Anagrelide: analysis of long-term efficacy, safety and leukemogenic potential in myeloproliferative disorders.

Appropriate treatment for nonreactive thrombocytosis resulting from a myeloproliferative disorder (MPD) is surrounded by controversy. Although few doubt the association of thrombocytosis with increased risk for life-threatening events such as thrombosis or hemorrhage, or the association between clonal myeloproliferation and the progression to acute leukemia or myelofibrosis, controversy exists regarding the timing and nature of appropriate therapeutic intervention. Studies have shown that treatment with myelosuppressive agents such as chlorambucil, busulfan, radiophosphorus (32P), and hydroxyurea reduces the platelet count. However, investigators have also identified an increased risk of drug-related leukemic transformation. An ideal cytoreductive treatment for long-term use should minimize thrombosis and avoid long-term complications, especially acute leukemia (AL). Anagrelide, an imidazoquinolin, inhibits megakaryopoiesis and more selectively reduces platelet production in humans. A retrospective analysis of an open-label, multicenter, international trial reviewing 3660 anagrelide-treated patients was performed to assess efficacy and long-term safety, specifically potential for increased leukemogenicity. The study included MPD patients with thrombocytosis diagnosed according to Polycythemia Vera Study Group (PVSG) criteria. Of all patients enrolled, 81% had previously received other myelosuppressive agents; of these, 33% were transferred from the original agent to anagrelide due to toxicity and 31% were transferred because of poor platelet control. Over 45% of patients were symptomatic due to thrombocythemia, most commonly vascular sequelae (25%). Dosage was titrated to achieve a platelet count < 600 x 10(9) L(-1) and ideally between 130 and 450 x 10(9) L(-1). The safety cohort of 3660 patients, including 2251 with essential thrombocythemia (ET), 462 with polycythemia vera (PV), and 947 with chronic myeloid leukemia (CML) and other MPDs, was analyzed to establish the incidence of leukemic transformation in patients with ET and PV. From the Safety Population, 12.8% (467/3660) of patients were treated with anagrelide as the sole cytoreductive agent (naive patients). Acute leukemia/myelodysplasia developed in 2.1% of ET patients (47/2251) with a maximum follow-up of 7.1 years. Of the PV patients, 2.8% developed acute leukemia/myelodysplastic syndrome (13/462), with a maximum follow-up of 7.0 years. ET and PV patients who transformed to AL had all been previously exposed to other cytotoxics; there were no ET or PV patients in the study who transformed to AL exposed solely to anagrelide. With maximum follow-up over 7 years, anagrelide achieved platelet control in over 75% of MPD patients and did not increase the conversion to acute leukemia during the treatment duration analyzed. Longer follow-up is required to confirm these important observations regarding the long-term safety of anagrelide.

Modern treatment strategies in polycythemia vera.

Polycythemia vera (PV), one of the chronic myeloproliferative disorders (MPD), is characterized by predominant erythroid proliferation and secondary platelet proliferation, and by progression from a proliferative stage to a metastatic phase and finally a malignant phase. These characteristics expose patients to increased risk for thrombohemorrhagic complications, myeloid metaplasia, myelofibrosis, and acute leukemic conversion irrespective of treatments. Currently, there are three agents-hydroxyurea (HU), interferon-alfa (IFN-alpha), and anagrelide-that differ in mechanisms of action and in treating specific phenotypic manifestations of PV, suggesting a potential role for combination therapy. They also differ widely in side effects profiles and severity. Because of the differing risks for long-term complications associated with these agents, age is an important variable in selecting treatments. Patients at high risk for thrombohemorrhagic complications all require cytoreduction, as do patients at intermediate risk who are not effectively managed by phlebotomy and low-dose aspirin. In younger patients, the safest and most effective combination treatment appears to be anagrelide plus IFN-alpha, while in older patients anagrelide plus hydroxyurea may be effective. HU is used sparingly in younger patients because of the long-term increased risk of mutagenicity and possibly leukemogenesis. IFN-alpha is particularly indicated for patients with myeloid metaplasia evidenced by splenomegaly. Anagrelide, which acts on the mature megakaryocyte to prevent platelet budding, is uniquely efficacious in the control of platelet counts.

Other secondary sequelae of treatments for myeloproliferative disorders.

Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic disorders for which there are no medical cures. Clinical sequelae of PV and ET fall into three categories: primary, such as thrombosis and hemorrhage; secondary, resulting from disease progression or treatment. The decision whether to treat the patient is based on the sequelae of no treatment versus short- and long-term toxicities of the three classes of drugs available for treatment: hydroxyurea, interferon-alpha, and anagrelide. Thrombosis is the most common short-term sequelae of untreated disease; the risk increases with age and after the first thrombotic complication. Hydroxyurea, a nonalkylating myelosuppressive agent, is mutagenic and probably leukemogenic over 5 to 15 years, which makes it unsuitable for treating most younger patients. Interferon-alpha, a cytokine that is myelosuppressive and immunomodulatory, has been shown to have a therapeutic effect in both PV and ET. Tolerance to the initial flu-like symptoms of interferon-alpha is usually developed, but dose-limiting symptoms of anorexia, asthenia, and neuropsychiatric disease can occur, along with exacerbation or development of autoimmune diseases. Anagrelide, a quinazoline that inhibits cyclic nucleotide phosphodiesterase, inhibits platelet aggregation and has an idiosyncratic effect of inhibiting megakaryocyte maturation and platelet budding at doses below those that affect platelet function. This agent is a vasodilator with positive inotropic activity and a side-effect profile that may include palpitations, forceful heartbeat, tachycardia, and headache. One in four patients develop fluid retention and/or edema that are controllable with diuretic therapy. Dizziness is frequent, but mild. Because these side effects usually abate in 2 to 4 weeks, successful management of patients taking anagrelide depends on encouraging them to maintain therapy. The availability of these three classes of drugs with differing modes of action suggests that combination therapy may offer the opportunity to achieve better control of proliferation while reducing short-term side effects as well as the risks of dose-related cumulative sequelae.