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Diagnosis and Treatment of Thrombocythemia in Myeloproliferative Disorders: Page 3 of 3

Diagnosis and Treatment of Thrombocythemia in Myeloproliferative Disorders: Page 3 of 3

Contemporary Pharmacologic Treatment

The history of drug development for essential thrombocythemia and polycythemia vera has been one of improving therapeutic efficacy while reducing leukemogenic, carcinogenic, and mutagenic potentials.[38]

Radiophosphorus and Alkylating Myelosuppressive Agents

Radioactive phosphorus (P-32) was introduced for the treatment of myeloproliferative disorders a half century ago and showed remarkable efficacy in reducing both thrombocytosis and erythrocytosis. For example, 98% of patients with polycythemia vera achieved a complete remission after P-32 treatment—in most cases, after a single dose. However, the isotope was also found to be associated with a high incidence of hematologic and nonhematologic malignancies.[4,39] Furthermore, the frequency of acute leukemia and myelodysplastic syndromes in polycythemia vera patients treated with P-32 was determined to be dose-related, increasing linearly beginning with year 5.[39]

In the 1970s, standard treatment consisted of P-32 and/or alkylating myelosuppressive agents such as chlorambucil (Leukeran), busulfan (Busulfex, Myleran), melphalan (Alkeran), and pipobroman (used principally in Europe). Like P32, the alkylating agents are nonspecific myelosuppressives that were found to be efficacious in reducing thrombocythemia and erythrocythemia in clinical trials. Between 1967 and 1978, the European Organization for the Research and Treatment of Cancer randomized 293 previously untreated polycythemia vera patients to P-32 or busulfan and found that busulfan significantly outperformed radiophosphorus with respect to hematologic control, thrombotic morbidity, disease-related mortality, and 10-year overall survival. There were two cases of acute leukemia in the radiophosphorus arm and three in the busulfan arm.[4,9]

The 1968-1974 PVSG study randomized 411 polycythemia vera patients to phlebotomy, radiophosphorus, or chlorambucil. At the end of the followup period, investigators reported a 10.6% incidence of acute leukemia in the chlorambucil arm, an 8.3% incidence in the P-32 arm, and a 1.5% incidence in the phlebotomy arm.[4] It was recommended that use of chlorambucil be discontinued.


Hydroxyurea was introduced in 1977, when the PVSG initiated a trial in 51 myelosuppressive naive polycythemia vera patients. Supplementary phlebotomy was used as necessary to control hematocrits below 45%. Excellent control of hematologic and thrombotic events was achieved throughout a median followup of 9.6 years and a maximum of 15.3 years.[40,41] Hydroxyurea’s efficacy in controlling platelet counts and thrombohemorrhagic complications has also been demonstrated in patients with essential thrombocythemia.[41,42]

Since 1980, hydroxyurea has been the agent of choice for the treatment of thrombocytosis and erythrocytosis due to essential thrombocythemia and polycythemia vera. It is a potent nonalkylating, nonspecific myelosuppressive agent with potential for dose-related cytoreduction of all myelogenous hematic components.[29] Its mechanism of action is the inhibition of DNA synthesis (by blocking the activity of the enzyme ribonucleoside reductase). Because it is a nonalkylating molecule, its use was greeted with the hope that its efficacy would not be offset by leukemogenicity. Those hopes have been largely unrewarded. Long-term safety studies have reported acute leukemic progression rates of 5.9% to 10% and higher.[41,43] A French study comparing the long-term safety risks of hydroxyurea and pipobroman in 292 polycythemia vera patients reported a 10% acute leukemia prevalence for each agent at 13 years and a 15% cancer risk at 14 years (annual incidence: 1.2%).[44]

Trial results regarding leukemic transformation after treatment with hydroxyurea for essential thrombocythemia are similar. The PVSG reported a 21.6% predicted probability of developing acute leukemia at 10 years, with the greatest risk occurring after year 5.[14] A French study in 357 patients compared transformation rates after hydroxyurea monotherapy with those following other myelosuppressive therapies and discontinuation of hydroxyurea. Acute leukemic transformation was significantly higher for all agents used after hydroxyurea, suggesting that hydroxyurea sensitizes myelogenous tissue and potentiates the leukemogenicity of other agents.[3,14] There is no evidence, however, of increased risk for leukemia when hydroxyurea is taken subsequent to withdrawal from other drugs.[14]

In light of its leukemogenicity, hydroxyurea is inappropriate for young patients, low-risk patients, and women of childbearing age. Moreover, the agent is associated with other side effects that may limit its use. These include megaloblastic erythropoiesis, aphthous stomatitis, gastric pain, diarrhea, leg ulcers that require withdrawal, dry skin, alopecia, increases in hepatic enzymes, and neurologic toxicity.[9]

In many patients, achieving adequate platelet control is difficult, except at doses that may induce oversuppression of red cells or neutrophils, making it also difficult to achieve stable maintenance. This situation is further complicated by rebound thrombocytosis that occurs with a reduction in dose or withdrawal of hydroxyurea.

The introduction of a new lower-dose formulation of hydroxyurea (Droxia) may facilitate management with monotherapy and create opportunities for combination therapy when single-agent treatment is inadequate.[38]


Following reports of the beneficial use of recombinant interferon-alpha (Intron A, Roferon-A) in chronic myelocytic leukemia and demonstration of its selective effect on the malignant clone, Gilbert[45] and Silver[47,48] reported its potential efficacy in polycythemia vera. The interferons are naturally occurring cytokines that modify biological response and modulate the immune system.[29] Interferon-alpha suppresses the proliferation of both pluripotent and lineage-committed hematopoietic progenitors and antagonizes the action of platelet-derived growth factor (produced by megakaryocytes), which mediates fibroblast proliferation.[20] By virtue of these actions, it can induce hematologic and cytogenic remissions in patients with myeloproliferative disorders and is uniquely able to reduce splenomegaly and reverse the process that produces myeloid metaplasia and myelofibrosis.[13,20,45,46] Thus, the foremost benefits of interferon-alpha therapy are seen in patients with polycythemia vera and post-polycythemia vera myeloid metaplasia.[13]

Clinical Trials: No long-term prospective trials comparing interferon-alpha with conventional therapies for essential thrombocythemia and polycythemia vera have been published to date, but several single-arm studies have been reported. One review of 11 such trials encompassing 212 patients with essential thrombocythemia calculated a response rate of 90%, although sustained unmaintained remissions occurred in only 12% of patients.[38,49]

A similar review of nine studies involving 185 patients reported a response rate of 86%. Remission of thrombocythemia was achieved at a median of 12 weeks (range: 3 to 26 weeks). Time to maximum hematologic remission correlated with the dose of interferon and the initial platelet count. Control of complications and symptomatic improvement occurred in 60% to 100% of patients among the studies reviewed. Long-term remission without maintenance therapy was observed in 7% of patients, but most study patients receiving low-dose maintenance therapy achieved long-term remission.[20]

Trial results in polycythemia vera were similar. A review of nine studies encompassing 49 subjects indicated a 60% complete response rate to interferon-alpha therapy and a 23% partial response rate, with complete response defined as not needing phlebotomy to maintain a hematocrit of 45%. A reduction in the size of the spleen and relief from pruritus were observed in 75% of patients. A maximum response was reported in 76% of patients within 6 months of initial treatment (range: 3 to 12 months). A study in 11 patients reported no thrombohemorrhagic events within a mean follow-up of 36 months.[50]

Safety: Interferon is not teratogenic because it does not cross the placenta.[20] Leukemogenicity has not been reported. Hydroxyurea, in contrast, is both teratogenic and leukemogenic. These important differences make interferon-alpha preferable for the treatment of younger patients with myeloproliferative disorders. The issue of treating pregnant women and women who wish to conceive remains cloudy, however. On one hand, it is thought that effective treatment prior to pregnancy—especially if followed by short-term remission through the first trimester—is safe, particularly compared to the use of hydroxyurea, alkylating agents, and radiophosphorus. Intermittent therapy for recurrent thrombocythemia during pregnancy may also be safe, because interferon does not appear to harm the fetus.[1,13] On the other hand, there are insufficient data on which to base such a recommendation. Consequently, manufacturers of interferon-alpha advise against its use during pregnancy.[20]

There are side effects from interferon that affect approximately 30% of patients and have forced 12% to 20% to withdraw from clinical trials.[9] Most common among them, and the one responsible for most trial withdrawals, is a flu-like syndrome that affects the majority of patients taking interferon-alpha. For most patients, this syndrome abates within 1 to 3 months, but for others, it persists.

Other side effects that most frequently result in trial withdrawals are involuntary weight loss, confusion, depression, myalgia, and increased pruritus. Because it is an immune system modulator, interferon may induce autoimmune disorders, especially autoimmune thyroiditis.[20] Also, because side effects are dose-limiting factors, preemptive acetaminophen, night-time administration, and an initial dose equal to half of the desired dose are all recommended. The cost of interferon-alpha may also preclude its use in some patients.[20]


Anagrelide hydrochloride (Agrylin), an oral quinazoline that inhibits cyclic nucleotide phosphodiesterase, is the only drug approved by the US Food and Drug Administration (FDA) for the treatment of thrombocythemia associated with essential thrombocythemia and polycythemia vera. The drug was originally noted for its antiaggregating effect on platelets, but tests on normal adults revealed an unanticipated, sudden, and progressively severe thrombocytopenia at doses lower than those needed for antiaggregation.[38,51] Because this has not been demonstrated in lower primates or other species, it is considered a species-specific action. A leading hypothesis is that a metabolic pathway present in most but not all humans, and in few if any other species, converts the molecule into an as yet unknown active metabolite.[51]

The mechanism of action of anagrelide has not been entirely elucidated, but it is known that the drug inhibits postmitotic megakaryocyte maturation and platelet budding.[52] It is, therefore, not a myelosuppressive agent but a drug that is specific for platelet reduction. A 10% drop in hematocrit has been observed in approximately 30% of patients, which may be due, at least in part, to hemodilution reflecting anagrelide-induced fluid retention.[32] However, it may be a biological effect resulting from the suppression of erythropoiesis. Anagrelide is indicated for thrombocythemia in myeloproliferative disorders to reduce an elevated platelet count and the risk of thrombosis, and to ameliorate associated symptoms including thrombohemorrhagic events.[1]

Clinical Trials: The pilot dose-ranging trial of anagrelide commenced in 1985, and the results were published in 1989.[53] Of the 20 patients enrolled, 17 had essential thrombocythemia, 2 had polycythemia vera, and 1 had CML. All but two patients with essential thrombocythemia responded with marked reductions in platelet counts.

These results led to formation of the Anagrelide Study Group and a subsequent trial in 577 patients, 424 of whom were evaluable. The median pretreatment platelet count was 990,000/µL. Patients were treated for a minimum of 4 weeks. Approximately 93% met the criteria for effective response, namely a 50% reduction in platelet count or a reduction in platelet count to 600,000/µL. The median time to achieving these goals was 11 days for patients with essential thrombocythemia and 15 days for patients with polycythemia vera. The median duration of first response was 28.6 months for essential thrombocythemia patients and 7.7 months for polycythemia vera patients, for an overall median of 16.7 months. Platelet counts in patients who withdrew from anagrelide therapy rose to pretreatment levels within 5 to 7 days.[54]

In 1997, Petitt summarized a subsequent analysis of 942 patients, including the Anagrelide Study Group mentioned above and additional patients treated on a compassionate basis. This group of patients included 58% with essential thrombocythemia, 12% with polycythemia vera, 19% with CML, and 11% with undifferentiated myeloproliferative disorders.[51] The mean pretreatment platelet count was 1,131,600/mL, and 86% had received prior treatment. Anagrelide therapy was indicated in young patients, those in whom other therapies had failed, and those who had been withdrawn from other therapies because of side effects. A complete response was defined as a 50% reduction in platelet count or reduction to 600,000/mL or more for at least 4 weeks. A partial response was defined as a 20% to 50% reduction from pretreatment levels for at least 4 weeks. All others were categorized as nonresponders. Among polycythemia vera patients, 66% responded completely, and 8% responded partially; among essential thrombocythemia patients, 73% responded completely and 9%, partially.[51]

Features of Three Classes of Drugs Used for Treatment of Thrombocythemia in Myeloproliferative Disease

The efficacy of anagrelide has not yet been evaluated in randomized, double-blind head-to-head trials of interferon or hydroxyurea. Furthermore, additional evidence is needed before it can be concluded that, by controlling platelet counts, anagrelide is efficacious in reducing the frequency of thrombohemorrhagic events in patients with essential thrombocythemia and polycythemia vera.[9,29]

Safety: More is known of the drug’s safety profile. There is no evidence of oncogenicity or leukemogenicity. Hence, anagrelide therapy is safe for older patients whose symptoms are refractory to other treatments as well as for young patients, but in light of concerns that it may pass through the placenta, it is not advised for women trying to conceive.

Anagrelide has a broad but not especially profound side-effect profile. It is a vasodilator with positive inotropic activity that can reduce renal blood flow, increase fluid retention, and induce palpitations, forceful heartbeat, and tachycardia. Hence, it is contraindicated in patients with congestive heart failure or cardiac arrhythmias.[55] The most common side effect is headache, which usually responds to acetaminophen. Mild dizziness, nausea, bloating, and diarrhea usually abate in 2 to 4 weeks. Nevertheless, in various trials, 10% to 17% of subjects withdrew because of intolerable side effects. Most are clinically manageable. Anagrelide must be administered on a chronic basis, and no remarkable side effects have been associated with long-term use.

Because anagrelide is specific for platelet reduction, polycythemia vera patients taking it may require concurrent phlebotomy, hydroxyurea, or interferon-alpha to achieve control of erythrocythemia. In both polycythemia vera and essential thrombocythemia patients, combination therapy with anagrelide may reduce the undesirable side effects associated with hydroxyurea and interferon by prompting dose reductions.[13] Table 4 provides a comparative summary of the salient biological and clinical features of interferon-alpha, hydroxyurea, and anagrelide.[1]



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