Imatinib, nilotinib, and dasatinib have been approved by the US Food and Drug Administration (FDA) as initial treatment for patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase—and another tyrosine kinase inhibitor (TKI), bosutinib, in my estimation, should have been approved as well. In addition, an ongoing trial is comparing imatinib with ponatinib in this patient group. Randomized trials comparing imatinib with dasatinib or nilotinib have shown somewhat higher response rates and more rapid and deeper molecular responses, as well as a slightly lower rate of progression to more advanced-stage CML, with the second-generation TKIs. Also, the short-term toxicity profiles of the latter have been favorable.[1,2]
Given these findings, why am I “defending” the use of imatinib as initial therapy in at least most newly diagnosed patients? For starters, the management of chronic-phase CML is more akin to a marathon than a sprint, with the expectation that most patients will be treated indefinitely, as the relapse rate is very high when treatment is stopped, even in patients who have been molecularly negative for years. Hence, considerations of long-term outcome and side effects, as well as cost, become quite important. The latter will appropriately be a dominant factor when generic versions of imatinib become available in the next 1 to 2 years, and I have already seen patients for whom insurers refused initial treatment with second-generation TKIs, in favor of imatinib.
In addition, not all patients continue on their initial TKI for their entire treatment course. It is estimated that only around 60% of patients are still on imatinib after 5 years of treatment, due to switches to other TKIs because of side effects or treatment failure. In the randomized trials, about 30% of patients treated initially with nilotinb or dasatinib discontinued these drugs within the first few years. There is little information about the nature of subsequent treatment in these patients, an unfortunate deficiency of most pharma-sponsored trials. Importantly, no differences in overall survival were seen between imatinib and second-generation TKIs in recent updates of these trials.
Although long-term imatinib treatment is associated with persistence of low-grade side effects—most notably fatigue, arthralgias, and diarrhea—a recent evaluation of more than 800 imatinib-treated patients followed in cytogenetic complete response (CCyR) for about 8 years did not show any evidence of increase in cardiovascular events, severe organ toxicity, or secondary cancers, and the overall survival was similar to a matched population of Italian adults.
There is less information about long-term results with other TKIs; however, there may be some concerns about cardiovascular events with these drugs. In the ENESTnd trial, with approximately 4 years of follow-up, the combined rates of peripheral arterial occlusive disease (PAOD), ischemic cardiac events, and ischemic central nervous system events were 6.1% and 8.3% in the two nilotinb-treated arms, compared with 1.4% in the imatinib controls. In addition, there have been other reports of catastrophic PAOD in nilotinib-treated patients. The package insert for ponatinib warns of an 8% incidence of “severe arterial thrombosis” in the phase II trials with this drug, while the occurrence of pleural and occasionally pericardial effusions with dasatinib is a well-described problem. Less well appreciated is the fact that pleural effusions can occur for the first time after many years of dasatinib treatment, while cases of severe pulmonary arterial hypertension, only some of which resolved with cessation of the drug, have recently been reported. The mechanism(s) responsible for these vascular events is not understood, and whether the incidence will increase with longer exposure is not known. It has always been intriguing that there are unique patterns of presumably “off-target” toxicities that are associated with each of these BCR-ABL–directed agents—and that are usually (but not always) ameliorated by switching agents.
To complicate the treatment decision a bit further, as your pharmaceutical representative is sure to remind you, there is growing evidence from many trials that patients who respond more rapidly enjoy higher rates of long-term cytogenetic and molecular response. However, the overall results after continuing imatinib in patients who do not reach these early “milestones” is still very good, and there is no evidence that early switching to a second-generation TKI improves their outcome. Nor is there evidence that the “deeper” responses after initial treatment with nilotinib or dasatinib will permit discontinuation of the TKI in a higher fraction of patients who become molecularly negative. Trials addressing these issues are in progress.
Based on these considerations, I am very comfortable in using imatinib as initial therapy in most patients who present in chronic phase, with the possible exception of patients with more advanced disease and higher Sokal scores, in whom I prefer (albeit with only modest evidence) to use a second-generation TKI. This assumes however, that patients are being monitored appropriately for response. It is hoped that new guidelines from the European LeukemiaNet will be helpful in this regard, although the absence of standardization of molecular monitoring in the United States creates reports that can be difficult to interpret and understand, sometimes resulting in inappropriate switching of therapy and even inappropriate referral for transplantation. More critically, recent analyses of billing and prescribing data have revealed that an appalling fraction of US patients who are prescribed TKIs for CML do not have any follow-up assessments for cytogenetics or BCR-ABL transcript quantification. Certainly CML patients deserve better than this, and referrals to centers with expertise should be encouraged.
Financial Disclosure: Dr. Schiffer receives grant support from Novartis, Bristol-Myers Squibb, and Ariad; he serves on the advisory boards of Novartis, Bristol-Myers Squibb, and Teva; and he serves on the data and safety monitoring boards of Novartis and Pfizer.
1. Larson RA, Hochhaus A, Hughes TP, et al. Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia. 2012;26:2197-203.
2. Kantarjian HM, Shah NP, Cortes JE, et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2012;119:1123-9.
3. Mahon FX, Rea D, Guilhot J, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 2010;11:1029-35.
4. Experts in Chronic Myeloid Leukemia. The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: from the perspective of a large group of CML experts. Blood. 2013;121:4439-42.
5. Gambacorti-Passerini C, Antolini L, Mahon FX, et al. Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib. J Natl Cancer Inst. 2011;103:553-61.
6. Larson RA, Hochhaus A, Saglio G, et al. Nilotinib versus imatinib in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): ENESTnd 4-year (y) update. J Clin Oncol. 2013;31(suppl):abstr 7052.
7. Aichberger KJ, Herndlhofer S, Schernthaner GH, et al. Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML. Am J Hematol. 2011;86:533-9.
8. Montani D, Bergot E, Gunther S, et al. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation. 2012;125:2128-37.
9. Cortes JE. Not only response but early response to tyrosine kinase inhibitors in chronic myeloid leukemia. J Clin Oncol. 2012;30:223-4.
10. Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013. [In press]
11. Chen C, Chen L, Dhanda R, et al. Types, frequency, and adherence of molecular tests in chronic myelogenous leukemia at chronic phase (CML-CP) in the U.S. community setting. J Clin Oncol. 2013;31(suppl):abstr 7096.