Choosing the right TKI for chronic myeloid leukemia: When the truth lies in “long‐term” safety and efficacy
Authors: Carlo Gambacorti‐Passerini, Rocco Piazza
Journal: American Journal of Hematology (2011)

Nilotinib was developed as a second generation Abl inhibitor, more powerful, and specific than imatinib [1]. Nilotinib is ∼ 30 times more potent than imatinib and active against a number of BCR/ABL1 mutants conferring resistance to imatinib [2]; it also blocks Abl more potently than platelet derived growth factor receptor (PDGFR) and KIT, the two other major targets of imatinib [3]. Its clinical activity in imatinib resistant or intolerant chronic myeloid leukemia (CML) patients is well documented [4, 5]. This issue of the Journal contains two reports [6, 7] focused on a potential new side effect of nilotinib: peripheral arterial occlusive disease (PAOD). The report from Aichberger et al. presents three cases of severe PAOD out of 24 consecutive patients affected by CML, who received nilotinib as second-line treatment. PAOD developed in these three cases 10, 11, and 39 months after starting nilotinib. PAOD was severe in the reported cases, with substantial morbidity, including multiple stents positioning and limb amputation. In addition, the authors (aa). report further four cases of arterial disease (one less severe PAOD, two infarcts, and one sudden death), which bring the total number of events to 7/24 (29%). In an accompanying case report [7], Tefferi signals two cases from the Mayo Clinic database that resemble those described by Aichberger, although the total number of patients treated is not mentioned, and therefore, the frequency of PAOD cannot be evaluated in this case. These two reports cannot be considered conclusive for a number of reasons: they represent retrospective collection of data, with all the limitations that this type of study carries with it; the numbers involved are very small, and therefore, the size of the problem is difficult to gauge (in the Aichberger report, for example (f.e.), the 95% Confidence Interval of the proportion of events observed is such that they could be as low as 11% or as high as 50%); some observed cases could be due to leukemia-associated factors. Having said that, the two reports identify a new, original, and potentially very serious side effect associated with nilotinib use, which needs to be thoroughly investigated. The databases of all nilotinib based studies should be opened to an independent analysis; Prospective and independent studies on the long-term effects of nilotinib should be performed, similar to what is already available for imatinib [8]. Experimental studies should be performed to identify the mechanisms responsible for the observed PAOD cases. In this respect, it is indeed surprising that the metabolic effects of nilotinib (hyperglycemia, hypercholesterolemia, and hyperlipidemia) are almost the opposite of what previously described for imatinib [9, 10] a molecule with a similar pattern of target specificity. Most of the data presented on nilotinib so far, including those published here, are related to its use as second-line treatment, a clinical setting in which imatinib already failed and where it is ethical to accept more risks, given the danger of not controlling the primary disease. The use of nilotinib as first-line treatment represents a completely different situation, in which a more conservative approach is justified, because the excellent long-term prospects for imatinib-treated patients, which includes a normal life expectancy for patients in Complete Cytogenetic Response after 2 years of imatinib treatment (Figs. 1 and [8]). Recent data from a single sponsored trial [11] indicate that nilotinib can achieve a higher rate of cytogenetic and molecular remissions when compared with imatinib as first-line treatment for CML. However, no differences in survival or progression free survival are present, and follow up is limited to 18–24 months. The only advantage demonstrated in that study (which, however, did not allow for cross-over and therefore could be not representative of the "real world" situation) is the protection of ∼ 3% of patients from progressing to Accelerated/Blast phase within the first year of therapy. In this setting, the occurrence of a serious toxicity such as PAOD, even in a minor proportion of patients, is critical and needs to be assessed with precision and beyond any possible doubt. For a disease where treatment is potentially life-long and patients enjoy an excellent prognosis, long-term data, in terms of both activity and toxicity, are essential to determine the real profile of a drug. CML patients and the public deserve nothing less.