Use Of Erythropoietic Stimulating Agents Research Articles

Does G6PD-Deficiency Related Oxidative Stress and Hemolysis Affect Erythroid Response to Erythropoietic Stimulating Agents (ESA) in Myelodysplastic Patients?

Background: Anemia is the most frequent cytopenia in Myelodysplastic Syndrome (MDS). Epoetin alfa, Epoetin beta and Darbepoetin alfa (ESA) have been investigated in several studies as useful to treat anemia in this category of patients. Available preclinical data support oxidative stress and hemolysis contributing to ESA resistance but not clinical data is today available. G6PD deficiency is an X-linked condition characterized by a markedly reduced capability to protect red blood cells from oxidative stresses. In the island of Sardinia the prevalence is reported to be as high as 12%. Patients and Methods: We retrospectively analyzed all MDS patients who had received ESA in our centre. Diagnosis of MDS was made according to WHO criteria. Patients were stratified based on International Prognostic Scoring System (IPSS). At diagnosis baseline EPO level and G6PD quantitative estimation were detected. G6PD deficiency was defined as an enzyme dosage of less than 0.96 UI/g of Hb in the peripheral blood. Red blood cell (RBC) transfusions requirement before starting treatment was evaluated. Erythroid hematologic improvement (HI-E) was evaluated according to the International Working Group (IWG) response criteria ( Cheson et al JCO 2006). Results: Thirty patients met the above specified criteria. Table 1 showed patients’ characteristics. Of them 7 were G6PD-defiecient and 23 had normal G6PD level values. Twenty four patients (80%) achieved an HI-E (14 major and 10 minor). In the G6PD-deficient group HI-E was observed in 7 over 7 patients ( major in 4 and minor in 3). In the control group HI-E was observed in 17 over 23 patients (major in 10 minor in 7). (P= 0.29). Conclusions: We evaluated 30 MDS lowrisk and Int I IPSS patients who received ESA in the last 20 years in our centre. Despite the common belief that oxidative stress and hemolysis may contribute to ESA resistance, no statistically significant difference to potentially resistance to ESA treatment in G6PD deficiency have been observed. We conclude that G6PD-deficiency does not contraindicate the use of ESA in this setting of patients.

New paradigms for managing preoperative anemia

To the Editor, In the Continuing Professional Development article, Assessment and treatment of preoperative anemia, Hare et al. present very interesting concepts and hypotheses. Despite the important concepts, implementation of the proposed protocol would inevitably result in delays as well as logistical and financial implications related to the supervised administration of intravenous iron and erythropoietic stimulating agents (ESAs). Also, it is questionable whether the evidence is sufficiently strong to incorporate the proposed protocol into routine clinical practice. The protocol in the article appears to be based on the Network for Advancement of Transfusion Alternatives (NATA) guidelines, which were directed specifically toward elective orthopedic surgical patients. The authors of the NATA guidelines made five recommendations graded as strong or weak according to the risk/benefit ratio, and they classified the respective quality of evidence as high, moderate, or low/very low. There are three strong recommendations regarding the timing of testing, laboratory tests, and the treatment of nutritional deficiency anemia, yet the recommendations are based on low/very low-quality evidence. Also, a weak recommendation regarding the target hemoglobin level is based on low/very low-quality evidence. The only recommendation based on high-quality evidence is the final weak recommendation regarding the use of ESAs in anemia where nutritional deficiency has been ruled out. The same group also produced a consensus statement regarding the use of intravenous iron wherein they concluded that intravenous iron may be indicated in the perioperative period in orthopedic patients who are expected to develop severe postoperative anemia. Again, this is a weak recommendation based on moderate/ lowquality evidence, and no evidence-based recommendations could be made for other types of surgery. With regard to the use of ESAs in cancer patients, the European Medicines Agency recommends that transfusion be the preferred method for correcting anemia in cancer patients, especially those with a long life expectancy. The Food and Drug Administration changed the product label for ESAs by adding a black box warning which specifies that ESAs are not indicated to treat cancer-induced anemia in patients not on chemotherapy or in patients with potentially curable cancer. These recommendations were echoed by the American Society of Clinical Oncology clinical practice guidelines.

Anemia and the Use of Erythropoietic-Stimulating Agents with Ruxolitinib in the COMFORT-II Study

Abstract 5147 Background:Ruxolitinib (INC424), a potent and selective oral JAK1 and JAK2 inhibitor, has demonstrated rapid and durable reductions in splenomegaly and improved disease-related symptoms, role functioning, and quality of life in 2 phase 3 studies (the COMFORT studies) in patients with primary myelofibrosis (PMF), post-polycythemia vera-MF (PPV-MF), and post-essential thrombocythemia-MF (PET-MF). Consistent with ruxolitinib's known mechanism of action, anemia was one of the most frequently reported adverse events (AEs) and was generally transient and manageable and led to discontinuation in only one patient. In clinical practice, anemia can be managed with erythropoietic-stimulating agents (ESAs), which promote red blood cell proliferation via cytokine receptors that signal through the JAK pathway. Because these agents act upstream of ruxolitinib in the JAK2 pathway, it is important to determine the effects of these medications on the safety and efficacy of ruxolitinib. Methods:COMFORT-II is an open-label, randomized, multicenter study in patients with MF. Patients were randomized (2:1) to receive ruxolitinib 15 or 20 mg twice daily or best available therapy (BAT; as selected by the investigator). Use of ESAs (eg, darbepoetin alfa, epoetin alfa), although not prohibited, was discouraged for patients randomized to ruxolitinib because they can increase spleen size, which could confound the efficacy analyses. This post hoc analysis evaluates the safety and efficacy of ruxolitinib in patients receiving concomitant ESAs in the COMFORT-II study. Results:Use of ESAs was reported for 9 (PMF, n=6; PET-MF, n=2; PPV-MF, n=1) of the 146 patients who were treated with ruxolitinib (darbepoetin alfa, 1.4% [n=2]; epoetin alfa, 4.8% [n=7]), with a median duration of exposure to ESAs of 22.1 weeks. The median dose intensity of ruxolitinib was numerically higher for patients who received ESAs (+ESA group; 39.2 mg/day) compared with those who did not receive ESAs (–ESA group; 30.0 mg/day). The mean change from baseline in spleen volume at week 48 was similar in both groups (+ESA, –29.8%; –ESA, –30.1%); 44.4% of the +ESA group (4 of 9 patients) and 27.0% of the –ESA group (37 of 137 patients) achieved ≥ 35% reduction in spleen volume from baseline at week 48. The mean number of packed red blood cell units received per month while on treatment was similar in both groups (+ESA, 0.78; –ESA, 0.86). The AEs reported in the +ESA group were similar to those reported in the –ESA group; serious AEs (SAEs) were reported for 4 patients in the +ESA group (patient 1: fracture of the distal radius after a fall; patient 2: urinary tract infection, abdominal pain, and anemia; patient 3: herpes zoster; patient 4: respiratory infection, decrease in general condition, and acute renal insufficiency). SAEs determined to be possibly related to study medication (respiratory infection and decrease in general condition) occurred in 1 patient who discontinued the study; this patient died from respiratory infection. At baseline, patients in the +ESA and –ESA groups had median creatinine levels of 70.2 and 75.4 μmol/L, respectively. Median changes from baseline at week 48 were similar for reticulocytes (+ESA, –13.6%; –ESA, –9.1%) and hemoglobin (+ESA, –5.8%; –ESA, –5.7%). The +ESA group had higher median levels of erythropoietin (39.0 and 7.0 pg/mL) at baseline and a larger increase at week 48 (485.0% and 185.2%). Conclusions:In the COMFORT-II study, ruxolitinib resulted in significant reduction in spleen size compared with BAT in patients with PMF, PPV-MF, or PET-MF. In these analyses, although the sample size is small, the use of ESAs did not appear to affect the efficacy of ruxolitinib concerning spleen size reduction, and no substantially different AEs were reported between patients receiving ESAs and those who did not. Additionally, concomitant use of ESAs may have allowed for an increased dose of ruxolitinib. The use of ESAs for the treatment of anemia is common in clinical practice, and further analyses in combination with ruxolitinib in this patient population are warranted. Disclosures:McMullin:Novartis: Honoraria; Amgen: Honoraria; Bristol Myers: Honoraria. Harrison:Novartis: Honoraria; Incyte: Honoraria; S*Bio: Honoraria; Celgene: Honoraria; Sanofi Aventis: Honoraria. Niederwieser:Novartis: Speakers Bureau. Sirulnik:Novartis: Employment. Wearver:Novartis Pharma AG: Employment. Stalbovskaya:Novartis Pharma AG: Employment. Kiladjian:Novartis: Honoraria; Celgene: Honoraria.

Long‐term prognostic impact of the use of erythropoietic‐stimulating agents in patients with chronic myeloid leukemia in chronic phase treated with imatinib

Anemia is a frequent side effect of imatinib in patients with chronic myeloid leukemia (CML). Erythropoietic-stimulating agents have been used for treatment of imatinib-induced anemia. There are no data on long-term safety of erythropoietic-stimulating agents in CML patients. The records of chronic phase CML patients who received treatment with imatinib were reviewed for use of erythropoietic-stimulating agents and occurrence of thrombotic events. Data on cytogenetic response and survival were analyzed by use of erythropoietic-stimulating agent. A total of 608 patients were included, and 217 patients received erythropoietic-stimulating agents. There were 30 thrombotic episodes. Patients who received erythropoietic-stimulating agents had a higher rate of thrombosis (8.5% vs 2.6%, P = .0025). There was no difference in cytogenetic response rate and survival by use of erythropoietic-stimulating agent. Development of grade 3-4 anemia occurred in 62 (10%) patients and was associated with significantly worse response and survival in patients in late chronic phase. By multivariate analysis, use of erythropoietic-stimulating agents was not a risk factor for event-free survival. In our cohort of chronic phase CML patients, use of erythropoietic-stimulating agents did not impact survival or cytogenetic response rate, but was associated with a higher thrombosis rate. Severe anemia is associated with worse survival and response.

Spanish Society of Medical Oncology consensus on the use of erythropoietic stimulating agents in anaemic cancer patients

Treatment of anaemia is a very important aspect in the management of cancer patients. In order to carry out a consensus process about the use of erythropoietic stimulating agents (ESAs) in cancer patients, the Spanish Society of Medical Oncology (SEOM) elaborated a working group which coordinated a panel of medical oncology specialists. This working group has reviewed the main issues about the use of ESAs. In addition a consensus meeting was held in Madrid on 25 April 2007. The following conclusions were made: Since ESA treatment increases the haemoglobin (Hb) level and decreases the red blood cell (RBC) transfusion requirements, ESAs should be used within the approved indications in patients undergoing chemotherapy treatment, beginning at a Hb level below 11 g/dl and maintaining it around 12 g/dl, with iron supplements if necessary. Neither increasing the ESA dose in nonresponders nor the use of ESAs in the treatment of chronic cancer-related anaemia is recommended.

Guidelines for Epo use in children with cancer

Guidelines for Epo use in children with cancer

Evaluation of Conflicts of Interest in Basic Science Studies Evaluating Erythropoietin and Erythropoietin Effects of Solid Cancer Cell Lines

Studies have found that when investigators have financial relationships with pharmaceutical manufacturers, they are less likely to criticize the safety, efficacy, or cost-effectiveness of agents supplied by the manufacturers. No study has evaluated the possibility of an association between basic science findings and pharmaceutical funding. This is important for erythropoietic stimulating agents (ESAs), where statements from the Centers for Medicaid and Medicaid Services, FDA, the National Comprehensive Cancer Network, the manufacturers, and the European Medicines Agency highlight tumor progression risks when ESAs are administered to anemic cancer patients. Safety signals originated in 2003 when two trials (BEST (breast cancer) and ENHANCE (head and neck cancer)) investigating the off-label use of ESAs in oncology identified increased mortality and tumor progression concerns. We sought to determine the presence or absence of whether there is an association between pharmaceutical industry support and findings related to erythropoietin receptors (EpoR) in solid cancer cell lines.A MEDLINE database search was conducted (Keywords: erythropoietin receptor, EpoR, cancer, tumor). Studies investigating EpoR presence, downstream effects of ESA administration (JAK2, STAT5/bcl, MAPK/ERK, PI3K, AKT, and/or NFkB), and/or stimulatory effects of ESA administration (cytoprotective, mitogenic, and/or invasive) in solid tumors were evaluated. Conflicts of interest, affiliations, and funding sources were abstracted. Of the 73 studies included, 5 studies were conducted by investigators who were employed by ESA manufacturers and 4 studies were conducted with research grants from ESA manufacturers. We defined these as “manufacturer-affiliated” studies. Sixty-four studies were conducted with no disclosures of independent of manufacturer affiliations or funding.Manufacturer-affiliated and non manufacturer-affiliated studies both identified EpoRs in solid cancer cell lines (67% vs 94%), but conflicted studies were less likely to identify downstream effects (JAK2, STAT5/Bclx, PI3, NFkB, AKT, MAPK, ERK) (0% vs 94%), or tumor stimulatory effects (cytoprotection, mitogenic, invasive) (0% vs 73%).Pharmaceutical company sponsorship of EpoR studies is associated with reduced likelihood of identifying EpoRs on tumor cells, downstream effects of Epo on solid cancer cell lines, or Epo stimulatory effects on tumor cell lines. These findings may have implications for other basic science research studies. Only further analyses can confirm or deny these preliminary findings, but the implications are significant and additional studies in this area are warranted.Conflict of InterestNo Conflict of InterestNumber of Studies that Positively DetectedTotal Number of Studies thatNumber of Studies that Positively DetectedTotal Number of Studies that InvestigatedEpoR presenceAntibodyC-20022223M-200156H-1940122m2her1122Other/Unspecified Antibodies342122Labeled Epo1244mRNA352930Total studies that detected EpoR466064Downstream EffectsJAK20079STAT5, Bclx001219PI3K, AKT, NFkB01912MAPK, ERK011114Other (Tyrosine Kinase)01Total studies that detected Downstream Effects023133Stimulatory EffectsCytoprotective021321Mitogenic011221Invasiveness0156Promote angiogenesis01Total studies that detected fects043041

Clinical Practice Guidelines for evidence-based use of erythropoietic-stimulating agents

BACKGROUND In patients with chronic kidney disease (CKD), anemia is associated with left ventricular hypertrophy and adverse cardiovascular and clinical outcomes. Moreover, anemia is associated with a reduction in quality of life, particularly when the hemoglobin level drops below 100 g/l. 1 Thus, the goal of treating anemia in iron-replete patients with erythropoietic-stimulating agents (ESAs) is to reduce the likelihood of cardiovascular events, improve patients’ survival, and improve patients’ quality of life while minimizing any deleterious effects of the drug. Given that ESAs increase blood pressure and have other potential side effects, it is also important to assess whether the quantity of the ESA used might contribute to adverse events such as more rapid deterioration of kidney function, earlier requirement for dialysis, and vascular access failure. It is acknowledged that, if left untreated, patients with severe anemia may require blood transfusions, which have associated risks and costs, and possible implications for patients awaiting a kidney transplant. In light of this, in most developed countries, the question for CKD patients with significant anemia has often not been whether to use ESAs, but when to use them and what target hemoglobin level to aim for. 2 The earliest anemia correction studies in nondialysischronic kidney disease (ND-CKD) and hemodialysis-chronic kidney disease (HD-CKD) patients compared the use of erythropoietin a with placebo. 3–5 Most early studies were not designed and powered to examine clinical outcomes other than quality of life, and no differences were apparent in such other outcomes. Several of the studies showed improvements in quality of life compared with placebo. 3–5 Subsequent randomized control trials (RCTs) have tended to examine the impact of using ESAs to achieve different target hemoglobin level ranges on surrogate endpoints, such as left ventricular (LV) mass, where patients with the lower hemoglobin target would be less likely to require the use of an ESA or would require lower doses to maintain the prespecified lower target hemoglobin. Two RCTs 6,7 in HDCKD patients compared with the use of ESAs to achieve intermediate hemoglobin and high hemoglobin targets. Although both studies showed no difference in progression of LV mass, the higher target hemoglobin led to improved quality of life in some of the domains, but the size of this

Erythropoietic-Stimulating Agents (ESAs): New Safety Warning

Recently the manufacturers of darbepoetin alfa (Aranesp), epoetin alfa (Epogen, Procrit) in collaboration with the Food and Drug Administration (FDA) released updated product information that includes a black box warning regarding the safety of erythropoietic-stimulating agents (ESAs). A higher chance of serious and life-threatening side effects or death with the use of ESAs was noted in 4 recent surgical studies and 2 studies in persons with chronic kidney disease when targeting hemoglobin values 12 g/dL. As a result, Amgen and Ortho Biotech cooperated with the FDA to examine safety signals from these studies and arrive at the following black box warning.