Nilotinib treatment‐associated peripheral artery disease and sudden death: Yet another reason to stick to imatinib as front‐line therapy for chronic myelogenous leukemia
Authors: Ayalew Tefferi, Louis Letendre
Journal: American Journal of Hematology (2011)

Aichberger and colleagues recently described an association between nilotinib therapy for chronic myelogenous leukemia (CML) and adverse vascular events, which occurred in eight (∼33%) of their 24 CML patients treated with nilotinib: severe peripheral artery disease (PAD; n = 3), less severe PAD (n = 1), sudden death (n = 1), myocardial infarction (n = 1), spinal infarction (n = 1), and subdural hematoma (n = 1) [1]. We were intrigued by these observations because of similar events that occurred in two of our patients receiving nilotinib therapy. A female patient developed severe and unrelenting PAD and coronary artery disease (CAD) after ∼3 years of treatment with nilotinib and the second patient died suddenly after receiving nilotinib therapy for 3 weeks. None of the two patients had history of cardiovascular disease, tobacco use, or diabetes mellitus. These observations are troubling and question the prudence of rushing to replace imatinib with nilotinib, for front-line therapy in CML. A 54-year-old, nonsmoking, nondiabetic female with no history of vascular disease was diagnosed with chronic phase CML in 1996. Initial treatment agents included hydroxyurea and interferon-alpha (IFN-α). Because of lack of complete hematologic remission (CHR) after more than one year of treatment with IFN-α, low-dose cytarabine was added in 1998 and resulted in transient CHR without cytogenetic response. Imatinib treatment was initiated in late 2000 (investigational treatment protocol) with subsequent achievement of CHR and major but not complete cytogenetic remission; side effects included periorbital edema, watery eyes, neutropenia, anemia, and elevation of serum transaminases. The addition of dendritic cell vaccine therapy (investigational treatment protocol) in 2003 did not restore loss of cytogenetic response on imatinib therapy and the patient was subsequently enrolled into a zarnestra plus imatinib treatment trial in 2004 (investigational treatment trial); side effects included severe neutropenia, thrombocytopenia, and neutropenic fever. Because of continued lack of response and progressive disease, patient was subsequently placed on nilotinib therapy (400 mg/day) in September, 2004 (investigational treatment trial). Initially, nilotinib therapy did not induce hematologic remission despite dose increase to 800 mg/day and concomitant treatment with anagrelide and hydroxyurea was instituted for control of thrombocytosis and leukocytosis, respectively. In November, 2004, nilotinib dosing was modified to 400 mg twice-a-day and this resulted in improved disease control and achievement of CHR. By January, 2006, the patient had achieved complete cytogenetic remission (CCyR) on nilotinib treatment alone. Side effects of nilotinib included severe xerodermia, pruritus of the scalp and skin, increased fasting blood glucose level, frequent nonsymptomatic elevations in serum amylase and lipase, and QTc prolongations with documented readings up to 531 ms. In 2007, the patient started complaining about lower extremity discomfort with activity, sometimes involving both extremities and buttocks. In 2008, she developed exertional chest discomfort and in May, 2008, she was hospitalized with acute chest pain and diagnosed as having unstable angina. Diagnostic angiography revealed high-grade right ostial lesion, a 70% left anterior descending lesion, and several noncritical lesions in the left coronary system. The patient underwent percutaneous transluminal coronary angioplasty (PTCA) of the right ostial lesion and successful deployment of a drug-eluting stent and was placed on combination antiplatelet drugs. Additional findings from angiography included fibromuscular dysplasia in both renal arteries and other arterial beds in the mesentry and lower extremity. By October, 2008, the patient's exertional lower extremity discomfort was getting worse and she was clinically diagnosed with peripheral artery disease (PAD) with limiting claudication; lower extremity angiography revealed, on the right, severe atheromatous stenoses of mid and distal superficial femoral artery (SFA) and diffusely diseased infrapopliteal vessels and, on the left, moderate distal SFA stenosis and diffuse disease involving infrapopliteal vessels. Patient was managed with percutaneous transluminal angioplasty (PTA) of the right SFA and placement of self expanding stent. In November 2008, she developed chest pain and dyspnea on exertion and a coronary angiogram revealed severe three-vessel coronary artery disease that necessitated four-vessel coronary artery bypass grafting. At this point, our suspicion of a possible association between her nilotinib therapy and her progressive atherosclerosis involving both the coronary system and peripheral arteries was documented in her hospital records and the matter was thoroughly discussed with the principle investigator of the nilotinib clinical trial. However, weighing the risk benefit balance in the context of her otherwise imatinib-refractory CML, it was decided to continue with nilotinib therapy. In April, 2009, the patient was again experiencing right lower extremity claudication and deteriorating walking distances and repeat angiography revealed 90% right SFA obstruction by multiple discrete lesions and severe in-stent restenosis. Also on the right, there was 50–60% popliteal stenosis at knee and diffuse disease in the infrapopliteal vessels. Similar diffuse arterial disease was also demonstrated in the left lower extremity. A successful right SFA angioplasty was performed reducing the obstruction from 90% to 10%. Patient obtained excellent symptomatic relief in the short term but she had recurrent symptoms in September, 2009. Repeat angiography revealed in-stent restenosis and right popliteal artery atherosclerosis that was managed by atherectomy and PTA for residual stenosis. In February 2010, patient was experiencing recurrent claudication symptoms and underwent right superficial femoral to below-knee popliteal artery bypass. At present, patient continues to be in complete cytogenetic remission of her CML on nilotinib 400 mg twice-a-day but her quality of life has significantly been compromised with recurrent treatment-refractory PAD and CAD as well as other comorbid conditions including upper gastrointestinal bleeding related to systemic anticoagulation therapy. A 63-year-old nonsmoking, nondiabetic man with no prior cardiovascular disease was diagnosed with chronic phase CML in February, 2000. Initial treatment with hydroxyurea (∼1 year), IFN-α (∼5 months), and/or cytarabine (∼1 year) was poorly tolerated and failed to induce hematologic or cytogenetic remission. Imatinib was instituted in June, 2001 and resulted in CHR without cytogenetic response. The addition of dendritic cell vaccine therapy (investigational treatment trial) in March, 2002 did not provide additional benefit. In March, 2003, imatinib was replaced with hydroxyurea because of loss of hematologic response and anagrelide was added to hydroxyurea because of refractory thrombocytosis. Patient was kept on hydroxyurea and anagrelide combination therapy until April 2005 when a treatment trial with imatinib was again tried but discontinued in July, 2005 because of lack of efficacy. While on imatinib therapy, the patient experienced retrosternal symptoms that were consistent with esophageal reflux and extensive cardiac evaluation was negative for CAD. Patient was started on nilotinib clinical trial (400 mg twice-a-day) on December 22, 2005, while concomitant treatment with hydroxyurea and anagrelide was continued until nilotinib treatment efficacy could be documented. Prenilotinib treatment, echocardiogram, and electrocardiogram (EKG) were performed and were largely unremarkable with no QTc prolongation. Follow-up EKG in the first 8 days of treatment with nilotinib did not reveal QTc prolongation and patient was tolerating the drug well during his day +15 visit, on January 5, 2005, and his only complaints were excessive gas and heartburn symptoms. Also, there were early indications of drug efficacy and the patient was advised to discontinue treatment with anagrelide and reduce the dose of hydroxyurea. On January 10, 2005, we received a call from the patient's wife stating that she found her husband dead sitting on his chair. She stated that the patient did not complain of shortness of breath or chest pain the previous evening. Two recent studies of patients with newly-diagnosed chronic-phase CML compared standard dose imatinib (400 mg/day) with either nilotinib (300 or 400 mg twice-a-day) [2] or dasatinib (100 mg/day) [3] and demonstrated a significantly superior major molecular response (MMR; 43–46% vs. 22–28%) and complete cytogenetic response (CCyR; 77–80% vs. 65–66%) at 12 months, favoring nilotinib or dasatinib over imatinib [2, 3]. However, both studies were flawed in their study design and their results have been inaccurately interpreted [4]. First, neither one of the two studies took into account current practice, which dictates switching treatment from imatinib to second generation anti-ABL tyrosine kinase inhibitor (SG-TKI) in the first 3–6 months of treatment, in patients with treatment failure (i.e., crossover was not permitted) [5]. Second, there was no significant difference in overall survival (OS) between the treatment arms and only one [2] of the two studies [2, 3] showed significant difference in progression-free survival (PFS) in favor of nilotinib. Third, the primary endpoint used in both studies (i.e., MMR) is not an accepted surrogate for OS and comparison of CCyR at 12 months undermines the full potential of standard dose imatinib (400 mg/day), which requires a longer period of time to peak [6, 7]. Other large randomized studies in chronic phase CML have shown that higher doses of imatinib (600–800 mg/day) can induce MMR rates (49–59%) at 12 months that are comparable to those obtained with SG-TKI, but without OS advantage over standard dose imatinib (400 mg/day) [8, 9]. Furthermore, in a most recent study involving 1,014 newly-diagnosed patients with CML [8], higher dose of imatinib did not result in improved PFS and patients with MMR (i.e., BCR-ABL1 transcript ratio of <0.1%) at 12 months did not necessarily fare better than those with CCyR without MMR (i.e., BCR-ABL1 transcript ratio of 0.1% to <1%), in terms of either OS or PFS. The lack of additional value for MMR in the context of CCyR has also been documented in previous studies [6, 7]. The fact of the matter is that over 50% of newly diagnosed patients with CML achieve optimal response (i.e., CCyR or PCyR) in the first 6 months of treatment with tolerability-adapted higher dose imatinib (600–800 mg/day) [8, 9] and that there is not an ounce of evidence to suggest that long-term PFS in such patients (estimated at >95%) [10] can further be improved with SG-TKI as front-line therapy. Furthermore, it is now common knowledge that the majority of imatinib-treated patients who do not achieve optimal response are effectively salvaged by SG-TKI therapy [11]. In this regard, there is no evidence to suggest that such patients would have fared better had they received front-line therapy with SG-TKI as opposed to starting with imatinib first followed by an early switch to SG-TKI in case of suboptimal response to imatinib in the first 3 to 6 months. Another extremely important point is the fact that long-term efficacy and safety data that has been gathered independent of sponsored clinical trials is available for imatinib [12] but not for nilotinib or dasatinib. In a recent drug company-independent study of 832 CML patients with imatinib-induced CCyR and treated for a median of almost 6 years, there were 139 recorded serious adverse events, of which only 19.4% were attributed to imatinib [12]. The number of patients with "imatinib-related" myocardial infarction (n = 1), heart failure (n = 2), or hepatic toxicity (n = 1) was remarkably low and PAD was not mentioned as a drug-related side effect. Only 19 patients (2.3%) discontinued imatinib because of drug-related toxic effects. Among 20 recorded deaths, only six were attributed to CML progression and OS and rate of second cancers were not statistically significantly different from that of the general population. Considering the possibility that Gleevec's (imatinib mesylate) market exclusivity ends soon, and a generic version becomes available, it is not surprising that the makers of nilotinib and dasatinib are attempting to undermine the aforementioned set of facts by diverting the focus from OS and long-term safety to OS-irrelevant treatment endpoints, such as MMR. On the other hand, the aforementioned observations from Aichberger et al. [1] and those of our own concerning nilotinib treatment-associated complications are disturbing and question the prudence of rushing to replace imatinib with SG-TKI as front-line therapy for CML. Ayalew Tefferi*, Louis Letendre*, * Division of Hematology, Department of Medicine, Mayo Clinic Rochester, Minnesota.