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www.TheOncologyPharmacist.com Conclusion These updates highlight the recent advances in the treatment of CML; they can help payers and providers to develop new approaches to the management of this chronic disease and encourage multistakeholder collaboration to provide value-based care for patients with CML. ● References 1. Rohrbacher M, Hasford J. Epidemiology of chronic myeloid leukaemia (CML). Best Pract Res Clin Haematol. 2009;22:295-302. 2. Altekruse SF, Kosary CL, Krapcho M, et al, eds. SEER cancer statistics review, 1975-2007. National Cancer Institute, 2010. http://seer.cancer.gov/csr/1975_2007/. Accessed August 10, 2010. 3. Kantarjian H, O’Brien S, Cortes J, et al. Therapeutic advances in leukemia and myelodysplastic syndrome over the past 40 years. Cancer. 2008;113(7 suppl):1933-1952. 4. Druker BJ. Translation of the Philadelphia chromosome into
therapy for CML. Blood. 2008;112:4808-4817. 5. O’Brien SG, Guilhot F, Larson RA, et al; for the IRIS Investigators. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994-1004. 6. Soverini S, Martinelli G, Rosti G, et al. ABL mutations in late chronic phase chronic myeloid leukemia patients with upfront cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia. J Clin Oncol. 2005;23:4100-4109. Epub 2005 May 2. 7. Hughes TP, Kaeda J, Branford S, et al; for the International Randomised Study of Interferon versus STI571 (IRIS) Study Group. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med. 2003;349:1423-1432. 8. Deininger M, O’Brien SG, Guilhot F, et al. International randomized study of interferon vs STI571 (IRIS) 8-year follow up: sustained survival and low risk for progression or events in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib. Blood. 2009;114:abstract 1126. 9. Branford S, Rudzki Z, Walsh S, et al. Detection of BCRABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood. 2003;102:276-283. Epub 2003 Mar 6.
10. Jabbour E, Kantarjian H, Jones D, et al. Frequency and clinical significance of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate. Leukemia. 2006;20:1767-1773. Epub 2006 Jul 20. 11. Branford S, Melo JV, Hughes TP. Selecting optimal second-line tyrosine kinase inhibitor therapy for chronic myeloid leukemia patients after imatinib failure: does the BCR-ABL mutation status really matter? Blood. 2009;114:5426-5435. Epub 2009 Oct 30. 12. Soverini S, Gnani A, Colarossi S, et al. Philadelphia-positive patients who already harbor imatinib-resistant Bcr-Abl kinase domain mutations have a higher likelihood of developing additional mutations associated with resistance to secondor third-line tyrosine kinase inhibitors. Blood. 2009;114:21682171. Epub 2009 Jul 9. 13. Larson RA, le Coutre PD, Reiffers J, et al. Comparison of nilotinib and imatinib in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): ENESTnd beyond one year. J Clin Oncol. 2010;28(suppl 15):abstract 6501. 14. Saglio G, Kim DW, Issaragrisil S, et al; for the ENESTnd Investigators. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362:2251-2259. Epub 2010 Jun 5. 15. Sokal JE, Cox EB, Baccarani M, et al. Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood. 1984;63:789-799.
16. Tasigna (nilotinib) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; June 2010. 17. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib compared to imatinib (IM) in patients (pts) with newly diagnosed chronic-phase chronic myelogenous leukemia in chronic phase (CML-CP): twelve-month efficacy and safety from the phase III DASISION study. J Clin Oncol. 2010;28(suppl 18):abstract LBA6500. 18. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362:2260-2270. Epub 2010 Jun 5. 19. Hasford J, Pfirrmann M, Hehlmann R, et al. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing committee for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer Inst. 1998;90:850-858. 20. Sprycel (dasatinib) package insert. Princeton, NJ: BristolMyers Squibb Company; June 2009. 21. Cortes JE, Kantarjian H, Brümmendorf T, et al. Safety and efficacy of bosutinib (SKI-606) in patients (pts) with chronic phase (CP) chronic myeloid leukemia (CML) following resistance or intolerance to imatinib (IM). J Clin Oncol. 2010;28(suppl 15):abstract 6502.
Linda Ritter, PhD, participated in the development of this article.
Redefining the Best Approach to CML Therapy By Michael Mauro, MD Associate Professor of Medicine, Oregon Health & Science University Knight Cancer Institute, Center for Hematological Malignancies, Portland
he International Randomised Study of Interferon versus STI571 (IRIS) provided proof of principle that a small molecule, BCR-ABL inhibitor, could be very effective and durable therapy for chronic-phase chronic myelogenous leukemia (CML).1 Response kinetics were clearly predictive of outcome—timely complete cytogenetic response (CCyR) and molecular response are protective against relapse and progression. Disease risk, as assessed by the prognostic Sokal and Hasford scores, has historically been predictive of lower response to interferon-alpha and chemotherapy, as well as relapse, regardless of response to therapy. In the IRIS trial, we saw that although high-risk disease was associated with reduced response, achievement of relevant response, such as CCyR, mitigated subsequent risk of relapse or progression. Unlike resistance to traditional chemotherapy, which typically involves activation of a salvage molecular pathway, identified resistance to imatinib is most often associated with kinase domain mutations altering or precluding imatinib binding, which can restore BCR-ABL activity. Perhaps the most favorable element of response kinetics to imatinib has been the finding that the modest number of loss-ofresponse and progression events in the IRIS trial occurred early and declined sharply thereafter rather than persisting as a continual or growing threat. What have we learned from the two studies, Evaluating Nilotinib Efficacy and Safety in Clinical Trials of Newly Ph+ CML Patients (ENESTnd)2 and Dasatinib versus Imatinib Study in
Treatment-Naïve CML Patients (DASISION)3? Nilotinib and dasatinib are both superior to imatinib for treating newly diagnosed patients with chronicphase CML. Both drugs provided higher rates of CCyR faster than imatinib. Better molecular responses were also observed with these agents when compared with imatinib, and optimal responses were seen across all prognostic groups. These two agents provided reduction in rates of progression to advanced phase or blast crisis at early time points.2,3 Emerging questions The investigational second-generation tyrosine kinase inhibitor (TKI), bosutinib, may soon represent an additional option for patients who are imatinib-resistant or -intolerant, although its common toxicities are different from those experienced by patients receiving imatinib, dasatinib, or nilotinib, and with comparable efficacy, toxicity comparison prominence increases. As new second-generation TKIs gain approval by the US Food and Drug Administration, we need to determine their place in our management strategies. Relevant questions in the context of this clinical debate include: • Why not continue to use imatinib as first-line therapy and then switch to a second-generation TKI at the earliest sign of inadequate response or intolerance? • Will early use of second-generation TKIs lead to more high-level resistance? • Does the benefit match the expense?
1. Why not continue to use imatinib as first-line therapy and then switch to a second-generation TKI at the earliest sign of inadequate response or intolerance? Waiting to use a more potent and more effective agent may simply be too risky. Aside from the Sokal and Hasford risk categorization scores, there is no prognostic tool available that will identify patients needing more potent firstline therapy. Treating patients with second-generation TKIs at suboptimal response or failure needs to be recognized as salvage therapy—disease biology has likely changed or resistance mechanisms have become dominant by this point, and optimal long-term outcomes are thus compromised, given lower response and uncertainty regarding response duration. In the absence of the ability to select or personalize therapy, the best strategy is to provide all patients every opportunity to achieve an early and deep response that is protective against progression by using secondgeneration TKIs as primary therapy. 2. Will early use of second-generation TKIs lead to more high-level resistance? We do not yet know if there is a plateau in progression-free survival (PFS) curves for the ENESTnd and DASISION trials, nor do we fully understand the kinetics of late resistance with the second-generation TKIs. We do know that mutations related to drug resistance, as well as emergence of additional mutations over time, increase after an initial suboptimal response or treatment failure, necessitating the increasing use of a third TKI or of stem-cell transplantation. The ENESTnd and DASISION trials
demonstrated that optimal response rates were significantly greater in patients receiving nilotinib or dasatinib compared with those receiving imatinib. Such significant gains in early response should functionally reduce the number of patients at risk for development of resistance, because the genesis of resistant disease is linked to disease volume. Although time will add strength to this argument, the early (12-18 months) differences in PFS, in light of the depth of these responses, may prove to be quite relevant, because increasing the rapidity of response may shorten the time frame during which resistance emerges. 3. Does the benefit match the expense? To answer this question, we must look ahead to one important, yet theoretical future benefit—will we be able to eventually discontinue therapy and essentially “cure” chronic-phase CML? The Stop Imatinib (STIM) study evaluated the persistence of complete molecular remission after stopping imatinib.4 In this pilot study, patients were required to be in complete molecular remission (then defined as polymerase chain reaction undetectable) for at least 2 years before entering the study. Of the 69 patients included in the study, 34 had previous interferon-alpha treatment and 35 were treated only with imatinib. Median follow-up was 17 months. Of these 69 patients, 41 patients relapsed (loss of complete molecular response) within the first 7 months, 37 relapsed within the first 6 months, and two relapsed after more than 6 months. At month 12, the probability of remainContinued on page 16
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