Elsevier

Leukemia Research

Volume 34, Issue 2, February 2010, Pages 129-134
Leukemia Research

Review
Nilotinib: A second-generation tyrosine kinase inhibitor for chronic myeloid leukemia

https://doi.org/10.1016/j.leukres.2009.08.031Get rights and content

Abstract

Imatinib mesylate is currently the standard of care for chronic myeloid leukemia (CML) patients in early chronic phase. However, the emergence of resistance and intolerance has dampened the enthusiasm for this drug. To overcome this phenomenon, different strategies have been developed, including novel targeted agents. Nilotinib, formerly known as AMN107, is a second-generation tyrosine kinase inhibitor 30-fold more potent than imatinib, with high affinity and selectivity on BCR/ABL, and also active against a wide range of mutant clones, except T315I mutation. Phase II trials of nilotinib showed high activity in imatinib-resistant or intolerant CML patients, whereas front-line treatment of the disease in chronic phase demonstrated rapid and stable cytogenetic responses and increasing molecular responses. We here review the development of nilotinib and the efficacy data in phase II and front-line trials. The aim of this review is to evaluate the pharmacology, pharmacokinetic and pharmacodynamic properties of the drug and the recent results of clinical trials performed in patients with CML and Ph+ acute lymphoblastic leukemia (ALL).

Introduction

Chronic myeloid leukemia (CML) is one of the most extensively studied and, arguably, best understood neoplasm [1]. The cytogenetic hallmark of CML is the Philadelphia chromosome (Ph), originated by a reciprocal translocation between chromosomes 9 and 22 (t[9;22] [q34;q11]). The conjugation of the breakpoint cluster region gene on chromosome 22 and the Abelson kinase gene on chromosome 9 creates the BCR–ABL oncogene, which codes for a deregulated tyrosine kinase. It has been reported that Bcr–Abl activates multiple signal transduction pathways in Ph+ cell lines, including Ras/Raf/mitogen-activated protein kinase (MAPK), phosphatidylinositol 3 kinase, STAT5/Janus kinase, and Myc. BCR–ABL activity leads to uncontrolled cell proliferation and reduced apoptosis, resulting in the malignant expansion of pluripotent stem cells in bone marrow [2].

CML normally progresses through three clinically recognized phases: about 90% of patients are diagnosed during the typically indolent chronic phase (CP), which is followed by an accelerated phase (AP) and a terminal blastic phase (BP). Twenty to 25% of patients progresses directly from CP to BP and the time course for progression can be extremely varied. The mechanisms behind CML progression are not fully understood [3]. There are increasing evidences that Src family kinases are involved in CML progression through induction of cytokine independence and apoptotic protection [4].

From the 1960s to 1970s, busulfan and hydroxycarbamide were used as anticancer agents for CML, but they did not significantly prolong survival, despite the reduction of the number of leukemic cells. From 1980s, interferon alpha (IFN) became a promising agent by inducing haematological and cytogenetic remission with prolonged survival: unfortunately not all the patients responded to IFN and a significantly high number of patients complained serious toxicity. In the 1970s, allogeneic transplant procedure was introduced as a potentially curative option for the treatment of CML: however, it is not an ideal option for all patients due to the lack of HLA-matched donor or the risk of transplantation related mortality [5].

The discovery of the BCR–ABL mediated pathogenesis of CML provided the rationale for the design of an inhibitory agent that targets the specific BCR–ABL kinase activity.

Imatinib mesylate, a 2-phenylaminopyrimidine-based ATP-competitive inhibitor, is a selective inhibitor of ABL and its derivative BCR–ABL, as well as other tyrosine kinases, and has dramatically improved the outcome in CML [6]. A phase I trial in 1998, showed significant anti-leukemic activity and good tolerability in CML patients in whom treatment with IFN had failed [7]. Imatinib provides an effective and durable therapy for CML: the follow-up at 7 years showed that the cumulative complete cytogenetic response (CCyR) rate is 89%, the estimated survival rate is 86% and freedom from progression rate (FFP) is 93%, with and event-free survival of 81% [8]. With the high rate of complete cytogenetic responders, the goal of therapy has become achieving molecular responses, as measured by the reduction or elimination of BCR–ABL transcript. Major molecular response (MMR) in the IRIS trial was defined as a >3 log reduction in transcript. Obtaining MMR was associated with significantly better long-term remission duration and progression free survival (PFS). At 60-month follow-up, achievement of CCyR and MMR by 12 months was associated to a PFS of 97% compared to 89% for patients with CCyR but with less than MMR [9]. Early molecular response predicted for better outcome: progression of disease correlated with failure to achieve a 1 log reduction in transcript level by 3 months and a 2 log reduction by 6 months [10]. In the first PCR dataset from IRIS study represented according to International Scale (IS), achievement of CCR correlated well with BCR–ABL/ABL ratio <1% from 6 months onwards, and at 18 months patients with ratio <1% had excellent long-term outcomes; furthermore, MMR rate and depth of molecular response increased over time [11].

Despite the benefits of imatinib, patients may develop primary or acquired resistance [12].

The IRIS study at 7-year follow-up provided an indication of imatinib resistance: 31% of patients had discontinued imatinib, with 15% of them discontinuing the drug for lack of efficacy [8]. The estimated annual rate of treatment failure after the start of imatinib therapy was 3.3% in the first year, 7.5% in the second year, 4.8% in the third year, 1.5% in the fourth year, 0.9% in the fifth year, 0.4% in the sixth year and 2% in the seventh year. The corresponding annual rates of progression to AP or BP were 1.5%, 2.8%, 1.6%, 0.9%, 0.6%, 0% in the sixth year and 0.4% in the seventh year, respectively [8].

Resistance can be defined on the basis of its time of onset: primary resistance is a failure to achieve a significant haematological or cytogenetic response, whereas secondary or acquired resistance is the progressive reappearance of the leukemic clone after an initial response to the drug [13], [14].

Imatinib resistance may be multifactorial and includes increased expression of BCR–ABL through gene amplification, decreased intracellular drug concentrations caused by drug intake proteins human organic cation transporter 1 (h-OCT1), clonal evolution, and over-expression of Src kinases involved in BCR–ABL-independent activation of alternative pathways, such as Lyn and Hck [13]. In chronic phase, more than 40% of resistance is attributed to the emergence of clones expressing mutated forms of BCR–ABL with amino acid substitutions in the ABL kinase domain that impair imatinib binding through either disruption of the critical contact point or by inducing a switch from the inactive to the active conformation [15], [16].

Second-generation tyrosine kinase inhibitors were developed to improve results obtained with imatinib and to overcome different mechanisms of resistance. In this review, we provide an overview of development and clinical results of Nilotinib, a new tyrosine kinase inhibitor that received approval by U.S. Food and Drug Administration (FDA) in October 2007, for the treatment of patients with CP and AP CML resistant or intolerant to imatinib.

Section snippets

Development of nilotinib and efficacy against BCR–ABL mutants

Nilotinib is structurally related to imatinib, but is 20–50-fold more potent and active against BCR–ABL. Based on the imatinib complex structural data, a more potent and selective compound could be designed by incorporating alternative binding groups for the N-methylpiperazine group, while retaining an amide pharmacophore to keep the H-bond interactions to Glu286 and Asp381 [17]. As compared to imatinib, nilotinib makes only four hydrogen-bond interactions with the ABL kinase domain, involving

Phase I

Kantarjian et al. [29] in 2006 reported the results of a phase I trial: 119 patients with CML (17 CP, 56 AP, 10 of whom with only clonal evolution, 24 myeloid BC and 22 lymphoid BC/ALL Ph+) were enrolled in this study and treated with nilotinib. The drug was given at the variable dose of 50, 100, 200, 400, 800 and 1200 mg daily until adverse events or disease progression occurred. Dose escalation was permitted only in patients with inadequate response and no dose-limiting toxicities. Nilotinib

Safety and tolerability

In phase I trial grade 3/4 thrombocytopenia occurred in 21% and neutropenia in 14% of treated patients, respectively. Major non-haematological adverse events included peripheral oedema, weight gain and skin rash. Fourteen percent of patients experienced grade 3–4 unconjugated hyperbilirubinaemia: this increase was not accompanied by an increase in levels of amino-transferase or evidence of increased haemolysis. This phenomenon is due to the nilotinib competition with UDP-glucuronil-transferase:

Nilotinib for early CP patients

Two major studies reported on the efficacy and safety of the drug in first line (Table 3). Cortes et al. described the MD Anderson Cancer Center (MDACC) experience in untreated CP (or with <1 month of imatinib therapy) and in a cohort of patients with previously untreated CML in AP: the primary endpoint was to obtain MMR at 12 months. The results at 12 months in 49 patients who received nilotinib at the standard dose of 400 mg twice daily were presented at last ASH meeting: median age of the

Conclusions

Nilotinib is an oral second-generation TKI indicated for the treatment of adult patients with resistant or intolerant CML in CP or AP. The rational development of nilotinib was based on the scaffold of imatinib, resulting in a compound with increased affinity and higher potency against BCR–ABL mutants, except T315I. It was also found to inhibit autophosphorylation of platelet-derived growth factor receptor (PDGF-R) and c-KIT, thus supporting its potential utility in treating gastrointestinal

Conflict of interest statement

None.

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