losartan-potassium and Leukemia--Myeloid--Acute

Myelodysplastic neoplasms (MDS), formerly known as myelodysplastic syndromes, are clonal hematopoietic malignancies that cause morphologic bone marrow dysplasia along with anemia, neutropenia, or thrombocytopenia. MDS are associated with an increased risk of acute myeloid leukemia (AML). The yearly incidence of MDS is approximately 4 per 100 000 people in the United States and is higher among patients with advanced age.. MDS are characterized by reduced numbers of peripheral blood cells, an increased risk of acute myeloid leukemia transformation, and reduced survival. The median age at diagnosis is approximately 70 years, and the yearly incidence rate increases to 25 per 100 000 in people aged 65 years and older. Risk factors associated with MDS include older age and prior exposures to toxins such as chemotherapy or radiation therapy. MDS are more common in men compared with women (with yearly incidence rates of approximately 5.4 vs 2.9 per 100 000). MDS typically has an insidious presentation, consisting of signs and symptoms associated with anemia, thrombocytopenia, and neutropenia. MDS can be categorized into subtypes that are associated with lower or higher risk for acute myeloid leukemia transformation and that help with therapy selection. Patients with lower-risk MDS have a median survival of approximately 3 to 10 years, whereas patients with higher-risk disease have a median survival of less than 3 years. Therapy for lower-risk MDS is selected based on whether the primary clinical characteristic is anemia, thrombocytopenia, or neutropenia. Management focuses on treating symptoms and reducing the number of required transfusions in patients with low-risk disease. For patients with lower-risk MDS, erythropoiesis stimulating agents, such as recombinant humanized erythropoietin or the longer-acting erythropoietin, darbepoetin alfa, can improve anemia in 15% to 40% of patients for a median of 8 to 23 months. For those with higher-risk MDS, hypomethylating agents such as azacitidine, decitabine, or decitabine/cedazuridine are first-line therapy. Hematopoietic cell transplantation is considered for higher-risk patients and represents the only potential cure.. MDS are diagnosed in approximately 4 per 100 000 people in the United States and are associated with a 5-year survival rate of approximately 37%. Treatments are tailored to the patient's disease characteristics and comorbidities and range from supportive care with or without erythropoiesis-stimulating agents for patients with low-risk MDS to hypomethylating agents, such as azacitidine or decitabine, for patients with higher-risk MDS. Hematopoietic cell transplantation is potentially curative and should be considered for patients with higher-risk MDS at the time of diagnosis.

Topics: Antineoplastic Agents; Azacitidine; Decitabine; Erythropoietin; Female; Hematinics; Humans; Leukemia, Myeloid, Acute; Male; Myelodysplastic Syndromes; Neutropenia; Prognosis; Thrombocytopenia

Topics: Antilymphocyte Serum; Azacitidine; Benzoates; Cyclosporine; Cytarabine; Deferasirox; Disease Progression; Drug Discovery; Drug Therapy, Combination; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Idarubicin; Immunosuppressive Agents; Iron Chelating Agents; Lenalidomide; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Quality of Life; Risk Assessment; Thalidomide; Triazoles

Myelodysplastic syndromes (MDS), clonal hematopoietic stem-cell disorders mainly affecting older adult patients, show ineffective hematopoiesis in one or more of the lineages of the bone marrow. Most MDS are characterized by anemia, and a number of cases progresses to acute myeloid leukemia (AML). Indeed, the molecular mechanisms underlying the MDS evolution to AML are still unclear, even though the nuclear signaling elicited by PI-PLCβ1 has been demonstrated to play an important role in the control of the balance between cell cycle progression and apoptosis in MDS cells. Here we review both the role of epigenetic therapy on PI-PLCβ1 promoter and the changes in PI-PLCβ1 expression in MDS patients treated for anemia.

Topics: Apoptosis; Bone Marrow; Cell Cycle; Cell Nucleus; Epigenesis, Genetic; Erythropoietin; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Phosphatidylinositols; Phospholipase C beta; Promoter Regions, Genetic; Signal Transduction

Myelofibrosis with myeloid metaplasia (MMM) is currently classified as a classic (ie, BCR-ABL-negative) myeloproliferative disorder characterized by anemia, multiorgan extramedullary hematopoiesis, constitutional symptoms, and premature death from either leukemic transformation or other disease complications. Stem cell transplantation can be curative, but many patients either are not appropriate candidates or do not choose to accept the significant risks associated with transplantation. Current pharmacologic therapy has been beneficial mainly in terms of palliating disease-associated cytopenias, constitutional symptoms, splenomegaly, and other organ damage from excess myeloproliferation. Novel treatment strategies are under investigation, including targeted inhibition of JAK2(V617F), the activating tyrosine kinase point mutation present in about half of patients with MMM. In this article, we review both the old and new pharmacologic options for MMM.

Topics: Aged; Alkylating Agents; Anemia; Antimetabolites, Antineoplastic; Blood Coagulation Disorders; Disease Progression; Drug Delivery Systems; Drugs, Investigational; Erythropoietin; Hematopoiesis, Extramedullary; Humans; Immunologic Factors; Janus Kinase 2; Leukemia, Myeloid, Acute; Middle Aged; Mutation, Missense; Palliative Care; Point Mutation; Primary Myelofibrosis; Protein Kinase Inhibitors; Signal Transduction; Thrombocytopenia

During the past 15 years, important progress has been made in the understanding of the biology and prognosis of myelodysplastic syndrome (MDS). MDS is a clonal disorder characterized by ineffective hematopoiesis, which can lead to either fatal cytopenias or acute myelogenous leukemia (AML). Risk-adapted treatment strategies were established because of the high median age (60-75 years) of the MDS patients and the individual history of the disease (number of cytopenias, cytogenetic changes, transfusion requirements). Allogeneic bone marrow transplantation currently offers the only potentially curative treatment, but this form of therapy is not available for the typical MDS patient, who is >60 years of age. Therapy with erythropoietin and G-CSF has improved the quality of life of selected patients. The development of small molecules directed against specific molecular targets with minimal adverse effects is the hope for the future. Innovative uses of immunomodulatory agents and the optimizing of cytotoxic treatment should continue to help in the treatment of MDS.

Topics: Aged; Bone Marrow Transplantation; Cause of Death; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Myeloid, Acute; Middle Aged; Myelodysplastic Syndromes; Pancytopenia; Prognosis; Survival Rate

With the identification and recombinant production of the hematopoietic growth factors, these cytokines have been evaluated in the treatment of primary bone marrow failure states and after myelosuppressive chemotherapy or radiotherapy. A lot of clinical trials with hematopoietic factors have been performed in patients with haematologic and oncologic diseases within the last decade. Granulocyte colony-stimulating factor [G-CSF], granulocyte macrophage colony-stimulating factor [GM-CSF], interleukin-3, interleukin-2, erythropoietin and in phase I/II trials thrombopoietin [TPO] are available for the clinical use. At the present, there is a broad use of growth factors. Most studies have been done with G-CSF and GM-CSF, their beneficial effects are proven regarding improvement of hematopoietic recovery after chemotherapy. This results in a marked reduction of infectious risks and a shortening of drug- and radiation-induced myelosuppression. CSFs are most important in mobilizing peripheral blood progenitor cells [PBPC] and have allowed high dose therapy to be given to patients who would not have been able to undergo conventional bone marrow transplantation. However, an improved outcome and improved survival rates with standard chemotherapy protocols couldn't be documented by studies up to now, even though higher chemotherapy doses are possible by the use of hematopoietic factors.

Topics: Colony-Stimulating Factors; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoiesis; Hematopoietic Cell Growth Factors; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Neoplasms; Thrombopoietin

The haemopoietic growth factors are a diverse group of hormones with effects on different haemopoietic cell lineages and at various points in their developmental differentiation. The biology of many of these factors is now well understood. They have entered clinical trials and have demonstrated benefits in particular clinical situations. The thrust of current phase II and III clinical investigations now is to use these factors, alone or in combinations, to modify various disease states and to ameliorate many of the side-effects of other therapeutic agents, particularly cytotoxic anticancer agents. Many other disease states also lend themselves to therapy with these growth factors. Other haemopoietic growth factors have not been as extensively studied in humans but hold great promise. In this chapter, the current status of the haemopoietic growth factors presently under clinical trial has been reviewed. In addition, several factors which have been recently described but which have not yet entered clinical trials have been discussed.

Topics: Acquired Immunodeficiency Syndrome; Animals; Antineoplastic Agents; Bone Marrow Diseases; Bone Marrow Transplantation; Clinical Trials as Topic; Drug Evaluation; Drug Evaluation, Preclinical; Erythropoietin; Haplorhini; Hematologic Diseases; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cells; Humans; Immunologic Factors; Leukemia, Myeloid, Acute; Mice; Neoplastic Stem Cells; Neutropenia; Recombinant Fusion Proteins

Topics: Animals; Bone Marrow Cells; Cell Differentiation; Cell Division; Cells, Cultured; Colony-Stimulating Factors; Dose-Response Relationship, Drug; Erythroblasts; Erythrocytes; Erythropoiesis; Erythropoietin; Hematopoiesis; Hematopoietic Stem Cells; Humans; Iron Radioisotopes; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Mice; Polycythemia

Topics: Cell Differentiation; Cell Division; Cells, Cultured; Colony-Forming Units Assay; Colony-Stimulating Factors; Erythroblasts; Erythropoiesis; Erythropoietin; Growth Substances; Hematopoietic Stem Cells; Hormones; Humans; Interleukin-3; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Lymphokines; Neoplastic Stem Cells; Polycythemia Vera; Primary Myelofibrosis; Thrombocytosis

Topics: Animals; beta 2-Microglobulin; Blood Cells; Cell Differentiation; Cell Division; Cell Membrane; Cells, Cultured; Colony-Stimulating Factors; Culture Media; Dialysis; Erythrocytes; Erythropoietin; Glycoproteins; Granulocytes; Hematopoietic Stem Cells; Histocompatibility Antigens; Humans; Lectins; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukocytes; Thymidine

Anemia is the major stimulus for erythropoietin (Epo) secretion. Various studies have reported increase of Epo following chemotherapy. The mechanism of this phenomenon is not yet clarified. In this study, the serum Epo levels have been evaluated before, during (7 and 14 days), and after (day 25) chemotherapy in patients with acute myeloblastic leukemia (n = 13) and lymphoblastic leukemia (n = 4). As a control group, 12 healthy age-matched subjects were evaluated. Epo levels were high in untreated leukemia patients compared to controls and continued to increase following chemotherapy. There was no significant difference in post-treatment values of Epo as compared with pre-treatment levels. In patients with pre-treatment values of Hb < or = 9 g/dl, Epo levels were inversely correlated with Hb (r = 0.552; p < 0.05). This correlation disappeared during and following treatment. There was no correlation between Epo levels and hematological or biochemical parameters. Therefore, elevated levels of Epo regardless of anemia may be due to a response to tissue hypoxia or increased synthesis of Epo in liver or bone marrow.

Topics: Antineoplastic Combined Chemotherapy Protocols; Erythropoietin; Female; Humans; Leukemia, Myeloid, Acute; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma

To investigate the expression of erythropoietin (EPO) and erythropoietin receptor (EPOR) in patients with acute leukemia (AL) and its clinical significance.. The levels of EPO and EPOR in plasma were determined by ELISA kit. mRNA expression levels of EPO and EPOR were determined by RT-RCR. The protein expression levels of EPO and EPOR were detected by Western blot.. The EPO protein levels in marrow plasma of ALL and AML group were significantly higher than those in the control group (P＜0.05), EPOR protein levels in ALL and AML group were significantly lower than those in the control group (P＜0.05). The mRNA levels of EPO and EPOR in ALL and AML groups were significantly higher than those in the control group (P＜0.05). The mRNA levels of EPO and EPOR in the high risk ALL and AML groups were significantly higher than those in the medium, low risk group and the control group (P＜0.05). The protein expression levels of EPO and EPOR in ALL and AML groups were significantly higher than that in control group (P＜0.05). The mRNA levels of EPO and EPOR in ALL and AML groups did not correlate with hemoglobin level and erythrocyte count (P＞0.05).. The expressions of EPO and EPOR is higher in ALL and AML patients. The expression levels of EPO and EPOR relate with the risk of ALL and AML. High risk patients have higher expression levels of EPO and EPOR, however, the expression levels of EPO and EPOR do not correlate with hemoglobin level and erythrocyte counting.. 急性白血病患者EPO、EPOR的表达及其临床意义.. 探讨急性白血病患者红细胞生成素（EPO）及红细胞生成素受体（EPOR）的表达及其临床意义.. 应用ELISA检测骨髓血浆中EPO和EPOR水平；RT-RCR法检测EPO和EPOR mRNA表达水平；Western blot法检测EPO和EPOR蛋白表达水平.. ALL及AML组骨髓血浆中EPO蛋白水平明显高于对照组（P＜0.05）；ALL及AML组骨髓血浆中EPOR蛋白水平明显低于对照组（P＜0.05）。在ALL及AML组骨髓中EPO及EPOR mRNA水平均高于对照组（P＜0.05）；在ALL、AML高危组EPO及EPOR mRNA水平较中危、低危及对照组均明显增高（P＜0.05）。在ALL及AML组骨髓中EPO、EPOR蛋白水平均高于对照组（P＜0.05）。ALL及AML组EPO、EPOR mRNA水平与血红蛋白及红细胞无相关性（P＞0.05）.. ALL及AML患者存在有EPO、EPOR高表达。EPO、EPOR表达水平与ALL及AML的危险度有关，在高危患者表达水平更高。EPO、EPOR水平与血红蛋白及红细胞之间无相关性.

Topics: Bone Marrow; Erythropoietin; Gene Expression; Humans; Leukemia, Myeloid, Acute; Receptors, Erythropoietin

Umbilical cord blood (UCB) transplantation is a promising option for hematopoietic stem cell transplantation in patients with hematologic malignancies who lack an HLA-matched sibling or well-matched unrelated donor; however, it has a higher incidence of delayed or failed engraftment because cell doses are low and bone marrow homing is inefficient. We have demonstrated that pre-treating irradiated immune-deficient mice with hyperbaric oxygen (HBO) prior to UCB CD34+ cell transplantation lowered host systemic erythropoietin (EPO) and improved UCB CD34+ cell homing and engraftment. These findings suggested that EPO-EPO-R signaling plays a role in UCB CD34+ homing and engraftment. In a pilot clinical trial, we showed that recipients of HBO therapy prior to UCB cell infusion had reduced systemic EPO, which was associated with improved kinetics of blood count recovery. Although early clinical outcomes at day 100 were encouraging, with improved overall survival, the long-term effects of HBO therapy on UCB-transplanted patients were not evaluated. In this study, we examined the long-term outcome of patients in our pilot study, compared with a historic control group, and correlated their clinical outcomes to serum EPO response to HBO. While 50% of HBO-treated patients received single UCB units, ~ 90% of the control patients received double UCB units. Although HBO patients had much better rates of survival at 6 months, their 1-year survival did not significantly differ from the control group. HBO-treated patients had on average lower relapse and non-relapse mortality rates, and less chronic graft versus host disease (GVHD), but had increased acute GVHD. However, these differences were not statistically significant, probably because of the small sample size. In the HBO-treated cohort, immune reconstitution analysis showed significant improvement in early B cell recovery, with a trend toward improvement in early NK cell recovery. When we evaluated the ratio of 8 h to baseline EPO levels, we found a non-significant trend toward lower EPO values in those who neither relapsed nor died by 1 year, compared to those who died or relapsed. This result suggests that EPO response to HBO may be associated with better outcomes. Disease progression-free survival was also improved in those who had more than 80% reduction in EPO levels in response to HBO. Our study highlights the long-term safety of HBO therapy when used prior to UCB transplantation. Future UCB transplant patients

Topics: Adolescent; Adult; Aged; Blood Cell Count; Cord Blood Stem Cell Transplantation; Disease-Free Survival; Erythropoietin; Female; Follow-Up Studies; Graft Survival; Humans; Hyperbaric Oxygenation; Leukemia, Myeloid, Acute; Male; Middle Aged; Neoplasm Proteins; Pilot Projects; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recovery of Function; Retrospective Studies; Survival Rate

Topics: Aged; Aneuploidy; Antimetabolites, Antineoplastic; Azacitidine; Chromosomes, Human, Pair 21; Erythropoietin; Fatal Outcome; Granulocyte Colony-Stimulating Factor; GTP Phosphohydrolases; Humans; Karyotyping; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Chronic; Male; Membrane Proteins; Neoplasms, Second Primary

New drug development for neoplasm treatment is nowadays based on molecular targets that participate in the disease pathogenesis and tumor phenotype. Herein, we describe a new specific pharmacological hematopoietic cell kinase (HCK) inhibitor (iHCK-37) that was able to reduce PI3K/AKT and MAPK/ERK pathways activation after erythropoietin induction in cells with high HCK expression: iHCK-37 treatment increased leukemic cells death and, very importantly, did not affect normal hematopoietic stem cells. We also present evidence that HCK, one of Src kinase family (SFK) member, regulates early-stage erythroid cell differentiation by acting as an upstream target of a frequently deregulated pathway in hematologic neoplasms, PI3K/AKT and MAPK/ERK. Notably, HCK levels were highly increased in stem cells from patients with some diseases, as Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML), that are associated with ineffective erythropoiesis These discoveries support the exploration of the new pharmacological iHCK-37 in future preclinical and clinical studies.

Topics: Adult; Aged; Cell Death; Enzyme Inhibitors; Erythropoiesis; Erythropoietin; Female; GATA1 Transcription Factor; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Molecular Targeted Therapy; Myelodysplastic Syndromes; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-hck; Signal Transduction; Young Adult

Topics: Aged; Anemia, Refractory, with Excess of Blasts; Azacitidine; Benzoates; Blood Transfusion; Chelation Therapy; Combined Modality Therapy; Deferasirox; Disease Progression; Drug Resistance; Epoetin Alfa; Erythropoietin; Fatal Outcome; Granulocyte Colony-Stimulating Factor; Humans; Iron; Iron Chelating Agents; Leukemia, Myeloid, Acute; Male; Recombinant Proteins; Triazoles

The myelodysplastic syndromes (MDS) are a group of clonal hematopoietic disorders characterized by bone marrow failure and a risk of progression to acute myeloid leukemia (AML). Anemia affects the course of disease, quality of life (QOL), and cognitive function of MDS patients. Erythroid-stimulating agents (ESAs) are effective; however, not all patients respond to ESAs. To evaluate the effectiveness of a biosimilar epoetin α (Binocrit) for the treatment of anemia in low-/intermediate-1 risk MDS patients and to evaluate the impact of ESAs on QOL and on cognitive function, 24 consecutive patients aged over 65 years were treated with Binocrit at 40,000 IU once a week for 12 weeks and were followed for at least 3 months. Responsive patients continued with 40,000 IU once a week for a further 12 weeks. Changes in QOL were assessed by the Functional Assessment of Cancer Therapy-Anemia (FACT-An), while cognitive assessment was carried out by mini-mental state examination (MMSE). All patients completed 12 weeks of therapy. Sixteen patients (66.67 %) achieved an erythroid response (ER), 15 patients (62.5 %) became transfusion independent and remained free from transfusion requirement for at least 3 months, while two patients had reduction in transfusion requirement of at least four RBC transfusions/8 weeks compared with the pretreatment transfusion requirement. Seven patients were nonresponders (29.1 %), of whom four patients were low risk and three intermediate-I risk. Seven transfusion-independent patients were low risk, and eight were intermediate-1 risk. Median hemoglobin (Hb) values were significantly higher after treatment in responders (p < 0.001). ER was maintained after 24 weeks. Statistically significant positive correlations between improvement in Hb and variations in patients' mini-mental (Spearman's Rho = 0.54, p < 0.01) and FACT-An scores (Spearman's Rho = 0.59, p < 0.003) were demonstrated. This preliminary study shows that Binocrit is promising for the treatment of anemia of MDS patients. ER positively correlates with improvements in patients' cognitive status and positive changes in QOL.

Topics: Aged; Aged, 80 and over; Anemia; Biosimilar Pharmaceuticals; Brain; Epoetin Alfa; Erythropoietin; Female; Humans; Leukemia, Myeloid, Acute; Male; Myelodysplastic Syndromes; Quality of Life; Recombinant Proteins; Retrospective Studies; Risk

This study was aimed to explore the effect and feasibility of reduced conditioning intensity allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of relapsed ETO positive acute myeloid leukemia (AML) patients. Fifteen cases of relapsed AML received the reducing conditioning intensity allo-HSCT from January 2011 to January 2013 in Beijing Military Command General Hospital. All patients were high-risk type of relapsed or refractory AML, including 10 males and 5 females, aged from 16 to 48 years old with mean age of 32.5 years. Ten cases are HLA-identical matching and other 5 cases are HLA-haploidentical.donors received granulocyte colony-stimulating factor (G-CSF) to mobilize the peripheral blood stem cell for transplantation. Conditioning regimen was fludarabine combined with busulfex, cytarabine and cyclophosphamide. The preventive donor's peripheral blood stem cell infusion were performed after 3 months of transplantation, and the toxicity, GVHD and disease-free survival were observed in patients after transplantation. The results showed that all patients achieved hematopoietic reconstitution, the average time of neutrophils ≥ 0.5 × 10⁹/L and platelets ≥ 20 × 10⁹/L were 15.5 d and 16.8 d respectively. Implantation was confirmed by the evidence of 100% donor hematopoiesis. Follow-up to June 2014, with a median follow-up duration of 27.5 months (18-54 months), GVHD occurred in 8 cases of all patients, one died of complication, the other 4 cases died of relapse and the other three patients remained in disease-free survival. The disease-free survival rate of 2-year was 66.7%,the longest disease-free survival time was up to 54 months. It is concluded that the reduced conditioning intensity allo-HSCT is the effective and safe method for relapsed AML with ETO-positive, and it may be chosen as a treatment method for relapsed ETO positive AML patients.

Topics: Adolescent; Adult; Allografts; Cytarabine; Disease-Free Survival; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Transplantation Conditioning; Vidarabine; Young Adult

Despite frequent anemia and multiple transfusions in patients undergoing chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia , recommendations for use of erythropoiesis-stimulating agents (ESAs) in these populations are still missing. The primary objective was the effect of ESA administration on patient's quality of life (QoL). Secondary objectives were hemoglobin (Hb) recovery, red blood cell (RBC) transfusions, overall survival, and event-free survival.. Adult patients with Hb ≤ 11 g/dL after consolidation chemotherapy for acute myeloid leukemia (group 1), or after allo-HSCT for any hematological diseases (group 2), were prospectively included. ESA was administered subcutaneously once per week during a maximum period of 6 months and was stopped when Hb level reached 12 g/dL. A paired-matched analysis using a historical control group was performed for secondary endpoints. Fifty-two patients were included in group 1, and 55 patients were in group 2.. For the global population, a significant improvement of QoL was noticed with ESA use; 83% (group 1) and 71% (group 2) of patients achieved an Hb level ≥ 12 g/dL without transfusion requirement. The pair-matched analysis showed a reduction of 4 RBC units per patient in group 1 (P = .0002) and 3 RBC units per patient in group 2 (P = .04). No significant difference in terms of thromboembolic events, overall survival, and event-free survival was observed between ESA and control groups. A RBC transfusion median savings of €1712 per patient was estimated in each group.. ESAs have a clinical and economic benefit on Hb recovery, could improve a patient's QoL, and lead to a significant reduction in number of RBC transfusions with no effect on survival.

Topics: Adult; Aged; Cost-Benefit Analysis; Disease-Free Survival; Erythropoietin; Female; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Prospective Studies; Quality of Life; Young Adult

Myelodysplastic syndrome (MDS) may be induced by certain mutagenic environmental or chemotherapeutic toxins; however, the role of susceptibility genes remains unclear. The G/G genotype of the single-nucleotide polymorphism (SNP) rs1617640 in the erythropoietin (EPO) promoter has been shown to be associated with decreased EPO expression. We examined the association of rs1617640 genotype with MDS.. We genotyped the EPO rS1617640 SNP in 189 patients with MDS, 257 with acute myeloid leukemia (AML), 106 with acute lymphoblastic leukemia, 97 with chronic lymphocytic leukemia, 353 with chronic myeloid leukemia, and 95 healthy controls.. The G/G genotype was significantly more common in MDS patients (47/187; 25.1%) than in controls (6/95; 6.3%) or in patients with other leukemias (101/813; 12.4%) (all P < 0.001). Individuals with the G/G genotype were more likely than those with other genotypes to have MDS (odd ratio = 4.98; 95% CI = 2.04-12.13). Clinical and follow up data were available for 112 MDS patients and 186 AML patients. There was no correlation between EPO promoter genotype and response to therapy or overall survival in MDS or AML. In the MDS group, the GG genotype was significantly associated with shorter complete remission duration, as compared with the TT genotype (P = 0.03). Time to neutrophils recovery after therapy was significantly longer in MDS patients with the G/G genotype (P = 0.02).. These findings suggest a strong association between the rs1617640 G/G genotype and MDS. Further studies are warranted to investigate the utility of screening for this marker in individuals exposed to environmental toxins or chemotherapy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Case-Control Studies; Erythropoietin; Genetic Association Studies; Genotype; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Middle Aged; Myelodysplastic Syndromes; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Promoter Regions, Genetic; Treatment Outcome; Young Adult

To assess the effect of erythropoietin (EPO) plus granulocyte-colony stimulating factor (G-CSF) treatment on survival and leukemic transformation in myelodysplastic syndrome (MDS).. We compared the long-term outcome of patients with MDS treated with EPO plus G-CSF (n = 121) with untreated patients (n = 237) with MDS using multivariate Cox regression with delayed entry, for the first time adjusting for all major prognostic variables (WHO classification, karyotype, cytopenias, level of transfusion-need, age, and sex).. The erythroid response rate to EPO plus G-CSF was 39%, and the median response duration 23 months (range, 3 to 116+). In the multivariate analysis, treatment was associated with improved overall survival (hazard ratio, 0.61; 95% CI, 0.44 to 0.83; P = .002). Interestingly, this positive association was primarily observed in patients requiring fewer than 2 units of RBCs per month. Treatment was not linked to the rate of acute myeloid leukemia in any defined subgroup, including patients with an increase of marrow blasts or an unfavorable karyotype.. The inherent risk of leukemic evolution in MDS makes the current investigation highly relevant, in light of the recent reports of potential negative effects of EPO treatment on outcome in patients with cancer. We conclude that treatment of anemia in MDS with EPO plus G-CSF may have a positive impact on outcome in patients with no or low transfusion need, while not affecting the risk of leukemic transformation.

Topics: Aged; Anemia; Blood Transfusion; Cell Transformation, Neoplastic; Clinical Trials, Phase II as Topic; Erythropoietin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Precancerous Conditions

This study was purposed to investigate the expression of erythropoietin receptor (EPOR) in leukemic cells and the relationship of serum erythropoietin level with anemia in acute leukemia patients, so as to provide a new theoretical basis for the cytokine therapy in acute leukemia with anemia. The EPOR in 30 AL patients was detected by using reverse transcription polymerase chain reaction (RT-PCR), the level of serum erythropoietin was detected by chemiluminescence analysis, the hemoglobin level was assayed by automatic blood counting instrument. The results indicated that EPOR was expressed in 18 out of 30 AL patients, the expression rate of EPOR in AL patients was 60%, however, but the EPOR expression rate in AML was 61.9% (13/21) and 55.6% (5/9) in ALL, the EPOR expression rate was no significant difference between AML and ALL. The EPOR expression rate was significantly lower than that in control group (86.7%) (p<0.05). The relative level of EPOR expression in AML was higher than that in ALL (p<0.05), the average level of EPOR expression in AL was significantly lower than that in control group (p<0.01). The level of sEPO in 30 AL patients was significantly higher than that in control group (p<0.01), and there was negative correlation between the levels of sEPO and Hb (p<0.01). It is concluded that the EPOR is expressed in cells of AL, but the expressive level is low. The EPOR expression rate shows no significant difference between AML and ALL. The mechanism of negative feedback to anemia in acute leukemia is intact. Anemia of acute leukemia is not completely associated with inadequate erythropoietin production and relates to hemopoiesis defect that considered as the main reason. Recombinant human erythropoietin is widely used in treatment of anemia caused by acute leukemia. Whether the treatment with rh-EPO for acute leukemia with anemia will enhance the proliferation of leukemia cells, this problem should be explored further.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Case-Control Studies; Child; Child, Preschool; Erythropoietin; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Receptors, Erythropoietin; Recombinant Proteins; Young Adult

Topics: Aspartate Aminotransferases; Bone Marrow Transplantation; Child, Preschool; Combined Modality Therapy; Erythropoietin; Female; Ferritins; Graft vs Host Disease; Hemochromatosis; Humans; Leukemia, Myeloid, Acute; Liver Function Tests; Myelodysplastic Syndromes; Phlebotomy; Recombinant Proteins

In concert with its ligand, the stem cell factor (SCF), the receptor tyrosine kinase c-Kit acts as a key signaling molecule for a number of cell types, including hematopoietic stem cells, mast cells, melanocytes and germ cells. Gain-of-function mutations in c-Kit have been described in a number of human cancers, including testicular germinomas, acute myeloid leukemia and gastrointestinal stromal tumors. Yet their contribution to neoplastic growth is incompletely understood. Now Kosmider et al report the acquisition of Kit mutations in 86% of late-stage eryhtroleukemias in Spi-1/PU.1 transgenic mice. Without Kit mutations, these mice suffer from a benign disease whose hallmark is erythropoietin-dependent expansion of undifferentiated red blood cell precursors. Newly acquired Kit mutations affect codon 814 or 818, and ectopic expression of these mutants in nonmalignant pro-erythroblasts confers erythropoietin independence and tumorigenicity. Using tyrosine kinase inhibitors PP1, PP2, and imatinib mesylate (a.k.a. Gleevac), the authors demonstrate that Kit mutations are important for the autonomous expansion of malignant cells via the MEK/Erk1/2 and PI3K/Akt pathways. These findings validate the notion that one differentiation-blocking (e.g., PU.1 activation) and one proliferative (e.g., c-Kit mutations) event are required for the development of frank leukemia.

Topics: Animals; Codon; Erythropoietin; Humans; Leukemia, Erythroblastic, Acute; Leukemia, Myeloid, Acute; Mice; Mutation; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-kit; Trans-Activators

We present the case of a 71 year-old man with secondary acute myeloblastic leukemia, who was successfully treated with low dose melphalan plus Epo plus G-CSF. We treated the patient with 2 mg of melphalan once a day orally, G-CSF 5 mg/kg 3 times a week and Epo 10.000 ui subcutaneously 3 times a week until the maximum response was obtained. Complete remission was achieved after 16 weeks of continuous treatment. Treatment-related toxicity was not significant. We recommend the use of low dose melphalan in elderly patients with high risk MDS as a treatment option.

Topics: Aged; Anemia, Refractory, with Excess of Blasts; Drug Therapy, Combination; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Myelodysplastic Syndromes; Remission Induction; Risk Assessment

ABO incompatibility in allogeneic bone marrow transplantation may be associated with incomplete or delayed erythroid engraftment, being pure red cell aplasia (PRCA) the most severe complication in this setting. Attempts for the treatment of PRCA have been made with erythropoietin or with plasmapheresis with relative success, and some authors have reported the reversibility of PRCA with antilymphocyte globulin (ALG or ATG), based on the assumption that PRCA might be immunologically mediated. We report herewith a patient with acute leukemia who developed post--BMT pure red cell aplasia. His sibling donor (sister) was HLA identical and ABO incompatible, having low agglutinin titers against donor's blood group. PRCA did not improve after treatment with erythropoietin or a boost of hematopoietic progenitor cells obtained from donor's peripheral blood but the problem was resolved completely after treatment with ALG.

Topics: ABO Blood-Group System; Adolescent; Antilymphocyte Serum; Blood Group Incompatibility; Erythropoietin; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Red-Cell Aplasia, Pure; Transplantation, Homologous

Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) can stimulate megakaryopoiesis in vitro in some myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) patients. We assessed PEG-rHuMGDF combined with granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), interleukin 3 (IL-3), IL6, stem cell factor (SCF) or erythropoietin in 40 MDS, 33 AML and 16 normal bone marrow samples. CD61-positive cells in suspension cultures increased with PEG-rHuMGDF alone in 20/25 RA + RAS, 11/14 RAEB + RAEBt and 29/33 AML cases. Further increases when IL-3 and/or SCF were added to PEG-rHuMGDF occurred in 14/20 RA + RAS, 8/13 RAEB + RAEBt and 18/26 AML cases. CFU-Mk growth was poor overall, but could be enhanced by PEG-rHuMGDF combinations in some patients. Stimulation of megakaryopoiesis by PEG-rHuMGDF can be augmented by IL-3 and SCF in many MDS and AML patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Case-Control Studies; Cell Division; Cells, Cultured; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Substances; Hematopoiesis; Humans; Interleukin-3; Interleukin-6; Leukemia, Myeloid, Acute; Male; Megakaryocytes; Middle Aged; Myelodysplastic Syndromes; Platelet Count; Platelet Glycoprotein GPIIb-IIIa Complex; Polyethylene Glycols; Recombinant Proteins; Stem Cell Factor; Stimulation, Chemical; Thrombopoietin

To report a case of post-allogeneic peripheral blood stem cell transplantation (allo-PBSCT) pure red cell aplasia(PRCA) and the treatment outcome.. A patient with acute non-lymphoblastic leukemia(M2a) was treated with allo-PBSCT. His post-PBSCT PRCA was treated with plasmapheresis(2-3 times weekly) and Epo(3,000 U/day, subcutaneously).. Reticulocyte count (Ret) recovered to 0.01 at day +131 and hemoglobin reached 110 g/L at day +154. Erythroid cells in the bone marrow recovered to 0.25, and BFU-E and CFU-E within normal range. This normalized hematopoiesis remained for over 5 months after the cessation of Epo.. Post allo-PBSCT PRCA can be successfully treated with plasma exchange and Epo.

Topics: Adult; Erythropoietin; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Plasma Exchange; Red-Cell Aplasia, Pure

A 55-year-old Jehova's Witness was treated for acute myelogenous leukemia (AML) by intensive chemotherapy with enocitabine, 6-mercaptopurine and daunorubicin. G-CSF, M-CSF and EPO were subsequently administered. Even though no blood transfusion was given for religious reasons, complete remission was achieved without serious infection and hemorrhage. The total cost for induction chemotherapy was less expensive than is the case for elderly AML patients. This case indicates that the administration of cytokines might reduce the incidence of infection and the necessity for blood products, which would result in favorable cost effectiveness for the treatment of elderly patients with AML.

Topics: Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Costs and Cost Analysis; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Myeloid, Acute; Macrophage Colony-Stimulating Factor; Male; Middle Aged; Remission Induction

Erythropoietin (Epo) is a cytokine known to stimulate proliferation and differentiation of erythroid cells. However, recent gene disruption experiments demonstrated that Epo receptor signaling is not an obligatory step in erythroid differentiation. Here, we describe the role of Epo in proliferation, terminal differentiation, and apoptosis in a novel human Epo-dependent cell line, AS-E2. Upon withdrawal of Epo, the cells ceased to proliferate and underwent apoptotic death. Accompanying this cell death, an increase in the number of hemoglobin-positive cells of approximately 2-fold was observed. This was associated with immediate up-regulation of the GATA-1:GATA-2 ratio and down-regulation of Bcl-xL. Treatment with Epo or 12-O-tetradecanoyl-phorbol-13-acetate (TPA) up-regulated expression of GATA-2 and Bcl-xL, and these elevations were inhibited by inhibitors of protein kinase C (PKC), H7 and H8. HA1004, a structural analogue of H7 but a poor inhibitor of PKC, had no inhibitory effect. Therefore, in AS-E2 cells, it is likely that Epo plays a role in (a) proliferation, (b) inhibition of differentiation, and (c) survival, by maintaining GATA-2 and Bcl-xL expression through activation of PKC.

Topics: Apoptosis; bcl-X Protein; Cell Differentiation; Cell Division; DNA-Binding Proteins; Enzyme Inhibitors; Erythropoietin; GATA2 Transcription Factor; Gene Expression; Humans; Leukemia, Myeloid, Acute; Protein Kinase C; Proto-Oncogene Proteins c-bcl-2; Receptors, Erythropoietin; Signal Transduction; Transcription Factors; Tumor Cells, Cultured; Up-Regulation

A cytogenetically normal man with severe aplastic anemia was treated with granulocyte colonystimulating factor (G-CSF), erythropoietin (EPO), cyclosporin A, anti-thymocyte globulin, and interleukin-6 (IL-6), which resulted in a gradual improvement in his neutrophil count and hemoglobin level. After 2 years of the therapy, monosomy 7 was detected during cytogenetic analysis of his bone marrow, which evolved during a period of 5 months into acute myeloblastic leukemia. An in vitro proliferation assay of cytokine responses showed that leukemic blasts were sensitive only to G-CSF, and not to EPO or IL-6. Although allogeneic bone marrow transplantation from an HLA-matched unrelated donor was carried out in the non-remission stage, the patient died of systemic fungal infection on day 25, without any evidence of hematological engraftment. As long-term use of cytokines and immunomo-suppressants in patients with severe aplastic anemia may induce or hasten the onset of a malignant transformation, careful attention must be paid to clonal evolution. Due to the poor prognosis of secondary myelodysplasia and leukemia, allogeneic bone marrow transplantation for such patients must be carried out early in the course of the disease.

Topics: Adult; Anemia, Aplastic; Antilymphocyte Serum; Bone Marrow Transplantation; Chromosomes, Human, Pair 7; Cyclosporine; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Interleukin-6; Leukemia, Myeloid, Acute; Male; Monosomy

Topics: Acquired Immunodeficiency Syndrome; Anemia, Aplastic; Antineoplastic Agents; Erythropoietin; Hematopoietic Cell Growth Factors; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Neutropenia; Transplantation

A 67-year-old female was admitted with fatigue. Peripheral blood examination showed severe pancytopenia. Bone marrow biopsy revealed hypoplastic marrow. She was diagnosed as having aplastic anemia. Steroid pulse therapy was not effective. After treatment with erythropoietin (EPO) and granulocyte colony-stimulating factor (G-CSF), blasts which were positive for CD13, CD33, CD34 and HLA-DR and negative for myeloperoxidase appeared in the peripheral blood. At this time, bone marrow biopsy revealed myelofibrosis with increased blasts. Chromosome analysis showed 46XX, add (1) (p36), add (1) (q44), -2, -5, del (7) (q11), -12, +3mar. She died of pneumonia despite chemotherapy with etoposide. Administration of EPO and G-CSF may have led to the rapid development of leukemia and myelofibrosis.

Topics: Aged; Anemia, Aplastic; Erythropoietin; Fatal Outcome; Female; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Myeloid, Acute; Primary Myelofibrosis

A 34-year-old man with acute myelocytic leukemia (AML: MO) and a 32-year-old woman with AML: M2 developed pure red cell aplasia (PRCA) after receiving a major ABO incompatible bone marrow transplant (BMT). The first patient responded to recombinant human erythropoietin (rhEPO) therapy, while the second did not. The second patient also received methylprednisolone (m-PSL) but developed reticulocytosis and hemolysis after the administration of m-PSL. Plasmapheresis was then performed and the patient promptly recovered from hemolysis and PRCA. We conclude that close attention must be paid when treating PRCA following major ABO-incompatible BMT with rhEPO and m-PSL, as there is always the potential for massive hemolysis.

Topics: ABO Blood-Group System; Acute Disease; Adult; Blood Group Incompatibility; Bone Marrow Transplantation; Erythropoietin; Female; Humans; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Male; Models, Immunological; Recombinant Proteins; Red-Cell Aplasia, Pure; Remission Induction; Transplantation, Homologous

Topics: Anemia; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Leukemia, Myeloid, Acute; Middle Aged

Short-term liquid marrow culture (STLMC) is a potential source for autografting in leukemia. In a preclinical setting, including candidates for autologous marrow transplantation, we have studied STLMC supported by a selected mixture of clinical available recombinant human haematopoietic growth factors. STLMC of leukemic marrow cells were prospectively performed to evaluate the purging effect. Bone marrow cells cultured and supported by the selected mixture of rhIL-3/rhGM-CSF/rhEpo revealed an increased number of day 10-12 cultured cells, parallelled by an increased proliferation rate when compared to unstimulated cultures. The median number of myeloid progenitors recognized as day 7 and day 14 granulocyte-macrophage colony-forming units (day 7/14 GM-CFU) was significantly increased in the supported STLMC to 145/305 from 105/115 per ml culture (n = 7, p < 0.01). Further addition of rhKL did not enhance the numbers of day 7 or day 14 GM-CFUs per ml culture. In no instance was the number of clonogenic cells at the end of culture greater than the input day 0, except in cultures of purified CD34-positive marrow progenitors which resulted in an expansion of late myeloid progenitors. Cytokine-supported cultures of leukemic marrow cells from acute myeloid (n = 14) and lymphoblastic (n = 7) leukemia patients were established at the time of diagnosis. In the supported cultures, the cell number increased for myeloblast but was unchanged for lymphoblast leukemic marrow cells compared to non-supported cultures. Immunophenotypic and cytogenetic studies of selected leukemic cell samples identified unchanged myeloid or slightly reduced frequencies of lymphoblastic leukemic cells at the end of culture. This preclinical study supports the idea that the addition of a mixture of clinical available haemopoietic cytokines to STLMC increases the recovery of detectable myeloid progenitors which may enhance myeloid regeneration after autografting. No substantial selective loss of myeloid leukemic cells was found in the cytokine-supported short-term culture system.

Topics: Bone Marrow; Bone Marrow Purging; Bone Marrow Transplantation; Culture Media; Cytokines; Erythropoietin; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cells; Humans; Interleukin-3; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recombinant Proteins; Time Factors; Tumor Cells, Cultured

Most children with leukaemia are anaemic at diagnosis and at various times during treatment. Serum erythropoietin (EPO) was estimated in 27 children with acute leukaemia (n = 26) or lymphoma (n = 1) at diagnosis (n = 16), in relation to treatment with high-dose methotrexate (MTX, n = 11) or cytosine arabinoside (Ara-C, n = 8), and during oral maintenance therapy (n = 10). At diagnosis, in children with anaemia serum EPO was increased, and was inversely related to haemoglobin (Hb). After treatment with high-dose MTX, in some children serum EPO increased where Hb was unchanged or increased. After treatment with high-dose Ara-C, Hb declined, and serum EPO increased markedly in everyone. During oral maintenance therapy without significant anaemia, serum EPO was slightly increased in some children. In conclusion, children with leukaemia respond to anaemia with increased serum EPO concentration, but in relation to treatment with high-dose MTX and Ara-C, additional mechanisms may influence the EPO concentration.

Topics: Adolescent; Anemia; Child; Child, Preschool; Cytarabine; Dose-Response Relationship, Drug; Erythropoietin; Female; Hemoglobins; Humans; Infant; Leukemia, Myeloid, Acute; Longitudinal Studies; Lymphoma, Non-Hodgkin; Male; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma

The effect of erythropoietin (Epo) on colony formation by blast progenitors in acute myeloblastic leukaemia other than erythroleukaemia was studied using a blast colony assay. Epo alone did not induce colony formation, but when it was used together with phytohaemagglutinin-stimulated leucocyte-conditioned medium (PHA-LCM) the number of leukaemic colonies significantly increased in nine out of 12 cases studies. Preincubation of Epo with anti-Epo antibody completely abolished this enhancement, indicating that the increase in colony numbers was caused by Epo itself. Cell surface phenotype analysis of colonies produced by Epo plus PHA-LCM showed no increase in percentages of erythroid and megakaryocyte lineages. The addition of Epo also increased the self-renewal capacity of leukaemic blast cells. Fresh leukaemic cells did not express Epo receptors, but they were induced after incubation with PHA-LCM. The present study thus showed that the proliferative response to Epo is not restricted only to the erythroid lineage, but also extends to AML blast cells other than those in erythroleukaemia in the presence of colony stimulating factors.

Topics: Antibodies; Binding, Competitive; Erythropoietin; Humans; Leukemia, Myeloid, Acute; Neoplastic Stem Cells; Phenotype; Phytohemagglutinins; Recombinant Proteins; Tumor Stem Cell Assay

The abilities of human recombinant IL-3, GM-CSF, G-CSF, M-CSF and Epo to induce maturation in human AML cells in vitro were investigated using cell specimens from 25 AML patients. The experiments were carried out under exactly defined serum-free culture conditions. In the absence of CSFs, monocytic and/or granulocytic maturation was detected in 14/25 cases. IL-3, GM-CSF, G-CSF and M-CSF elevated the proportions of monocyte/macrophages in 3/25, 2/25, 1/25 and 6/25 cases respectively, and increased the percentages of mature granulocytes in 2/25, 1/25, 1/25 and 0/25 cases, and if so only to a limited extent (values below 50%). The 3H-thymidine (3H-TdR) uptake studies revealed that IL-3, GM-CSF, G-CSF and M-CSF were efficient stimulators of DNA synthesis of AML cells in 19, 15, 13 and four of those cases, respectively. Thus, although the cells in most cases responded to CSFs by activation of DNA synthesis, they were unable to give rise to terminally differentiated stages. Provision of CSFs in combination was more frequently effective in enhancing maturation and also increased the magnitude of maturation response. Monocytic versus granulocytic maturation of AML cells after culture did not correlate with the FAB cytology nor with the type of CSF presented; but generally granulocytic maturation was an infrequent phenomenon. Epo stimulated erythroid differentiation and DNA synthesis only in the case of erythroleukaemia, but it had no effect on the cells of 10 other AML cases. Extrapolation of these in vitro findings would suggest that CSFs would have a limited therapeutic utility to induce AML cell maturation in vivo and that hazards of stimulating blast cell proliferation with these factors may be anticipated.

Topics: Cell Transformation, Neoplastic; Colony-Stimulating Factors; Erythropoietin; Granulocyte-Macrophage Colony-Stimulating Factor; Granulocytes; Growth Substances; Humans; Interleukin-3; Leukemia, Myeloid, Acute; Macrophage Colony-Stimulating Factor; Macrophages; Monocytes; Tumor Cells, Cultured

Fresh and/or frozen bone marrow cells from five healthy individuals and seven patients with myeloid leukemia were studied using growth factors and a cytogenetic technique which allows simultaneous analysis of karotype and cell lineage. Cell lineages were identified using monoclonal antibodies in an alkaline phosphatase antialkaline phosphatase staining method. In general, cultures stimulated with a colony stimulating factor containing conditioned medium (CSF) and erythropoietin (EPO) had a higher (approximately 2-fold) mitotic index (MI) than cultures without these growth factors (maximum 7.0 vs. 3.8 after 4-day culture). The significantly higher MI in cultures with growth factors was shown to result from an increase in both erythrocytic and granulocytic-monocytic mitoses. Every culture with CSF and EPO had more erythrocytic metaphases than the identical culture without these growth factors (mean erythrocytic MI 3.1 vs. 0.3, p = 0.01 in healthy subjects; 6.9 vs. 0, p = 0.05 in leukemia). In each of the three patients showing an increased MI where lineage-specific MI was studied, the granulocytic-monocytic MI increased (mean 4.0 vs. 2.1, p = 0.05). These data suggest that growth factors increase the number of metaphases available for cytogenetic analysis from fresh or frozen marrow, and may be used to stimulate metaphases from specific lineages.

Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal; Bone Marrow; Bone Marrow Cells; Cells, Cultured; Colony-Stimulating Factors; Culture Media; Erythrocytes; Erythropoietin; Female; Granulocytes; Growth Substances; Humans; Immunoenzyme Techniques; Interphase; Karyotyping; Leukemia, Myeloid, Acute; Male; Metaphase; Middle Aged; Mitotic Index; Monocytes; Tumor Cells, Cultured

Serum erythropoietin (Epo) was measured in 23 patients before, during and after intensive cytostatic treatment courses for acute leukaemia or before bone marrow transplantation. A marked increase was seen in all patients, starting 1 or 2 d after initiation of treatment. A peak was reached after about 7 d, at levels as high as 1450 IU/l, after which Epo fell rapidly, even in patients who were anaemic at that time. In 13 of the patients there was no fall in Hb level that could explain the increase in Epo. The increase was too large to be explained by an altered Epo metabolism or marrow utilization. Cytostatic drugs cause an increase in Epo production not mediated through anaemia, possibly initiated by a cytostatic effect on the kidneys or by an unknown stimulatory factor, responsive to bone marrow inhibition.

Topics: Antineoplastic Agents; Bone Marrow Transplantation; Erythropoietin; Hemoglobins; Humans; Leukemia, Myeloid, Acute; Time Factors; Whole-Body Irradiation

Serial erythropoietin measurements by RIA were performed in six patients with acute leukemia treated by intensive chemotherapy. In all cases erythropoietin titers increased after the onset of treatment, although the hemoglobin concentration remained at stable values. Subsequently the erythropoietin titers gradually returned to baseline levels. In same patients this reduction occurred at the end of chemotherapy, in others coincident with infections and antibiotic therapy. In four patients this decrease occurred at the time of bone marrow recovery. The explanation for this inappropriate increase in erythropoietin titers is not clear but may be related to a direct or indirect effect of a suppressed marrow on sites of erythropoietin production or catabolism.

Topics: Adult; Aged; Antineoplastic Agents; Asparaginase; Cyclophosphamide; Cytarabine; Daunorubicin; Erythropoietin; Female; Humans; Leukemia; Leukemia, Myeloid, Acute; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Vincristine

The effects of human recombinant erythropoietin (rEpo) in the presence of other stimulators on the growth of clonogenic leukemic blast cells from ten Japanese patients with acute myeloblastic leukemia were studied with an in vitro leukemic blast colony assay in methylcellulose culture. With the addition of rEpo alone, no leukemic blast colony formation was stimulated in any of the cases examined. However, when rEpo and phytohemagglutinin lymphocyte-conditioned medium (PHA-LCM) were added to the culture simultaneously, in contrast to results with PHA-LCM alone, the number of leukemic blast colonies formed was significantly increased in two of the ten cases (P less than .01). These two cases were classified as M1 according to the French-American-British (FAB) classification. This enhancing effect of rEpo was observed with human recombinant granulocyte/macrophage colony-stimulating factor (rGM-CSF) or human recombinant interleukin-3 (rIL-3) but was not observed with human recombinant granulocyte CSF (rGCSF).

Topics: Cell Division; Clone Cells; Colony-Stimulating Factors; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Substances; Humans; In Vitro Techniques; Interleukin-3; Leukemia, Myeloid, Acute; Recombinant Proteins; Tumor Cells, Cultured

The response of human acute myeloid leukemia (AML) cells to the distinct hematopoietic growth factors (HGFs), ie, recombinant interleukin-3 (IL-3), granulocyte-macrophage-CSF (GM-CSF), granulocyte-CSF (G-CSF), macrophage-CSF (M-CSF), and erythropoietin (Epo) was investigated under well-defined serum-free conditions. Proliferative responses to these factors, when added separately as well as in combinations, were analyzed in 25 cases of human AML using 3H-thymidine incorporation and colony assays. The 3H-thymidine uptake data revealed that IL-3, GM-CSF, G-CSF, and M-CSF were stimulators of AML proliferation in 19, 15, 13, and 4 cases, respectively. Epo only stimulated DNA synthesis in the cells of the single erythroleukemia case. GM-CSF stimulation was seen only in IL-3 reactive cases and GM-CSF, when combined with IL-3, could not further elevate the DNA synthesis evoked by IL-3 alone. On the other hand, in six cases, G-CSF enhanced the IL-3- or GM-CSF-stimulated thymidine uptake. These results suggest that subpopulations of AML cells that are activated by distinct CSFs (eg, IL-3/GM-CSF-responsive cells and G-CSF-responsive cells) coexist. The 3H-thymidine incorporation assay was more sensitive for measuring CSF responses than methylcellulose colony cultures, since activation of DNA synthesis was more frequently seen than induction of colony formation. DNA synthesis experiments revealed eight different CSF response patterns among these 25 cases. CSF phenotyping may be a useful addition to the morphologic classification of AML, since these patterns directly reflect the ability of the proliferating subsets of AML cells to respond to the CSFs.

Topics: Cell Division; Cells, Cultured; Colony-Stimulating Factors; DNA Replication; Erythropoietin; Hematopoietic Stem Cells; Humans; Interleukin-3; Leukemia, Myeloid, Acute; Neoplastic Stem Cells

In vitro erythropoietin (Ep) responsiveness of human bone marrow mononuclear cells was determined in 12 normal human volunteers and four patients with erythroleukemia (EL), two patients with refractory anaemia with excess blasts (RAEB), and one patient with de novo acute myelogenous leukaemia (AML). The bone marrow cells were cultured in a microtitre methylcellulose system containing 30% human AB serum and human urinary Ep in concentrations ranging from 0 to 2 units/ml. Erythroid colony growth from normal marrow cultures was Ep-dependent. It was augmented by added Ep and inhibited by Ep antiserum. Marrow cells from one patient with EL and one patient with RAEB after transformation to AML had no erythroid colony formation with or without added Ep. All of the remaining patients formed 'spontaneous' or endogenous erythroid colonies (EEC) without the addition of Ep. In three of these (two with EL and one with de novo AML), the erythroid colony formation was augmented by added Ep. In three other patients (one with EL and two with RAEB), erythroid colony growth was unaffected by added Ep or Ep antiserum, and thus appeared to be Ep-independent.

Topics: Aged; Anemia; Bone Marrow; Cell Count; Cells, Cultured; Colony-Forming Units Assay; Erythropoietin; Female; Humans; Immune Sera; Leukemia, Erythroblastic, Acute; Leukemia, Myeloid, Acute; Male; Middle Aged

Topics: Bone Marrow Cells; Cells, Cultured; Chromosomes, Human, 21-22 and Y; Colony-Forming Units Assay; Demecolcine; Erythrocytes; Erythropoietin; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Monocytes

The development since 1966 of a technology for growing stem cells in vitro has provided new insights into the controls of blood cell production. Hematopoietic hormones have been purified and important cellular interactions in hematopoiesis have been defined.

Topics: Anemia, Aplastic; Cell Communication; Erythrocytes, Abnormal; Erythropoietin; Forecasting; Granulocytes; Growth; Hematopoiesis; Hematopoietic Stem Cells; Leukemia, Myeloid, Acute; Models, Biological; Polycythemia; Preleukemia; Syndrome; Technology

Erythroid colonies were grown in vitro in plasma clot cultures. Normal adult rat bone marrow responded to exogenous erythropoietin with the formation of an average of 2 colonies/10(3) cells plated. No erythroid colonies were observed in cultured normal spleen preparations. Shay chloro-leukemia cells administered iv induced an acute myelogenous leukemia. During the progressive stages of the disease, the numbers of erythrocyte colony forming units (CFU-E) in the marrow decreased; concomitantly, these progenitors appeared in leukemic spleen cultures. Paralleling changes in CFU-E, the numbers of nucleated red blood cells in the marrow declined but increased in the leukemic spleen. However, compensatory spleen erythropoiesis was transient, due to continued leukemia cell colonization. The loss of erythroid progenitor cells from the bone marrow played a significant role in the anemia associated with this leukemia.

Topics: Animals; Bone Marrow; Bone Marrow Cells; Cell Division; Clone Cells; Erythropoietin; Leukemia, Experimental; Leukemia, Myeloid, Acute; Male; Rats; Spleen

Erythropoietin level in the serum and urine of adult patients with acute leukaemia (AML, ALL, MML) was estimated by polycythaemic mouse bioassay in order to obtain more information about the associated anaemia. In AML and ALL patients the serum erythropoietin level as found to be increased and in a negative correlation with the blood haemoglobin concentration. In ALL patients erythropoietin in urine was increased regularly while in AML patients it was not. No correlation between the serum level and the urinary excretion of ESF, or between the blood Hb and the serum ESF, was found in MML patients. The results show that anaemia in leukaemia is not due to the low ESF level.

Topics: Acute Disease; Adult; Anemia; Animals; Erythropoiesis; Erythropoietin; Humans; Iron; Leukemia; Leukemia, Lymphoid; Leukemia, Monocytic, Acute; Leukemia, Myeloid, Acute; Mice; Mice, Inbred CBA

Topics: Animals; Bone Marrow; Bone Marrow Cells; Cells, Cultured; Erythropoietin; Heme; Leukemia, Lymphoid; Leukemia, Myeloid, Acute

Topics: Binding Sites, Antibody; Bone Marrow; Bone Marrow Cells; Cells, Cultured; Culture Techniques; Erythropoietin; Hematopoiesis; Hematopoietic Stem Cells; Humans; Leukemia, Lymphoid; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukocytes; Macrophages; Methods; Microscopy, Electron; Mitosis; Multiple Myeloma; Neoplasms; Phagocytosis; Thymidine; Tritium; Waldenstrom Macroglobulinemia

Topics: Erythropoietin; Humans; Leukemia, Lymphoid; Leukemia, Myeloid, Acute