Therapeutic options for essential thrombocythemia and polycythemia vera

Therapeutic Options for Essential Thrombocythemia and Polycythemia Vera Lawrence A. Solberg, Jr Several options exist for treating essential thrombocythemia and polycythemia vera. One approach is to assign the patient to a risk category from which treatment recommendations follow. The principal risks of essential thrombocythemia include thrombosis, major hemorrhage, and conversion to leukemia or myelofibrosis. Risk factors for thrombosis include age and prior thrombosis. Smoking and obesity have been implicated in isolated series. High-risk patients with essential thrombocythemia can be defined as those 60 years of age or older or those who have had a thrombosis at any age. These patients should be treated with hydroxyurea. If hydroxyurea cannot be tolerated, anagrelide and interferon-alpha (IFN-␣) are alternatives. Low-dose aspirin (40 to 325 mg) can be used for patients whose platelet counts are < 1,500 ⴛ109/L. Low-risk patients are those less than 60 years old who have not had thrombosis, who have no cardiovascular risk factors, and whose platelet counts are < 1,500 ⴛ 109/L. These patients can be observed or placed on low-dose aspirin. Intermediate-risk patients are those less than 60 years who have not had thromboses, but who have platelet counts > 1,500 ⴛ 109/L or who have significant cardiovascular risk factors. These patients should have their risk factors treated and may be given low-dose aspirin if the platelet count is < 1,500 ⴛ 109/L. They can be observed or treated with anagrelide, hydroxyurea, or IFN-␣. The Mayo Clinic experience suggests that no specific treatment affects outcomes of pregnancies. In high-risk pregnant women who need treatment, IFN-␣ is used. The principal risks of polycythemia vera are thrombosis, postpolycythemia myeloid metaplasia, and acute leukemia. Risk factors for thrombosis include age, the use of phlebotomies, the rate of phlebotomies, and a prior history of thrombosis. Platelet counts have not been definitively linked to an increased risk of thrombosis. High-risk polycythemia vera patients are those 60 years of age or older (some groups use 70 years) or those of any age who have had thrombosis. They should be treated with phlebotomy and hydroxyurea or IFN-␣. Selected patients may be treated with anagrelide. A typical target range for phlebotomy is a hematocrit of < 42% for women and < 45% for men. Low-dose aspirin can be used if the platelet count is < 1,500 ⴛ 109/L. Low-risk patients are those less than 60 years old who have had no thrombosis, no

From the Mayo Medical School, Mayo Clinic and Foundation, Jacksonville, FL. Address reprint requests to Lawrence A. Solberg, MD, PhD, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224. Copyright 2002, Elsevier Science (USA). All rights reserved. 0093-7754/02/2903-1003$35.00/0 doi:10.1053/sonc.2002.33755 10

cardiovascular risk factors, and whose platelets are < 1,500 ⴛ 109/L. These patients can be managed with phlebotomy alone or phlebotomy and low-dose aspirin. Intermediate-risk patients are those who are less than 60 years old, who have not had thrombosis, but who have platelet counts > 1,500 ⴛ 109/L or who have cardiovascular risk factors. The cardiovascular risk factors should be treated, along with phlebotomy alone or with IFN-␣. Low-dose aspirin is reasonable for those with platelet counts < 1,500 ⴛ 109/mL. Anagrelide can be used with phlebotomy in selected patients. Women of childbearing age who are in the low-risk or intermediate-risk group can be treated with phlebotomy alone and low-dose aspirin if the platelet count is < 1,500 ⴛ 109/L. For high-risk patients or pregnant patients, IFN-␣ can be added. Semin Oncol 29 (suppl 10):10-15. Copyright 2002, Elsevier Science (USA). All rights reserved.

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EVERAL options exist for treating patients with essential thrombocythemia (ET) and polycythemia vera (PV). In selecting a treatment plan, the physician should consider the risks of the disease itself, of the proposed treatment, and the risk category of the patient. If more than one treatment is possible, positive and negative aspects about each should be described and the patient engaged in the final decision as much as possible. Randomized, controlled studies do not exist to illuminate many situations encountered in patients with ET or PV. In such cases, the physician must integrate the literature, personal experience, and the judgment of the patient to decide about treatment. RISK-ADJUSTED TREATMENT FOR ESSENTIAL THROMBOCYTHEMIA

The principal risks from ET include thrombosis, major hemorrhage requiring hospitalization or transfusion (20 times less frequent than thrombosis), conversion to leukemia (rare to 4%), or conversion to myelofibrosis (rare to 6%). Erythromelalgia and other vasomotor symptoms of microvasculature occlusion can be troubling, but do not typically carry the risk of thrombosis. Patient characteristics implicated in increasing the risk of thrombosis include age and prior thrombosis. Some series have implicated smoking and obesity. Risk factors for leukemia include treatment Seminars in Oncology, Vol 29, No 3, Suppl 10 (June), 2002: pp 10-15

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Table 1. Risk-Adjusted Treatment for Essential Thrombocythemia Reduce Cardiovascular Risk Factors

Risk Category

Low-Dose Aspirin for Erythromelalgia and to Reduce Thrombosis*

Other Therapy

Low (age ⬍ 60, platelet count ⬍ 1,500 ⫻ 10 /L and no prior/concurrent thrombosis) Intermediate, (not fitting low or high)

Yes

Yes

Observation†

Yes

High (age ⬎ 60 or prior thrombosis)

Yes

Yes (unless bleeding or platelet count ⬍ 1,500 ⫻ 109/L) Yes (but not if platelets ⬎ 1,500 ⫻ 109/L or bleeding)

Observation,† hydroxyurea, or anagrelide, or IFN-␣ Hydroxyurea, or anagrelide, or IFN-␣, or busulfan, or 32P

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* Not established yet by randomized controlled trial. † Still controversial. See for example references 13 and 14.

with chlorambucil, radioactive phosphorous, and melphalan. Hydroxyurea has been suspected, but not proven, to increase the risk of acute leukemia. Patients of any age who have had or who present with major hemorrhage (gastrointestinal bleeding, bleeding requiring transfusion or hospitalization) or thrombotic complications should be treated to reduce the risk of recurrent complications (Table 1). Hydroxyurea, administered as described in Table 2, can be used as treatment.1 Anagrelide2,3 can be used in lieu of hydroxyurea if the patient is less than 60 years of age, or older than 60 and free of symptomatic cardiovascular disease. It is important to note, however, that only hydroxyurea has been proven in a randomized trial to reduce the risk of thrombosis in high-risk patients 60 years of age or older.1 Anagrelide is also useful for the patient who does not respond to or cannot tolerate hydroxyurea. Interferon-alpha (IFN-␣) (Table 2) is the author’s preferred treatment for pregnant females who need treatment. It is also useful for patients who cannot tolerate hydroxyurea or anagrelide.4-6 IFN-␣ can be reasonably used as first-line treatment in selected patients. Busulfan has been used and, if necessary, might best be given in short 6-week intervals, as described by Berrebi et al.7 However, hydroxyurea and anagrelide have less risk than busulfan, which can cause pulmonary fibrosis. Leukemia arising after busulfan therapy has been reported in patients who received enough drug to develop aplasia. Melphalan and chlorambucil should be avoided because they are leukemogenic. Radioactive phosphorous (32P) may rarely play a role in the treatment of an older patient who cannot

tolerate oral medications. Aspirin, 81 to 325 mg/d, can be used to treat the symptoms of erythromelalgia concomitantly with the use of other agents provided the platelet count is less than 1,500 ⫻ 109/L and the patient has not had any hemorrhage.8-10 Allopurinol, 100 to 300 mg/d, is used to reduce the risk of hyperuricemia. All patients should be counseled to reduce cardiovascular risk factors. TREATMENT OF PATIENTS AT HIGH RISK FOR BLEEDING

Patients of any age whose platelet counts are greater than 1,500 ⫻109/L, and according to some observations if greater than 1,000 ⫻ 109/L, are at increased risk for major bleeding. Aspirin aggravates this risk, particularly if patients have acquired von Willebrand’s disease. Aspirin or nonsteroidal anti-inflammatory drugs should be avoided in these patients. Treatment to reduce platelet counts, as previously described for highrisk ET patients, can be initiated for these patients also. Another strategy, if the patients are young and have had no thrombosis, is to withhold aspirin, to have the patient try to improve cardiovascular risk factors, and to treat any potential areas at risk for gastrointestinal bleeding, such as symptoms of peptic ulcer disease. Several studies support observation of these patients, advising them to reduce cardiovascular risk factors.8,11 This is particularly reasonable if the patients are less than 40 years old. Vasomotor symptoms, including erythromelalgia, headache, and dizziness, can be treated with aspirin, 40 to 325 mg/d, and need not trigger medications to

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LAWRENCE A. SOLBERG, JR

Table 2. Details of Treatment of Essential Thrombocythemia Treatment

Details

Observation

CBC and differential every 3 months; office visit every 3 months (may vary depending on clinical circumstances and patient anxiety). Low-dose (81 to 100 mg per day) or standard dose, 325 mg per day, for erythromelalgia or possible reduction in risk of thrombosis); do not use if platelet counts ⬎ 1,500 ⫻ 109/L (some increased risk above 1,000 ⫻ 109/L) or if acquired von Willebrand’s disease present at lower platelet counts, or if patient has had significant bleeding. 500 mg tabs; two to three tabs each day as a single oral dose. The goal is to get the platelet count to ⬍ 400 ⫻ 109/L (author’s policy — the platelet count target for the randomized study by Cortellazo et al1 was 600 ⫻ 109/L) and keeping the ANC greater than 1,000 (or WBC ⬎ 3,000). Median time to platelets ⬍ 600 ⫻ 109/L is 30 days. Follow CBC and DIFF weekly until platelet count plateaus, then adjust frequency of monitoring. If patient very stable on hydroxyurea, reduce monitoring to monthly (I have done this less frequently if patient stable for a long time, eg, every 2 months). The main side effects leading to the stopping of chronic hydroxyurea are leg ulcers and apthous ulcers, occurring an average of 6 years after starting hydroxyurea. 0.5 mg tabs. Start with 0.5 mg orally 4 times per day. OK to give at the same time as hydroxyurea if patient is being crossed over. Do not give, or give cautiously, if creatinine ⬎ 2.0 mg/dL or AST ⬎ 1.5 times upper normal limit. Avoid anagrelide if patient has any symptomatic cardiovascular disease/symptoms. OK to increase dose after 5 days, but best not exceed a total dose of 3.0 mg per day and be careful about increasing total daily dose by more than 0.5 mg per day at any one time. Check CBC, creatinine, and LFT’s weekly when treatment is initiated, then CBC monthly when platelet count stabilizes. Monitor liver function tests and creatinine every 3 months when stable. The target platelet count should be ⬍ 600 ⫻ 109/L (manufacturer’s recommendation) (⬍ 400 ⫻ 109/L, author’s policy). If patient stable on anagrelide alone can reduce monitoring to CBC every 2 months. Time to 50% platelet reduction in ET is 11 days and in PV 15 days. For maintenance the lowest effective dose should be used. About 15% of patients won’t be able to tolerate anagrelide. 5 million units SQ daily then 2.5 million units per day or 3 million units 3 times per week; when counts plateau reduce to 3 times per week or less if possible (can take 3 months for maximum response). About 20% of patients won’t be able to tolerate IFN-␣. Consider use as per Berrebi7 below. Busulfan, 2 mg tabs: Two tablets of 4 mg per day every day for one week, 2 mg per day for the next 3 weeks then 2 mg every other day until maximal sustained response, approximately 3 months. Then stop busulfan. 2.7 to 2.9 mCi per meter squared, not to exceed 5 mCi per dose. Can repeat after 3 months.

Aspirin

Hydroxyurea

Anagrelide

IFN-␣

Busulfan

P32

Abbreviations: ANC, absolute neutrophil count; AST, aspartate aminotransferase; CBC, complete blood count; DIFF, differential blood count; LFT, liver function test; SQ, subcutaneous; WBC, white blood cell/count.

reduce platelet counts. Avoiding hydroxyurea in young patients is reasonable because of observations that its use has been associated with 17p deletions.12 Pilot studies of low-dose aspirin, 40 to 100 mg/d, have not shown an increase in severe hemorrhage and have pointed toward a reduction in thrombosis risk. Platelet cyclooxygenase levels are inhibited at the 40-mg/d dose. A randomized trial is underway to see if low-dose aspirin compared with placebo in asymptomatic patients will reduce the risk of thrombosis. However, not all clinical series,13,14 support observing these asymptomatic patients so that therapy with aspirin, anagrelide, and IFN-␣ can be administered. Pearson et al14 have reviewed the literature and suggest that patients under 40 years of age without thrombotic complications can be observed and cytoreductive therapy avoided, but

find that the intermediate age group, 40 to 60 years, presenting without complications are at an increased risk of complications if left untreated. Results of the Medical Research Council Polycythemia Vera Trial No. 1, in which these intermediate risk patients are randomized to cytoreductive therapy or no treatment, are awaited with great interest. RISK-ADJUSTED TREATMENT FOR POLYCYTHEMIA VERA

The principal risks of PV are thrombosis, postpolycythemia myeloid metaplasia (10% after 10 years, 50% after 20 years), and acute leukemia (3% to 4% if phlebotomy only; up to 30% if treated with chlorambucil). In the first Polycythemia Vera Study Group (PVSG-01), 43% of deaths of patients who were only phlebotomized were from

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Table 3. Risk-Adjusted Treatment for Polycythemia Vera Risk

Risk Category 60 years old or any age with thrombosis ⱕ 60 years and no thrombosis (some authors say ⬍ 50)

Reduce Cardiovascular Risk Factors

Phlebotomy

Yes

Yes

Yes

Yes

Other Therapy Hydroxyurea, IFN-␣, busulfan, anagrelide, 32P, low-dose aspirin (if no hemorrhage and platelets ⬍ 1,000 to 1,500 ⫻ 109/L) Some author’s use low-dose aspirin (eg, 40 mg per day with phlebotomy for patients ⬍ 40). Anagrelide can be considered for elevated platelet counts (eg, ⬎ 600 ⫻ 109/L*)

* No randomized data support this, but one strategy is to treat the elevated platelet count in PV like that in ET.

thrombosis. It is likely this high proportion of deaths from thrombosis in this study was because the target hematocrit was 52%. Additional risk factors for thrombosis identified in the PVSG studies and analyses include age, the use of phlebotomy itself, the rate of phlebotomies, and prior thrombosis (Table 3). Platelet counts have not been definitively linked to an increased risk of thrombosis in PV, but a reasonable, common strategy is to consider elevated platelet counts in PV like those in ET and use the same management principles until randomized trials provide more data. Additional risks for postpolycythemia myeloid

metaplasia may include use of hydroxyurea; for acute leukemia, it may include use of chlorambucil, radioactive phosphorous, and hydroxyurea, although the latter is unproven. Phlebotomy is recommended for all patients at any age with PV. A reasonable target range for the hematocrit is less than 42% in women and 45% in men (see Table 4). Patients who have had thrombosis or hemorrhage might benefit from additional cytoreductive treatment, as do those 70 years of age or older (many groups use the age of 60 or older). The heavily cited study reported in 1962 by Chievitz and Thiede15 gave an average survival of

Table 4. Specific Aspects of Treatment for Polycythemia Vera Treatment

Treatment Details

Phlebotomy

250 to 500 mL every other day; adjust according to patient’s age and performance status; aim for Hct of 42% to 45%. Try to have red cell mass normalized for 2 to 4 months before elective surgery. After disease is stabilized, a CBC and differential and office visit may occur every 1 to 3 months depending on clinical circumstances and patient anxiety. Low-dose aspirin (40 to 81 mg per day) is reasonable to add to phlebotomy alone for prophylaxis until results of randomized trials confirm effectiveness, particularly if patients have erythromelalgia or elevated platelet counts (but ⬍ 1,000 to 1,500 ⫻ 109/L). For patients with symptomatic vessel occlusions, 325 mg per day can be started. 500 mg tabs; two to three tabs each day as a single oral dose (in PV the goals can include Hct ⬍ 50% with hydroxyurea alone or less than 45% with hydroxyurea and phlebotomy, and a platelet count less than 400 ⫻ 109/L), hydroxyurea may increase risk of PPMM in PV. See comments in Table 1. 3 million units SQ 3 times per week up to 5 million units per day. Can be used as a single agent or with phlebotomy; 82% patients will have reduction in frequency of phlebotomies; 50% CR; 21% intolerant of therapy. Randomized trial against hydroxyurea underway in Europe. Can be used for severe pruritus also. When counts plateau, reduce to 3 times per week or less if possible (can take 3 months for maximum response). Consider use as per Berrebi7 below. Busulfan, 2 mg tabs: Two tablets of 4 mg per day every day for 1 week, 2 mg per day for the next 3 weeks then 2 mg every other day until maximal sustained response, approximately 3 months. The busulfan is stopped. Relapses can be treated similarly. 2.7 mCi per meter squared IV, not to exceed 5 mCi per dose, every 3 months.

Observation Aspirin

Hydroxyurea

Anagrelide IFN-␣

Busulfan

P32

Abbreviations: Hct, hematocrit; PPMM, postpolycythemia myeloid metaplasia; SQ, subcutaneously.

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untreated patients with PV of 18 months and the average survival of phlebotomized patients of 3.5 years. In PVSG-01, the overall survival of the phlebotomized arm exceeded 10 years. The populations of patients with PV reported in the Scandinavian series from 1962 and the PVSG-01 group must have differed significantly in their underlying characteristics or in the level of other associated medical care. The PVSG-01 study showed that phlebotomy itself and the rate of phlebotomies both contribute to increased risk of major thrombosis in patients with PV during the first 3 years of treatment. Of 43 deaths on the phlebotomy-only arm, 43% were from major thrombosis. This compared with 23% and 27% of deaths in the chlorambucil- and 32Ptreated arms. Other contributing factors were age ⬎ 70 years and prior thrombosis. Patients who are 70 years or older (some groups use 60 years), or who are any age and have had major thrombosis, need treatment in addition to phlebotomy alone. Also, if patients have severe pruritus, splenomegaly, or systemic B-like symptoms, treatment may be required in addition to simply treating the red cell mass with venesection. PVSG-08, which started in 1977, addressed the issue of hydroxyurea in PV. In addition to hydroxyurea, phlebotomies were allowed, but not to exceed 6 per year. Eighty percent of patients achieved a normal hematocrit in 12 weeks and 65% of patients with platelet counts greater than 1,000 ⫻ 109/L had counts reduced to less than 600 ⫻ 109/L within 3 weeks. By comparing PVSG-01 and PVSG-08, Kaplan et al16 were able to show that thrombotic events occurred less frequently in the hydroxyurea-treated group (9.8%) versus the phlebotomy-alone group (32.8%). This advantage was maintained during 6 years of treatment. Also, Kaplan et al’s analysis showed no difference in the risk of leukemia in the groups treated with phlebotomy alone versus phlebotomy and hydroxyurea during the same 6 years. There was no statistically significant difference in survival, although there was a trend in favor of hydroxyurea treatment. IFN-␣ has significant activity in PV.4-6 It is particularly useful in refractory pruritus or for patients with myeloproliferation uncontrolled after phlebotomy. However, 21% of patients typically stop IFN-␣ because of side effects. In a recent review, Lengfelder et al5 summarized data on 279 patients in 16 different nonrandomized trials. Ini-

LAWRENCE A. SOLBERG, JR

tial IFN-␣ doses ranged from 3 to 35 MIU per week. IFN-␣ reduced phlebotomies in 82% of patients; 50% had a complete remission defined as a hematocrit ⬍ 45% not requiring phlebotomies; 81% had control of pruritus; and 77% had a reduction in splenomegaly. Some unmaintained remissions lasted up to 4.8 years. A randomized trial of IFN-␣ versus hydroxyurea is now underway in Europe. Radioactive phosphorous can be used in PV, but its use should be restricted to asymptomatic older patients or to symptomatic younger patients whose disease cannot be controlled by other means.17 In PVSG-01, 15 of 141 patients (11%) treated with 32 P developed acute leukemia after a mean interval of 7.3 years, and 23 patients (17%) developed nonhematologic malignancies primarily of the gastrointestinal tract and skin (2 times that of agematched controls). Chlorambucil should not be used in PV. In PVSG-01, 20 of 141 patients (14%) treated with chlorambucil developed acute leukemia after a median time of 4.2 years. Five patients (4%) developed large cell lymphoma and 24 patients (17%) developed nonhematologic malignancies primarily of the gastrointestinal tract and skin. Hydroxyurea and IFN-␣ often, but not always, control the platelet count in PV. In addition, there are patients intolerant of hydroxyurea or IFN-␣ or for whom the clinician may not want to use hydroxyurea (eg, young patients). One approach is to manage the thrombocytosis secondary to PV in the same way as the thrombocytosis secondary to ET, modeling these conditions as “thrombocytosis secondary to myeloproliferative disorders.” It is important to note that this approach of reducing platelet counts is logical, but has not been subjected to controlled studies. Patients with platelet counts greater than 1,500 ⫻ 109/L or who have had serious bleeding should not be given antiplatelet therapy. Anagrelide can be considered and is effective for reducing elevated platelet counts in PV, but it does not control red cell mass. Platelet count levels that have been used to trigger treatment with anagrelide have ranged from 400 to 600 ⫻ 109/L. Low-dose aspirin (40 to 81 mg/d) is reasonable to add to phlebotomy alone for prophylaxis until results of randomized trials confirm effectiveness, particularly if patients have erythromelalgia, but platelet counts below 1,500 ⫻ 109/L. For patients with symptomatic vascular occlusion, 325 mg/d can be started.

THERAPEUTIC OPTIONS

CONCLUSION

Treatment strategies for ET and PV remain quite empirical. One reasonable approach is riskbased therapy, which individualizes treatment. High-risk patients with ET, defined as those 60 years of age or older or those of any age who have had a thrombosis, should be treated with hydroxyurea. If hydroxyurea cannot be tolerated, anagrelide and IFN-␣ are alternatives. Intermediate-risk ET patients, those less than 60 years who have not had thromboses but whose platelet counts are ⬎ 1,500 ⫻ 109/L or who have significant cardiovascular risk factors, should be given low-dose aspirin if the platelet count is ⬍ 1,500 ⫻ 109/L. These patients should also have their cardiovascular risk factors treated. They can be observed or treated with anagrelide, hydroxyurea, or IFN-␣. Low-risk ET patients are less than 60 years old, have not had thromboses, and have platelet counts ⬍ 1,500 ⫻ 109/L. These patients may be observed or placed on low-dose aspirin. Patients with PV, if they are high risk, defined as 60 years or older or those of any age who have had thrombosis, should be treated with phlebotomy and adding hydroxyurea or IFN-␣ is reasonable. Selected patients may be treated with anagrelide. Intermediate-risk PV patients, those who are less than 60 years old, who have not had thrombosis, but whose platelet counts are ⬎ 1,500 ⫻109/L or who have cardiovascular risk factors, should have their cardiovascular risk factors treated along with phlebotomy alone. If their platelet counts are ⬍ 1,500 ⫻ 109/L, low-dose aspirin is a reasonable choice of therapy. Anagrelide or IFN-␣ may be used with phlebotomy in selected patients. For low-risk PV patients, those less than 60 years old and who have had no thrombosis, have no cardiovascular risk factors, and whose platelets are ⬍ 1,500 ⫻ 109/L, phlebotomy alone or phlebotomy and low-dose aspirin may be used. REFERENCES 1. Cortellazo W, Finazzi G, Riggeri M, et al: Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med 332:1132-1136, 1995

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2. Petitt RM, Silverstein MN, Petrone M: Anagrelide for control of thrombocythemia in polycythemia and other myeloproliferative disorders. Semin Hematol 34:51-54, 1997 3. Silverstein MN, Tefferi A: Treatment of essential thrombocythemia with anagrelide. Semin Hematol 36:23-25, 1999 4. Gilbert HS: Long term treatment of myeloproliferative disease with interferon-alpha-2b: Feasibility and efficacy. Cancer 83:1205-1213, 1998 5. Lengfelder E, Berger U, Hehlmann R: Interferon alpha in the treatment of polycythemia vera. Ann Hematol 79:103-109, 2000 6. Silver RT: Interferon-alpha-2b: A new treatment for polycythemia vera. Ann Intern Med 119:1091-1092, 1993 7. Berrebi A, Shvidel L, Shtalrid M, et al: Short course of busulfan in essential thrombocythaemia: remodeling of an old strategy. Br J Haematol 109:249-250, 2000 8. Michiels JJ: Normal life expectancy and thrombosis-free survival in aspirin treated essential thrombocythemia. Clin Applied Thromb Hemost 5:30-36, 1999 9. van Genderen PJ, Mulder PG, Waleboer M, et al: Prevention and treatment of thrombotic complications in essential thrombocythaemia: Efficacy and safety of aspirin. Br J Haematol 97:179-184, 1997 10. Willoughby S, Pearson TC: The use of aspirin in polycythaemia vera and primary thrombocythaemia. Blood Rev 12:12-22, 1998 11. Ruggeri M, Finazzi G, Tosetto A, et al: No treatment for low-risk thrombocythaemia: Results from a prospective study. Br J Haematol 103:772-777, 1998 12. Sterkers Y, Preudhomme C, Lai JL, et al: Acute myeloid leukemia and myelodysplastic syndromes following essential thrombocythemia treated with hydroxyurea: High proportion of cases with 17p deletion. Blood 91:616-622, 1998 13. Bazzan M, Tamponi G, Schinco P, et al: Thrombosisfree survival and life expectancy in 187 consecutive patients with essential thrombocythemia. Ann Hematol 78:539-543, 1999 14. Pearson TC, Bareford D, Craig J, et al: MPD (UK) Study Group: The management of “low-risk” and “intermediate risk” patients with essential thrombocythaemia. Br J Haematol 106: 833-834, 1999 15. Chievitz E, Thiede E: Complications and causes of death in polycythemia vera. Acta Med Scand 172:513-523, 1962 16. Kaplan ME, Mack K, Goldberg JD, et al: Long-term management of polycythemia vera with hydroxyurea: A progress report. Semin Hematol 23:161-171, 1986 17. Najean Y, Rain JD: Treatment of polycythemia vera: Use of 32P alone or in combination with maintenance therapy using hydroxyurea in 461 patients greater than 65 years of age. Blood 89:2319-2327, 1997