitals from four university and five central hospital districts managing 67.5% of Finnish in-hospital deliveries. The impact of the transfusion of 1-2 RBC units vs. no transfusion on the length of hospital stay was evaluated for three different haemoglobin levels: 7-7.9, 8-8.9 and 9-10 g/dl. Results: Of the 1954 moderately anaemic mothers in hospital for delivery, 13.3% were transfused with RBC. The mean length of hospital stay was 5.2 days vs. the average Finnish hospital delivery stay of 3.5 days. No differences in stay were found between patients with comparable anaemia transfused with 1-2 RBC units or none (at the three haemoglobin levels: P= 0.50, P= 0.07 and P= 0.54, respectively). The final haemoglobin value was higher (P < 0.001) in transfused patients. Conclusion: The duration of admission for delivery in moderately anaemic parturients was longer than the average length of hospital stay in Finnish parturients. However, 1-2 RBC units had no impact on the length of stay, suggesting that unnecessary RBCs are transfused after delivery. Thus, transfusion practices in obstetrics are not always optimal.

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Support Care Cancer. 2007 Apr 13; [Epub ahead of print]
Correlation between variation in quality of life and change in hemoglobin level after treatment with epoetin alfa 40,000 IU administered once-weekly.
Carteni G, Giannetta L, Ucci G, De Signoribus G, Vecchione A, Pinotti G, Puglisi F, Contillo A, Pezzella G, Orecchia S, Beccaglia P; OBI/EPO-ITA-01/1 study group .
Department of Medical Oncology, Cardarelli Hospital, Via Cardarelli, 9, 80131, Napoli, Italy, giacomo.carteni@ospedalecardarelli.it.

INTRODUCTION: Anemia is frequently associated with cancer due to the disease itself and antineoplastic treatments. This open-label, uncontrolled, multi-center study evaluated the effects of once-weekly (qw) epoetin alfa 40,000 IU on hemoglobin (Hb) levels and quality of life (QoL) in anemic patients receiving chemotherapy for solid tumors. MATERIALS AND METHODS: A total of 522 patients with Hb level </=12 g/dL received epoetin alfa 40,000 IU qw subcutaneously for 9-20 weeks to reach and maintain Hb range of 12-14 g/dL. QoL was assessed with the Functional Assessment of Cancer Therapy-Anemia (FACT-An [anemia sub-scale]) and Cancer Linear Analogue Scale (CLAS) at study entry, after two chemotherapy cycles, and at study end. RESULTS: Mean baseline Hb was 10.43 g/dL. Hb increases (g/dL) from baseline after 4, 8, 12 weeks and at study end were 1.07, 1.77, 1.92 and 1.71 g/dL, respectively. Response rates (Hb increase >/=1 and >/=2 g/dL during trial) were 81% and 61%, respectively. Mean increases in the FACT-An score from baseline (mean 55.4) were 3.1 after two chemotherapy cycles and 3.3 at study end; mean increases in the CLAS score from baseline (58.4 mm) were 5.9 mm after two chemotherapy cycles and 6.5 mm at study end. DISCUSSION: The greatest QoL increase was recorded when patients approached Hb level of 12 g/dL, independent of the baseline Hb level. Hb changes from baseline to trial end were related to corresponding changes in the FACT-An score. A positive correlation was also observed in patients with progressive disease. Adverse events were essentially those associated with chemotherapy. Incidence of thrombovascular events (6.7%) did not differ from the expected standard treatment in cancer patients. Epoetin alfa 40,000 IU qw increased Hb levels and improved or preserved QoL.

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Am J Gastroenterol. 2007 Apr;102(4):880-9.
Strategies for managing anemia in hepatitis C patients undergoing antiviral therapy.
McHutchison JG, Manns MP, Brown RS Jr, Reddy KR, Shiffman ML, Wong JB.
Duke Clinical Research Institute, Division of Gastroenterology Duke University, Durham, North Carolina, USA.

Anemia is a common side effect that begins soon after the initiation of peginterferon/ribavirin in the treatment of hepatitis C virus (HCV) infection. It can cause symptoms that negatively impact quality of life (QOL) and is the most common reason for reducing the dose and temporarily or permanently discontinuing ribavirin. Such dose modifications have been shown to reduce the efficacy of treatment. Administering erythropoietin can improve anemia caused by peginterferon and ribavirin therapy and is more effective than dose reduction at improving QOL during treatment. However, erythropoietin, which is not approved by the U.S. Food and Drug Administration (FDA) for use in patients with HCV infection, adds another parenteral drug to the patient's treatment regimen, and is associated with additional costs, inconvenience, and potential side effects. A new ribavirin analog, viramidine, is expected to be associated with a lower incidence of anemia and, if proven effective, may eventually be substituted for ribavirin in combination with peginterferon to treat chronic hepatitis C. In the meantime, physicians must make the best possible use of the available options for managing anemia, especially in select patient groups who are most at risk for anemia and its complications.

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Neonatology. 2007 Apr 10;92(3):174-181 [Epub ahead of print]
Myocardial Adaptation to Anemia and Red Blood Cell Transfusion in Premature Infants Requiring Ventilation Support in the 1st Postnatal Week.
Cambonie G, Matecki S, Milesi C, Voisin M, Guillaumont S, Picaud JC.
Neonatal Intensive Care Unit, Arnaud de Villeneuve Hospital, University Hospital Centre of Montpellier, Montpellier, France.

Background: Although transfusion practice in very premature infants is becoming more restrictive, little is known about myocardial adaptation to anemia during the 1st postnatal week. Objectives: To determine the central hemodynamic effects of anemia and red blood cell transfusion in very preterm infants undergoing intensive care. Methods: Twenty-nine neonates of less than 30 weeks gestational age were treated for respiratory distress syndrome, following a strict protocol. Echocardiographies were performed at the 4th and 6th postnatal days, which corresponded to, respectively, just before and 48 h after an erythrocyte transfusion of 15 ml/kg in the 12 anemic infants. Results: Anemic infants had increased stroke volume [2.1 (1.8-2.3) vs. 1.5 (1.3-1.6) ml/kg] and left ventricular (LV) output [312 (271-345) vs. 206 (177-240) ml/min/kg]. The relationship of the heart rate-corrected velocity of circumferential fiber shortening to LV end-systolic meridional wall stress indicated a higher contractile state in the anemic infants, with a higher y-intercept (p = 0.03) and a steeper slope (p = 0.05) of the regression line than in the nonanemic patients. Posttransfusion, the stroke volume, LV output, shortening fraction, and contractile state decreased to the values observed in the nonanemic infants. Conclusions: Myocardial contractility was a major component of the circulatory adjustments in the anemic premature infants requiring ventilation support in the early neonatal period. Changes in LV performance associated with anemia were reversed by transfusion with no detrimental effect on right ventricular function, LV preload or the respiratory status of these patients. Copyright (c) 2007 S. Karger AG, Basel.

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Med Klin (Munich). 2007 Apr;102(4):309-316.
[Current Therapeutic Strategies in the Management of Acute Myeloid Leukemia.]
[Article in German]
Fiegl M, Hiddemann W, Braess J.

Acute myeloid leukemia (AML) is a rare disease of the hematopoietic stem cell leading to uncontrolled proliferation of immature progenitor cells. This results in a replacement of healthy hematopoiesis and in pancytopenia with corresponding symptoms (anemia, thrombo- and granulocytopenia). Diagnosis can reliably be confirmed by bone marrow aspiration, which also allows risk stratification by cytogenetic and molecular analysis.Therapy of AML that should preferentially be performed in clinical studies comprises induction therapy for achievement of complete cytomorphological remission (CR) and postremission strategies consisting of consolidation and maintenance therapy for eradication of residual blasts. The backbone of polychemotherapy is cytarabine and anthracyclines. Different regimens exist that achieve CR rates of 60-80%. As a consequence, pancytopenias up to 6 weeks will be experienced, that will lead to specific problems such as infections by atypical pathogens.To date, induction therapy will be performed independently of the individual risk constellation (with the exception of acute promyelocytic leukemia); however, postremission therapy is highly dependent on individual risk stratification. Besides conventional strategies, allogeneic stem cell transplantation has to be considered in certain risk groups depending on the availability of a matched donor. Taken together, cure can be achieved in about 40% of patients, however, with large interindividual variability.

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Acta Haematol. 2007 Apr 10;118(1):19-26 [Epub ahead of print]
Decreased Treatment Failure Rates following Duodenal Release Ferrous Glycine Sulfate in Iron Deficiency Anemia Associated with Autoimmune Gastritis and Helicobacter pylori Gastritis.
Hershko C, Ianculovich M, Souroujon M.
Department of Hematology, Shaare Zedek Medical Center, Jerusalem, Israel.

Background and Objectives: Since gastric acidity and ascorbate play a critical role in the solubilization and reduction of iron for subsequent absorption, the achlorhydria associated with autoimmune and Helicobacter pylori gastritis may explain the poor response of such patients to oral iron treatment. In order to circumvent this problem, we explored the therapeutic potential of a duodenal formulation of ferrous glycine sulfate consisting of micropellets that do not dissolve at the acid environment of the stomach but, owing to their solubility at a higher pH, discharge their content directly into the duodenum. Design and Methods: In a case-control study, the treatment results of 39 patients with iron deficiency anemia receiving a duodenal formulation of ferrous glycine sulfate (group A) were compared with the results of 39 patients receiving other oral iron compounds (group B). Autoimmune gastritis, H. pylori gastritis or both were present in over 75% of patients in each group. Results: After 1 and 3 months of treatment, mean hemoglobin in group A increased from 9.5 +/- 1.2 to 11.2 +/- 1.3 and 12.8 +/- 1.3 g/dl, respectively. By comparison, in group B, the corresponding values increased from 9.3 +/- 1.3 to 10.2 +/- 1.5 (p = 0.019) and 11.1 +/- 1.7 g/dl (p = 0.022). A favorable response, defined as a more than 2 g/dl increase in basal hemoglobin or hemoglobin exceeding 12 g/dl, was obtained in 33 of 39 patients in group A compared with only 18 of 39 in group B (p = 0.009). Because of treatment failure, 14 patients in group B were subsequently referred for intravenous ferric sucrose therapy versus only 3 in group A (p < 0.0001). Conversely, of 5 patients in group A managed by intravenous iron prior to referral, 4 became independent of parenteral iron after starting the duodenal formulation of ferrous glycine sulfate. Interpretation and Conclusions: In patients with iron deficiency anemia associated with autoimmune and H. pylori gastritis with a high rate of refractoriness to oral iron treatment, satisfactory response to a duodenal formulation of ferrous glycine sulfate can be elicited in the vast majority of cases, obviating the need for expensive, inconvenient and occasionally risky intravenous iron administration. Copyright (c) 2007 S. Karger AG, Basel.

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Health Technol Assess. 2007 Apr;11(13):1-220.
A systematic review and economic evaluation of epoetin alfa, epoetin beta and darbepoetin alfa in anaemia associated with cancer, especially that attributable to cancer treatment.
Wilson J, Yao GL, Raftery J, Bohlius J, Brunskill S, Sandercock J, Bayliss S, Moss P, Stanworth S, Hyde C.
Department of Public Health and Epidemiology, University of Birmingham, UK.

OBJECTIVES: To assess the effectiveness and cost-effectiveness of epoetin alfa, epoetin beta and darbepoetin alfa (referred to collectively in this report as epo) in anaemia associated with cancer, especially that attributable to cancer treatment. DATA SOURCES: Electronic databases were searched from 2000 (1996 in the case of darbepoetin alfa) to September 2004. REVIEW METHODS: Using a recently published Cochrane review as the starting point, a systematic review of recent randomised controlled trials (RCTs) comparing epo with best standard was conducted. Inclusion, quality assessment and data abstraction were undertaken in duplicate. Where possible, meta-analysis was employed. The economic assessment consisted of a systematic review of past economic evaluations, an assessment of economic models submitted by the manufacturers of the three epo agents and development of a new individual sampling model (the Birmingham epo model). RESULTS: In total 46 RCTs were included within this systematic review, 27 of which had been included in the Cochrane systematic review. All 46 trials compared epo plus supportive care for anaemia (including transfusions), with supportive care for anaemia (including transfusions), alone. Haematological response (defined as an improvement by 2 g/dl) had a relative risk of 3.4 [95% confidence interval (CI) 3.0 to 3.8, 22 RCTs] with a response rate for epo of 53%. The trial duration was most commonly 16-20 weeks. There was little statistical heterogeneity in the estimate of haematological response, and there were no important differences between the subgroups examined. Haemoglobin (Hb) change showed a weighted mean difference of 1.63 g/dl (95% CI 1.46 to 1.80) in favour of epo. Treatment with erythropoietin in patients with cancer-induced anaemia reduces the number of patients who receive a red blood cell transfusion (RBCT) by an estimated 18%. Health-related quality of life (HRQoL) data were analysed using vote counting and qualitative assessment and a positive effect was observed in favour of an improved HRQoL for patients on epo. Published information on side-effects was of poor quality. New trials provided further evidence of side-effects with epo, particularly thrombic events, but it is still unclear whether these could be accounted for by chance alone. The results of the previous Cochrane review had suggested a survival advantage for epo (HR 0.84, 95% CI 0.69 to 1.02), based on 19 RCTs. The update, based on 28 RCTs, suggests no difference (HR 1.03, 95% CI 0.88 to 1.21). Subgroup analysis suggested some explanations for this heterogeneity, but it is difficult to draw firm conclusions without access to the substantial amounts of missing or unpublished data, or more detailed results from some of the trials with heterogeneous patient populations. The conclusions are, however, broadly in line with those of a Food and Drug Administration (FDA) safety briefing, which recommended that patients with a haemoglobin above 12 g/dl should not be treated; the target rate of rise in Hb should not be too great, and further carefully conducted trials are required to determine which subgroups of patients may be harmed by the use of these products, in particular through the stimulation of tumour activity. Five published economic evaluations identified from the literature had inconsistent results, with estimates ranging from a cost per quality-adjusted life-year (QALY) under pound10,000 through to epo being less effective and more costly than standard care. The more favourable evaluations assumed a survival advantage for epo. The three company models submitted each relied on assumed survival gains to achieve relatively low cost per QALY, from pound13,000 to pound28,000, but generated estimates from pound84,000 to pound159,000 per QALY when no survival gain was assumed. Each of these models relied on Hb levels alone driving utility, and each assumed gradual normalisation of Hb in the standard treatment arm after the end of treatment. The Birmingham epo model followed the company models in regard to the relationship between Hb levels and utility, and also assumed normalisation in the base case. With no survival gain, the incremental cost per QALY was pound150,000, falling to pound40,000 when the lower, more favourable, confidence interval for survival was used. CONCLUSIONS: Epo is effective in improving haematological response and reducing RBCT requirements, and appears to have a positive effect on HRQoL. The incidence of side-effects and effects on survival remains highly uncertain. However, if there is no impact on survival, it seems highly unlikely that epo would be considered a cost-effective use of healthcare resources. The main target for further research should be improving estimates of impact on survival, initially through more detailed secondary research, such as the individual patient data meta-analysis started by the Cochrane group. Further trials may be required, and have been recommended by the FDA, although many trials are in progress, completed but unreported or awaiting mature follow-up. The Birmingham epo model developed as part of this project contains new features that improve its flexibility in exploring different scenarios; further refinement and validation would therefore be of assistance. Finally, further research to resolve uncertainty about other parameters, particularly quality of life, adverse events, and the rate of normalisation, would also be beneficial.

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J Thorac Oncol. 2007 Mar;2(3):210-20.
A randomized trial comparing immediate versus delayed treatment of anemia with once-weekly epoetin alfa in patients with non-small cell lung cancer scheduled to receive first-line chemotherapy.
Crawford J, Robert F, Perry MC, Belani C, Williams D; Anemia Prevention in NSCLC Group.
Duke Medical Center, Durham, NC 27710, USA. crawf006@mc.duke.edu

INTRODUCTION: This study evaluated the safety/efficacy of once-weekly (QW) epoetin alfa measured by quality of life (QOL), hemoglobin (Hb), transfusion incidence, tumor response, and survival in patients with chemotherapy-naive, advanced non-small cell lung cancer (NSCLC). METHODS: Stage IIIB/IV NSCLC patients with Hb > or = 11 to < 15 g/dl scheduled for at least 8 weeks of first-line chemotherapy were randomized to subcutaneously receive 40,000 U of epoetin alfa QW at chemotherapy initiation (immediate) or no epoetin alfa unless Hb decreased to < or = 10 g/dl (delayed). The primary efficacy variable was change in QOL for immediate versus delayed intervention. Target accrual was 320 patients. RESULTS: The study was terminated early because of slow accrual; of 216 patients enrolled, 211 were evaluable for efficacy. Hb was maintained in the immediate group, but it decreased in the delayed group (12.9 versus 11.6 g/dl final values, respectively). Numerically, fewer immediate patients required transfusions versus delayed patients. Mean QOL scores, modestly declining in both groups from baseline to final measurement, were not significantly different between groups. Tumor response and median overall survival were similar between groups. Epoetin alfa was well tolerated, with a similar thrombovascular event rate between groups. CONCLUSION: Epoetin alfa in subcutaneous doses of 40,000 U QW, given immediately at chemotherapy initiation for advanced NSCLC, was well tolerated, and it effectively maintained Hb, leading to a reduced transfusion incidence versus delayed epoetin alfa. Overall QOL scores were higher than typical in this population, decreasing slightly during treatment in both groups. Overall survival was similar between groups, with no evidence of a negative effect by early epoetin alfa intervention.

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Cad Saude Publica. 2007 Feb;23(2):269-81.
[Effect of food fortification with iron on childhood anemia: a review study.]
[Article in Portuguese]
Assuncao MC, Santos IS.
Faculdade de Nutricao, Universidade Federal de Pelotas, Pelotas, Brasil.

A systematic review was conducted to identify studies assessing the effect of food fortification with iron on childhood anemia. The MEDLINE, LILACS, and PubMed databases and WHO and PAHO sites were searched with no time limitation, including articles published in Portuguese, English, or Spanish, using the following key words and their combination: food fortification, iron, effectiveness, efficacy, anemia, flour, staple foods, interventions, and children. Of 21 studies reviewed, only one failed to report a positive, favorable effect of iron fortification, indicating the possibility of publication bias. The studies showed important methodological limitations. The two studies with the best methodological scores showed opposite results, highlighting the need for larger trials with better planning to explore this hypothesis.

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Br J Haematol. 2007 Jan 11; [Epub ahead of print]
Effect of myeloablative bone marrow transplantation on growth in children with sickle cell anaemia: results of the multicenter study of haematopoietic cell transplantation for sickle cell anaemia.
Eggleston B, Patience M, Edwards S, Adamkiewicz T, Buchanan GR, Davies SC, Dickerhoff R, Donfield S, Feig SA, Giller RH, Haight A, Horan J, Hsu LL, Kamani N, Lane P, Levine JE, Margolis D, Moore TB, Ohene-Frempong K, Redding-Lallinger R, Roberts IA, Rogers ZR, Sanders JE, Scott JP, Sleight B, Thompson AA, Sullivan KM, Walters MC; for the Multicenter Study of HCT for SCA*.
Blood and Marrow Transplantation Program, Children's Hospital and Research Center, Oakland, CA, USA.

Although haematopoietic cell transplantation (HCT) is curative for sickle cell anaemia (SCA), concerns about its short- and long-term toxicities limit its application. A potential toxicity is an adverse effect on growth. To identify an HCT growth effect, serial height and weight measurements from 53 children and adolescents with SCA after receiving a transplant were compared to historical controls. Hierarchical Linear Models for longitudinal data were used for analysis. In general growth was not impaired by HCT for SCA in young children; however, diminished growth may occur if HCT is carried out near or during the adolescent growth spurt.

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Br J Haematol. 2007 Jan 10; [Epub ahead of print]
An update on the management of severe idiopathic aplastic anaemia in children.
Davies JK, Guinan EC.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

The current outlook for a child with severe idiopathic aplastic anaemia (AA) is very much better than in previous decades. In part, this may reflect better differentiation of idiopathic and inherited marrow failure. For children with idiopathic AA and a human leucocyte antigen (HLA)-matched sibling donor (MSD), allogeneic haematopoietic stem-cell transplantation (AHSCT) is the primary therapy of choice, offering long-term disease-free survival of 90%, although graft-versus-host disease remains a cause of long-term morbidity. A greater treatment challenge remains for those children without a MSD. Combination immunosuppressive therapy (IST) is associated with response rates of 70% or more. However, relapse and clonal evolution with transformation to myelodysplasia or acute myeloid leukaemia remain significant problems after IST and long-term event-free survival rates are less impressive. For children who do not have a sustained response to IST, alternate donor AHSCT should be considered. New HLA typing technologies, novel stem cell sources, reduced-intensity conditioning and graft engineering have reduced toxicity and improved the outcome after alternate donor AHSCT. Emerging therapies that capitalise on recent advances in our understanding of the pathophysiology of idiopathic AA and the immunobiology of AHSCT and IST may further improve the long-term outcome of this disease.

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Pediatr Nephrol. 2007 Jan 6; [Epub ahead of print]
Iron therapy for renal anemia: how much needed, how much harmful?
Horl WH.
Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Wahringer Gurtel 18-20, 1090, Vienna, Austria, walter.hoerl@meduniwien.ac.at.

Iron deficiency is the most common cause of hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) in end-stage renal disease (ESRD) patients. Iron deficiency can easily be corrected by intravenous iron administration, which is more effective than oral iron supplementation, at least in adult patients with chronic kidney disease (CKD). Iron status can be monitored by different parameters such as ferritin, transferrin saturation, percentage of hypochromic red blood cells, and/or the reticulocyte hemoglobin content, but an increased erythropoietic response to iron supplementation is the most widely accepted reference standard of iron-deficient erythropoiesis. Parenteral iron therapy is not without acute and chronic adverse events. While provocative animal and in vitro studies suggest induction of inflammation, oxidative stress, and kidney damage by available parenteral iron preparations, several recent clinical studies showed the opposite effects as long as intravenous iron was adequately dosed. Thus, within the recommended international guidelines, parenteral iron administration is safe. Intravenous iron therapy should be withheld during acute infection but not during inflammation. The integration of ESA and intravenous iron therapy into anemia management allowed attainment of target hemoglobin values in the majority of pediatric and adult CKD and ESRD patients.

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Aliment Pharmacol Ther. 2006 Dec;24(11-12):1507-23.
Systematic review: managing anaemia in Crohn's disease.
Kulnigg S, Gasche C.
Department of Medicine, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.

BACKGROUND: Anaemia is a serious complication of Crohn's disease that triggers hospitalization and, if not interfered with, may lead to death. AIMS: To systematically summarize and compare the literature on anaemia in Crohn's disease. METHODS: For this systematic review the literature was searched for English-language articles using anaemia, Crohn* and IBD as key words. 144 articles were identified and sorted according to the following topics: prevalence, aetiology, diagnostic tests and therapy. RESULTS: The reported prevalence of anaemia varied between 6.2% and 73.7%, with higher reported frequencies in older studies and in in-patients. Iron deficiency is the most common underlying condition. Vitamin B12 deficiency is related to the extent of ileal resection but has rarely impact on anaemia. Diagnostic criteria are not established and treatment guidelines are missing. Oral iron supplementation seems effective for short periods but intolerance leads to discontinuation in up to 21%. Eleven of 11 studies show that oral iron enhances intestinal inflammation and colon carcinogenesis in animal models of colitis. Intravenous iron supplementation with iron sucrose has been tested in over 250 Crohn's disease patients, is safe, effective and does not carry such hazards. CONCLUSIONS: As disease activity is determining the degree of anaemia in Crohn's disease, implementation of more effective therapy for Crohn's disease will lower its incidence. However, further studies regarding the safety and effectiveness of iron supplementation are needed.

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Nephrology (Carlton). 2006 Dec;11(6):542-8.
Renal anaemia: Recent developments, innovative approaches and future directions for improved management (Review Article).
Kerr PG.
Department of Nephrology, Monash Medical Centre, Melbourne, Victoria, Australia.

The morbidity, mortality and economic burden of chronic kidney disease (CKD) and associated anaemia are substantial. With the increasing numbers of patients who are likely to be affected in the future, approaches are required to improve anaemia management without increasing the burden on health-care professionals. A multidisciplinary approach to treatment, where early initiation of erythropoiesis-stimulating agents (ESA) is encouraged, may improve patient outcomes. Recent studies also suggest that the early use of iron therapy in patients with CKD not on dialysis may be associated with beneficial effects on haemoglobin levels. Another strategy to reduce the burden on health-care providers is to simplify anaemia management by extending the administration interval of ESA. Indeed, recent studies have explored the efficacy of extending the administration interval of ESA in clinical practice in CKD patients on dialysis and not on dialysis. The ability to maintain haemoglobin levels within guideline ranges at extended administration intervals may improve patient care and reduce the workload of health-care providers.

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