EPO and G-CSF Treatment Yields Positive Impact in Myelodysplastic Syndrome

The hallmark of Myelodysplastic Syndrome (MDS) is ineffective production of myeloid blood cells and a risk of transformation to acute myelogenous leukemia (AML). Anemia requiring blood transfusion is present in 90% of patients. Therapy with erythropoietin (EPO) alone or with granulocyte-colony stimulating factor (G-CSF) is currently the standard of care for anemia in low risk MDS. Recent reports have raised concerns over whether treatment with these hematopoietic growth factors negatively affects outcomes in cancer patients; increasing relapses and decreasing overall survival in several types of cancers. In contrast to these findings, a recent study by Park et al suggests a positive impact of growth factors on survival in MDS without affecting the rate of progression to AML, but the multivariate analysis used in the study did not adjust for all currently used prognostic factors.¹

In this study, Jädersten and colleagues sought to confirm these findings with a cohort analysis using a multivariate regression that does adjust for all major prognostic variables; WHO classification, karyotype, cytopenias, level of transfusion need, age and sex. The EPO plus G-CSF treatment cohort (n = 121) included all patients from 3 Nordic trials. All patients had refractory anemia with ringed sideroblasts or excess blasts in combination with hemoglobin less than 10 g/dL or regular transfusion need. The control cohort (n= 237) was selected from an Italian cohort of untreated patients based on the same criteria as the EPO plus G-CSF group. Both cohorts were enrolled during the same time period (1990-1999) in Western Europe with detailed recording of prognostic factors. The EPO plus G-CSF patients were significantly older and more frequently transfused than untreated patients, which would imply a worse prognosis in this group than the untreated group.

EPO plus G-CSF treatment was associated with longer survival mainly in patients with low transfusion needs, defined as fewer than 2 units of red blood cells per month. This result correlates with the observation that patients in this subgroup had a better response to EPO plus G-CSF treatment than the more heavily transfused. No association with survival was seen in this more heavily transfused group. There was no association between treatment and the risk of AML progression in any group.

The authors conclude that treatment of anemia in MDS with EPO and G-CSF may have a positive impact on survival in patients with low or no transfusion need, while not affecting the risk of leukemic transformation. They opine that these findings are highly relevant in light of recent reports of potential negative effects of EPO treatment on outcome in cancer patients. Jädersten and colleagues feel that therapy with EPO and G-CSF should remain the standard of care for anemia in low risk MDS.

Jädersten M, Malcovati L, Dybedal I, Della Porta MG, Invernizzi R, Montgomery SM, Pascutto C, Porwit A, Cazzola M, Hellström-Lindberg E. Erythropoietin and granulocyte-colony stimulating factor treatment associated with improved survival in myelodysplastic syndrome. J Clin Oncol. 2008 Jul 20;26(21):3607-13.

NAAC Expert Commentary:
This report offers some reassurance in these days of heightened anxiety regarding the use of growth factors and cancer progression. In this case, patients with MDS were treated with both G-CSF and EPO without apparent acceleration of disease or more frequent transformation to acute leukemia. The latter is of particular importance because although most MDS patients do not progress to overt leukemia, a fair percentage do. Even though there are hypothetical reasons that growth factors such as these may be considered risky interventions, this analysis supports what clinicians have observed: that EPO and G-CSF can be used safely in MDS patients.

The data on improved survival is interesting, but must be interpreted with caution. These were two distinct cohorts from two different European countries; one on clinical trial (G-CSF + EPO) and the other receiving 'supportive care' off protocol. Although the authors make every effort to match control (untreated patient) with their protocol-registered patients, definitive conclusions regarding survival benefit from treatment are best drawn from randomized, prospective studies. Clearly these randomized, prospective studies need to be conducted in order to determine if the survival advantage suggested by this retrospective cohort comparison could actually be confirmed in a controlled clinical trial setting.

References

1. Park S, Grabar S, Kelaidi C, Beyne-Rauzy O, Picard F, Bardet V, Coiteux V, Leroux G, Lepelley P, Daniel MT, Cheze S, Mahé B, Ferrant A, Ravoet C, Escoffre-Barbe M, Adès L, Vey N, Aljassem L, Stamatoullas A, Mannone L, Dombret H, Bourgeois K, Greenberg P, Fenaux P, Dreyfus F; GFM group (Groupe Francophone des Myélodysplasies). Predictive factors of response and survival in myelodysplastic syndrome treated with erythropoietin and G-CSF: the GFM experience. Blood. 2008 Jan 15;111(2):574-82.

Extended ESA Dosing Schedules for CKD Patients Not on Dialysis

The use of epoetin alfa to correct anemia in patients with chronic kidney disease (CKD) improves exercise tolerance and patient-reported functioning. Although the recommended initiation dosage of epoetin alfa is 50 to 100 IU/kg three-times-weekly, several studies reported that the epoetin alfa is still effective in achieving and maintaining hemoglobin (Hb) target levels when given subcutaneously up to every four weeks. The objective of this study was to determine the pharmacokinetics, pharmacodynamics, and safety of giving epoetin alfa to patients who had CKD and who were not on dialysis, using the following dosing regimens: (1) 50 IU/kg three times weekly, (2) 10,000 IU once weekly, (3) 20,000 IU every 2 weeks, and (4) 40,000 IU every 4 weeks. The study was a prospective, open-label, randomized, multicenter study of 39 adult patients with anemia secondary to CKD. Patients were randomly assigned to one of the four regimens using a 1:1:1:1 ratio. Dosage adjustment was not allowed during the study. Patients were given oral elemental iron at a dosage of 200 to 400 mg/day. Patients discontinued the study treatment if Hb levels were ≥13 g/dL or increased by >1 g/dL in any 2-week period. Transfusions of red blood cells were given as necessary. A safety population was created from patients who were randomly assigned and who received one dose or more of the study drug.

The safety population was comprised of 38 patients, of which, 36 (95%) completed the study. Baseline endogenous erythropoietin concentrations ranged from below the quantification limit (<7.8 mU/mL) to 56.8 mU/mL. Erythropoietin concentrations declined multi-exponentially to baseline values by approximately day 8 following: (1) the third scheduled dose of epoetin alfa on day 5 in the three times-weekly group; and (2) after the first dose of epoetin alfa in the once-weekly, every-2-weeks, and every-4-weeks groups on day 1. There was substantial variability associated with most pharmacodynamics parameters (>50% of standard deviation). Mean percentage of reticulocyte responses over 1, 2, and 4 weeks (AUC) were similar for the once-weekly group compared with the three-times-weekly group. Mean percentage of reticulocytes showed a dose-dependent trend for the first week and a similar overall response across all regimens over the first 2 weeks. The reticulocyte response for the every-4-weeks group was initially greater than for the other dosing regimens. Mean overall response, based on Hb levels and total red blood cell count was similar across all dosing regimens, except in the once-weekly group, in which the mean observed overall response was lower over the first week, possibly because of a inter-patient variation. Although there were modest differences among the pharmacokinetics of the four different dosing regimens, the pharmacodynamics effects and safety of the extended interval regimens was comparable to the current recommendations for 50 IU/kg three-times-weekly.

McGowan T, Vaccaro NM, Beaver JS, Massarella J, Wolfson M. Pharmacokinetic and pharmacodynamic profiles of extended dosing of epoetin alfa in anemic patients who have chronic kidney disease and are not on dialysis. Clin J Am Soc Nephrol. 2008 Jul;3(4):1006-14.

NAAC Expert Commentary:
As reported in the article by McGowan et al, the use of epoetin alfa in patients with anemia associated with CKD results in improved exercise tolerance as well as patient perception of better functional levels. The current recommended initiation dosage requires administration of epoetin alfa three-times-weekly. However, several studies have confirmed the effectiveness of off-label dosing schedules where an ESA is administered subcutaneously every 1 to 4 weeks.¹

In this small scale study of 39 patients, subjects received one of four epoetin alfa dosing regimens, with each regimen providing a similar dose of the medication over a 4-week period. Mean change in hemoglobin levels during the study was similar across the four dosing regimens.

To prevent the progression of CKD, it has become typical for some nephrologists with a substantial CKD patient population to use an extended dosing regimen in the treatment of anemia-related CKD. Significant improvement in exercise tolerance and resultant improvement in quality of life is extremely significant to patients. More notably, the majority of these same patients have greater than two risk factors for cardiovascular disease, the major cause of death and disability for CKD patients.² The prevalence rate of CKD has increased by more than 20% in the last decade,³ causing loss of life and sky-rocketing healthcare costs. Therefore, it is essential to develop a regimen for managing CKD-related anemia that is efficacious, cost effective, and acceptable to the patient. Although this study included the examination of a three-times-weekly dosing regimen, it is important to note that this dosing regimen is rarely practiced by nephrologists.

While larger scale prospective studies are needed to demonstrate that the less frequent epoetin alfa dosing regimens positively affect mortality and morbidity rates as well as improve quality of life, the current study gives some scientific basis to support the practice common among those physicians currently treating anemia of CKD.

References

1. Provenzano R, Bhaduri S, Singh AK, PROMPT Study Group. Clin Nephrol. 2005 Aug;64(2):113-23. Extended epoetin alfa dosing as maintenance treatment for the anemia of chronic kidney disease: the PROMPT study.
2. Greenlund et al. Arch Intern Med. 2004, 164; 181-188, CDC; MMWR Morb Mortal Wkly Rep. 2005;54: 113-117
3. NephrOnline. Link. Accessed: October 27, 2008.

Adverse Outcomes Transfusing Anemic Patients with Subarachnoid Hemorrhage

Although the transfusion of allogeneic red blood cells (RBCs) can correct anemia by raising hemoglobin levels, its clinical benefit has not been proven unequivocally. Some research points to ineffective and even harmful effects from liberal transfusions. These findings are of particular concern in neurocritical care patients, given that decreased oxygen delivery is an important cause of secondary brain injury. Specifically, patients with aneurysmal subarachnoid hemorrhage (SAH) commonly present with anemia, which has been identified as a predictor of death and infarction. There are no clinical data that show the benefit of aggressive transfusions in alleviating these risks, and some studies indicate that transfusion may exacerbate vasospasm and contribute to adverse respiratory effects. Kramer et al recently addressed these concerns in a study that assessed the association between anemia, transfusions, and adverse outcomes.

The retrospective cohort study included 245 patients with SAH who were admitted to a health care center over a 4-year period. The study examined hemoglobin (Hb) levels, the use of blood transfusions, development of vasospasm, and the relationship between anemia or transfusion and the combined outcome of death, severe disability, or delayed infarction. Optimal Hb concentrations were defined at 10 g/dL: 39% of patients developed Hb levels below this concentration at baseline; 35% of patients received transfusion; and 26% of patients were diagnosed with clinical vasospasm. The odds of reaching the primary outcome were higher in both anemic and transfused patients (OR 2.7 and 4.8 respectively) than in non-anemic and non-transfused patients. Transfusion remained the only significant variable associated with the combined outcome after multivariate analysis (OR 4.3). However, anemia had the stronger predictive association in patients with vasospasm whereas transfusion was the stronger predictor in those with no vasospasm. A strong association was observed between transfusion and the subsequent development of infection. The age of the transfused blood had no discernible impact, although the cutoff for storage duration was 21 days.

Although no previous studies have attempted to separate the effects of anemia from those of transfusion, the present study showed a strong association between transfusion and adverse effects. Transfusion can increase blood viscosity, cause vasoconstriction by depleting endothelial nitric oxide, and adversely affect RBC deformability and microvascular flow through blood storage. Despite these associations, the study’s results should only be considered hypothesis generating until further studies are conducted. The authors contend that one possible explanation for these associations is that physicians tend to transfuse patients who are “sicker,” which could introduce confounding variables that were not adjusted for in the study. Also, the presence or absence of vasospasm may be important for determining transfusion thresholds. Further studies, such as randomized trials of liberal versus restrictive transfusion, should be considered.

Kramer AH, Gurka MJ, Nathan B, Dumont AS, Kassell NF, Bleck TP. Complications associated with anemia and blood transfusion in patients with aneurysmal subarachnoid hemorrhage. Crit Care Med. 2008 Jul;36(7):2070-5.

NAAC Expert Commentary:
Kramer et al’s study of the impact of anemia and transfusion in patients with ischemic brain injury from subarachnoid hemorrhage (SAH) is an important contribution to our understanding of not only which patients may or may not benefit from blood transfusion, but also of the relationship of anemia and transfusion to adverse outcomes. As the authors note, transfusion has long been thought to be required therapy in anemic, SAH patients to prevent cerebral ischemia. However, evidence to support this practice has not been forthcoming. This study’s evidence of a strong association between transfusion and adverse outcome in SAH should prompt all those who treat these patients to be more cautious with transfusion in the future.

Moreover, the study shows that anemia and transfusion are independent predictors of adverse outcome. This raises the question of how we should treat anemia in SAH patients. Will patients benefit from iron and erythropoietin treatment to raise hemoglobin levels while avoiding RBC transfusion? Will patients benefit from a non-hemoglobin based oxygen therapeutic to increase cerebral oxygen? Answers to these questions and to the question of the role of RBC transfusion in anemic SAH patients await study through prospective, randomized trials.