Low Endogenous Erythropoietin Levels Research Articles

Predictors of Response to Erythropoietin in Autoimmune Hemolytic Anemia

Predictors of Response to Erythropoietin in Autoimmune Hemolytic Anemia

S901 COMBINED GENE PANEL SEQUENCING AND EKTACYTOMETRY - THE NEXT GENERATION OF RED CELL DIAGNOSTICS

Background: Autoimmune hemolytic anemia (AIHA) is clinically heterogeneous, from chronic compensated to abrupt hemolysis. Together with the rate of antibody mediated erythrocyte destruction, bone marrow reticulocyte compensation is a recently recognized determinant of outcome. Erythropoietin (EPO) has been anecdotally used in AIHA to ameliorate bone marrow response, but only one systematic series has been published and predictors of response are not knownAims: To evaluate EPO efficacy and its predictors in a cohort of AIHA patients Methods: Data on primary and secondary AIHA cases who had received EPO either alone or concomitantly to other therapies were retrospectively collected using a preformed survey. Efficacy was evaluated at 15 and 30 days, and then at 3,6 and 12 months; Hb response was considered partial (PR, ≥2 g/dL Hb increase or >10 g/dL) or complete (CR, >12 g/dL) and hemolytic markers (LDH, reticulocytes) were registered Results: 29 AIHA cases followed from June 2007 to February 2019 at 7 centers in Italy, France, Norway, Austria, and UK were included in the study. Main AIHA types (warm, cold, mixed, and DAT negative) were present, and 3 cases were secondary to a lymphoproliferative disorder (not active and without specific treatment at the moment of the study). Patients’ characteristics are shown in table 1: at diagnosis 74% of cases presented with severe anemia and 95% displayed inadequate reticulocytosis (i.e. bone marrow responsiveness index<121). Bone marrow evaluation at diagnosis (N = 16) showed hypercellularity with dyserythropoiesis in 7 cases, and reticulin fibrosis in 3; a lymphoid infiltrate was found in 13 patients (T-cell in 4, B-cell in 7, mixed in 2), greater than 10% in the 3 secondary cases only. All patients had received at least one previous therapy, and the majority (69%) started EPO because of non-response to ongoing treatment (steroids 15, immunosuppressor 4, sutimlimab 1). Six patients had received rituximab during the 3 months before EPO start (median 1 month, range 0–5). At EPO initiation, 21% of cases displayed severe anemia, 73% had inadequate reticulocytosis, and 89% (of 18 tested) showed inappropriately low endogenous EPO levels. Patients were treated for a median of 7 months and responses were observed in about 70% of cases at month+1 and +3 (table1), with a median Hb and reticulocyte increase of 21.5 (2–48) g/L (p < 0.001) and 25(0–220)x109/L at month+1; and 29 (0–66) g/L (p < 0.001) and 49 (0–195)x109/L at month+3, respectively. Notably, 64% of patients responded as soon as at day+15; this finding supports an activity of EPO although recent or concomitant treatments may have contributed. At last follow up, 13 cases had discontinued EPO: 6 for long standing CR and 7 because of NR (3 with hemolytic flares). We observed an association of response to EPO and primary AIHA (73 vs 33% in secondary), inadequate reticulocytosis (76 vs 50% with adequate reticulocytosis), and not-warm (85 vs 50% in warm cases) not transfusion dependent cases (76 vs 50% transfusion dependent), although the small number did not allow statistical significance Summary/Conclusion: Use of EPO is effective in about 70% of AIHA patients unresponsive to ongoing/previous treatments, particularly in cases with inadequate reticulocytosis. Although preliminary, these data advise EPO use to stimulate bone marrow compensatory response

Pre-Transplant Erythropoiesis-Stimulating Agent Hypo-Responsiveness and Post-Transplant Anemia

BackgroundAt the time of kidney transplantation (KT), almost all patients have anemia caused by low levels of endogenous erythropoietin (EPO), along with several other factors. After KT, anemia improves because of secretion of EPO from the allograft. But some recipients have persistent anemia. Whether or not erythropoiesis-stimulating agent (ESA) hypo-responsiveness before KT affects post-transplant anemia (PTA) remains unknown. MethodsSixty-eight patients received KT between January 2007 and July 2012 through the Department of Urology at Kobe University Hospital, and 35 of these patients were enrolled. Exclusion criteria included age <18 years, unknown ESA dosage at transplantation, ESA start within 1 year after transplantation, and other criteria. We evaluated post-transplant hemoglobin (Hb) levels from the pre-transplant ESA responsive index (ERI): pre-transplant ESA dosage/Hb × body weight at 1 year after transplantation. ResultsThe mean (±SD) Hb of all patients rose from 11.3 ± 1.0 mg/dL to 12.7 ± 1.4 mg/dL at 1 year after transplantation (P < .01). The pre-transplant low ERI group (<10) showed significantly higher hemoglobin levels compared with the pre-transplant high ERI group (≥10; 12.9 ± 1.14 mg/dL versus 11.8 ± 1.76 mg/dL, respectively; P = .03). ConclusionsESA hypo-responsiveness before KT carried over after KT. Low pre-transplant ERI might be a sentinel marker for PTA.

Development and validation of a model to predict platelet response to romiplostim in patients with lower-risk myelodysplastic syndromes.

Low endogenous erythropoietin levels and limited red blood cell transfusion history can predict response to erythropoiesis-stimulating agents in anaemic patients with myelodysplastic syndromes (MDS). The relationship between endogenous thrombopoietin (THPO) levels and platelet response to romiplostim is unknown. Variables including baseline endogenous THPO levels, transfusion needs, and platelet response were analysed in a randomized trial of 250 thrombocytopenic, lower-risk MDS patients (International Prognostic Scoring System low/intermediate-1). A predictive scoring system was developed based on log-likelihood ratios and logistic coefficients. Patients with HI-P (haematological improvement - platelets) responses had lower mean baseline THPO levels (P = 0·0497) and were more likely to have <6 platelet units transfused in the past year (P = 0·0027), as did patients with platelet responses ≥50% of weeks on romiplostim (P = 0·001 and P = 0·0037, respectively). A model for predicting response to romiplostim was developed and validated in a separate MDS cohort (N = 72). Patients in low-, intermediate-, and high-response groups had response rates of 17·4%, 29·6%, and 50·7%, respectively, for HI-P, and 17·4%, 33·8%, and 65·2%, respectively, for ≥50% response. For thrombocytopenic patients with lower-risk MDS, lower baseline THPO levels (<500 pg/ml) and limited platelet transfusion history predicted a greater likelihood of a subsequent platelet response to romiplostim.

Low erythropoietin production as non-oncogenic co-factor contributing to disease-manifestation in low-risk MDS: A hypothesis supported by unique case reports

Little is known about factors contributing to disease-evolution in early-phase myelodysplastic syndromes (MDS). In this article, low erythropoietin (EPO) production is discussed as a ‘non-oncogenic’ co-factor responsible for disease-manifestation in a group of patients with low-risk MDS. The hypothesis is based on the observations that (i) individuals with bone marrow dysplasia and MDS-related karyotypes but relatively high EPO levels may present without anemia and thus without frank MDS over years, (ii) several elderly patients with idiopathic anemia are low EPO producers and their anemia can be corrected with EPO therapy, and (iii) the well-known fact that low-risk MDS patients typically respond to EPO therapy when they have low endogenous EPO levels.

Molecularly Confirmed Polycythemia Vera with Elevated Endogenous Serum Erythropoietin Level: Diagnostic Algorithms Revisited.

Background: It is widely accepted that an elevated serum endogenous erythropoietin (EPO) level in a patient presenting with erythrocytosis and a genuinely increased red cell mass makes a diagnosis of polycythemia vera (PV) extremely unlikely (Mossuz et al Haematologica 2004:1194; Tefferi and Gilliland Mayo Clin Proc 2005:947.) However, in the absence of a definitive molecular marker for PV, there is often uncertainty, especially when PV-associated clinical features are present. Here we describe 4 patients presenting with Budd-Chiari syndrome (BCS) and erythrocytosis who had EPO levels well above the normal reference range (Levy et al Hepatology 1985:858), yet all had the newly described JAK2 V617F point mutation in myeloid cells, confirming PV.Methods and Results: A 30-year-old man presented in March 2005 with ascites, mild splenomegaly, abnormal liver tests, and erythrocytosis (hemoglobin (Hb) 18.6 g/dL) with a normal platelet count (187 x 10(9)/L). BCS was diagnosed by Doppler ultrasonography, transjugular venogram, and liver biopsy. While bone marrow examination showed hypercellularity and megakaryocyte clustering consistent with chronic myeloproliferative disorder (CMPD), his EPO level was elevated to 32 U/L (normal 4–16 U/L), suggesting secondary erythrocytosis. Arterial oxygen saturation, Hb oxygen-dissociation curves (P50), molecular studies of the globin loci, Hb chromatography, and CT scans of the body were all normal. Granulocyte DNA demonstrated the JAK2 V617F mutation (heterozygous/mixed clonality), absent in buccal cells, confirming PV. Karyotype was normal and BCR/ABL was not present. The patient was treated with phlebotomy, warfarin, and hydroxyurea. One month later, his EPO level was markedly reduced at 13 U/L. We hypothesized that since hepatocytes express low levels of EPO, a remnant of fetal erythropoiesis, acute necrosis from BCS could lead to transient EPO surge even in the presence of chronic EPO suppression from PV. We then reviewed clinical data from all 33 patients at our institution since 1995 with BCS that was ultimately believed to be associated with PV. We identified 13 such patients in whom endogenous EPO levels were measured. Most had a low EPO level at the time of diagnosis (range of <1.5 to 9 U/L), but 3 of these patients were found to have an elevated EPO level. DNA was extracted from archival samples from these 3 patients; JAK2 V617F mutation was detected in all 3. Clinical presentations were as follows:Patient 1: 21-year-old woman with BCS and pulmonary embolus, Hb 15.9 mg/dL, EPO 28 U/L. Bone marrow biopsy was consistent with PV. Subsequent EPO level was 19U/L in the setting of progressive liver failure.Patient 2: 48-year-old woman with known PV receiving intermittent phlebotomy presented with BCS, Hb 17.2 mg/dL, EPO 25 U/L. Marrow was consistent with CMPD.Patient 3: 33-year-old woman presented with BCS, Hb 18.8 mg/dL, EPO 53 U/L. Bone marrow biopsy showed early CMPD.Conclusion: Elevated EPO levels do not exclude the diagnosis of PV, especially in the presence of BCS with hepatic necrosis. These cases highlight the continuing challenges in accurate PV and CMPD diagnosis and emphasize the importance of complementing clinical assessment with molecular genetic testing, including JAK2 mutation analysis.

Fetal Globin Induction—Can It Cure β Thalassemia?

The beta thalassemias are one of a few medical conditions in which reactivation of a gene product that is expressed during fetal life can functionally replace a deficiency of essential proteins expressed at a later developmental stage. The fetal globin genes are present and normally integrated in hematopoietic stem cells, and at least one fetal gene appears accessible for reactivation, particularly in beta degrees thalassemia. However, rapid cellular apoptosis from alpha globin chain precipitation, and relatively low levels of endogenous erythropoietin (EPO) in some beta(+) thalassemia patients contribute to the anemia in beta thalassemia syndromes. In clinical trials, three classes of therapeutics have demonstrated proof-of-principle of this approach by raising total hemoglobin levels by 1-4 g/dL above baseline in thalassemia patients: EPO preparations, short chain fatty acid derivatives (SCFADs), and chemotherapeutic agents. Although thalassemic erythrocytes survive only for a few days, the magnitude of these responses is similar to those induced by rhu-EPO in anemic conditions of normal erythrocyte survival. New oral therapeutic candidates, which stimulate both fetal globin gene expression and erythropoiesis, and combinations of therapeutics with complementary molecular actions now make this gene-reactivation approach feasible to produce transfusion independence in many patients. Development of the candidate therapeutics is hindered largely by costs of drug development for an orphan patient population.

Molecular Pathways of Response to Recombinant Human Erythropoietin (rHuEpo) in Myelodysplastic patients Assayed with Macroarrays.

Recently, among myelodysplastic syndromes with IPSS low/intermediate 1 risk classes, promising results have been obtained in the treatment of anemia by high dosage recombinant human erythropoietin (rHuEPO) treatment, in the cases with low endogenous erythropoietin (EPO). We have reproduced these clinical results in the patients treated at our Institution. Based on these premises, in order to evaluate the molecular basis of the rHuEPO response in MDS patients, we investigated the differential gene expression in the bone marrow erythroid cells expressing glycophorin (Gly+) of EPO-responders (ER) and EPO-non responders (ENR) MDS patients, using commercially available macroarrays (Clontech), comparing gene level of expression with a baseline represented by a pool of erythoid cells isolated from normal bone marrow donors. We analysed 4 ER and 4 ENR MDS patients (RA and RARS). BM erythroid cells, after Ficoll density gradient, were separated by positive selection using an immunomagnetic procedure (MACS, glycophorin isolation kit; Miltenyi Biotech, Auburn, CA). The purity of Gly+ cells after magnetic immunosorting was tested by flow-cytometry and was superior to 97%, in all the cases. RNA extraction, cDNA synthesis and macroarrays hybridization and analysis were performed following manufacturer instructions (Clontech Laboratories, Palo Alto, CA). The data were validated on 4 differentially expressed genes by real time RT-PCR TaqMan technology, obtaining results that were superimposable to the macroarrays ones. Using a cut off of an at least two fold difference in gene expression, we obtained a differential pattern of expression in ER and ENR patients, BM Gly+ erythroid cells, with respect to normal donors. In particular, ER patients presented the up-regulation of interleukin-1 beta, apolipoprotein E precursor, CREB2, high mobility group protein (HMG-I), transducin beta-1 subunit and the down regulation of protein kinase MLK-3, cAMP-dependent phosphodiesterase (PDE43), IL-5R-alpha, caspase-9. On the other hand, in ENR group, we found a down regulation of proliferating cyclic nuclear antigen (PCNA), B-myb, prothymosin alpha, phenylethanolamine N-methyltransferase, thymosin beta-10 and an up regulation of homeobox protein HOX-A5, monocarboxylate transporter 1, interleukin-6, deoxyribonuclease II, sterol regulatory element-binding protein, metalloproteinase inhibitor 1 precursor, rap1 GTPase activating protein 1 (RAP1GAP). In conclusion, ER and ENR MDS patients erythroid cells present a different pattern of gene expression with respect to normal. These results may provide the basis for early testing of the genes differentially expressed in ER and ENR patients in order to elucidate their role in the prognostication of rHuEPO response in MDS patients with low endogenous EPO levels.

Anemia in the oncology patient: cognitive function and cancer.

Cancer-related anemia often develops from the infiltration of marrow by malignant cells, impaired hemoglobin (Hb) production related to chemotherapy or radiation therapy, iron deficiency, or low endogenous erythropoietin levels. Patients with cancer-related anemia may experience cognitive dysfunction including decreased mental alertness, poor concentration, and memory problems. Anemia-mediated cerebral hypoxia may cause symptoms such as headache, vertigo, tinnitus, and dizziness. These symptoms often are exacerbated in the elderly patient with cancer and related to underlying low Hb concentrations. Restoring Hb levels via the administration of iron supplements, blood transfusions, or, more recently, erythropoiesis-stimulating therapy (epoetin alfa) results in significant improvement of cognitive function. The use of epoetin alfa as a treatment option for patients with chemotherapy-associated anemia and an Hb concentration less than 10 g/dL has been recommended by the American Society of Clinical Oncology and the American Society of Hematology. Erythropoiesis-stimulating therapies are a promising treatment option for cancer-related anemia that may improve cognitive function and quality of life for patients with cancer.

Blunted erythropoietin response to anemia in patients with Type 1 diabetes.

It is known that patients with renal failure have normochromic normocytic anemia due to impaired endogenous erythropoietin (EPO) synthesis. The aim of this work was to determine whether low serum erythropoietin (s-EPO) levels play a role in the pathogenesis of anemia in patients with Type 1 diabetes without overt nephropathy. We included in the study 13 patients with Type 1 diabetes whose Hb levels were <11 g/dl. Blood cell count, s-EPO, urinary albumin excretion rate (AER), HbA(1c), glomerular filtration rate, serum iron, serum ferritin, the presence of neuropathy, retinopathy and nephropathy were determined. Ten out of 13 patients with anemia (77%) had a blunted EPO response to anemia. All ten patients with low EPO levels had autonomic neuropathy; five had clinical nephropathy but with serum creatinine<1.6 mg/dl. Three patients were treated with rHuEPO and showed an improvement in their anemia after treatment. The majority of patients with Type 1 diabetes who had anemia also had low EPO levels. The pathogenesis of this phenomenon is probably multifactorial. Autonomic neuropathy appears to play a role, but it is not sufficient, per se, to be the only cause. Dysautonomia might enhance the effect of renal damage.

Erythropoietin in Cancer Surgery

SUMMARY Patients with gastrointestinal cancer usually have a sideropenic anemia unresponsive to iron supplementation which is characterized by low levels of endogenous erythropoietin. Anemic patients are not suitable for preoperative autologous blood donation programs and are at high risk for perioperative homologous blood transfusions. Preoperative treatment with recombinant human erythropoietin (r-HuEPO) has allowed anemic patients to donate autologous blood and reduced homologous blood transfusion after surgery. A dose-response study showed that 400 U/kg of r-HuEPO, divided in four doses administered every four days, is the minimum effective dose which increases hemoglobin levels about 10 g/L/week. The red blood cell (RBC) gain was 268 ± 79 mL, which is grossly equivalent to the RBC content of two units of predonated autologous blood. The total charge for this treatment ($280) was substantially lower than in other experiences in which higher doses of r-HuEPO were given. To maximize erythropoietic response, it is necessary to provide supplementary IV iron (125 mg daily). This results in a normalization of circulating and stored iron, suggesting that the amount was adequate both to sustain the production of new RBCs and to replace tissue stores during r-HuEPO treatment.

Epoetin in cancer-related anaemia.

Cancer-related anaemia has a number of causes, not least the underlying malignancy itself which plays a role in suppressing erythropoiesis. Anaemia is often exacerbated by cancer treatments, in particular routinely used cytotoxic chemotherapy. Chronic anaemia of cancer is often characterized by inappropriately low levels of endogenous erythropoietin for the degree of anaemia, and manifests clinically with generalized hypoxia and resultant severe fatigue. Epoetin alfa is one recombinant form of erythropoietin, the primary human growth factor responsible for promoting proliferation and survival of erythroid progenitor cells. Epoetin alfa has been widely studied for the treatment of anaemia associated with renal failure and is now recognized as having significant potential in the management of cancer-related anaemia. Studies suggest that epoetin alfa is an effective treatment in a proportion of cancer patients with symptomatic anaemia. It also appears useful for the prevention of chemotherapy-induced anaemia. Studies in a number of different cancer settings have shown that epoetin alfa significantly increases haemoglobin and haematocrit, reduces transfusion requirements and improves quality of life for the patient.

Pathophysiology and treatment of the anemia of prematurity.

Increased understanding of the pathophysiology of anemia of prematurity (AOP) has emerged over the past years. It is apparent that low levels of endogenous erythropoietin (Epo) is the basis for this phenomenon. This has resulted in an effective therapeutic approach for this condition. Administration of Epo can ameliorate the signs and symptoms of AOP and lessen, and in many cases avoid, the necessity for blood transfusion.