The Indolent Natural History of Essential Thrombocythemia: A Challenge to New Drug Development

Abstract

Essential thrombocythemia (ET) is a diagnosis to be considered when neither reactive thrombocytosis nor an otherwise defined myeloid malignancy explains a persistently increased platelet count.1Tefferi A Murphy S Current opinion in essential thrombocythemia: pathogenesis, diagnosis, and management.Blood Rev. 2001; 15: 121-131Abstract Full Text PDF PubMed Scopus (87) Google Scholar The disease was first described in 19342Epstein E Goedel A Hämorrhagische thrombocythamie bei vascularer schrumpfmilz.Virchows Arch A Pathol Anat Histopathol. 1934; 293: 233-236Google Scholar and subsequently classified as a myeloproliferative disorder (MPD) in 1951.3Dameshek W Some speculations on the myeloproliferative syndromes.Blood. 1951; 6: 372-375Crossref PubMed Google Scholar Over the years, remarkably little has been accomplished by way of controlled treatment trials in ET.4Cortelazzo S Finazzi G Ruggeri M et al.Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis.N Engl J Med. 1995; 332: 1132-1136Crossref PubMed Scopus (727) Google Scholar, 5Finazzi G Ruggeri M Rodeghiero F Barbui T Second malignancies in patients with essential thrombocythaemia treated with busulphan and hydroxyurea: long-term follow-up of a randomized clinical trial.Br J Haematol. 2000; 110: 577-583Crossref PubMed Scopus (206) Google Scholar Physicians, therefore, have relied mostly on carefully conducted prospective cohort studies6Ruggeri M Finazzi G Tosetto A Riva S Rodeghiero F Barbui T No treatment for low-risk thrombocythaemia: results from a prospective study.Br J Haematol. 1998; 103: 772-777Crossref PubMed Scopus (144) Google Scholar, 7Green A Campbell P Buck G et al.The Medical Research Council PT1 trial in essential thrombocythemia [abstract].Blood. 2004; 104 (Abstract 6.)Google Scholar and large retrospective studies8Fenaux P Simon M Caulier MT Lai JL Goudemand J Bauters F Clinical course of essential thrombocythemia in 147 cases.Cancer. 1990; 66: 549-556Crossref PubMed Scopus (273) Google Scholar, 9Bazzan M Tamponi G Schinco P et al.Thrombosis-free survival and life expectancy in 187 consecutive patients with essential thrombocythemia.Ann Hematol. 1999; 78: 539-543Crossref PubMed Scopus (102) Google Scholar, 10Besses C Cervantes F Pereira A et al.Major vascular complications in essential thrombocythemia: a study of the predictive factors in a series of 148 patients.Leukemia. 1999; 13: 150-154Crossref PubMed Scopus (202) Google Scholar, 11Cortelazzo S Viero P Finazzi G D'Emilio A Rodeghiero F Barbui T Incidence and risk factors for thrombotic complications in a historical cohort of 100 patients with essential thrombocythemia.J Clin Oncol. 1990; 8: 556-562PubMed Google Scholar, 12Passamonti F Rumi E Pungolino E et al.Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia.Am J Med. 2004; 117: 755-761Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar to guide them in patient management.13Tefferi A Solberg LA Silverstein MN A clinical update in polycythemia vera and essential thrombocythemia.Am J Med. 2000; 109: 141-149Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar, 14Barbui T Barosi G Grossi A et al.Practice guidelines for the therapy of essential thrombocythemia: a statement from the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation.Haematologica. 2004; 89: 215-232PubMed Google Scholar Accordingly, evidence-based management currently dictates the use of hydroxyurea in high-risk patients (age ≥60 years or positive history of thrombosis) while drug therapy has not been shown, in a controlled setting, to have an advantage over observation alone in either low-risk (age <60 years and negative history of thrombosis and platelet count <1500 × 109/L and absence of cardiovascular risk factors) or indeterminate-risk (neither high- nor low-risk) patients.4Cortelazzo S Finazzi G Ruggeri M et al.Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis.N Engl J Med. 1995; 332: 1132-1136Crossref PubMed Scopus (727) Google Scholar, 14Barbui T Barosi G Grossi A et al.Practice guidelines for the therapy of essential thrombocythemia: a statement from the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation.Haematologica. 2004; 89: 215-232PubMed Google Scholar This, however, has not stopped the pervasive use of alternative cytoreductive agents including anagrelide, interferon alfa, and pipobroman (not available in the United States) across all risk categories in ET, based on demonstration of “treatment efficacy” from uncontrolled single arm studies.15Mazzucconi MG Redi R Bernasconi S et al.A long-term study of young patients with essential thrombocythemia treated with anagrelide.Haematologica. 2004; 89: 1306-1313PubMed Google Scholar, 16Anegrelide Study Group Anagrelide, a therapy for thrombocythemic states: experience in 577 patients.Am J Med. 1992; 92: 69-76Abstract Full Text PDF PubMed Scopus (211) Google Scholar, 17Radin AI Kim HT Grant BW et al.Phase II study of alpha2 interferon in the treatment of the chronic myeloproliferative disorders (E5487): a trial of the Eastern Cooperative Oncology Group.Cancer. 2003; 98: 100-109Crossref PubMed Scopus (45) Google Scholar, 18Gilbert HS Long term treatment of myeloproliferative disease with interferon-alpha-2b: feasibility and efficacy.Cancer. 1998; 83: 1205-1213Crossref PubMed Scopus (105) Google Scholar, 19De Sanctis V Mazzucconi MG Spadea A et al.Long-term evaluation of 164 patients with essential thrombocythaemia treated with pipobroman: occurrence of leukaemic evolution.Br J Haematol. 2003; 123: 517-521Crossref PubMed Scopus (29) Google Scholar, 20Passamonti F Malabarba L Orlandi E et al.Pipobroman is safe and effective treatment for patients with essential thrombocythaemia at high risk of thrombosis.Br J Haematol. 2002; 116: 855-861Crossref PubMed Scopus (33) Google Scholar, 21Steurer M Gastl G Jedrzejczak WW et al.Anagrelide for thrombocytosis in myeloproliferative disorders: a prospective study to assess efficacy and adverse event profile.Cancer. 2004; 101: 2239-2246Crossref PubMed Scopus (84) Google Scholar Such a noncritical approach to drug therapy becomes particularly unnerving considering the potential occurrence of serious adverse effects associated with some of these drugs including anagrelide-associated cardiomyopathy22Jurgens DJ Moreno-Aspitia A Tefferi A Anagrelide-associated cardiomyopathy in polycythemia vera and essential thrombocythemia.Haematologica. 2004; 89: 1394-1395PubMed Google Scholar and interferon alfa–associated neuropathy.23Vardizer Y Linhart Y Loewenstein A Garzozi H Mazawi N Kesler A Interferon-alpha-associated bilateral simultaneous ischemic optic neuropathy.J Neuroophthalmol. 2003; 23: 256-259Crossref PubMed Scopus (54) Google Scholar An equally important issue from the patient's perspective is that both anagrelide and interferon alfa are substantially more toxic as well as more expensive than hydroxyurea.1Tefferi A Murphy S Current opinion in essential thrombocythemia: pathogenesis, diagnosis, and management.Blood Rev. 2001; 15: 121-131Abstract Full Text PDF PubMed Scopus (87) Google Scholar, 7Green A Campbell P Buck G et al.The Medical Research Council PT1 trial in essential thrombocythemia [abstract].Blood. 2004; 104 (Abstract 6.)Google Scholar, 24Storen EC Tefferi A Long-term use of anagrelide in young patients with essential thrombocythemia.Blood. 2001; 97: 863-866Crossref PubMed Scopus (164) Google Scholar, 25Birgegard G Bjorkholm M Kutti J et al.Adverse effects and benefits of two years of anagrelide treatment for thrombocythemia in chronic myeloproliferative disorders.Haematologica. 2004; 89: 520-527PubMed Google Scholar What then is the impetus to use drugs other than hydroxyurea in patients with ET and how can one best determine their efficacy? This analysis is problematic in that median survival in ET exceeds 2 decades and might not be inferior to that of an age- and sex-matched control population.12Passamonti F Rumi E Pungolino E et al.Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia.Am J Med. 2004; 117: 755-761Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar, 14Barbui T Barosi G Grossi A et al.Practice guidelines for the therapy of essential thrombocythemia: a statement from the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation.Haematologica. 2004; 89: 215-232PubMed Google Scholar, 26Tefferi A Fonseca R Pereira DL Hoagland HC A long-term retrospective study of young women with essential thrombocythemia.Mayo Clin Proc. 2001; 76: 22-28Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, 27Rozman C Giralt M Feliu E Rubio D Cortes MT Life expectancy of patients with chronic nonleukemic myeloproliferative disorders.Cancer. 1991; 67: 2658-2663Crossref PubMed Scopus (245) Google Scholar Therefore, it is next to impossible to show a survival advantage attached to a “new” drug. It is equally statistically challenging to demonstrate the value of a new drug in the control of disease-related complications because of the low baseline rates seen with conventional therapy. For example, in a recent large retrospective study of 435 patients with ET, the 15-year cumulative risks of thrombosis and clonal evolution into either acute myeloid leukemia (AML) or myelofibrosis with myeloid metaplasia (MMM) were 17%, 2%, and 4%, respectively.12Passamonti F Rumi E Pungolino E et al.Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia.Am J Med. 2004; 117: 755-761Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar Furthermore, the risk of both thrombosis and bleeding in low-risk patients who are not receiving any cytoreductive therapy may not be significantly different from that of the age- and sex-matched control population.6Ruggeri M Finazzi G Tosetto A Riva S Rodeghiero F Barbui T No treatment for low-risk thrombocythaemia: results from a prospective study.Br J Haematol. 1998; 103: 772-777Crossref PubMed Scopus (144) Google Scholar On the other hand, the antithrombotic value of cytoreductive therapy for high- or intermediate-risk ET has been addressed by 2 randomized treatment trials, both of which clearly documented the therapeutic superiority of hydroxyurea over both observation alone or anagrelide therapy.4Cortelazzo S Finazzi G Ruggeri M et al.Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis.N Engl J Med. 1995; 332: 1132-1136Crossref PubMed Scopus (727) Google Scholar, 7Green A Campbell P Buck G et al.The Medical Research Council PT1 trial in essential thrombocythemia [abstract].Blood. 2004; 104 (Abstract 6.)Google Scholar In the first study, treatment with hydroxyurea was compared to observation alone in 114 patients, and the risk of thrombosis was significantly less in the treated group (3.6% vs 24% at a median follow-up of 27 months).4Cortelazzo S Finazzi G Ruggeri M et al.Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis.N Engl J Med. 1995; 332: 1132-1136Crossref PubMed Scopus (727) Google Scholar Only one minor gastrointestinal bleeding episode occurred in patients treated with hydroxyurea. The results from the second study have recently been communicated at a major international meeting (December 5, 2004) and published as an abstract.7Green A Campbell P Buck G et al.The Medical Research Council PT1 trial in essential thrombocythemia [abstract].Blood. 2004; 104 (Abstract 6.)Google Scholar In the particular study, 809 patients were assigned to treatment with either hydroxyurea or anagrelide, both in combination with aspirin therapy. After a median follow-up of 39 months, the composite risk of both thrombosis and bleeding was once again favorably affected by hydroxyurea treatment (36 vs 55 events in the anagrelide arm). What about the impact of new drugs on the issue of clonal progression as well as possible drug leukemogenicity associated with hydroxyurea use? In the aforementioned large retrospective study of ET (N=435),12Passamonti F Rumi E Pungolino E et al.Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia.Am J Med. 2004; 117: 755-761Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar the 15-year cumulative risk of either AML (2%) or MMM (4%) was not significantly influenced by single-agent chemotherapy of any kind including hydroxyurea.12Passamonti F Rumi E Pungolino E et al.Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia.Am J Med. 2004; 117: 755-761Abstract Full Text Full Text PDF PubMed Scopus (364) Google Scholar In addition, the fact that these episodes of clonal evolution occurred at a median of 14.5 and 10.9 years, respectively, again underscores the magnitude of the problem of sample size and duration of follow-up necessary for a controlled study to allow statistically valid conclusions. Two other smaller retrospective studies involving 25 and 35 patients reported no cases of leukemia after 5-14 years28Finazzi G Ruggeri M Rodeghiero F Barbui T Efficacy and safety of long-term use of hydroxyurea in young patients with essential thrombocythemia and a high risk of thrombosis [letter].Blood. 2003; 101: 3749Crossref PubMed Scopus (66) Google Scholar and 2-12 years,29Randi ML Fabris F Girolami A Second malignancies in patients with essential thrombocythaemia [letter].Br J Haematol. 2002; 116: 923-924Crossref PubMed Scopus (13) Google Scholar respectively, of treatment with hydroxyurea. Consistent with the observation from these retrospective studies, the risk of leukemic transformation in the aforementioned randomized treatment trials was not adversely affected by the use of hydroxyurea alone, whereas patients treated with anagrelide experienced a significantly higher rate of transformation into MMM (16 vs 5 events on the hydroxyurea arm after a median follow-up of 39 months).7Green A Campbell P Buck G et al.The Medical Research Council PT1 trial in essential thrombocythemia [abstract].Blood. 2004; 104 (Abstract 6.)Google Scholar Similarly, another recent communiqué, involving 90 patients with ET, suggested a substantial increase in bone marrow fibrosis after treatment with interferon alfa.30Gugliotta L Bulgarelli A Tieghi A et al.Bone marrow biopsy and aspirate evaluation in 90 patients with essential thrombocythemia treated with PEG interferon alpha-2b: preliminary results [abstract].Blood. 2004; 104 (Abstract 1523.)PubMed Google Scholar Therefore, at this juncture, there is no hard evidence to implicate hydroxyurea use in ET as being leukemogenic, whereas new information suggests that both anagrelide and interferon alfa may increase the risk of transformation into MMM.7Green A Campbell P Buck G et al.The Medical Research Council PT1 trial in essential thrombocythemia [abstract].Blood. 2004; 104 (Abstract 6.)Google Scholar, 30Gugliotta L Bulgarelli A Tieghi A et al.Bone marrow biopsy and aspirate evaluation in 90 patients with essential thrombocythemia treated with PEG interferon alpha-2b: preliminary results [abstract].Blood. 2004; 104 (Abstract 1523.)PubMed Google Scholar Where do we go from here? Based on the aforementioned discussions, it is reasonable to question the practical impact as well as return value of additional randomized treatment trials in ET. Instead, it might be more cost-effective to direct resources and effort toward basic and translational research that focuses on disease pathogenesis and leads to curative therapy. In this regard, the National Institutes of Health recently sent out a request for applications (expiration date, February 17, 2005) for MPD research that focuses on the cellular and genetic characteristics of these disorders (http://grants1.nih.gov/grants/guide/rfa-files/rfa-hl-04-034.html). In the meantime, current evidence continues to support the use of hydroxyurea as the preferred drug of choice for high-risk patients with ET. The remarkably low incidence of AML in hydroxyurea-treated patients with either ET or polycythemia vera,31Finazzi G Caruso V Marchioli R ECLAP Investigators et al.Acute leukemia in polycythemia vera: an analysis of 1,638 patients enrolled in a prospective observational study.Blood. 2004 December 7; ([Epub ahead of print])Available at: www.bloodjournal.org/cgi/reprint/2004-09-3426v1Google Scholar despite the fact that it is usually administered to patients who are vulnerable to clonal evolution because of either aggressive disease phenotype or advanced age, should dispel the unsubstantiated fear of drug leukemogenicity and provides much-needed comfort to physicians who practice evidence-based medicine and use this particular agent for prevention of MPD-associated thrombosis.4Cortelazzo S Finazzi G Ruggeri M et al.Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis.N Engl J Med. 1995; 332: 1132-1136Crossref PubMed Scopus (727) Google Scholar, 28Finazzi G Ruggeri M Rodeghiero F Barbui T Efficacy and safety of long-term use of hydroxyurea in young patients with essential thrombocythemia and a high risk of thrombosis [letter].Blood. 2003; 101: 3749Crossref PubMed Scopus (66) Google Scholar, 32Tefferi A Is hydroxyurea leukemogenic in essential thrombocythemia? [letter].Blood. 1998; 92: 1459-1460PubMed Google Scholar, 33Cheung MC Hicks LK Pendergrast J Thrombocytosis [letter].N Engl J Med. 2004; 350: 2524-2525Crossref PubMed Scopus (5) Google Scholar Finally, the experience in ET should serve as a lesson in discouraging the blanket use of new drugs in polycythemia vera before their value is properly evaluated in a randomized setting.