Efficacy, safety and tolerability of anagrelide in the treatment of essential thrombocythaemia

Background : Essential thrombocythaemia (ET) has an associated risk of thrombotic and haemorrhagic complications, which can be minimised by control of the platelet count. Anagrelide selectively lowers the platelet count, however, there is little Australasian experience with its use and scant data on symptom control.
Aims : To evaluate the efficacy of anagrelide for platelet reduction and symptom control in a broad cohort of patients with well-defined ET, and to determine the safety and tolerability in such a population.
Methods : Seventeen patients with ET and a platelet count >600X10⁹/L were prospectively enrolled. The evaluable four males and 12 females with a median age of 58 years (range 14–79) included ten patients (63%) previously treated with two or more agents and 12 patients (75%) who had failed other therapies. The median follow-up was seven months (range 15 days to 36 months).
Results : Anagrelide, in an average dose of 1.9 mg/day, reduced the platelet count from a mean of 728X10⁹/L (95% CI 611-845X10⁹/L) to 412X10⁹/L (95% CI 319-504X10⁹/L) ( p <0.001) and maintained it at this level. Fourteen patients (88%) had a platelet reduction to <600X10⁹/L. All symptomatic patients had improvement in symptoms attributable to thrombocythaemia. There were three haemorrhagic and three thrombotic episodes in a total of three patients (19%), including one death from an intracerebral haemorrhage. Six patients (37%) were removed from therapy due to toxicity after a median of 151 days. Side effects included palpitations, abdominal pain and cough.
Conclusions : Anagrelide is efficacious and safe in ET, both for platelet and symptom control. Minor side effects are common, however, tend to occur early and resolve spontaneously in most cases.     

Iron stores in essential thrombocythaemia

Summary The iron status of 26 patients with essential thrombocythaemia (ET) was evaluated at diagnosis by means of bone marrow iron and blood studies, including serum ferritin determination. Nine patients were males, 17 females, and the mean age was 53 years (range 7–81). A decreased or absent iron level by semiquantitative estimation on bone marrow smears was observed in 77% of patients, and 81% had a low sideroblast score. Such a marrow pattern of iron depletion was equally distributed between both sexes. Contrasting with this, normal Hb, MCV, serum iron and serum ferritin were registered in the majority of cases. According to these results, absent or decreased marrow iron would be a common feature in ET, generally not reflecting true iron deficiency, as it occurs in the remaining chronic myeloproliferative disorders. Thus, in patients in whom ET is suspected, the diagnostic criterion of ruling out iron deficiency would be better served by serum ferritin measurement than by bone marrow iron estimation.     

Chronic lymphocytic leukaemia in a patient with essential thrombocythaemia

A patient who developed chronic lymphocytic leukaemia 6 years after an initial diagnosis of essential thrombocythaemia is described. This association, which was not treatment related, is extremely rare and only two other cases have been previously described in the literature.     

Studies of platelet volume, chemistry and function in patients with essential thrombocythaemia treated with Anagrelide

Anagrelide (imidazoquinazolin derivative) is a new compound proposed for the treatment of myeloproliferative disorders. In this study, Anagrelide was given to patients with essential thrombocythaemia (ET) in a compassionate-use protocol. The aim of this study was to test the effect of this drug not only on the platelet count but also on platelet volume, chemistry and function, which has not previously been reported. Thus, in ET, different functional or structural platelet abnormalities were reported: a shortening of the bleeding time, hypoaggregation to several agonists, and in particular a lack of response to adrenalin, an increase in the amount of total platelet glycoprotein IV (or CD36), and an abnormal migration of thrombospondin on electrophoresis. These different parameters were studied before and during therapy with Anagrelide. Although the platelet count was corrected, no functional or chemical abnormality was improved. Furthermore, platelet volume was shown to be constantly increased under Anagrelide. Thus, Anagrelide, in reducing the platelet count, may possibly decrease the risk of thrombosis and haemorrhage. Nevertheless, if the risk of thromboses and/or myelofibrosis is related not only to the platelet count but also to the platelet abnormalities, the persistence of a thrombocytopathy in patients treated with Anagrelide must be taken in consideration. Our data suggest that thromboses and myelofibrosis are clinical end-points which should be included in future large-scale use of Anagrelide.     

Thrombopoietin measurement in thrombocytosis: dysregulation and lack of feedback inhibition in essential thrombocythaemia

Essential thrombocythaemia (ET), a myeloproliferative disorder (MPD) manifested by excessive platelet production, lacks a specific diagnostic test to facilitate differentiation from other thrombocytoses. We studied thrombopoietin (TPO) levels in 41 patients with thrombocytosis: 25 ET patients, eight with other MPD, and eight with reactive thrombocytosis. Mean age and platelet counts for these groups were comparable. TPO levels for 96 healthy individuals provided a reference range for normal. The majority of ET patients (19/25 or 76%) had normal TPO levels. No patient with ET had a TPO level below 75 pg/ml, compared with 57% of healthy donors and 8/16 (50%) patients with other thrombocytoses ( P  < 0.05). TPO levels in ET are not appropriately down-regulated, as occurs with cytokines relevant to other MPD. In thrombocytosis, a TPO level <75 pg/ml indicates that ET is unlikely.     

Essential Thrombocythaemia: A Single Institution Experience of 16 Years

This presentation is a clinical narrative and long term follow up (6–16 years) of 21 prospectively studied patients with essential thrombocythaemia (ET) in Kuwait. The median age (55.9 years) is younger than reported by others. Two patients were below the age of 40 years with one of them presenting as post-polycytheamia ET at 16 years of age. Twelve patients (57.1 %) remained asymptomatic throughout the period of follow up. Four patients complained of erythromelalgia, three (19 %) suffered from thrombotic episodes and only one (4.3 %) had excessive bleeding. Four patients presented with splenomegaly. Intensity of thrombocytosis or duration of very high platelet count had no relationship with these complications. Two patients transformed to post-ET myelofibrosis and one patient developed chronic myeloid leukaemia (CML). None transitioned to acute leukaemia. All patients are still alive after follow up for 6–16 years. Janus kinase 2 mutation was positive in eight (38 %) patients. It had no bearing on transition of our ET patients to post-ET myelofibrosis or CML. Platelet aggregation tests were performed in 14 patients. Six (42.9 %) showed defective response to ADP. Only one of these patients suffered from bleeding. All patients were given aspirin (81 mg/day). Cyto-reductive therapy with hydroxyurea was taken by six (42.9 %) subjects. Two patients who were treated with anagrelide and one with alpha-interferon did not continue treatment for long.     

Prevention and treatment of thrombotic complications in essential thrombocythaemia: efficacy and safety of aspirin

The efficacy and safety of aspirin in the prevention and treatment of thrombosis in essential thrombocythaemia (ET) was retrospectively analysed in a cohort of 68 ET patients. 41 patients presented with thrombosis, five patients with bleeding; two patients had a paradoxical combination of bleeding and thrombosis at presentation. At presentation, patients with bleeding had significantly higher platelet and leucocyte counts than patients with thrombosis. During long-term follow-up the incidence of thrombosis was significantly reduced in patients receiving aspirin, either as monotherapy or in combination with cytoreduction. However, treatment with aspirin (500 mg/d) was associated with an increase in (minor) bleeding complications. In patients receiving aspirin, bleeding occurred particularly at platelet counts exceeding 1000×10⁹/l. The overall 5- and 10-years survival probability was 93% and 84% respectively, indicating that life expectancy in ET is close to normal. Although our data need confirmation in prospective clinical trials, they suggest that aspirin, particularly in lower doses (100 mg/d), may be a safe antithrombotic agent in ET with an acceptable risk for bleeding, if applied to patients with a platelet count <1000×10⁹/l and/or absence of a bleeding history.     

The determination of spontaneous megakaryocyte colony formation is an unequivocal test for discrimination between essential thrombocythaemia and reactive thrombocytosis

Summary. Spontaneous colony formation from bone marrow megakaryocyte progenitors (BMsCFU-Mk) was studied in 24 patients with essential thrombocythaemia (ET), 20 patients with reactive thrombocytosis (RT), 20 patients with polycthaemia rubra vera with thrombocytosis (PRVtr), 16 patients with chronic myeloid leukaemia with thrombocytosis (CMLtr) and 18 normal control subjects (C).
The culture medium which was used in the methylcellu-lose assay in vitro contained 30% of plasma from a single patient with hereditary haemochromatosis. Remarkable BMsCFU-Mk growth was recorded in all patients with ET but in none with RT or in C. BMs-CFU-Mk were present in 11/20 patients with PRVtr and 7/16 patients with CMLtr.
Spontaneous bone marrow erythroid progenitors (BMsBFU-E) were also determined in these patients. BMsBFU-E were found in 21/24 patients with ET and none in the patients with RT and C. All patients with PRVtr and one patient with CMLtr showed BMsBFU-E.
We conclude that our implementation of the in vitro methylcellulose assay allows the BMsCFU-Mk to be used as an unequivocal test for discrimination between ET and RT which has not been shown in previously published studies.
In addition, we present evidence that in 10 patients BMsCFU-Mk and/or BMsBFU-E growth in the test persisted after long-lasting haematological remission.     

Acute lymphoblastic transformation of essential thrombocythaemia

Essential thrombocythaemia is a myelopro-Iterative disorder which may transform to acute myeloid leukaemia, especially following therapy with alkylating agents or radioactive phosphorus. We describe the rare occurrence of acute lymphoblastic leukaemia transformation in a patient with known essential thrombocythaemia.     

Use of splenic volume estimation to distinguish primary thrombocythaemia from reactive thrombocytosis

Splenic volume was measured by visual assessment of planar images of the spleen, and also by single photon emission computerised tomography (SPECT) using 99mtechnetium tin colloid, in a group of 33 patients with primary thrombocythaemia (PT) or reactive thrombocytosis. Volumes greater than 337 cm3 correlated strongly though not absolutely with PT, all patients with volumes greater than this figure being in the PT group. Simple visual assessment of planar images by an experienced observer matched measured splenic volumes very closely.     

Thrombopoietin-responsive essential thrombocythaemia with myelofibrosis

Platelet-derived growth factor (PDGF) and other cytokines released from megakaryocytes are thought to play a crucial role in the pathogenesis of myelofibrosis. We describe a patient with essential thrombocythaemia (ET) who developed myelofibrosis with an increased level of serum thrombopoietin (TPO). Recombinant human (rh) TPO stimulated the proliferation and spontaneous megakaryocyte colony formation of the neoplastic cells in the peripheral blood. Moreover, serum concentrations of PDGF, platelet factor 4, and β-thromboglobulin were elevated and the production of these growth factors from the megakaryocyte progenitors was augmented with the addition of rhTPO in vitro . These results indicate that TPO may contribute to the development of myelofibrosis in ET.     

Guideline for investigation and management of adults and children presenting with a thrombocytosis

Acute lymphoblastic leukaemia (ALL) remains the most frequent cause of cancer‐related mortality in paediatrics and outcome is poor for patients who have high‐risk ALL or relapse. HA22 (CAT‐8015) is an immunotoxin composed of an anti‐CD22 variable fragment linked to a 38 kDa truncated protein derived from Pseudomonas exotoxin A. Using a bone marrow mesenchymal cell culture assay to support ALL cell viability, we investigated the in vitro cytotoxicity of HA22 against ALL blasts from newly diagnosed (n = 13) and relapsed patients (n = 22). There was interpatient variability in sensitivity to HA22. Twenty‐four of 35 patient samples tested were sensitive (median 50% lethal concentration 3 ng/ml, range 1–80 ng/ml). Blasts from the other 11 patients were not killed by 500 ng/ml HA22. The median 50% lethal concentration was 20 ng/ml for all patients. There was no significant difference in HA22 sensitivity between diagnosis and relapse samples but peripheral blood ALL blasts were more sensitive to HA22 than those from bone marrow (P = 0·008). Thus, HA22, at concentrations achievable in patients, is highly cytotoxic to B‐lineage ALL cells. These results provide a strong rationale for clinical testing of this agent in children with drug‐resistant ALL and offers the potential to reduce morbidities of treatment while improving outcome.     

Long-term evaluation of 164 patients with essential thrombocythaemia treated with pipobroman: occurrence of leukaemic evolution

Essential thrombocythaemia (ET) is usually considered an indolent disease, but it may progress during its natural course into acute leukaemia (AL); however, an influence of myelosuppressive agents in the blastic transformation of ET cannot be excluded. We performed a retrospective study to assess the incidence of AL in ET patients treated with pipobroman (PB) as first-line therapy. One hundred and sixty-four patients with ET were managed with PB at a dose of 1 mg/kg/d until a stable platelet count below 400 x 10(9)/l was achieved. Maintenance therapy was given at a planned dose ranging between 0.2 and 1 mg/kg/d according to platelet count, in all cases, with a median daily dose of 25 mg (range 7-75 mg/d). The median treatment time was 100 months (range 25-243 months). The patients were evaluated for the occurrence of AL and/or secondary malignancies and survival end-points. AL was observed in nine patients (5.5%) after a median treatment time of 153 months (range 79-227 months). The overall survival (OS) and the event-free survival (EFS) at 120 months were 95% and 97%, whereas at 180 months, they were 84% and 76% respectively. In conclusion, this retrospective analysis shows a low incidence of AL in a large group of patients consecutively treated with PB as first-line chemotherapy. Therefore, an investigation of the role of myelosuppressive agents in the blastic transformation of ET would be of interest.