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PubMed2005

[Successful treatment with interferon-alpha in a case of acute myeloid leukemia with del (20q) following polycythemia vera].

Polycythemia vera (PV) is a hematopoietic stem cell clonal disorder, 5 to approximately 10% of which will evolve into acute leukemia. The pathophysiology of leukemic transformation and the best therapy for the leukemic phase of PV is still unknown. A 73-year-old woman was given a diagnosis of PV 17 years previously. However, laboratory data revealed myeloblasts in the peripheral blood with macrocytic anemia and thrombocytosis in March 2003. Bone marrow examination in October 2003 revealed 32.8% myeloblasts with trilineage dysplasia. Chromosomal analysis of the bone marrow cells revealed that 18/22 of mitotic cells had del(20q) and 3/22 of had t(2; 12). The leukemic phase of PV was diagnosed. She achieved not only a hematologic remission, but also cytogenetic remission after interferon (IFN)-alpha treatment. As far as we know, this is the first report of the introduction of IFN-alpha in the treatement of the leukemic phase of PV. Further monitoring of this patient will provide valuable information concerning the pathophysiology of leukemic transformation and the development of effective therapy for the leukemic phase of PV.

Antineoplastic Agents↗
PubMed1998

Gain of 9p in the pathogenesis of polycythemia vera.

Polycythemia vera (PV) is a clonal stem cell disorder characterized by excessive erythrocyte production, resulting in absolute erythrocytosis. No specific structural chromosomal abnormalities have been reported in PV to date. We have observed two cases of PV with an extra i(9)(p10) as the sole anomaly, and FISH analysis using a 9p-specific chromosome microdissection probe showed that two other PV patients previously identified as having an add(18p) and an add(1p) as the primary changes actually carried a der(18)t(9;18)(p12;p11.2) and a der(1)t(1;9)(p12;p12), respectively. The same FISH assay was employed to evaluate domain signals on interphase cells of 15 more cases of PV with normal karyotypes and five normal controls. Two patients were observed with a significant increase in the percentage of cells with three domain signals. Our results strongly indicate that an additional i(9)(p10) is a new and recurrent primary chromosome anomaly in PV, and, in consideration of trisomy 9 being one of the most common anomalies in PV, amplification of a gene or genes on 9p, but not on 9q, may play a crucial role in the pathogenesis of PV.

Adult↗
PubMed2003

Modern treatment strategies in polycythemia vera.

Polycythemia vera (PV), one of the chronic myeloproliferative disorders (MPD), is characterized by predominant erythroid proliferation and secondary platelet proliferation, and by progression from a proliferative stage to a metastatic phase and finally a malignant phase. These characteristics expose patients to increased risk for thrombohemorrhagic complications, myeloid metaplasia, myelofibrosis, and acute leukemic conversion irrespective of treatments. Currently, there are three agents-hydroxyurea (HU), interferon-alfa (IFN-alpha), and anagrelide-that differ in mechanisms of action and in treating specific phenotypic manifestations of PV, suggesting a potential role for combination therapy. They also differ widely in side effects profiles and severity. Because of the differing risks for long-term complications associated with these agents, age is an important variable in selecting treatments. Patients at high risk for thrombohemorrhagic complications all require cytoreduction, as do patients at intermediate risk who are not effectively managed by phlebotomy and low-dose aspirin. In younger patients, the safest and most effective combination treatment appears to be anagrelide plus IFN-alpha, while in older patients anagrelide plus hydroxyurea may be effective. HU is used sparingly in younger patients because of the long-term increased risk of mutagenicity and possibly leukemogenesis. IFN-alpha is particularly indicated for patients with myeloid metaplasia evidenced by splenomegaly. Anagrelide, which acts on the mature megakaryocyte to prevent platelet budding, is uniquely efficacious in the control of platelet counts.

Age Factors↗
PubMed2004

Multiple signaling pathways are involved in erythropoietin-independent differentiation of erythroid progenitors in polycythemia vera.

Polycythemia vera (PV) is a myeloproliferative disorder arising in a multipotent hematopoietic stem cell. The pathogenesis of PV remains poorly understood; however, the biologic hallmark of this disease is the presence of erythropoietin (Epo)-independent colony formation (endogenous erythroid colony [EEC]) and cytokine hypersensitivity. We have developed a simple liquid culture from CD34+ cells to study PV erythroid differentiation. PV erythroid differentiation was characterized in this culture system by two types of abnormalities: 1) an increased proliferation of progenitors in response to cytokines, associated with strict cytokine dependency for preventing apoptosis; and 2) Epo-independent terminal erythroid differentiation in the presence of stem cell factor and interleukin-3 as evidenced by the acquisition of glycophorin A. The level of Epo-independent terminal differentiation correlates in PV patients with the number of EEC. Epo-independent terminal differentiation as well as normal Epo-induced differentiation were repressed by inhibitors of JAK2 (AG490), PI3K (LY294002), and the Src family kinases (PP2). In contrast, an inhibitor of the ERK/MAP kinase pathway (PD98059) had no effect on Epo-independent terminal differentiation. These signaling abnormalities were not mediated by a decreased expression or activity of the membrane tyrosine phosphatase CD45, which dephosphorylates JAK2 and Src family kinases. This study demonstrates that early steps of PV erythroid differentiation are strictly cytokine dependent. In contrast, late erythroid differentiation is an Epo-independent phenomenon that is mediated by signaling pathways identical to those in Epo-induced differentiation.

Antigens, CD34↗
PubMed2003

Karyotypic abnormalities in myelofibrosis following polycythemia vera.

Polycythemia vera (PV) is a chronic myeloproliferative disease characterized by an increase of total red cell volume; in 10% to 15% of cases, bone marrow fibrosis complicates the course of the disease after several years, resulting in a hematologic picture mimicking myelofibrosis with myelocytic metaplasia (MMM). This condition is known as post polycythemic myelofibrosis (PPMF). Among 30 patients with PPMF followed in Northern France, 27 (90%) expressed one or two abnormal clones in myelocytic cell cultures. Of these, 19 (70%) had partial or complete trisomy 1q. This common anomaly either resulted from unbalanced translocations with acrocentric chromosomes, that is, 13, 14, and 15, or other chromosomes, that is, 1, 6, 7, 9, 16, 19, and Y, or from partial or total duplication of long arm of chromosome 1. A single patient had an isochromosome 1q leading to tetrasomy 1q. In all cases, a common trisomic region spanning 1q21 to 1q32 has been identified. Given that most patients had previously received chemotherapy or radio-phosphorus to control the polycythemic phase of their disease, this study illustrates the increased frequency of cytogenetic abnormalities after such treatments: 90% versus 50% in de novo MMM. Moreover, karyotype can be used to distinguish PPMF-where trisomy 1q is the main anomaly-from primary MMM where trisomy 1q is rare and deletions 13q or 20q are far more common. Whether trisomy 1q is or is not a secondary event remains a matter of debate, as well as the role of cytotoxic treatments.

Adult↗
PubMed2005

Quantification of clonal hematopoiesis in polycythemia vera.

Polycythemia vera (PV) is believed to represent a clonal trilineage myeloaccumulative hematopoietic disorder. This study was undertaken to estimate for the first time the proportion not only of the neoplastic clone but also of clonal and residual nonneoplastic CD34(+) progenitor cells. Chromosomal abnormalities, including trisomy 8 or 9, are phenomena associated in about 20% of PV patients. Therefore, we screened peripheral blood (PB) mononuclear cells of PV patients in the chronic phase of the disease and looked for chromosomal abnormalities performing comparative genomic hybridization. Two of the ten patients revealed cytogenetic changes, including trisomy 8 or 9. To quantify the proportion of cytogenetic abnormal cells in these patients, we applied fluorescence in situ hybridization (FISH) technique on immunomagnetically enriched cell fractions. Ninety percent of the mononuclear cells and up to 79% of PB-derived CD34(+) progenitor cells presented three signals for chromosome 8 or 9. The diagnostic value of FISH to detect trisomies in trephine biopsies was then tested in all patients under study. Although the probability to detect FISH signals in a certain section plane is reduced, constantly 10-15% of the cells revealed three signals. Concerning the CD34(+) progenitor cell pool, a distinct nonclonal population exists in these patients. Our data underline the stem cell character of PV and additionally quantify the proportion of clonal CD34(+) progenitor cells for the first time. The finding of a distinct, not aberrant, CD34(+) progenitor cell population in chronic phase PV may offer perspectives in treatment of the disease. Finally, FISH analysis of bone marrow biopsies can be helpful to consolidate diagnosis of early PV.

Adult↗
PubMed2005

Distinct gene expression pattern of malignant hematopoietic stem and progenitor cells in polycythemia vera.

Polycythemia vera (PV) is a chronic myeloproliferative disorder with an expansion of multipotent hematopoietic progenitor cells. Although it is known that hematopoietic progenitors in PV are erythropoietin independent and hypersensitive to several cytokines, the molecular oncogenic mechanisms in PV are largely unknown. In this study, we examined gene expression profiles of CD34(+) cells from bone marrow of patients with de novo PV and from healthy volunteers to identify molecular changes associated with the malignant growth of hematopoietic stem and progenitor cells in this myeloproliferative disorder. Using cDNA arrays, we found significant differences (P < .01) in the expression of 107 genes. Proapoptotic genes (CASP2, CASP3, DAPK1, ALG2) were expressed at lower levels in PV-CD34(+) cells, reflecting a lower apoptotic activity. Fibrosis-stimulating growth factors (transforming growth factor beta1, transforming growth factor beta2, bone morphogenetic protein 2, and endothelial growth factor) were expressed at significantly higher levels in PV-CD34(+) cells. Furthermore, PV-CD34(+) cells overexpressed several receptors, protein kinases, and proteasome subunits, which might be targets for directed therapeutic approaches. It is interesting that three retinoid receptors were overexpressed in PV-CD34(+) cells--retinoic acid receptor beta (RARbeta), retinoid X receptor beta (RXRbeta), and cellular retinoic acid binding protein 2 (CRABP2). Using methylcellulose colony-forming assays, we found that the formation of erythroid colonies derived from PV hematopoietic progenitors was inhibited by all-trans-retinoic acid (ATRA), a natural ligand of those receptors, in a dose-dependent manner, showing a maximum inhibition of 89% at 10 microM; the growth of myelomonocytic colonies was not significantly affected. These data suggest that the use of ATRA could be of therapeutic benefit for patients with PV.

Gene Expression↗
PubMed1993

Thromboembolic complications of polycythemia: polycythemia vera versus smokers' polycythemia.

PURPOSE: This report compares patients with the hypercoagulable state of polycythemia vera to patients with secondary polycythemia caused by tobacco use to determine whether the incidence of thromboembolic events is equivalent. METHODS: The medical records of 146 patients with the diagnosis of polycythemia between 1977 to 1990 were reviewed. Patients with transient, relative, or stress polycythemia were excluded from this study as were patients with polycythemia as a result of cardiac or pulmonary anomalies or both. The diagnosis of polycythemia vera (n = 43) was verified by use of the guidelines of the Polycythemia Vera Study Group. The diagnosis of polycythemia caused by smoking (n = 27) was based on an elevated total red blood cell volume, decreased oxygen saturation on arterial blood gas measurement, evidence of chronic obstructive pulmonary disease, and elevated carboxyhemoglobin levels. RESULTS: Twenty-six patients (60%) with polycythemia vera and 11 patients (41%) with smoker's polycythemia had at least one thromboembolic problem. No significant differences existed between the groups with regard to age, hematocrit, or number of cardiac and cerebrovascular events. Overall, patients with polycythemia vera had a greater number of thromboembolic events per patient (p < 0.05) and more peripheral arterial thromboemboli (p < 0.005) than did patients with polycythemia as a result of smoking (Fisher's Exact Test). CONCLUSIONS: Thus the results of this study demonstrate that smokers' polycythemia does not represent a hypercoagulable state equivalent to that of polycythemia vera.

Analysis of Variance↗
PubMed2002

The diagnosis and management of polycythemia vera in the era since the Polycythemia Vera Study Group: a survey of American Society of Hematology members' practice patterns.

The Polycythemia Vera Study Group (PVSG) was organized in 1967 to identify the optimal approach to the diagnosis and treatment of polycythemia vera (PV). Nevertheless, a systematic assessment of US physicians' approach to PV has not been performed. To determine practice patterns in the management of PV, a random sample of the US American Society of Hematology (ASH) membership was surveyed. Thirty-three percent of 3000 surveys were returned. Significant variations in diagnostic and therapeutic approach were evident by region, practice type, specialty, and clinical experience. Red cell volume determinations (78% of respondents), serum erythropoietin levels (76%), and arterial blood gases (75%) were the most frequent tests used in the diagnosis of PV. Sixty-nine percent of physicians use phlebotomy as their first choice for erythrocytosis. Phlebotomy plus hydroxyurea (27.8%) and hydroxyurea alone (10%) were used less often. Despite PVSG recommendations, almost 16% of physicians used a target hematocrit of 0.55 (50%) or 0.55 (55%) for phlebotomy therapy. Eighty-two percent of physicians treated thrombocytosis only when platelet counts exceeded 1000 x 10(9)/L (1 000 000/microL) or in the event of symptoms. Hydroxyurea (62.8%) and anagrelide (35.4%) were the primary agents used to treat thrombocytosis. Thus, this national survey of US hematologists and oncologists has identified substantial variation in the approach to the diagnosis and treatment of PV. A significant minority of physicians undertreat erythrocytosis, and little consensus exists regarding the treatment of thrombocytosis.

Data Collection↗
PubMed1984

Increased prevalence of polycythemia vera in parents of patients on polycythemia vera study group protocols.

An investigation of relatives of 652 patients entered on studies of the Polycythemia Vera Study Group yielded five documented cases of the disease among the parents of patients. When compared with expected values based on the Connecticut Tumor Registry and other population studies a significant increase was found in the lifetime incidence of polycythemia vera in parents of these patients.

Adult↗
PubMed1997

Polycythemia vera. V. Enhanced proliferation and phosphorylation due to vanadate are diminished in polycythemia vera erythroid progenitor cells: a possible defect of phosphatase activity in polycythemia vera.

Erythropoietin (EP) and stem cell factor (SCF) are essential growth factors for erythroid progenitor cell proliferation and differentiation in serum-free culture. It has been previously shown that burst-forming units-erythroid and colony-forming units-erythroid from patients with polycythemia vera (PV) have enhanced sensitivity to EP and SCF compared with normal erythroid progenitors, but little is known about the mechanism for this difference. In the present investigation, the effect of EP and SCF on protein tyrosine phosphorylation in day-8 normal and PV erythroid colony-forming cells, which give rise to colonies of 2-49 hemoglobinized cells, was studied. EP rapidly induced tyrosine phosphorylation of the EP receptor, whereas the most prominent phosphorylated protein induced by SCF was identified as the SCF receptor. No additional phosphorylated proteins were evident when PV cells were compared with normal cells. Culture of normal erythroid progenitors with orthovanadate, an inhibitor of protein tyrosine phosphatases, resulted in an increased number of erythroid colonies and enhanced protein tyrosine phosphorylation. However, in contrast, little enhancement was evident with PV cells. These results indicate that, although vanadate may be acting in normal erythroid progenitors as a phosphatase inhibitor that potentiates the kinase activity induced by SCF and EP, this function is diminished in PV cells. Because erythropoiesis is regulated by a balance between protein tyrosine kinase activity and protein tyrosine phosphatase activity, PV patients may have an abnormal phosphatase activity allowing increased cell proliferation.

Cell Division↗
PubMed2005

Polycythemia vera and other primary polycythemias.

PURPOSE OF REVIEW: Diagnosis and therapy of polycythemia vera are controversial since the molecular basis of polycythemia vera remains unknown. Distinguishing between polycythemia vera and other polycythemic disorders can be very challenging. The purpose of this review is to discuss the recent progress in this area and critically review the published data in context of our knowledge of other polycythemic disorders. RECENT FINDINGS: Erythropoietin is the principal regulator of regulator of erythropoiesis; its production is regulated by the degree of hypoxia. Our knowledge of cellular responses to hypoxia has recently exploded and led to the elucidation of the molecular basis of a polycythemia caused by augmentation of hypoxic sensing, Chuvash polycythemia. Similar progress in understanding the molecular basis of polycythemia vera has been elusive. A simple, readily available laboratory test to establish a diagnosis of polycythemia vera would be highly desirable; however, none exists. The value of quantization of neutrophil PRV-1 mRNA, platelet c-mpl expression, in vitro assays of erythroid progenitor cells, serum erythropoietin levels, establishing clonality in female subjects using assays employing X-chromosome-based polymorphism assays, and the progress in the chromosomal location of the gene is discussed. Integration of this information underlies the complexity of the molecular biology of polycythemia vera and indicates likely interaction of multiple genetic events in the genesis of polycythemia vera. SUMMARY: The existence of family clustering of PV may facilitate the search for PV molecular basis. Only collaborative interaction of clinical researchers and laboratory scientists will lead to meaningful progress in determining the molecular basis of PV.

Diagnosis, Differential↗
PubMed1992

Isolated cerebellar infarction as a presenting symptom of polycythemia vera.

Although polycythemia vera is one of the reported causes for cerebral infarction, isolated cerebellar infarction, a rare disorder, was never reported in combination with polycythemia vera. This is a report of a 72-year-old woman in whom isolated cerebellar infarction was the presenting manifestation of polycythemia vera. The patient was treated with recurrent phlebotomies until the hematocrit decreased to < 45%. This treatment was followed by marked neurological improvement. A better awareness of the possibility of cerebellar infarction in polycythemia vera may disclose additional cases.

Aged↗
PubMed1997

Retinopathy secondary to anemia from myeloid metaplasia in polycythemia vera.

BACKGROUND: Polycythemia vera is a chronic clonal disorder associated with excessive proliferation of erythrocytes, leukocytes, and thrombocytes, as well as an accompanying splenomegaly. Ocular manifestations of polycythemia vera include occipital cortex transient ischemic attacks, transient monocular blindness, vaso-occlusive disease, and retinal hemorrhages. CASE REPORT: A 56-year old man with longstanding polycythemia vera sought treatment for a chief symptom of blurred vision in the left eye and a red tinge to things first noticed on awakening that morning. He had preretinal and intraretinal hemorrhages and was subsequently found to be severely anemic as a result of postpolycythemic myeloid metaplasia after years of phlebotomy. Splenectomy controlled his anemia and thrombocytopenia, allowing transient improvement of the retinal hemorrhages. Acute leukemia subsequently developed and the patient died 7 weeks after initial examination. CONCLUSION: In this case, preretinal and intraretinal hemorrhages were found in a patient with longstanding polycythemia vera. The exact origin of these hemorrhages is uncertain. They are probably secondary to anemia, but the possibility that they are sites of extramedullary hematopoiesis must be considered. The appearance of retinal hemorrhages warrants careful investigation to rule out diabetes, hypertension, and anemia, as well as the various other blood dyscrasias.

Anemia↗
PubMed1989

Comparison of erythroid progenitor cell growth in vitro in polycythemia vera and chronic myelogenous leukemia: only polycythemia vera has endogenous colonies.

The ability of erythroid cultures to distinguish among myeloproliferative disorders was examined. We studied 14 patients with polycythemia vera (PV), 11 with chronic myelogenous leukemia (CML), four with non-PV erythrocytosis, two with agnogenic myeloid metaplasia, as well as three normal fetuses and greater than 25 normal adults. Endogenous, i.e. grew without added erythropoietin, bone marrow CFU-E-derived colonies were observed in all but one PV patient. However, endogenous blood BFU-E-derived bursts were observed in only eight of 14 PV patients. Endogenous erythroid colonies were not seen in cultures from any normal adults or fetuses, or patients with CML, erythrocytosis, or myeloid metaplasia. In PV, relative HbF synthesis was always greater in cultures without erythropoietin, while in cultures from all other patients relative HbF synthesis was similar to that observed in cultures from normal individuals. We conclude that PV and CML are distinguishable in culture since CML patients do not have endogenous growth. Most important, endogenous bone marrow CFU-E-derived colonies are the only consistently unique observation in patients with PV, and endogenous CFU-E- and BFU-E-derived colonies and bursts are not uniformly observed in PV blood cultures. In-vitro studies of erythropoiesis to confirm the diagnosis of PV, therefore, require marrow when endogenous colonies and bursts are absent from blood cultures.

Adolescent↗
PubMed2006

Leukocytosis as a major thrombotic risk factor in patients with polycythemia vera.

In polycythemia vera, vascular risk assessment is based on age and thrombotic history, while the role of other potential predictors of this risk is still uncertain. Thus, we exploited the large database collected by the observational study of the European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP) to investigate the association of hematologic variables and cardiovascular risk factors with the thrombotic risk. Among 1638 polycythemic patients followed for 2.7 +/- 1.3 years, there were 205 thromboses. Subjects with hypertension had a mild nonsignificant increase in the risk of arterial thrombosis, while this risk was significantly increased by smoking (hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.15-3.14; P = .012). The time-dependent analysis adjusted for potential confounders showed that patients with a white blood cell count above 15 x 10(9)/L, compared with those with a white blood cell count below 10 x 10(9)/L, had a significant increase in the risk of thrombosis (HR, 1.71; 95% CI, 1.10-2.65; P = .017), mainly deriving from an increased risk of myocardial infarction (HR, 2.84; 95% CI, 1.25-6.46; P = .013). Thus, leukocyte count may help in defining the vascular risk of polycythemic subjects.

Aged↗
PubMed1994

[A clinical study of sixteen polycythemia vera cases--acute myeloblastic leukemia in patients with polycythemia vera].

The clinical course of 16 patients with polycythemia vera (PV), treated in the period 1982 to 1993, was shown. Splenomegaly occurred in three fourths of these patients (75%), and hypertension was a major symptom. Thrombosis such as myocardial infarction and cerebral infarction was noted. Eight patients was treated with myelosuppressive agents and the 8 other patients were treated with phlebotomy. A 70-year-old male who was treated with mitobronitol (DBM) developed acute myeloblastic leukemia (AML) 11 years later. He was treated with multi-combination chemotherapy (BHAC-DMP), and entered complete remission, followed by early relapse. He became refractory to chemotherapy and died of acute pneumonia 6 months later. Median survival of 16 cases of PV was more than 10 years, and long-term treatment and care are necessary.

Adult↗