A clinical update in polycythemia vera and essential thrombocythemia.

Polycythemia vera and essential thrombocythemia pose specific management issues that distinguish them from other chronic myeloproliferative disorders. They are associated with a better prognosis, as well as a variable risk of thrombohemorrhagic complications. In addition, essential thrombocythemia occurs comparatively more often in young people and women. Treatment strategies for patients with polycythemia vera and essential thrombocythemia must consider the possibility of long-term survival, morbidity from thrombotic complications, transformation into myelofibrosis with myeloid metaplasia or acute myeloid leukemia, and the effect of specific therapies on the incidence of leukemic transformation and on pregnancy. There is increasing concern about the possible leukemogenic effect of hydroxyurea. Newer therapeutic agents, including interferon alpha and anagrelide, are being used more often. Ongoing studies are reexamining the effects of low-dose aspirin in preventing thrombotic complications.

Splenectomy in myelofibrosis with myeloid metaplasia: a single-institution experience with 223 patients.

In a 20-year period, 223 patients (median age, 64.8 years) with myelofibrosis with myeloid metaplasia (MMM) had therapeutic splenectomy at our institution. Primary indications for surgery were transfusion-dependent anemia (45.3%), symptomatic splenomegaly (39. 0%), portal hypertension (10.8%), and severe thrombocytopenia (4.9%). Operative mortality and morbidity rates were 9% and 31%, respectively. The 203 survivors of surgery had a median postsplenectomy survival time (PSS) of 27 months (range, 0-155). Among preoperative variables, thrombocytopenia (platelet count less than 100 x 10(9/)L) and nonhypercellular bone marrow were identified as independent risk factors for decreased PSS. Durable remissions in constitutional symptoms, transfusion-dependent anemia, portal hypertension, and severe thrombocytopenia were achieved in 67%, 23%, 50%, and 0% of the patients, respectively. Histologic or cytogenetic features of bone marrow obtained before splenectomy did not predict a response in cytopenias. After splenectomy, substantial enlargement of the liver and marked thrombocytosis occurred in 16.1% and 22.0% of the patients, respectively. The thrombocytosis was associated with an increased risk of perioperative thrombosis and decreased PSS. The rate of blast transformation (BT) was 16.3%, and the risk of BT was higher in the presence of increased spleen mass and preoperative thrombocytopenia. However, the PSS of patients with BT was not significantly different from that of patients without BT. We conclude that presplenectomy thrombocytopenia in MMM may be a surrogate for advanced disease and is associated with an increased risk of BT and inferior PSS. However, the development of BT after splenectomy may not affect overall survival and does not undermine the palliative role of the procedure for the other indications.

Population-based incidence and survival figures in essential thrombocythemia and agnogenic myeloid metaplasia: an Olmsted County Study, 1976-1995.

To provide basic information about occurrence and outcome of essential thrombocythemia (ET) and agnogenic myeloid metaplasia (AMM), we used the Rochester Epidemiology Project medical record linkage system for residents of Olmsted County, Minnesota. We identified all residents who were diagnosed with ET or AMM from 1976 to 1995. Community inpatient and outpatient medical records were reviewed to verify the diagnosis of ET or AMM, and patients were followed passively through their medical records to determine the outcome after diagnosis. We identified 39 cases of ET and 21 of AMM, with age- and sex-adjusted incidence rates of 2.53 and 1.46 cases/100,000 population annually, respectively. The respective median ages at diagnosis were 72 and 67 years. The female-to-male ratios were 1.8 and 1.6 for ET and AMM, respectively, and when adjusted for age, there was no difference in risk. The median follow-up period was 62.9 months for ET and 33.2 months for AMM. Five- and 10-year survivals were 74.4% and 61.3%, respectively, for ET and were significantly lower than expected for age-matched controls (P = 0.012). Prognosis was worse for AMM, with a median progression time of 7 months and a 3-year survival of 52.4%. This was significantly worse than for age-matched controls (P < 0.001). This study provides population-based incidence and comparative survival figures in ET and AMM.

Treatment of essential thrombocythemia with anagrelide.

Essential thrombocythemia (ET), the most common of the chronic myeloproliferative disorders, is characterized by thrombotic and hemorrhagic complications. Thrombotic complications predominate, endangering especially the older population and those with prior history of thrombotic episodes. However, because the life expectancy of ET patients is generally of normal length, caution must be exercised in treating these patients, and the complications of treatment must be weighed against the complications of the disease. Historically, most drugs used in the treatment of ET, such as alkylating agents and radiophosphorus, were carcinogenic themselves. Even hydroxyurea has recently come under investigation for its long-term mutagenicity. The newest drug, anagrelide, approved in March 1997 specifically for ET, appears to be safe and well tolerated.

Splenic irradiation for symptomatic splenomegaly associated with myelofibrosis with myeloid metaplasia.

Twenty-three patients who had myelofibrosis with myeloid metaplasia (MMM) were treated at our institution with 50 courses of splenic irradiation (SI) for symptomatic splenomegaly. The median dose of radiation per course was 277.5 cGy, administered in a median of 7.5 fractions. 8/23 patients received multiple courses of SI. Of 49 evaluable courses of SI, 46 (93.9%) resulted in an objective decrease in spleen size. The median duration of response was 6 months (range 1-41). Reduction in spleen size was associated with symptomatic relief in all patients. Overall median survival after SI was 22 months. Significant cytopenia occurred in 10 (43.5%) patients, or 16 (32%) of the 50 courses of SI. Prolonged, life-threatening pancytopenia after a single course of SI occurred in six patients (26%), resulting in fatal sepsis or haemorrhage in three (13%). Nine patients underwent subsequent splenectomy: the perioperative mortality rate was 11%. One third of patients experienced postoperative intra-abdominal haemorrhage necessitating surgical re-exploration. SI can provide symptomatic relief and a reduction in spleen size in most MMM patients. The increased risk of postoperative bleeding in patients requiring subsequent splenectomy dictates against considering SI as an alternative to splenectomy for patients who are otherwise good surgical candidates.

Treatment of polycythaemia vera and essential thrombocythaemia.

The clinical course in both polycythaemia vera (PV) and essential thrombocythaemia (ET) is characterized by significant thrombohaemorrhagic complications and variable risk of disease transformation into myeloid metaplasia with myelofibrosis or acute myeloid leukaemia. Randomized studies have shown that the risk of thrombosis was significantly reduced in ET with the use of hydroxyurea (HU) and in PV with the use of chlorambucil or 32P. However, the use of chlorambucil or 32P has been associated with an increased risk of leukaemic transformation. Subsequently, other studies have suggested that both HU and pipobroman may be less leukaemogenic and as effective as chlorambucil and 32P for preventing thrombosis in PV. However, the results from these prospective studies have raised concern that even HU and pipobroman may be associated with excess leukaemic events in both ET and PV. The recent introduction of anagrelide as a specific platelet-lowering agent, the demonstration of treatment efficacy with interferon-alpha, and the revived interest in using low-dose acetylsalicylic acid provide the opportunity to initiate prospective randomized studies incorporating these treatments.

2-Chlorodeoxyadenosine treatment after splenectomy in patients who have myelofibrosis with myeloid metaplasia.

2-Chlorodeoxyadenosine (2-CdA) is a purine nucleoside analogue with therapeutic activity in low-grade lymphoproliferative disorders. In addition, 2-CdA has a potent myelosuppressive effect, and it has been shown to be toxic to malignant myeloid cells both in vitro and in vivo. In this pilot study we treated nine patients who had advanced myelofibrosis with myeloid metaplasia (MMM) and progressive hepatomegaly or symptomatic thrombocytosis after therapeutic splenectomy. 2-CdA was administered at 0.05-0.1 mg/kg/d for 7 d for one to five treatment cycles. A reduction in liver size associated with marked improvement in fatigue and control of thrombocytosis and leucocytosis was achieved in seven of the nine patients (78% response rate). In four of the seven responding patients the reduction in liver size was durable (4-28 months) and was associated with a decrease in serum alkaline phosphatase levels. However, no patient had improvement in anaemia, and two of the seven initially responding patients have since died of acute leukaemia or progressive disease. Improvement in bone marrow fibrosis was noted in two of five available post-treatment marrow examinations. Toxicity was mainly myelosuppression, which was severe in two patients. 2-CdA may be considered a palliative therapeutic agent after splenectomy in noncytopenic patients with MMM who have progressive hepatomegaly or extreme thrombocytosis.

The effects of anagrelide on human megakaryocytopoiesis.

Anagrelide, an inhibitor of platelet aggregation, decreases the number of platelets in normal subjects and in patients with myeloproliferative disorders. We describe studies aimed at discovering the general mechanism(s) by which anagrelide acts. We examined three hypotheses: (1) anagrelide shortens platelet survival, (2) anagrelide inhibits the proliferation of megakaryocytic-committed progenitor cells (CFU-M), and (3) anagrelide inhibits maturation of megakaryocytes. We observed that anagrelide did not shorten platelet survival. Proliferation of CFU-M in vivo was not affected by anagrelide, although high concentrations of anagrelide inhibited CFU-M in vitro. In-vivo and in-vitro anagrelide altered the maturation of megakaryocytes, causing a decrease in their size and changing other morphometric features. We conclude that anagrelide decreases the number of platelets primarily by interfering with the maturation of megakaryocytes.

New drugs in essential thrombocythemia and polycythemia vera.

Among the chronic myeloproliferative disorders, polycythemia vera and essential thrombocythemia are unique because of their association with thrombohemorrhagic manifestations and their relatively indolent clinical course. Patients with essential thrombocythemia may not have a significant shortening of life-expectancy and most may not require specific therapy. However, patients with polycythemia vera have a significant risk of transformation of polycythemia vera into acute leukemia or postpolycythemic myelofibrosis (or both). 'High-risk-for-thrombosis' patients with either polycythemia vera or essential thrombocythemia require specific therapy with a platelet-lowering agent to prevent thrombotic complications. Currently, the standard agent used for this is hydroxyurea. However, its tetratogenic and leukemogenic potential has been of concern. As a result, new platelet-lowering agents are being evaluated in the treatment of polycythemia vera and essential thrombocythemia. Anagrelide and interferon alfa are two such agents and have been shown to be effective in reducing platelet counts in patients with chronic myeloproliferative disorders. The putative mechanism of action of these drugs, their specific activity in polycythemia vera and essential thrombocythemia, side-effect profile, and current indications are discussed herein.

Anagrelide as a new platelet-lowering agent in essential thrombocythemia: mechanism of actin, efficacy, toxicity, current indications.

Anagrelide is an oral imidazoquinazoline agent with an anti-cyclic AMP phosphodiesterase activity and inhibits platelet aggregation in both humans and animals. In addition, it has in humans a species-specific platelet-lowering activity observed at dose levels lower than those required to inhibit platelet aggregation. Because of this, the drug has been tested in patients with clonal thrombocytosis and has been shown to have potent platelet-reducing activity in essential thrombocythemia (ET) and related disorders. The mechanism of action may involve the drug's interference with megakaryocyte maturation. More than 90% of patients with ET respond to anagrelide regardless of the presence or absence of previous therapy. The responses are durable with a median maintenance dose of approximately 2 to 2.5 mg/day. Side effects are related mostly to the drug's direct vasodilating and positive inotropic effects and include headache, fluid retention, tachycardia, and arryhthmias. The place of anagrelide therapy in the current management of patients with ET is discussed.

Current perspective in agnogenic myeloid metaplasia.

Agnogenic myeloid metaplasia (AMM) carries the worst prognosis among the chronic myeloproliferative disorders. Substantial bone marrow fibrosis, extramedullary hematopoiesis, anemia and hepatosplenomegaly are the characteristic features of the disease. AMM is currently incurable and the available treatment agents are mostly palliative and do not prolong life. Two pathogenetic processes are responsible for the impaired hematopoiesis and the clinical manifestations. The primary disease process is a clonal hematopoietic stem cell disorder which results in chronic myeloproliferation and atypical megakaryocytic hyperplasia. The secondary process of bone marrow fibrosis is the result of non-clonal fibroblastic proliferation and hyperactivity induced by growth factors abnormally shed from clonal megakaryocytes. Therefore, experimental treatment strategies may be directed towards either one or both of these disease processes. This report summarizes the current management options and new therapeutic endeavours.

Measurement of blood volume and red cell mass: re-examination of 51Cr and 125I methods.

Comparison of results of red cell mass (RCM) measurement by 51Cr and 125I methods in 119 patients showed virtual equivalence. Both methods have an acceptable coefficient of variation (CV) that is < 5%. The 125I method is simpler and much less expensive. Unrealistically narrow "normal ranges" for RCM are likely to lead to misdiagnosis of polycythemia vera. Upper normal limits of 39 mL/kg (males) and 32 mL/kg (females) are consistent with originally published data in normal persons; use of these limits as criteria would reduce the risk of misdiagnosis. No cases of "stress erythrocytosis" or Gaisbock Syndrome were encountered among the 119 cases reviewed.

Outcome analysis of 34 pregnancies in women with essential thrombocythemia.

OBJECTIVE: To evaluate the clinical impact of essential thrombocythemia on the outcome of pregnancy or vice versa. DESIGN: A retrospective study. SETTING: All patients were seen at our tertiary referral center, and most were followed up by their local physicians. PATIENTS: From 1975 through 1991, 73 women younger than 50 years with essential thrombocythemia were seen at our institution. All patients were followed up through patient or physician contact. A detailed obstetric history, including peripartum complications and management, was obtained. RESULTS: Among the 73 women, 34 pregnancies occurred in 18 patients. There were two uncomplicated elective abortions and one ectopic pregnancy. Of the 31 other pregnancies, 17 (55%) resulted in live birth and 14 (45%) ended in spontaneous abortion (all but two in the first trimester). Abortion could not be predicted from history of disease complications before or during pregnancy or by the presence or absence of specific therapy during pregnancy. Preconception platelet counts in women whose pregnancies resulted in live birth were similar to those of women whose pregnancies ended in abortion. Other complications during pregnancy were rare. CONCLUSIONS: Patients with essential thrombocythemia have an increased risk of first-trimester abortion, which does not appear to be predictable or influenced by therapy. However, most patients are able to carry pregnancies to term with little or no risk of obstetric or thrombohemorrhagic complications during or after delivery. Overall, specific therapy during pregnancy did not appear to modify the clinical outcome, and the benefit of platelet apheresis during delivery could not be substantiated.

Trends in the incidence of polycythemia vera among Olmsted County, Minnesota residents, 1935-1989.

To investigate the suggestion that the incidence of polycythemia vera has increased in recent decades, we ascertained secular trends in the incidence of polycythemia vera in Olmsted County, Minnesota, over the 55-year period, 1935-1989. The inpatient and outpatient medical records of all potential cases of polycythemia vera in Olmsted County residents were reviewed and the diagnostic criteria of the Polycythemia Vera Study Group were applied. We found no indication of an increase in the age- and sex-adjusted incidence of polycythemia vera, which averaged 1.9 per 100,000 person-years (95% C.I., 1.4-2.5) over the study period. Incidence rates increased with age, and age-adjusted incidence rates were greater for men (2.8 per 100,000 person-years; 95% C.I., 1.8-3.9) than for women (1.3 per 100,000 person-years; 95% C.I., 0.7-1.9), with the highest incidence rate (23.5 per 100,000 person-years) among men aged 70-79 years. Survival was reduced in this inception cohort of 50 cases, compared to that expected for individuals of like age and sex (P < 0.0001); median survival following diagnosis was 7.2 years.

Outcome of portal-systemic shunt surgery for portal hypertension associated with intrahepatic obstruction in patients with agnogenic myeloid metaplasia.

Life-threatening portal hypertension (PHN) in patients with chronic myeloproliferative disorders may result from increased portal flow caused by marked splenomegaly or an increased resistance to portal flow from either a large vein thrombosis or an intrahepatic obstruction usually associated with agnogenic myeloid metaplasia (AMM). The former cause is correctable by splenectomy alone, whereas the latter requires portal-systemic shunt surgery. Few data exist regarding the outcome of portal-systemic shunt surgery in patients with AMM and intrahepatic obstruction. During the past 25 years, 13 patients with chronic myeloproliferative disorders underwent portal-systemic shunt surgery at our institution. The cause of PHN was intrahepatic obstruction in ten patients and hepatic vein thrombosis in three. Ten of the thirteen patients had AMM as initial diagnosis. Only one patient had intraoperative complications, and four patients had either sepsis or thrombosis during the postoperative period. Twelve patients survived the postoperative period and had a median postsurgical survival of 3 years (range, 0.25 to 19 years). The long-term complications of the operation were very few and included hepatic encephalopathy (one patient), portal vein thrombosis (one patient), and shunt occlusion (one patient). The procedure was successful in alleviating complications of PHN in all but one patient. Deterioration of hepatic function and subsequent hepatomegaly were unusual. Portal-systemic shunt surgery seems to be a useful option in patients with AMM and life-threatening PHN from intrahepatic obstruction.