losartan-potassium and Primary-Myelofibrosis

Anemia and thrombocytopenia are frequent clinical manifestations of myelofibrosis as well as important prognostic factors of the disease. Concerning the treatment of anemia, the first step should be the correction of reversible contributing factors, such as possible iron, folate and vitamin B12 deficiency. Then, treatment options include erythropoiesis stimulating agents, androgens, immunomodulating drugs, corticosteroids, and splenectomy. Anemia responses may also be observed in some patients treated with JAK inhibitors. However, most patients eventually fail to such therapies and become transfusion dependent. Some of the aforementioned therapies can also improve thrombocytopenia, but the responses are usually observed in patients with moderate platelet count decrease. Allogeneic hematopoietic stem cell transplantation, the only curative treatment of myelofibrosis, can be an alternative for selected patients with cytopenias who are refractory to conventional therapies. However, for the majority of patients, the management of anemia and severe thrombocytopenia remains an unmet need.

Topics: Algorithms; Anemia; Disease Management; Erythropoietin; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Factors; Incidence; Primary Myelofibrosis; Protein Kinase Inhibitors; Risk Factors; Splenectomy; Thrombocytopenia; Transplantation, Homologous

Anaemia is a common finding at diagnosis in myelofibrosis, and becomes a symptomatic problem in most patients with time. There are several treatment options for specific anaemia treatment, none of which has been tested in large, randomized, controlled trials. However, as myelofibrosis is not a disease with spontaneous remissions, even non-randomized trials carry weight. In this survey, the existing evidence will be analysed, both for the commonly used treatments like erythropoiesis-stimulating agents, androgens and thalidomide and for the new drugs in the area, and conclusions will be drawn concerning standard clinical anaemia treatment in myelofibrosis, which according to evidence from studies has a 40-50% chance of response in patients with not too advanced disease.

Topics: Androgens; Anemia; Blood Transfusion; Erythropoietin; Hematinics; Humans; Immunosuppressive Agents; Interferons; Lenalidomide; Nitriles; Oxymetholone; Primary Myelofibrosis; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Thalidomide

The concept of prodromal chronic myeloproliferative neoplasms has been endorsed by the WHO classification implicating a stepwise evolution of disease. Histology of the bone marrow (BM) and borderline to mildly expressed clinical features play a pivotal role for diagnosing prefibrotic-early primary myelofibrosis. By lowering the platelet count for essential thrombocythemia and regarding BM morphology, early manifestations are tackled. Pre-polycythemic stages of polycythemia vera with a low hemoglobin level at onset are diagnosed by positive JAK2V617F mutation status, a low erythropoietin value, and characteristic BM features. The revised WHO classification incorporates hematological, morphological, and molecular-genetic parameters to generate a consensus-based working diagnosis.

Topics: Bone Marrow Examination; Disease Progression; Erythrocyte Volume; Erythropoietin; Female; Humans; Janus Kinase 2; Male; Mutation; Platelet Count; Polycythemia Vera; Primary Myelofibrosis; Risk; Thrombocythemia, Essential; World Health Organization

Optimal clinical management of patients with primary myelofibrosis and post-essential thrombocythemia/polycythemia vera myelofibrosis is a challenge, given the typically advanced age of presentation and variability of the disease course and prognosis. Current medical therapeutic options have not demonstrated an impact on the disease course, which exceeds the palliation of disease-related extramedullary hematopoiesis and alleviation of cytopenias. In contrast, allogeneic stem cell transplantation (SCT) can lead to 'cure' but is limited due to patient's age or comorbidities. Currently, in patients, who are reasonable candidates, SCT (frequently with a reduced intensity conditioning regimen) is employed for intermediate- to high-risk disease. Current pharmaco-medical therapy is used as a bridge to transplant, or instead of transplant in poor transplant candidates. Pathogenetic insights, especially the discovery of the Janus kinase (JAK)2(V617F) mutation, have ushered in a host of new potential therapeutic agents that may augment the role of medical therapy. Similarly, the boundaries of transplantation continue to alter with strategies that decrease conditioning-related toxicity, improved antimicrobial prophylaxis and decreased graft-versus-host disease. The potential for continued improvements in both medical and transplant therapy suggests that for the immediate future the optimal choices for an individual patient will remain potentially volatile and present complex decisions.

Topics: Adult; Androgens; Clinical Trials as Topic; Cytostatic Agents; Disease Management; Drugs, Investigational; Erythropoietin; Etanercept; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin G; Janus Kinase 2; Middle Aged; Myeloablative Agonists; Palliative Care; Polycythemia Vera; Primary Myelofibrosis; Prognosis; Receptors, Tumor Necrosis Factor; Risk; Thrombocythemia, Essential; Transplantation Conditioning; Treatment Outcome

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

The clinical criteria for the diagnosis of essential thrombocythemia (ET) according to the polycythemia vera study group (PVSG) do not distinguish between ET and thrombocythemia associated with early stage PV and prefibrotic chronic idiopathic myelofibrosis (CIMF). The clinical criteria of the PVSG for the diagnosis of polycythemia vera (PV) only detects advanced stage of PV with increased red cell mass. The bone marrow criteria of the World Health Organization (WHO) are defined by pathologists to explicitly define the pathological criteria for the diagnostic differentiation of ET, PV, and prefibrotic and fibrotic CIMF. As the clinical PVSG and the pathological WHO criteria show significant shortcomings, an updated set of European Clinical and Pathological (ECP) criteria combined with currently available biological and molecular markers are proposed to much better distinct true ET from early PV mimicking ET, to distinguish ET from thrombocythemia associated with prefibrotic CIMF, and to define the various clinical and pathological stages of PV and CIMF that has important therapeutic and prognostic implications. Comparing the finding of clustered giant abnormal megakaryocytes in a representative bone marrow as a diagnostic clue to MPD, the sensitivity for the diagnosis of MPD associated with splanchnic vein thrombosis was 63% for increased red cell mass, 52% for low serum EPO level, 72% for EEC, and 74% for splenomegaly indicating the superiority of bone marrow histopathology to detect masked early and overt MPD in this setting. The majority of PV and about half of the ET patients have spontaneous EEC, low serum EPO levels and PRV-1 over-expression and are JAK2 V617F positive. The positive predictive value for the diagnosis of PV of spontaneous growth of endogenous erythroid colonies (EEC) of peripheral blood (PB) and bone marrow (BM) cells is about 80-85% when either PB or BM EEC assays, and up to 94% when BM and PB EEC assays were performed. The diagnostic impact of low serum EPO levels (ELISA assay) in a large study of 186 patients below the normal range (<3.3 IU/l) had a sensitivity specificity and positive predictive value of 87%, 97% and 97.8%, respectively, for the diagnosis of PV. There is a significant overlap of serum EPO levels in PV versus control and controls versus SE. The specificity of a JAK2 V617F PCR test for the diagnosis of MPD is high (near 100%), but only half of ET and MF (50%) and the majority of PV (up to 97%) are JAK2 V617F positi

Topics: Amino Acid Substitution; Biomarkers; Blood Cell Count; Bone Marrow; Cell Lineage; Colony-Forming Units Assay; Disease Progression; Enzyme-Linked Immunosorbent Assay; Erythrocyte Volume; Erythroid Precursor Cells; Erythropoietin; GPI-Linked Proteins; Humans; Isoantigens; Janus Kinase 2; Membrane Glycoproteins; Mutation, Missense; Point Mutation; Polycythemia Vera; Polymerase Chain Reaction; Predictive Value of Tests; Primary Myelofibrosis; Receptors, Cell Surface; Sensitivity and Specificity; Thrombocythemia, Essential; World Health Organization

Topics: Benzamides; Chronic Disease; Darbepoetin alfa; Erythropoietin; Hematopoietic Stem Cell Transplantation; Humans; Hydroxyurea; Imatinib Mesylate; Interferon-alpha; Piperazines; Primary Myelofibrosis; Protein-Tyrosine Kinases; Pyrimidines; Quinazolines; Recombinant Proteins; Splenectomy; Thalidomide

The pathogenetic mechanisms underlying the clonal myeloproliferation and reactive marrow fibrosis that characterize myelofibrosis with myeloid metaplasia (MMM) are poorly understood. Recent advances into the pathophysiology of the disease have not yet translated into effective therapeutic options for patients. There is no standard treatment, and no therapies identified yet, besides allogeneic stem cell transplantation, that will significantly change the natural history of MMM. Treatment is therefore palliative and is geared towards alleviating symptoms of the disease and improving blood counts. Conventional therapies for anemia include androgens and corticosteroids. Cytoreductive agents such as hydroxyurea are indicated for symptomatic organomegaly and the control of leucocytosis or thrombocytosis. Several novel agents have been investigated in the recent past, and include antiangiogenic agents and signal transduction inhibitors that target the angiogenic and fibrogenic cytokines that have been implicated in the pathogenesis of the detrimental bone marrow stromal reaction. Ultimately, an improved understanding of the biological factors that cause the clonal myeloproliferation in MMM will lead to the development of effective therapeutic interventions.

Topics: Androgens; Angiogenesis Inhibitors; Antineoplastic Agents; Azacitidine; Benzamides; Chronic Disease; Decitabine; Erythropoietin; Humans; Imatinib Mesylate; Piperazines; Primary Myelofibrosis; Pyrimidines; Quinolones; Recombinant Proteins

Recombinant human erythropoietin (rHuEPO) is an effective treatment for the anaemia that occurs secondary to various conditions, but its role in myelofibrosis with myeloid metaplasia (MMM) is not well established. rHuEPO, at an initial dose of 10 000 U thrice a week, was given to 20 patients with MMM and anaemia. Complete response (CR) was defined as transfusion cessation with normal haemoglobin (Hb) levels and partial response (PR) as a transfusion decrease > or =50% and Hb > 10 g/dl maintained for at least 8 weeks. Nine patients (45%) showed a favourable response to treatment, including four CR and five PR, four of whom have maintained their response at a median follow-up of 12.5 months (range: 4-21 months) from the start of treatment. The pretreatment factors associated with a favourable response were lack of transfusion requirement (P = 0.002) and higher Hb at start treatment of (P = 0.01). An analysis of the present series (n = 20) and 31 patients from the literature identified 28 (55%) favourable responses to rHuEPO, including 16 CR and 12 PR. In the multivariate analysis, serum erythropoietin level <125 U/l was found to be associated with a favourable response to rHuEPO, whereas lack of transfusional support had borderline significance.

Topics: Aged; Aged, 80 and over; Anemia; Erythropoietin; Female; Humans; Male; Middle Aged; Primary Myelofibrosis; Recombinant Proteins

Anemia is a common finding in patients with hematologic malignancies and most commonly can be attributed to the anemia of chronic disease compounded by the myelotoxic effects of chemotherapy. Symptoms of anemia include fatigue, and the patient's quality of life may be impaired. Possible treatments for the anemia are to do nothing, to transfuse with red cells, or to treat with recombinant human erythropoietin (rhEPO). rhEPO has become standard treatment for the anemia in chronic renal failure and has been successfully used in anemia secondary to malignancy. In patients with lymphoproliferative diseases, rhEPO increases the hemoglobin concentration, decreases the need for transfusion, and improves the patients' quality of life. Disadvantages of rhEPO include its cost, efficacy in only around 60% of patients, and delay of 4 to 8 weeks before maximum benefit is achieved. The anemia in patients with myelodysplasia responds less well to rhEPO. Misuse of rhEPO is common in the clinical setting but usually not of clinical importance. Misuse to enhance sporting prowess is probably rare but has potentially serious consequences.

Topics: Anemia; Doping in Sports; Erythropoietin; Humans; Lymphoproliferative Disorders; Medication Errors; Myelodysplastic Syndromes; Primary Myelofibrosis; Treatment Outcome

Topics: Aged; Erythropoietin; Fatal Outcome; Hematopoiesis, Extramedullary; Humans; Iron Overload; Leukemia, Erythroblastic, Acute; Male; Postoperative Complications; Primary Myelofibrosis; Spleen; Splenectomy; Splenomegaly; Transfusion Reaction

Experience with recombinant human erythropoietin (rHuEPO) in the treatment of the anemia secondary to myelofibrosis with myeloid metaplasia (MMM) is slight up to now. We present our results of the treatment of 6 patients and a review of the literature in search of possible parameters predicting response to this treatment.. From January 1994 to June 1996 all transfusion-dependent patients with MMM diagnosed in our hospital were included in this study. We established a minimum period of 4 weeks of treatment and a maximum of 12 if no response was observed. Initial dosages used were 100 U/kg s.c. 3 times weekly, increasing by 50 U/kg every 4 weeks where no response was observed. Response was defined as a reduction > or = 30% of the previous transfusional needs. The review of the literature was made using a MEDLINE search (January 1990-December 1996) on the keywords erythropoietin, myelofibrosis, and agnogenic myeloid metaplasia. A statistical study was made in search of possible parameters to predict response. The parameters studied include age, sex, hemoglobin, serum erythropoietin (sEPO) levels, transfusional dependency, transfusional requirements per month prior to treatment, maximum dosages used and dosage at which response was obtained.. Only 2 of our 6 patients responded, both at a dosage of 600 U/kg/week (200 U/kg 3 times weekly s.c.). In addition to our 6 patients we have found only 28 other patients in the literature. For statistical calculation 2 of our patients were not considered as they did not complete the period of study. The overall rate of response was 17/32 (53.1%). In the univariate analysis comparing responders and non-responders we found a tendency to significance with respect to sex (p = 0.07), sEPO (p = 0.07) and transfusional needs in units of packed red blood cells per month (PRBC/m) (p = 0.13). In this way patients with low sEPO, females and those with low transfusional needs (< 3 PRBC/m) respond better. This better response in females could be explained by the fact that their disease situation was more stable (with both lower sEPO levels and transfusional dependency). The best cut-off point in the sEPO to predict response was 123 mU/mL. No important side-effects have been observed except three cases of aggravation of splenomegaly. In two cases this condition improved when the rHuEPO was discontinued. The association of rHuEPO with hydroxyurea or interferon does not seem to affect the response.. Though the number of patients is low, our data suggest that some MMM patients, in particular females and individuals with low sEPO levels and with low transfusional needs, might benefit from rHuEPO in terms of elevation of hemoglobin levels. Unfortunately, transfusion dependent-patients, i.e. those in whom a beneficial effect of rHuEPO would be most welcome, are unlikely to respond, and more generally, treatment is not cost effective in medically responsive patients.

Topics: Aged; Aged, 80 and over; Anemia; Erythropoietin; Female; Humans; Male; Primary Myelofibrosis; Recombinant Proteins

Idiopathic myelofibrosis is the least common and carries the worst prognosis of the chronic myeloproliferative disorders. The primary disease process is a clonal haematopoietic stem cell disorder which results in a chronic myeloproliferation and an atypical megakaryocyte hyperplasia. In contrast, the characteristic stromal proliferation is a reactive phenomenon, resulting from the inappropriate release of megakaryocyte/platelet-derived growth factors, including PDGF, TGF-beta bFGF and calmodulin. The median survival is approximately 4 years, although individual survival varies greatly. A variety of prognostic schema have been developed which enable the identification of high-risk patients, for whom bone marrow transplantation should be considered. Management for the majority of patients, however, is directed towards the alleviation of symptoms and improvement in quality of life. This review summarizes the recent advances in our understanding of the disease's pathogenesis and discusses the limited therapeutic options available to clinicians.

Topics: Anemia; Animals; Bone Marrow; Bone Marrow Transplantation; Cladribine; Combined Modality Therapy; Disease Models, Animal; Erythropoietin; Growth Substances; Hematopoietic Stem Cells; Humans; Hydroxyurea; Interferon-alpha; Karyotyping; Megakaryocytes; Mice; Polyethylene Glycols; Primary Myelofibrosis; Prognosis; Recombinant Proteins; Splenectomy; Stromal Cells; Thrombopoietin; Vitamin D

Polycythemia vera shares basic features of pathogenesis with other subtypes of the group of chronic myeloproliferative disorders. All myelopoietic cells are derived from one transformed hemopoietic stem cell. Genetic instability of mitotic clonal cells explains the risk of leukemic transformation, which may be enhanced by cytoreductive treatment. Recent data show that erythroid hyperplasia is not due to erythropoietin hypersensitivity, but rather to abnormal stimulation by other cytokine growth factors. Treatment as established by clinical trials has almost normalized life expectancy in older patients, but the optimal strategy for subgroups of patients is still unknown. For younger patients, new and potentially curative approaches should be investigated.

Topics: Animals; Chronic Disease; Clinical Trials as Topic; Cytokines; Disease Progression; Erythropoietin; Growth Substances; Humans; Life Expectancy; Polycythemia Vera; Practice Guidelines as Topic; Primary Myelofibrosis; Rabbits

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: Arteries; Basophils; Blood Platelets; Blood Volume Determination; Bone Marrow; Erythrocytes; Erythropoiesis; Erythropoietin; Granulocytes; Hematocrit; Hemoglobins; Hepatomegaly; Humans; Megakaryocytes; Myeloproliferative Disorders; Osteosclerosis; Oxygen Consumption; Polycythemia; Polycythemia Vera; Primary Myelofibrosis; Splenomegaly

Erythropoiesis-stimulating agents (ESAs) are commonly used to treat the anemia of myelofibrosis (MF), but information on the predictors of response is limited.. Results of ESA therapy were analyzed in 163 MF patients with severe anemia, most of whom had inadequate erythropoietin (EPO) levels (<125 U/L) at treatment start.. Besides the already established predictive value of EPO levels, these data can help to identify which MF patients are more likely to benefit from ESA treatment.

Topics: Aged; Anemia; Disease-Free Survival; Erythropoietin; Female; Ferritins; Hematinics; Humans; Leukocyte Count; Male; Middle Aged; Primary Myelofibrosis; Sex Factors; Spain; Survival Rate; Thrombosis

Patients with chronic idiopathic myelofibrosis (CIMF) usually present with anaemia. Treatment is often palliative and the majority of patients receive regular red blood cell (RBC) transfusions. Although recombinant human erythropoietin (rhu-EPO) has been proved effective for the treatment of anaemia in several chronic diseases, including haematological malignancies, its role in the treatment of the anaemia in CIMF is not well established. We report the beneficial effect of rhu-EPO administration in 20 patients with CIMF and discuss the parameters predicting favourable response.. Twenty patients with CIMF (9 women and 11 men) regularly treated with supportive RBC transfusions were included in the study. The median age was 70 years (range 45-81 years). Rhu-EPO, 10,000 U, was given subcutaneously 3 times a week. The median duration of therapy was 83 months, ranging from 13 to 87 months.. Treatment was considered effective if haemoglobin levels increased over 2 g/dl within 12 weeks after enrolment or the RBC transfusion requirements were reduced by 50% within the same interval. Twelve patients (60%) responded to therapy. Responders were mainly female, had smaller spleen size (p = 0.024), low RBC transfusion requirements (< or = 1-2 units per month), and significantly lower endogenous serum erythropoietin (EPO) and beta2-microglobulin (beta2-M) levels when compared with non-responders (p < 0.0001 and 0.00001, respectively). Treatment was well tolerated and none of the patients was withdrawn from the treatment protocol because of side effects.. Rhu-EPO administration is an effective, safe and well-tolerated treatment for patients with CIMF and anaemia leading to a significant reduction in RBC transfusion requirements. Factors predicting favourable response are low endogenous EPO and beta2-M serum levels and slight to moderate splenomegaly.

Topics: Aged; Aged, 80 and over; Anemia; beta 2-Microglobulin; Chronic Disease; Erythrocyte Transfusion; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Primary Myelofibrosis; Recombinant Proteins; Spleen; Treatment Outcome

Darbepoetin-alpha, a novel hyperglycosylated erythropoiesis-stimulating protein, was administered to 20 patients with myelofibrosis with myeloid metaplasia and anaemia. The initial weekly dose, 150 mug, was increased to 300 mug when no response was observed after 4-8 weeks. Eight patients (40%) responded to treatment, including six complete and two partial responses, and five maintained their response at a median follow-up of 12 months (range 4-22). Univariate analysis indicated that older age was the only factor associated with a favourable response to treatment (P = 0.006). None of the patients with appropriate serum erythropoietin levels responded. Treatment was usually well tolerated.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Anemia; Darbepoetin alfa; Erythropoietin; Female; Follow-Up Studies; Humans; Male; Middle Aged; Primary Myelofibrosis; Treatment Outcome

Topics: Adrenal Cortex Hormones; Child, Preschool; Drug Therapy, Combination; Erythropoietin; Female; Humans; Infant; Male; Primary Myelofibrosis; Remission Induction; Thalidomide; Treatment Outcome

Thirteen patients with idiopathic myelofibrosis (5 osteomyelosclerosis) were treated with recombinant human erythropoietin (rHuEpo) for transfusion-dependent anemia. All but 7 patients were concomitantly treated with alpha interferon, and 5 patients also received a interferon before the start of erythropoietin (EPO) treatment. All but two patients became transfusion independent. The highly positive results of the present study of transfusion-dependent patients with idiopathic myelofibrosis calls for further studies to delineate more precisely in larger series those patients who are likely to respond to rHuEpo.

Topics: Aged; Aged, 80 and over; Anemia; Blood Transfusion; Danazol; Drug Therapy, Combination; Erythropoietin; Female; Hemoglobins; Humans; Interferon-alpha; Male; Middle Aged; Primary Myelofibrosis; Recombinant Proteins

The efficacy and safety of recombinant human erythropoietin (rhEPO) were tested when given subcutaneously (s.c.) in an escalating dose of 2000-10,000 units (U) daily in 60 patients with cancer-related anaemia (CRA). A positive response, defined as an increase in haemoglobin more than 2 g/dl and independence of blood transfusions was observed in 23 of 48 evaluable patients (48%) within a median of 8 wk. In detail, rhEPO corrected anaemia in 11 of 14 patients (79%) with malignant lymphoma, in 8 of 15 patients (53%) with multiple myeloma and in 4 of 10 patients (40%) with a solid tumour. The median dose of rhEPO in successful cases was 5000 U daily. Four patients with agnogenic myeloid metaplasia and 5 with myelodysplastic disorder failed to respond to rhEPO. No patient had any severe side effects. Pretreatment serum erythropoietin levels appeared to be a weak predictor for response to rhEPO treatment. In conclusion, rhEPO seems to be safe and effective in correcting CRA in certain groups of patients.

Topics: Adolescent; Adult; Aged; Anemia; Blood Transfusion; Erythropoietin; Female; Ferritins; Hematocrit; Hemoglobins; Humans; Injections, Subcutaneous; Iron; Lymphoma; Male; Middle Aged; Multiple Myeloma; Myelodysplastic Syndromes; Neoplasms; Primary Myelofibrosis; Recombinant Proteins; Reticulocyte Count; Transferrin

We have used recombinant human erythropoietin (rHuEPO) in a phase I/II clinical trial to evaluate its ability to reverse refractory anemia in hematologic disorders. rHuEPO was administered subcutaneously 5 days per week at escalating doses (50 to 150 U/kg per day). The aim of treatment was a hemoglobin (Hb) level greater than or equal to 10 g/dL without blood transfusion. Of 25 patients treated, 17 were evaluable, most of them with a regular need for transfusion. Eight of these had lymphoproliferative disorders (three cases of malignant lymphoma and five of monoclonal gammopathy) and were exposed to cytotoxic therapy. The other nine patients had hematopoietic stem cell disorders (four cases of myelodysplastic syndrome, three of idiopathic myelofibrosis, and two of chronic myelogenous leukemia). All patients with lymphoproliferative disorder had serum EPO levels inappropriately low for the degree of anemia, while patients with stem cell disorder showed variable values. Erythroid marrow activity was inadequate in all cases. Seven of eight patients with lymphoproliferative disorder responded to treatment maintaining Hb above 10 g/dL without transfusion. The median dose of rHuEPO required for correction of anemia was 75 U/kg. In four cases response was maintained with 50 U/kg, three times per week. There was no complete response among patients with hematopoietic stem cell disorder, although transfusion requirement was eliminated or reduced in four cases. Four patients developed functional iron deficiency during rHuEPO treatment and required iron supplementation to obtain response. Aggravation of splenomegaly was observed in two cases of myeloproliferative disorder. We conclude that: (1) subcutaneous administration of rHuEPO can be effective and safe in patients with lymphoproliferative disorder exposed to chemotherapy and showing inappropriate EPO response to anemia; (2) this is less likely in hematopoietic stem cell disorders, although favorable responses may be observed in occasional patients; and (3) functional iron deficiency as a cause of nonresponse to rHuEPO is frequent also in nonrenal anemia.

Topics: Adult; Aged; Anemia, Refractory; Bone Marrow; Drug Evaluation; Erythroid Precursor Cells; Erythropoietin; Female; Ferritins; Hematologic Diseases; Humans; Iron; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Lymphoproliferative Disorders; Male; Middle Aged; Myelodysplastic Syndromes; Primary Myelofibrosis; Receptors, Transferrin; Recombinant Proteins

According to the current treatment recommendations, anagrelide, an oral antiplatelet agent, is recommended as a second-line therapy for patients with high-risk essential thrombocythemia experiencing intolerance or refractoriness to first-line approach, such as hydroxyurea or pegylated interferon alpha-2a. If there is a need for introduction of cytoreductive treatment in young patients with a perspective of lifelong exposure, both the efficacy and long-term outcomes should be known. We present the analysis of 48 young patients, diagnosed with essential thrombocythemia below the age of 60, who were exposed to anagrelide treatment for over 10 years. Our observations show that the highest proportion of complete remissions without adverse events and disease progression is seen in the JAK2-mutated patients. By evaluating the changes in hemoglobin concentration and serum erythropoietin throughout the study, we were able to reveal the development of progressive anemia, resulting from diminished susceptibility to erythropoietin and unrelated to bone marrow fibrosis, in patients harboring CALR mutation. Additionally, occurrence of new bone marrow fibrosis was confirmed in seven JAK2-unmutated patients at the end of the study. In summary, in young patient population, we recommend limiting the use of anagrelide to JAK2-mutated subgroup, reducing exposure time and underline the importance of periodic monitoring for the presence of bone marrow fibrosis.

Topics: Child; Erythropoietin; Humans; Platelet Aggregation Inhibitors; Primary Myelofibrosis; Quinazolines; Thrombocythemia, Essential

Topics: Calreticulin; Disease Progression; DNA Mutational Analysis; Erythropoietin; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Factors; Janus Kinase 2; Male; Middle Aged; Mutation; Polycythemia Vera; Primary Myelofibrosis; Transplantation, Homologous; Treatment Outcome

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Disease Progression; Erythropoietin; Female; Humans; Male; Middle Aged; Phenotype; Polycythemia Vera; Primary Myelofibrosis; Prognosis; Thrombocythemia, Essential; Young Adult

We describe a novel ERBB1/EGFR somatic mutation (p. C329R; c.985 T > C) identified in a patient with JAK2

Topics: Amino Acid Sequence; Cell Differentiation; Cell Line, Tumor; Clone Cells; ErbB Receptors; Erythroblasts; Erythropoietin; Gene Expression; Humans; Janus Kinase 2; Leukemia, Erythroblastic, Acute; Mutation; Polycythemia Vera; Primary Myelofibrosis; Protein Multimerization; Sequence Alignment; Sequence Homology, Amino Acid; Signal Transduction

Polycythemia Vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms respectively characterized by erythrocytosis and thrombocytosis; other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus, and risk of leukemic or fibrotic transformation.. PV is defined by a JAK2 mutation, whose absence, combined with normal or increased serum erythropoietin level, makes the diagnosis unlikely. JAK2, CALR, and MPL mutations are the mutually exclusive "driver" mutations in ET with respective incidences of 55%, 25%, and 3%; approximately 17% are triple-negative. However, the same molecular markers might also be present in prefibrotic myelofibrosis, whose morphological distinction from ET is prognostically relevant.. Median survivals are approximately 14 years for PV and 20 years for ET; the corresponding values for younger patients (age <60 years) are 24 and 33 years. Life-expectancy in ET is inferior to the control population. Driver mutational status has not been shown to affect survival in ET whereas the presence of JAK2/MPL mutations has been associated with higher risk of arterial thrombosis and that of MPL with higher risk of fibrotic progression. Risk factors for overall survival in both ET and PV include advanced age, leukocytosis and thrombosis. Leukemic transformation rates at 20 years are estimated at <10% for PV and 5% for ET; fibrotic transformation rates are slightly higher. Most recently, ASXL1, SRSF2, and IDH2 mutations have been associated with inferior overall, leukemia-free or fibrosis-free survival in PV; similarly adverse mutations in ET included SH2B3, SF3B1, U2AF1, TP53, IDH2, and EZH2.. Current risk stratification in PV and ET is designed to estimate the likelihood of recurrent thrombosis. Accordingly, PV includes two risk categories: high-risk (age >60 years or thrombosis history) and low-risk (absence of both risk factors). In ET, risk stratification includes four categories: very low risk (age ≤60 years, no thrombosis history, JAK2/MPL un-mutated), low risk (age ≤60 years, no thrombosis history, JAK2/MPL mutated), intermediate risk (age >60 years, no thrombosis history, JAK2/MPL un-mutated), and high risk (thrombosis history or age >60 years with JAK2/MPL mutation). In addition, presence of extreme thrombocytosis (platelets >1000 × 10(9)/L) might be associated with acquired von Willebrand syndrome (AvWS) and, therefore, risk of bleeding.. The main goal of therapy in PV and ET is to prevent thrombohemorrhagic complications. All patients with PV require phlebotomy to keep hematocrit below 45% and once-daily aspirin (81 mg). In addition, high-risk patients with PV require cytoreductive therapy. Very low risk ET patients might not require any form of therapy while low-risk patients require at least once-daily aspirin therapy. Cytoreductive therapy is also recommended for high-risk ET patients but it is not mandatory for intermediate-risk patients. First-line drug of choice for cytoreductive therapy, in both ET and PV, is hydroxyurea and second-line drugs of choice are interferon-α and busulfan. We currently do not recommend treatment with ruxolutinib or other JAK2 inhibitors in PV or ET, unless in the presence of severe and protracted pruritus or marked splenomegaly that is not responding to the aforementioned drugs. Screening for AvWS is recommended before administrating aspirin, in the presence of extreme thrombocytosis. Am. J. Hematol. 92:95-108, 2017. © 2016 Wiley Periodicals, Inc.

Topics: Aspirin; Calreticulin; Diagnosis, Differential; Erythropoietin; Humans; Hydroxyurea; Interferon-alpha; Janus Kinase 2; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mutation; Polycythemia Vera; Primary Myelofibrosis; Receptors, Thrombopoietin; Risk Assessment; Thrombocythemia, Essential; Thrombocytosis

Myelofibrosis (MF) is characterized by shortened survival and a greatly compromised quality of life. Weight loss and cachexia seem to be the most important factors influencing survival in patients with MF. The aim of this study was to assess the efficacy of an integrated supportive therapy in improving cachexia and MF-related symptoms.. We reported on a case of a patient with MF who presented with weight loss and cachexia associated with severe anemia, fatigue, fever, and bone pain. The circulating levels of inflammatory, oxidative stress parameters, hepcidin, and erythropoietin were evaluated and were above normal ranges. The patient was treated with a multitargeted approach specifically developed for cachexia including oral l-carnitine, celecoxib, curcumin, lactoferrin, and subcutaneous recombinant human erythropoietin (EPO)-α.. Surprisingly, after 1 y, cachexia features improved, all MF symptoms were in remission, and inflammatory and oxidative stress parameters, hepcidin, and EPO were reduced.. Because our protocol was targeted at inflammation and the metabolic state, its effectiveness may emphasize the role of inflammation in the pathogenesis of MF symptoms and demonstrates a need for the study of new integrated therapeutic strategies.

Topics: Anemia; C-Reactive Protein; Cachexia; Carnitine; Celecoxib; Curcumin; Erythropoietin; Fatigue; Ferritins; Fever; Hepcidins; Humans; Interleukin-6; Iron; Lactoferrin; Male; Middle Aged; Oxidative Stress; Patient Compliance; Primary Myelofibrosis; Quality of Life; Reactive Oxygen Species; Recombinant Proteins; Treatment Outcome; Tumor Necrosis Factor-alpha; Weight Loss

Myeloproliferative neoplasms (MPNs) are associated with recurrent activating mutations of signaling proteins such as Janus kinase 2 (JAK2). However, the actual downstream signaling events and how these alter myeloid homeostasis are poorly understood. We developed an assay to measure basal levels of phosphorylated signaling intermediates by flow cytometry during myeloid differentiation in MPN patients. Our study provides the first systematic demonstration of specific signaling events and their comparison with disease phenotype and JAK2 mutation status. We demonstrate increased basal signaling in MPN patients, which occurs in both early and later stages of myeloid differentiation. In addition, the pattern of signaling is not correlated with JAK2 mutation status and signaling intensity is poorly correlated with mutant JAK2 allele burden. In contrast, signaling differences are detected between different MPN disease phenotypes. Finally, we demonstrate that signaling can be inhibited by a JAK2-selective small molecule, but that this inhibition is not JAK2 V617F specific, because MPN patients with mutant JAK2, wild-type JAK2, and control patients were inhibited to a similar degree. Our data suggest that, in addition to JAK2 mutations, other factors contribute significantly to the MPN phenotype, results that are relevant to both the pathogenesis and therapy of MPN.

Topics: Aged; Blotting, Western; Cell Line, Tumor; Erythropoietin; Female; Flow Cytometry; Genotype; Hematopoietic Stem Cells; Humans; Intracellular Space; Janus Kinase 2; Male; Middle Aged; Mutation; Myeloproliferative Disorders; Phenotype; Phosphoproteins; Phosphorylation; Polycythemia Vera; Primary Myelofibrosis; Pyrimidines; Signal Transduction; Sulfonamides; Thrombocythemia, Essential

Tn order to set up a mouse model of myelofibrosis (MF) induced with high dose recombinant human erythropoietin (rhEPO). 60 mice were collected and divided into EPO and control groups, the former was injected with rhEPO and the latter with normal saline intraperitoneally. 5 mice from each group were executed on day 6, 30, 60, 90, 120 and 150 respectively. Their WBC count, Hb level, MCV, RDW and platelet amount were measured by automatic blood cell analyzer; CD34(+) cell ratio in bone marrow were analyzed by flow cytometry; liver and spleen coefficients were measured; pathological changes of liver, spleen, femur were observed by HE staining and reticular fibers staining; cortex thickness, femoral canal diameter and lumbar spine density were determined by computerized tomography (CT). The results indicated that as compared with normal control group in EPO induced group, WBC count was increased slightly in whole period, but without statistic significance (p > 0.05), Hb level and RDW increased at day 6 and 30 significantly (p < 0.05), MCV increased at day 6 significantly (p < 0.05), but platelet amount decreased significantly at all time points (p < 0.05). Most mice in EPO-induced group had hepatomegalia and their liver and spleen coefficient increased significantly at day 60 (p < 0.05), while most mice had splenomegaly and its coefficient was increased significantly at all time-points (p < 0.05). CD43(+) cell ratio of EPO group increased significantly in whole period (p < 0.05). CT scanning displayed femoral cortical thickening, medulla canal narrowing and lumbar spine density increasing at day 150, meanwhile, HE staining and reticular fiber staining showed the fatty degeneration or vacuolization in liver, splenomegaly with megakaryocytic proliferation, femur bone marrow fibrosis and osteosclerosis. It is concluded that the mouse induced by high dose of rhEPO displays the myelofibrosis associated with splenic extramedullary hemopoiesis, and this study is useful to establish a practical MF model, and to explore its pathological mechanism.

Topics: Animals; Disease Models, Animal; Erythropoietin; Female; Humans; Mice; Mice, Inbred Strains; Primary Myelofibrosis; Recombinant Proteins

Topics: Aged; Erythrocyte Transfusion; Erythropoietin; Female; Follow-Up Studies; Hematinics; Humans; Male; Primary Myelofibrosis

Previous prognostic studies in primary myelofibrosis have focused on risk factors for overall survival and have resulted in the establishment of several prognostic scoring systems. However, to the authors' knowledge, information regarding risk factors for leukemic transformation in primary myelofibrosis is limited.. The current retrospective study examined clinical variables at the time of diagnosis and specific treatment modalities for their effect on leukemic transformation in 311 patients with primary myelofibrosis who were seen at the Mayo Clinic.. Univariate analysis of parameters at the time of diagnosis revealed a significant association between inferior leukemia-free survival and a peripheral blood blast percentage>or=3 (P<.0001), a platelet count<100x10(9)/L (P=.004), a monocyte count>or=1x10(9)/L (P=.02), the presence of hypercatabolic symptoms (P=.03), a low hemoglobin level (P=.04), and a high leukocyte count (P=.04). The first 2 parameters were found to maintain their statistical significance during multivariate analysis. Neither leukemia-free nor overall survival was found to be affected by the presence of <3% peripheral blood blasts or JAK2V617F mutation. The evaluation of treatment effect on leukemic transformation unexpectedly revealed a significant and independent association with previous therapy with either erythropoiesis-stimulating agents (P=.004) or danazol (P=.007), even when the aforementioned prognostic indicators at the time of diagnosis were added as covariates to the multivariate model. In contrast, leukemia-free survival was not found to be affected by a treatment history with hydroxyurea, thalidomide, or other drugs.. A peripheral blood blast percentage>or=3 and/or a platelet count<100x10(9)/L at the time of diagnosis were found to be strong and independent predictors of leukemic transformation in patients with primary myelofibrosis. The unexpected association between leukemic transformation and a history of treatment with erythropoiesis-stimulating agents or danazol requires validation by prospective studies.

Topics: Cell Transformation, Neoplastic; Danazol; Erythropoietin; Female; Humans; Leukemia; Male; Middle Aged; Primary Myelofibrosis; Risk Factors

Patients who have myelofibrosis with myeloid metaplasia (MMM) display recurrent, albeit nonspecific cytogenetic abnormalities that are diverse prognostically. For the current study, the authors explored the relation between specific cytogenetic clones and JAK2(V617F) mutational status in patients with MMM and the effects on treatment response to erythropoietin (Epo).. Concomitantly collected blood granulocytes and bone marrow were processed for JAK2(V617F) mutation analysis and cytogenetic studies, respectively. Genomic DNA was amplified by polymerase chain reaction, and fluorescent dye chemistry sequencing was performed by using the same primers that were used for amplification.. Among 105 study patients, cytogenetic abnormalities were detected in 47 patients (45%), and the JAK2(V617F) mutation was detected in 52 patients (50%). Comparison of mutational frequencies between favorable (normal, sole 13q-, or 20q- clones; n = 70 patients) and unfavorable (all other abnormalities; n = 35 patients) cytogenetic categories revealed a significantly different incidence of homozygous JAK2(V617F) between them (9% vs. 23%, respectively; P = .04). Furthermore, the mutant allele coexisted with several recurrent cytogenetic lesions. Among 25 patients who received Epo either alone (n = 17 patients) or in combination with hydroxyurea (n = 8 patients), 4 patients (16%) achieved a response, and none of them were homozygous for JAK2(V617F). Conversely, a response was more likely (P = .0001) in the presence of favorable cytogenetic abnormalities (i.e., 3 of 4 responders carried sole 13q- or 20q- clones).. Unfavorable and favorable cytogenetic clones in MMM clustered with homozygosity for JAK2(V617F) and treatment response to Epo-based therapy, respectively.

Topics: Clone Cells; DNA Mutational Analysis; Erythropoietin; Homozygote; Humans; Janus Kinase 2; Mutation; Primary Myelofibrosis; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Signal Transduction; Treatment Outcome

Activation of JAK2 by chromosomal translocation or point mutation is a recurrent event in hematopoietic malignancies, including acute leukemias and myeloproliferative disorders. Although the effects of activated JAK2 signaling have been examined in cell lines and murine models, the functional consequences of deregulated JAK2 in the context of human hematopoietic cells are currently unknown. Here we report that expression of TEL-JAK2, a constitutively active variant of the JAK2 kinase, in lineage-depleted human umbilical cord blood cells results in erythropoietin-independent erythroid differentiation in vitro and induces the rapid development of myelofibrosis in an in vivo NOD/SCID xenotransplantation assay. These studies provide functional evidence that activated JAK2 signaling in primitive human hematopoietic cells is sufficient to drive key processes implicated in the pathophysiology of polycythemia vera and idiopathic myelofibrosis. Furthermore, they describe an in vivo model of myelofibrosis initiated with primary cells, highlighting the utility of the NOD/SCID xenotransplant system for the development of experimental models of human hematopoietic malignancies.

Topics: Animals; Erythropoiesis; Erythropoietin; Gene Expression; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Oncogene Proteins, Fusion; Primary Myelofibrosis; Recombinant Proteins; Signal Transduction; Transduction, Genetic; Transplantation, Heterologous

Topics: Acute Disease; Anemia, Refractory; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cytarabine; Erythropoietin; Etoposide; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Myeloid; Male; Methotrexate; Middle Aged; Mitoxantrone; Peripheral Blood Stem Cell Transplantation; Postoperative Complications; Primary Myelofibrosis; Recombinant Proteins; Transplantation Conditioning; Transplantation, Autologous; Whole-Body Irradiation

Controversy continues to persist about the role of histopathology regarding diagnosis of polycythemia vera (PV). For this reason, a clinicopathological study was performed on 334 patients presenting with a sustained borderline to marked erythrocytosis (hemoglobin >17 g/dl in men and >15 g/dl in women). The aim was to elucidate the discriminating impact of bone marrow biopsy examinations in an independent fashion from laboratory parameters. According to morphological findings based on a semiquantitative evaluation of standardized features, cellularity, megakaryocytes (quantity, size, pleomorphous aspect, clustering, nuclear lobulation), eosinophils, cellular debris, perivascular plasmacytosis and iron-laden macrophages exerted a distinctive value. Comparison with clinical data and follow-up revealed that in only 13 patients (4%), histopathology failed to differentiate clearly between PV (208 patients) and secondary polycythemias (113 patients). In conclusion, certain sets of morphological parameters allow a distinction between autonomous and reactive polycythemias and therefore enhance significantly diagnostic validity.

Topics: Adult; Aged; Bone Marrow; Bone Marrow Cells; Bone Marrow Examination; Cell Count; Cell Size; Eosinophils; Erythropoietin; Female; Hematocrit; Humans; Iron; Macrophages; Male; Megakaryocytes; Middle Aged; Neoplasms; Organelles; Plasma Cells; Pneumonia; Polycythemia; Polycythemia Vera; Primary Myelofibrosis; Reticulin; Retrospective Studies; Sensitivity and Specificity; Smoking

Thrombopoietin (TPO) regulates megakaryocytopoiesis and platelet production in vivo and in vitro. Exogenous overexpression of TPO in vivo by viral-mediated gene transfer induced bone marrow (BM) fibrosis and osteosclerosis. On the other hand, transgenic mice (Tg) overexpressing TPO using a liver-specific apolipoprotein E (Apo-E) promoter did not exhibit myelofibrosis or osteosclerosis. These discrepancies in phenotype are not fully understood. Then we have investigated the consequences of long-term in vivo overexpression of TPO in a mouse model. Murine TPO Tg mice driven by the IgH promoter were generated. The number of platelets and neutrophils in peripheral blood, and the number of megakaryocytes and granulocytic immature cells in the BM was elevated, together with the number of progenitor cells for megakaryocyte and myeloid cells. TPO Tg mice demonstrated anemia but the number of progenitor cells for the erythrocyte was increased. TPO Tg mice developed myelofibrosis and osteosclerosis as they aged with extramedullary hematopoiesis in the spleen. As plasma transforming growth factors (TGF)-beta1 and osteoprotegerin (OPG) levels were higher in TPO Tg mice than in wild-type mice, the development of myelofibrosis and osteosclerosis depends on local TPO levels in BM and might be due to elevated TGF-beta1 and OPG.

Topics: Animals; Apolipoproteins E; Bone Marrow Cells; Cloning, Molecular; DNA Primers; Erythropoietin; Gene Rearrangement; Globins; Immunoglobulin Heavy Chains; Mice; Mice, Transgenic; Osteosclerosis; Polymerase Chain Reaction; Primary Myelofibrosis; Promoter Regions, Genetic; Rabbits; Reference Values; Thrombopoietin

Topics: Blood Transfusion; Disease Management; Drug Resistance; Drug Synergism; Drug Therapy, Combination; Erythropoietin; Humans; Male; Middle Aged; Primary Myelofibrosis; Thalidomide; Treatment Outcome

Topics: Adult; Darbepoetin alfa; Epoetin Alfa; Erythropoiesis; Erythropoietin; Female; Hematinics; Humans; Middle Aged; Osteomyelitis; Polycythemia Vera; Primary Myelofibrosis; Recombinant Proteins; Stem Cell Transplantation; Treatment Failure; Treatment Outcome

Topics: Aluminum; Anemia; Anemia, Hypochromic; Drug Resistance; Erythropoiesis; Erythropoietin; Humans; Inflammation Mediators; Iron Deficiencies; Isoantibodies; Nutrition Disorders; Primary Myelofibrosis; Recombinant Proteins; Renal Dialysis; Treatment Failure

Topics: California; Erythropoietin; Fraud; Humans; Insurance Coverage; Male; Medicare; Patients; Primary Myelofibrosis; United States

Topics: Aged; Epoetin Alfa; Erythropoietin; Humans; Injections, Subcutaneous; Male; Mouth Diseases; Polycythemia Vera; Primary Myelofibrosis; Recombinant Proteins; Skin Diseases

The present study revises the criteria of the Polycythemia Vera Group (PVSG) for the diagnoses of essential thrombocythemia (ET) and polycythemia vera (PV) in view of accumulating data on in vitro cultures of hematopoietic progenitors and by adding histopathology from bone marrow biopsies. The majority of ET patients show spontaneous megakaryocyte or erythroid growth or both, but in about 35% the growth pattern is normal. So far none of the patients with reactive thrombocytosis have shown either spontaneous megakaryocyte or erythroid colony growth. Virtually all PV patients show spontaneous or endogenous erythroid colony (EEC) formation, whereas patients with secondary erythrocytosis and healthy controls do not show any erythroid colony growth in the absence of erythropoietin (EPO). Some rare patients with a disorder other than a myeloproliferative disease (MPD) may show spontaneous growth of erythroid colonies caused by a mutation in the EPO receptor. Megakaryocytes in bone marrow smears and biopsy material from ET and PV patients are typically increased in number and size. Enlarged megakaryocytes with mature cytoplasm and multilobulated nuclei and the tendency of these megakaryocytes to cluster in a normal or slightly increased cellular bone marrow represent the diagnostic hallmark of ET. Increase and clustering of enlarged, mature, and pleiomorphic megakaryocytes in a moderate to marked hypercellular bone marrow with hyperplasia of dilated sinuses is the diagnostic feature of untreated PV. In reactive thrombocytosis and secondary erythrocytosis the size and morphology of megakaryocytes remain normal and there is no tendency of the megakaryocytes to cluster. Both spontaneous EEC and histopathology of bone marrow biopsies appear to offer specific clues to the diagnosis of overt and latent ET or PV and have the potential to differentiate ET from reactive thrombocytosis and PV from secondary erythrocytosis. Moreover, bone marrow histopathology has the diagnostic power to distinguish and to stage the various MPDs without regard to clinical and laboratory data.

Topics: Biopsy; Bone Marrow; Bone Marrow Examination; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Female; Humans; Male; Megakaryocytes; Myeloproliferative Disorders; Polycythemia Vera; Primary Myelofibrosis; Thrombocythemia, Essential

Seven patients, 3 men and 4 women 48-72 years of age and suffering from idiopathic myelofibrosis were given a combination of recombinant human erythropoietin (r-hu-Epo), interferon-alpha-2b (IFN) and GM-CSF, in an attempt to treat their pancytopenia and marrow fibrosis. The dose of r-hu-Epo was 200 U/kg 3 times weekly, that of IFN was 3 x 10(6)/U 3 times weekly, and that of GM-CSF was 250 micrograms/m2/daily. The duration of therapy ranged from 3 to 6 months for r-hu-Epo and IFN and was 3 weeks for GM-CSF. The treatment regimen had a beneficial effect on all patients. The levels of hemoglobin increased in all patients but particularly in 5 (2 of whom had been dependent on red blood cell transfusions). Splenomegaly decreased significantly in 4 patients. Fibrosis in the bone marrow decreased in 2 patients. Three patients also had an increase in the number of white blood cells during the therapy with GM-CSF. We observed mild side effects in 6 of our patients. One patient had severe side effects from IFN and treatment was discontinued. In conclusion, the combination of r-hu-Epo, IFN and GM-CSF may improve the anemia (due to r-hu-Epo), increase the white blood cell count (due to GM-CSF) and reduce the marrow fibrosis (probably due to IFN) in patients with idiopathic myelofibrosis.

Topics: Aged; beta 2-Microglobulin; Bone Marrow; Erythropoietin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Hemoglobins; Humans; Interferon alpha-2; Interferon-alpha; Leukocyte Count; Male; Middle Aged; Platelet Count; Primary Myelofibrosis; Recombinant Proteins; Spleen

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

Topics: Aged; Aged, 80 and over; Anemia; Erythropoietin; Humans; Male; Middle Aged; Primary Myelofibrosis; Recombinant Proteins

Different response patterns to recombinant human erythropoietin (rHuEpo) administration to anemic patients with myelodysplastic syndromes (MDS) are described. The biology of rHuEpo effect on erythropoiesis in patients with MDS has not been elucidated. However, until more biological information is obtained, it could be prudent to consider these response patterns as guidelines in the treatment of MDS. In the small but interesting series of nine patients with MDS only one responded to rHuEpo within the treatment period of eight weeks. Two additional patients continued the treatment on their own, and after 16 weeks a response was noted for the first time. A third patient was treated for only six weeks and a delayed response was recorded while off treatment for ten weeks. This response was also recorded 16 weeks from treatment initiation-as in the other two patients. A fourth patient with MDS developed transfusion related hemosiderosis and during iron chelation therapy the RBC transfusion rate dropped to a rate lower than the rate needed before the rHuEpo treatment. It is emphasized that in non responders, non-routine approaches should be considered.

Topics: Aged; Aged, 80 and over; Anemia, Refractory; Anemia, Sideroblastic; Blood Transfusion; Chelation Therapy; Combined Modality Therapy; Deferoxamine; Erythrocyte Count; Erythropoietin; Female; Follow-Up Studies; Hemochromatosis; Humans; Male; Myelodysplastic Syndromes; Primary Myelofibrosis; Recombinant Proteins; Remission Induction; Transfusion Reaction; Treatment Outcome

Topics: Adult; Aged; Erythropoietin; Humans; Primary Myelofibrosis; Prospective Studies; Recombinant Proteins

In a dose titration study we tested the efficacy and tolerance of recombinant human erythropoietin (rhEPO) in 10 patients with myelodysplasia (MDS) and 2 patients with idiopathic myelofibrosis. Patients with a haemoglobin level < 100 g/l were treated as out-patients for 12 weeks with daily doses ranging from 30 U/kg body weight (BW) up to 240 U/kg BW in non-responders. Of the 10 patients with MDS, 6 were suffering from refractory anaemia with sideroblasts (RAS) and 4 from refractory anaemia with an excess of blasts. The median age was 73 years (range 41-81). Two patients with RAS responded with a rise in haemoglobin concentration to > 130 g/l. They had not been transfusion-dependent prior to treatment. Both patients had relatively low serum concentrations of immunoreactive EPO. There was neither a rise in haemoglobin nor a reduction in transfusion dependence in any of the other patients. It may be concluded that rhEPO is possibly effective in a subgroup of MDS patients where the disease is less advanced. None of the transfusion-dependent patients benefited.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Refractory; Anemia, Refractory, with Excess of Blasts; Blood Transfusion; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Primary Myelofibrosis; Recombinant Proteins

During the last three years 77 patients with myelofibrosis were studied by scintigraphy, using 99m Tc colloids and 111 In transferrin as tracers. Low axial uptake of the colloids, extension of the indium uptake beyond the axis towards the knees and sometimes the ankles and elbows, and splenic indium uptake are valuable diagnostic criteria, particularly useful to exclude myelofibrosis associated with a malignant disorder. The clinical severity of the disease, and in particular the disappearance of a physiologically active bone marrow (indium uptake) can be predicted from isotopic studies. Bone marrow scintigraphy could contribute to the difficult decision of splenectomy.

Topics: Adult; Bone Marrow; Erythropoietin; Female; Humans; Leukemia; Male; Middle Aged; Polycythemia Vera; Primary Myelofibrosis; Prognosis; Radionuclide Imaging; Splenomegaly; Thrombocythemia, Essential

We evaluated a newly developed enzymeimmunoassay for serum erythropoietin (Epo) and investigated relationship between Epo levels and hematological disorders. This method has several advantages including simplicity, high sensitivity, good precision. Moreover, the procedure requires only about 2.5 hours. Samples from 134 healthy subjects showed a normal logarithmic distribution, and its normal range was 4.5 approximately 21.3 mU/ml. The levels of Epo in normal subjects and various hematological disorders were as follows: 10.5 +/- 4.1 (mean +/- SD mU/ml) in normal subjects, 2.2 +/- 1.7 in polycythemia vera (PV), 6.1 +/- 3.1 in essential thrombocythemia, 17.8 +/- 27.3 in chronic myelogeneous leukemia, 3.6 +/- 1.8 in stress erythrocytosis, 39.4 and 14.1 in two cases of primary myelofibrosis, 1289 +/- 4798 in iron deficiency anemia and 6564 +/- 10870 in aplastic anemia. In patients with PV, serum Epo were low and did not correlate with hemoglobin concentration. However, inverse correlation was found between changes of Epo levels and hemoglobin levels in most patients. In cases in which PV progressed into myelofibrosis, anemia developed and Epo levels increased accordingly. These results suggest that the method is thought to be useful and reliable for the diagnosis and monitoring of PV and related hematological disorders.

Topics: Erythropoietin; Hematologic Diseases; Hemoglobins; Humans; Immunoenzyme Techniques; Polycythemia Vera; Primary Myelofibrosis; Sensitivity and Specificity

Anemia is common in patients with chronic renal insufficiency and secondary hyperparathyroidism. Erythropoietin therapy is effective, but the dose required varies greatly. One possible determinant of the efficacy of erythropoietin therapy is the extent of marrow fibrosis caused by hyperparathyroidism. We examined the relation between the erythropoietic response to erythropoietin and hyperparathyroidism in a cross-sectional study of 18 patients undergoing hemodialysis who had received erythropoietin therapy for one to three years. In 7 patients (the poor-response group), the dose of intravenous erythropoietin needed to maintain a mean (+/- SD) target hematocrit of 35 +/- 3 percent was > 100 units per kilogram of body weight three times a week, and in 11 patients (the good-response group) it was < or = 100 units per kilogram. In all patients, indexes of the adequacy of dialysis and the extent of hyperparathyroidism and aluminum toxicity were determined monthly, and bone histomorphometry was performed.. The mean (+/- SD) dose of erythropoietin required to maintain the target hematocrit was 174 +/- 33 units per kilogram three times a week in the poor-response group and 56 +/- 18 units per kilogram in the good-response group. The mean ages, duration and adequacy of dialysis, increment in hematocrit, iron requirements, and serum concentrations of calcium, phosphate, and aluminum were similar in the two groups. The percentages of osteoid volume and surface, the osteoid thickness, and the stainable aluminum content of bone were similar in the two groups. In contrast, the mean serum parathyroid hormone concentration, the percentages of osteoclastic and eroded bone surfaces, and the degree of marrow fibrosis were greater in the poor-response group than in the good-response group (P = 0.03, P = 0.04, P = 0.009, and P = 0.009, respectively).. In patients with uremia, the dose of erythropoietin needed to achieve an adequate hematocrit response may depend on the severity of secondary hyperparathyroidism and the extent of bone marrow fibrosis.

Topics: Adult; Aged; Anemia; Cross-Sectional Studies; Erythropoietin; Female; Hematocrit; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Primary Myelofibrosis; Prospective Studies; Renal Dialysis; Uremia

A patient with acquired pure red cell aplasia and agnogenic myeloid metaplasia (AMM) was treated with rHuEPO. She became transfusion independent. Weekly injections of rHuEPO have maintained the response without side-effects or disease progression. In addition, marrow fibrosis and splenomegaly have decreased. Therefore, rHuEPO may be effective therapy for some patients with acquired PRCA and/or AMM.

Topics: Aged; Blood Transfusion; Erythrocyte Count; Erythropoietin; Female; Humans; Primary Myelofibrosis; Red-Cell Aplasia, Pure; Reticulocytes; Time Factors

Serum erythropoietin levels (s-Epo) were measured by radioimmunoassay in 61 consecutive anaemic patients (Hb < 12 g/dl) with myelofibrosis with myeloid metaplasia (MMM). S-Epo was inversely correlated with Hb (r = -0.48, P < 0.0001). When observed s-Epo values were compared with predicted levels based on the relationship between s-Epo and Hb in control subjects, all but eight patients (87%) had s-Epo levels appropriate for the degree of anaemia. The observed/predicted (O/P) s-Epo ratio was significantly lower in patients with signs of active disease, and a significant inverse correlation was found between the O/P ratio and erythrokinetic measurement of the extent of erythropoiesis (r = 0.31; P = 0.02). Circulating Epo levels were appropriate for the variations in Hb during the postsplenectomy period in three patients. In conclusion, this study does not support the idea that therapy with erythropoietin should be extensively used in anaemic patients with MMM, but rather that it should be considered only in selected cases.

Topics: Adult; Aged; Anemia; Anemia, Hypochromic; Blood Component Transfusion; Erythropoiesis; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Primary Myelofibrosis; Splenectomy; Thalassemia

Nine patients with myelodysplastic syndromes and one patient with agnogenic myeloid metaplasia have been treated with recombinant human erythropoietin (rhEpo), at the dose of 150 U/kg/day. Although serum Epo levels were correlated with hemoglobin concentrations in the whole population of patients, they clearly appeared inadequate in some instances, if compared to those of a group of control subjects with iron deficiency anemia. Moreover, no correlation was found between serum Epo and reticulocytes. Six patients showed a partial or complete response to the treatment and the outcome was not correlated with the pre-therapy serum Epo levels; however, serum Epo was less than 100 mU/ml in three of four patients who achieved a complete response. The mechanism(s) by which Epo stimulated erythrocyte production in myelodysplastic patients is unclear, because the number of both the reticulocytes and erythroid progenitors remained unchanged during and at the conclusion of a three months' therapy. Further studies are needed to better define the optimal dosage required to correct anemia in myelodysplastic syndromes, and to clarify rhEpo mechanism of action in these diseases.

Topics: Aged; Bone Marrow; Erythrocyte Count; Erythroid Precursor Cells; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Primary Myelofibrosis; Recombinant Proteins; Remission Induction; Reticulocytes

Topics: Adolescent; Adult; Aged; Erythropoietin; Humans; Middle Aged; Primary Myelofibrosis; Recombinant Proteins; Renal Dialysis

Megakaryocyte colony formation, as identified by conventional techniques, was observed in precursor cell cultures from peripheral blood in 8 of 20 consecutive patients with diagnosis of myeloproliferative disease (4/11 patients with polycythemia vera, 3/5 with essential thrombocythemia, 1/2 with primary osteomyelofibrosis and 2 with a myeloproliferative syndrome not further assessable), but not in 50 healthy controls (p less than 0.0001). 7 cultures showed spontaneous erythroid colonies, but were negative for megakaryocyte colonies. Megakaryocyte colony formation was independent of added erythropoietin, plasma or human leukocyte-conditioned medium, but was dependent on the presence of accessory cells. The cells in megakaryocyte colonies had the characteristic morphology of megakaryocytes and stained positively with the IIIa/IIb monoclonal anti-platelet antibody. Thus, megakaryocyte colony formation by precursor cells from peripheral blood in the absence of exogenous stimulating factors seems to be a phenomenon specific for myeloproliferative disease. Differential diagnosis of thrombocythemia may be facilitated by demonstration of endogenous megakaryocyte colony formation, which does not occur in secondary disease.

Topics: Cell Nucleus; Cells, Cultured; Colony-Forming Units Assay; Culture Media; Cytoplasm; Diagnosis, Differential; Erythropoietin; Fluorescent Antibody Technique; Hematopoietic Stem Cells; Humans; Leukocytes; Megakaryocytes; Myeloproliferative Disorders; Polycythemia Vera; Primary Myelofibrosis; Thrombocythemia, Essential

The antigenic characteristics of erythropoietin (Ep) dependent and independent ("endogenous") erythroid progenitor cells (BFU-E and CFU-E) from patients with polycythaemia vera (PV) and idiopathic myelofibrosis (MF) were studied using 9 selected murine monoclonal antibodies (McAbs) in a complement dependent cytotoxicity assay followed by culture in methyl cellulose. McAbs L343 (HLA-DR antigen) S3-13 and S17-25 reacted with about 50% of BFU-E in MF and PV. In contrast HLA-DR antigens were not presented on CFU-E. McAbs R1.B19, WHGS29.1, PMN29 and PM81 recognized the antigens on less than 25% of BFU-E and CFU-E. The reactivity of Ep-dependent and Ep-independent BFU-E and CFU-E was similar with the majority of McAbs. However, McAbs S4-7 and VIM-2 reacted with a higher proportion of Ep-independent BFU-E than of Ep-dependent BFU-E. These results indicate that Ep independent, neoplastic BFU-E in PV and MF are more mature than their Ep dependent counterparts. The antigens expressed on erythroid progenitor cells from patients with PV and MF were earlier found on BFU-E and CFU-E from normal bone marrow and peripheral blood, usually on a higher proportion of cells, than in myeloproliferative disorders.

Topics: Aged; Antibodies, Monoclonal; Antigens, Surface; Cytotoxicity Tests, Immunologic; Erythropoietin; Humans; Middle Aged; Polycythemia Vera; Primary Myelofibrosis; Stem Cells

Serum erythropoietin (ESF) levels and the numbers of marrow and blood erythroid progenitors (CFU-Es) of patients with chronic myeloproliferative disorders (CMPD) were studied simultaneously. The numbers of marrow and blood CFU-Es per 1 x 10(5) cells were normal or greatly elevated. There was an inverse correlation between the hemoglobin concentration and the serum ESF level in patients with chronic myelogenous leukemia when the hemoglobin concentration ranged from 9.0 to 13.0 g/100 ml. The serum ESF level was closely related to the hemoglobin concentration in CMPD and it was suggested that the negative feedback mechanism might operate in anemic patients with CMPD.

Topics: Adult; Animals; Bone Marrow Cells; Cell Count; Chronic Disease; Erythropoietin; Female; Hematopoietic Stem Cells; Hemoglobins; Humans; Leukemia, Myeloid; Male; Mice; Middle Aged; Myeloproliferative Disorders; Polycythemia Vera; Primary Myelofibrosis; Thrombocytosis

The ability of circulating progenitor cells from patients with polycythaemia vera (PV) and myelofibrosis with myeloid metaplasia (MMM) to develop erythroid colonies was studied in cultures with and without erythropoietin. In all normal controls, patients with secondary polycythaemia and MMM, erythroid colonies developed only after the addition of erythropoietin. Only in patients with PV, both in the active and spent phases of the disease, erythroid colonies developed in the absence of erythropoietin. The results indicate the perpetuation of erythropoietin-dependent, as well as erythropoietin-independent progenitors in both phases of this disease. Although spent PV often clinically resembles MMM, there is a basic difference in the behaviour of the circulating erythroid progenitors in these diseases which may serve as a useful tool in discriminating MMM from spent PV, when there is no history of active PV.

Topics: Adult; Aged; Cells, Cultured; Colony-Forming Units Assay; Erythrocyte Count; Erythropoietin; Hematopoietic Stem Cells; Humans; Middle Aged; Polycythemia Vera; Primary Myelofibrosis

We studied circulating erythroid and granulocyte-monocyte progenitors in 18 patients with idiopathic myelofibrosis and in healthy controls, using the methyl cellulose assay. 9 of the patients had been splenectomized prior to the study. The median number of circulating erythroid burst-forming units (BFU-E) was 8 times higher than that of the controls. 12 patients also had CFU-E (colony-forming unit, erythroid) in the blood. 10 patients had spontaneous BFU-E colony formation, and 8 patients had spontaneous CFU-E colony growth. Granulocyte-monocyte progenitors (CFU-GM) were increased 47 times compared to the controls. There were no differences in colony numbers between splenectomized and non-splenectomized patients. We conclude that in myelofibrosis, circulating erythroid and granulocyte-monocyte progenitors are usually markedly increased in number, but erythroid precursors to a lesser extent than granulocyte-monocyte precursors. Many patients, but not all, show spontaneous erythroid colony formation.

Topics: Adult; Bone Marrow; Cells, Cultured; Colony-Forming Units Assay; Erythroblasts; Erythropoietin; Female; Granulocytes; Hematopoietic Stem Cells; Humans; Male; Middle Aged; Primary Myelofibrosis; Splenectomy

In the last decade a large increase of our basic understanding concerning erythropoietin and the regulation of erythropoiesis has led to improved methods for the cell culture of human bone marrow cells. These culture methods in turn have been applied to bone marrow failures with a remarkable increase in our knowledge of the pathogenesis of some of these conditions, particularly the aplasias. The pathogenesis of pure red cell aplasia has been elucidated, and 60% of these patients have been shown to respond to cytotoxic, immunosuppressive treatment. Bone marrow transplantation has proved to be very helpful in the treatment of aplastic anemia and has provided impetus for increased knowledge concerning the pathogenesis of the aplasia. Some of these patients may have suppression of marrow hematopoiesis by the marrow T-cells and can be successfully treated with antilymphocyte globulin or high-dose prednisolone. The future looks bright for further clinical advances concerning the bone marrow failures, but more must be learned about the pathogenesis of these anemias if improved methods of treatment are to be developed.

Topics: Aged; Anemia, Aplastic; Anemia, Sideroblastic; Animals; Bone Marrow; Cyclophosphamide; Erythropoiesis; Erythropoietin; Female; Humans; Pancytopenia; Prednisone; Primary Myelofibrosis

Peripheral blood mononuclear cells from patients with polycythemia vera or myelofibrosis with myeloid metaplasia were studied for their erythroid colony growth characteristics in plasma clot cultures. In both diseases, erythroid colonies formed early in culture in the absence of added erythropoietin (endogenous colonies). In no instance did early, endogenous colony formation occur with peripheral blood cells from normals or patients with secondary polycythemia. A normal response to erythropoietin was observed with both control and patients' peripheral blood cells. Spleen mononuclear cells obtained from one patient with myelofibrosis also produced endogenous colonies and showed a response to erythropoietin. This study suggests that culture of peripheral blood mononuclear cells might serve as a useful tool in discriminating polycythemia vera from secondary polycythemia.

Topics: Cells, Cultured; Erythrocyte Count; Erythrocytes; Erythropoiesis; Erythropoietin; Humans; Polycythemia; Polycythemia Vera; Primary Myelofibrosis; Spleen

Serum of patients suffering from a chronic myeloproliferative disorder (polycythaemia, era, osteomyelofibrosis, chronic myeloid leukaemia) and serum of lethally irradiated rats injected before application of a single doses of erythropoietin did not enhance the effect of erythropoietin -- measured with the iron incorporation rate of polycythemic mice. The rationale for these experiments is to try to find a "myeloproliferative factor", which augments the number of stem cells as described in sera of patients with polycythaemia vera, osteomyelofibrosis, and lethally irradiated mice.

Topics: Adult; Aged; Drug Synergism; Erythropoietin; Humans; Leukemia, Myeloid; Middle Aged; Myeloproliferative Disorders; Polycythemia Vera; Primary Myelofibrosis

Peripheral blood precursor cells from all of 12 patients with polycythaemia vera (PV) formed hemoglobinized colonies in vitro without addition os was strictly epo-dependent in 30 normals and 8 patients with erythrocytosis of other origin. By addition of 1 U epo/ml to the cultures, colony formation was increased up to 5-fold in PV. Untreated patients with a short history had the highest numbers of such epo-responsive precursor cells. In 3 patients with concomitant myelofibrosis, erythroid in vitro growth was abundant, but scattered, single colonies could hardly be identified and their hemoglobinization was poor. This picture did not change with addition of epo, and hemoglobinization did not improve. In vitro grown colonies in PV had morphological abnormalities as compared to colonies grown from normal precursor cells: all stages of erythroid differentiation and up to 50% necrotic cells were found within single colonies. Scattered colonies contained an excess of large, immature, vacuolated erythroblasts. It is concluded that these functionaland morphological abnormalities of in-vitro erythropoiesis are a reliable indicator of PV. Further, transition to myelofibrosis is recognized by a characteristic growth pattern with decreased epo-responsiveness.

Topics: Cells, Cultured; Diagnosis, Differential; Erythropoietin; Hematopoietic Stem Cells; Humans; Polycythemia; Polycythemia Vera; Primary Myelofibrosis

Topics: Androgens; Anemia; Bone and Bones; Bone Marrow Diseases; Erythropoietin; Estrogens; Female; Folic Acid; Gonadal Steroid Hormones; Hematopoiesis; Humans; Hyperparathyroidism; Kidney; Male; Osteoporosis; Polycythemia; Primary Myelofibrosis; Uremia

Topics: Adult; Aged; Animals; Blood Cell Count; Blood Platelets; Blood Transfusion; Erythropoietin; Female; Hematocrit; Hematopoietic Stem Cells; Humans; Injections, Subcutaneous; Iron; Iron Radioisotopes; Leukemia, Myeloid; Leukocyte Count; Leukocytosis; Male; Mice; Middle Aged; Polycythemia Vera; Primary Myelofibrosis

Topics: Adult; Aged; Alkaline Phosphatase; Anemia, Aplastic; Aspartate Aminotransferases; Bilirubin; Blood Transfusion; Bone Marrow Diseases; Chromium Isotopes; Erythropoiesis; Erythropoietin; Female; Hematocrit; Humans; Iron; Iron Isotopes; Lymphoma; Male; Middle Aged; Multiple Myeloma; Oxymetholone; Primary Myelofibrosis

Topics: Adolescent; Adult; Aged; Blood Platelets; Bone Marrow Diseases; Diagnosis, Differential; Erythrocyte Count; Erythropoietin; Female; Hematocrit; Hemoglobinometry; Humans; Leukemia, Myeloid; Leukocyte Count; Male; Middle Aged; Myeloproliferative Disorders; Polycythemia Vera; Primary Myelofibrosis; Retrospective Studies

Topics: Acid-Base Equilibrium; Adolescent; Anemia; Anemia, Aplastic; Animals; Bicarbonates; Biological Assay; Erythrocytes; Erythropoietin; Humans; Hydrogen-Ion Concentration; Iron; Iron Isotopes; Kidney; Kidney Function Tests; Male; Mice; Middle Aged; Peptide Hydrolases; Primary Myelofibrosis

Topics: Adult; Anemia, Aplastic; Erythropoietin; Female; Fluoxymesterone; Hemoglobinuria, Paroxysmal; Humans; Male; Methods; Middle Aged; Multiple Myeloma; Primary Myelofibrosis; Sex Factors; Time Factors

Topics: Blood Cell Count; Bone Marrow Examination; Epoetin Alfa; Erythropoietin; Hepatomegaly; Humans; Polycythemia; Polycythemia Vera; Primary Myelofibrosis; Splenectomy; Splenomegaly