Therapeutic effectiveness of ranimustine chemotherapy for elderly essential thrombocythemia*

Background: We studied the clinical effectiveness of ranimustine (MCNU) chemotherapy for essential thrombocythemia (ET). Methods: MCNU chemotherapy was carried out in 14 ET patients who were 60 years of age or older, including six men and eight women. Their ages ranged between 61 and 88 years (median age: 73 years). The patients’ mean platelet count before the treatment was 1.157 ± 0.284 × 10⁶/µL. Five of the studied patients had experienced a thrombotic episode, and one had a profuse epistaxis. Patients were treated mainly by intravenous administration of MCNU. In 12 patients, the platelet count was controlled to a level less than 500 × 10³/µL, while in two patients, it was controlled to less than 700 × 10³/µL. Results: Cerebral infarction occurred in only one patient during or after MCNU therapy. Even in the cases in which thrombosis had occurred before MCNU treatment, further thrombotic events occurred in only one case. In the patient with a profuse epistaxis, bleeding improved during treatment and normal platelet count was maintained after chemotherapy. Conclusion: It was suggested that MCNU chemotherapy may be useful for the prevention of complications in elderly ET patients.     

Treatment of symptomatic patients with essential thrombocythemia: effectiveness of anagrelide

We prospectively evaluated the effect of anagrelide (ANA) on platelets, PF4, F1+2, PAP, PAI-1, and TFPI and erythromelalgia in patients with essential thrombocythemia (ET) receiving anti-aggregants both pre- and post-ANA. At first, we observed a successful reduction of platelets, which was associated with normalization of platelet coagulant and endothelial function and disappearance of erythromelalgia. Secondly, we found a correlation between PF4 and TFPI and between TFPI and thrombosis, suggesting that erythromelalgia may be caused by platelet-mediated endothelial activation. These data may indicate that ANA may be efficacy in the treatment of symptomatic patients with ET.     

Thrombospondin in essential thrombocythemia

Essential thrombocythemia is a myeloproliferative disorder characterized by frequent bleeding and thrombotic complications. On a molecular level, two abnormalities of platelet thrombospondin have been identified: abnormal glycosylation of the intact 185,000-dalton chain has been detected and a shortened form of the thrombospondin chain is present. We have used two monoclonal antibodies and Lens culinaris lectin to probe the structure of thrombospondin in the platelets from three patients with essential thrombocythemia; one patient with polycythemia vera and two patients with secondary thrombocytosis. The presence of abnormal thrombospondin fragments with molecular weights of 160,000 and 30,000 was detected in the intact platelets and in the supernatant from thrombin-treated platelets, in all of the individuals except one of the secondary thrombocytosis patients. Monoclonal antibody binding studies indicate that both fragments are produced by proteolysis at a single site, which results in the removal of a 30,000- dalton fragment from the NH2-terminal. Lens culinaris lectin-binding studies revealed that some of the carbohydrate moieties of thrombospondin are near this cleavage site. The results are consistent with the hypothesis that the abnormal thrombospondin fragments observed under conditions of increased platelet production are due to increased susceptibility to proteolysis which, in turn, may be due to defective glycosylation.     

Persistent thrombocytosis in elderly patients with rare hyposplenias that mimic essential thrombocythemia

When elderly patients present with persistent thrombocytosis, myeloproliferative disease, iron-deficiency anemia or post-splenectomy status are suspected along with autoimmune diseases. Reported here are the cases of two elderly patients with persistent thrombocytosis due to hyposplenia, which is very rarely diagnosed in old age. Case 1 was a 72-year-old man whose thrombocytosis was due to non-familial type isolated congenital asplenia. Case 2 was a 74-year-old man whose thrombocytosis was caused by an atrophied spleen resulting from perforated stomach ulcer-related panperitonitis that had been treated 20 years previously. Both patients had thrombocyte counts exceeding >500,000/μl in association with small vestigial spleen tissue on a computed tomography scan and positive Howell-Jolly bodies on the blood smear. A correct diagnosis is essential for the management of persistent thrombocytosis.     

Treatment of essential thrombocythemia

PURPOSE: Essential thrombocythemia (ET) is a myeloproliferative syndrome that rises many therapeutic problems. This affection is rarely life threatening, but hemorrhagic and thrombotic complications must be prevented when possible. The rarity of these complications makes difficult the assessment of treatment efficiency. Few randomised clinical trials were done, and treatment often rests on retrospective studies. The potential toxicity of treatments, their leukemogenicity in particular, rises a decisional problem for young patients. We propose to review available data in order to propose the most rational treatment for each patient. CURRENT KNOWLEDGE AND KEY POINTS: After numerous years when we only disposed of retrospective studies, non-randomised prospective studies or isolated case-reports, two randomised trials allows us to more precisely define ET treatment. The first trial proved the efficiency of the hydroxyurea-aspirin association in the prevention of thrombotic events in high-risk patients. The second trial signalled to our attention the increased risk of bleeding of the association anagrelide-aspirin, with also the possibility of increased appearance of myelofibrosis. FUTURE PROSPECTS AND PROJECTS: New perspectives in the treatment of ET will require to get more insights in the role of hydroxyurea and anagrelide in particular by longer follow-up. But not less important is a better definition of the thrombosis risks (who has to be treated?) and also of the diagnostic groups since ET can, in some particular cases, be misdiagnosed with polycythemia vera or idiopathic myelofibrosis.     

羟基脲联合血小板去除术治疗老年原发性血小板增多症的临床疗效分析

目的观察羟基脲联合血小板去除术治疗老年原发性血小板增多症（ET）的临床疗效。方法根据有无临床症状,将28例老年ET患者分为有临床症状组及无临床症状组。所有患者均采用口服羟基脲（Hu）治疗,剂量为O．5～3g／d。对血小板计数〉1000×10^9／L者,确诊后即采用血小板去除术1～3次,并且于血小板去除术后开始接受羟基脲治疗。结果有临床症状组的患者发病时外周血血小板计数（1469．00±521．40）×10^9／L明显高于无临床症状组（892．00±302．10）×10^9／L（P〈0．01）。所有患者治疗前后血小板计数为（1023．00±606．30）VS（468．00±236．20）×10^9／L（P〈0．01）。所有患者接受治疗后CR16例（57．1％）,PR11例（39．3％）,NR1例（3．6％）。结论羟基脲联合血小板去除术治疗老年ET疗效明确,不良反应较少,耐受性良好。     

Arterial thrombosis in essential thrombocythemia

The course of essential thrombocythemia has been observed in ten patients, ages 46 to 83, of whom nine were followed for a period af 4 months to 9 years. In contrast to the experience with essential thrombocythemia recorded in the literature, manifestations of arterial thrombosis were far more common than hemorrhage. In six of the ten patients, the presenting complaints were ascribable to incipient gangrene of the toes and several of these patients additionally developed occlusion of tibial and larger arteries while under our observation. All patients with incipient gangrene showed marked clinical improvement accompanying busulfan-induced reduction and normalization of the platelet count. Relapses in five patients after 2 to 87 months responded well to retreatment with busulfan. No patient has shown evolution to another myeloproliferative disorder. Essential thrombocythemia should be considered in the differential diagnosis of occlusive arterial disease.     

Neurological disorders in essential thrombocythemia

Patients with essential thrombocythemia often complain of various subjective neurological symptoms. This prospective study aims to assess their incidence and response to therapy. Among 37 consecutive patients with essential thrombocythemia, 11 presented with neurological symptoms. Among them 4 had thrombotic events, 7 complained of transient or fluctuating subjective symptoms, and one had both. Brain magnetic resonance imagery failed to detect any substratum in patients with subjective symptoms. JAK2V617F mutation was found in 9 of 11 patients with neurological symptoms versus 14 of 26 patients without symptoms. Ten patients received low-dose aspirin for these symptoms: complete resolution was observed in 3, improvement with persisting episodes in 2, and resistance to aspirin in 2 patients, in whom addition of cytoreductive therapy became necessary to resolve those disabling symptoms. In this prospective cohort, 30% of patients with essential thrombocythemia presented neurological symptoms. Aspirin was fully efficient in only 30% of cases. JAK2V617F mutation could be a risk factor for such symptoms.     

Pathogenic markers in essential thrombocythemia

Although long recognized as a clinical entity, the diagnosis of essential thrombocythemia (ET) still relies on the exclusion of reactive conditions and other myeloproliferative disorders. Recent studies have attempted to identify new markers for this disorder and suggest that part of the problem may relate to its heterogeneity. Cytogenetic abnormalities are rare, but analysis using X-chromosome inactivation patterns indicates that nearly 50% of evaluable patients have polyclonal myelopoiesis and this is associated with a lower risk of thrombosis. Reduced and heterogeneous staining of c-Mpl in bone marrow biopsies may help to distinguish ET and a reactive thrombocytosis. Increased expression of PRV-1 (polycythemia ruba vera) in granulocytes may assist in discriminating between polycythemia vera and at least some cases of ET. The contribution of these markers to disease pathogenesis is unknown and prospective studies are needed to evaluate their usefulness for predicting clinical outcome and directing patient therapy.     

Indications for lowering platelet numbers in essential thrombocythemia

Essential thrombocythemia (ET), one of the chronic myeloproliferative disorders, exposes individuals to significantly increased risk for thrombohemorrhagic complications. Epidemiologic data indicate that the two most prominent risk factors for thrombosis are age greater than 60 years or a history of or presentation with thrombosis at any age. Age is an important factor in selecting among therapeutic options, as the agents used to treat ET may contribute to acute leukemic transformation and other secondary malignancies. Whether or not hydroxyurea (HU) carries these risks is controversial and unresolved, but the uncertainty is a basis for avoiding it in young patients. Alternatives to HU that have established efficacy in lowering platelet counts in ET are interferon and anagrelide. Both are highly effective in reducing platelet numbers, and are apparently not associated with leukemogenicity or mutagenicity. However, approximately 30% of patients find interferon intolerable for long-term therapy. Anagrelide offers the advantage of oral dosing and long-term effectiveness at managing platelet counts. A recent long-term study of young ET patients treated with anagrelide found that all thrombohemorrhagic events occurred in patients with platelet counts greater than 0.4 × 10⁹/L, adding to the evidence that reduction of platelet counts to normal may be required for optimal control of risk. Semin Hematol 40(suppl 1):22-25. © 2003 Elsevier Inc. All rights reserved.     

Neurologic manifestations of essential thrombocythemia

Essential thrombocythemia is a clonal myeloproliferative disorder, characterized predominantly by a markedly elevated platelet count without known cause. We report a case that was recognized during investigation of a transient ischemic attack, and review the neurologic findings in 33 patients with unequivocal essential thrombocythemia under prospective study by the Polycythemia Vera Study Group. Twenty-one patients had neurologic manifestations at some point during their course, including headache (13 patients), paresthesiae (10), posterior cerebral circulatory ischemia (9), anterior cerebral circulatory ischemia (6), visual disturbances (6) and epileptic seizures (2). All patients with neurologic symptoms responded satisfactorily to treatment, although continuous or repeated treatment was often required. Therapeutic recommendations include plateletpheresis for major thrombo-hemorrhagic phenomena, or megakaryocyte suppression with radioactive phosphorus, alkylating agents (such as melphalan), or hydroxyurea; minor symptoms may respond to platelet antiaggregating agents.     

Pipobroman therapy of essential thrombocythemia

We report our results with pipobroman (PB) therapy in patients with essential thrombocythemia (ET). 21 consecutive untreated patients were treated with PB from 1975 to 1984. PB was given at a dose of 1 mg/kg/d until platelet count dropped below 600 X 10(9)/l. In 18 patients (86%) a hematological remission was obtained. Median duration of induction phase was 49 d. In all cases a maintenance regimen was required at a dose ranging from 0.2 mg/kg/d to 0.5 mg/kg/d, according to platelet number. Follow-up of responder patients ranged from 6 to 108 months (median 17 months). Treatment was well tolerated and we observed only a very moderate and transient hematological toxicity. No patient had relapsed or developed secondary neoplasms at the time of writing. Median survival time of all patients was 24 months (range 10-115).     

alpha-Interferon in the treatment of essential thrombocythemia]

Two patients with essential thrombocythemia were successfully treated by administering native alpha-interferon (alpha-IFN). One patient was a 38-year-old man in whom thrombocytosis was found accidentally. His platelet count on admission was 880,000/microliters and megakaryocytes increased. Three million units of alpha-IFN was administered subcutaneously everyday, and the platelet count decreased gradually to about 500,000/microliters within 2 weeks. The other patient was a 66-year-old woman who visited our hospital complaining of tenderness and swelling of the fingertips. Her platelet count was 1,610,000/microliters, and megakaryocytes increased and showed abnormal morphology. Six million units of alpha-IFN was administered subcutaneously every other day. The tenderness and swelling of the fingertips disappeared soon after the beginning of alpha-IFN administration. The platelet count decreased to about 500,000/microliters within 10 days, but she developed itching of the skin over the entire body. Therefore, alpha-IFN treatment was discontinued. It was suggested that alpha-IFN suppresses not only the maturation and proliferation of the progenitors of megakaryocytes but also the production of platelets from megakaryocytes. Administration of alpha-IFN should be considered in treating patients with essential thrombocythemia, because effects appear soon and alpha-IFN does not induce a second malignancy.