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(2009) 23, 1698–1707 & 2009 Macmillan Publishers Limited All rights reserved 0887-6924/09 $32.00 www.nature.com/leu SPOTLIGHT REVIEW

Class effects of inhibitors in the treatment of chronic myeloid leukemia

FJ Giles1, M O’Dwyer2 and R Swords1

1Institute for Drug Development, Therapy and Research Center at the University of Texas Health Science Center at San Antonio, San Antonio, TX, USA and 2Department of Hematology, University College Hospital, Galway, Ireland

Tyrosine kinase inhibitors have revolutionized the treatment of during treatment.8–11 Several strategies are available to treat chronic myeloid leukemia (CML), offering patients several -resistant patients, including imatinib dose escalation, targeted therapeutic options that provide the possibility of sustained remissions and prolonged survival. With the avail- dose adjustment based on pharmacokinetic assessments and the ability of imatinib, and , physicians must use of novel TKIs (Figure 1, Table 1). weigh the efficacy and safety profile of each agent when Nilotinib and dasatinib are potent inhibitors of BCR-ABL that choosing the best therapeutic option for individual patients. are US Food and Drug Administration approved for the

SPOTLIGHT Each agent targets tyrosine within the uniquely to treatment of patients resistant to, or intolerant of, prior therapy, cause the desired antiproliferative effect. In addition to inhibit- including imatinib. These second-generation TKIs have shown ing the BCR-ABL kinase, imatinib and nilotinib target the same 12–14 array of other tyrosine kinases, including c-KIT and platelet- efficacy in all imatinib-resistant or -intolerant CML patients. derived (PDGFR), albeit with differing Thus far, nilotinib and dasatinib appear to be similar with regard 15 potencies. While targeting BCR-ABL with the highest potency to clinical efficacy, although they display differential safety among approved agents in CML, dasatinib also targets a broad profiles.16 Other new kinase inhibitors are in early clinical array of off-target kinases, including SRC family members, trials as alternatives to imatinib therapy, including , PDGFR and EPHB4. The differences in kinase inhibition profiles MK-0457 and INNO-406 (Figure 1, Table 1). Larger prospective, among these agents in vitro probably account for the differing clinical safety profiles of these agents. This paper reviews the randomized studies are needed to determine the place of these various kinases inhibited by imatinib, nilotinib and dasatinib, new therapies in the treatment algorithm of CML. However, the and describes the potential impact of kinase inhibition on the potential for increased potency of these drugs could eventually efficacy and safety of each agent. lead to their replacement of imatinib as first-line CML therapy. Leukemia (2009) 23, 1698–1707; doi:10.1038/leu.2009.111; Although these new therapies are already changing the land- published online 28 May 2009 scape of CML therapy, it is important to distinguish the Keywords: CML; imatinib; nilotinib; dasatinib; TKI; BCR-ABL differences between these agents regarding target kinase profile, safety and efficacy. This article will review the similarities and differences in the kinase inhibition profiles of imatinib, nilotinib, dasatinib and newer BCR-ABL kinase inhibitors, with a focus on the safety of each agent. Although no randomized clinical Introduction trials have been conducted comparing nilotinib and dasatinib treatments, one must use the data from the available studies to The introduction of the small inhibitor (TKI), make an informed choice between the two agents for patients imatinib, has revolutionized the treatment of chronic myeloid who have become resistant or intolerant to imatinib therapy. leukemia (CML).1 Imatinib is a relatively specific inhibitor The following sections will highlight pre-clinical and clinical of BCR-ABL, the product of the t(9;22) chromosomal data to assist in choosing between the currently available translocation event that forms the Philadelphia chromo- second-generation agents. some characteristic of CML and some acute lymphocytic .2,3 The fusion of BCR-ABL results in the constitutive activity of the ABL tyrosine kinase, which ultimately drives Differential kinase inhibition profiles of TKIs in CML transformation of hematopoietic progenitor cells. treatment Imatinib was approved by the US Food and Drug Adminis- tration in 2002 for the first-line treatment of CML based on Inhibition of the BCR-ABL tyrosine kinase is considered to be the its high cytogenetic and molecular response rates, long-term underlying mechanism of clinical activity of imatinib, nilotinib efficacy and superior tolerability over (IFN)-based and dasatinib in the treatment of CML. As the first-generation therapy.4,5 Imatinib is widely accepted as the standard therapy TKI in this class of agents, imatinib inhibits BCR-ABL, albeit to a for newly diagnosed chronic-phase CML patients in addition to lesser extent than nilotinib or dasatinib. Imatinib also inhibits all CML patients who have failed transplant or IFN-a c-KIT and platelet-derived (PDGFR) at therapy.6,7 Imatinib serves as a model for the utility of targeted clinically relevant concentrations (Table 1). Nilotinib inhibits agents in the treatment of cancer. For a relatively few CML most imatinib-resistant BCR-ABL forms, except T315I, in vitro at patients, resistance to imatinib is present before, or develops 17 concentrations approved for and tested in patients. Nilotinib is 30-fold more potent than imatinib at inhibiting BCR-ABL Correspondence: Dr FJ Giles, CTRC at The UT Health Science Center (Table 2).18,19 Early data on nilotinib in newly diagnosed CML at San Antonio, Institute for Drug Development, 7979 Wurzbach patients suggest clinical activity with the potential to exceed Road, San Antonio, TX 78229, USA. 20 E-mail: [email protected] first-line imatinib efficacy, pending longer follow-up data. 18,19 Received 19 March 2009; revised 6 April 2009; accepted 17 April Similar to imatinib, nilotinib inhibits c-KIT (IC50 ¼ 90 nM) 13,19 2009; published online 28 May 2009 and PDGFR (IC50 ¼ 72 nM). Nilotinib also inhibits the Class effects of TKIs in the treatment of CML FJ Giles et al 1699 ABL-related kinase ARG, DDR1 kinase, the 325-fold more potency than imatinib at inhibiting BCR-ABL NQO2,20,21 and has some activity against the receptor (Table 2).14 Dasatinib also inhibits c-KIT and PDGFR with EPHB4, but displays no activity against the Src family of greater potency, and has a broad range of inhibitory activity kinases.13,22 Similar to nilotinib, dasatinib also inhibits most against a number of other tyrosine kinases (Table 2), including imatinib-resistant BCR-ABL forms, except T315I, in vitro.14,23 the tyrosine kinase, Src and Src family kinases However, it displays greater inhibition, with approximately (FGR, FYN, HCK, , LYN and YES).22,24 Lack of selectivity in binding Src family kinases probably derives from the fact that, unlike imatinib and nilotinib, dasatinib binds to the active conformation of the ABL kinase domain. In its active conforma- tion, ABL bears remarkable structural resemblance to the Src family kinases.25 Although both nilotinib and dasatinib have shown activity against a range of BCR-ABL kinase , there exist a number of specific mutations that are less sensitive to each of these agents. For nilotinib, these mutations include E255K/V, Y253H, F359V and T315I, and for dasatinib, these mutations include Q252H, E255K/V, F317L, V299L and T315I.26–28

The relationship of kinase inhibition profile with safety

Wild-type ABL inhibition: cardiac events All currently approved TKIs for CML treatment inhibit wild-type ABL kinase. ABL is a key mediator of normal cardiac function and is expressed in the cardiac and other tissues (Figure 2). A link between the imatinib inhibition of ABL and cardiac events was first suggested by Kerkela et al.29 In this retrospective study, 10 subjects with normal baseline cardiac function developed left ventricular dysfunction during imatinib therapy. Correlative studies in mice and cell lines revealed that imatinib-induced inhibition of ABL led to an endoplasmic reticulum stress response, collapse of the mitochondrial membrane potential,

Table 2 IC50 values for bosutinib, imatinib, dasatinib and nilotinib against BCR-ABL expressed in Ba/F3-transfected cells108

IC50 values (nM)

Bosutinib Imatinib Dasatinib Nilotinib

BCR-ABL 41.61 527 1.83 17.69 Figure 1 Structures of current and investigational tyrosine kinase inhibitors for the treatment of CML.100 Adapted from Weisberg et al.106 Adapted from Redaelli et al.108

Table 1 Novel tyrosine kinase inhibitors currently in clinical trials for the treatment of CML105 SPOTLIGHT Tyrosine kinase inhibitor Kinase targets Drug Drug Company administration development status

Imatinib (STI571) ABL, PDGFR, c-KIT Oral Approved Novartis Pharmaceuticals, San Carlos, CA, USA Dasatinib (BMS-34825) ABL, PDGFR, c-KIT, FGR, FYN, HCK, LCK, Oral Approved Bristol-Myers Squibb, LYN, SRC, YES, EPHB4 New York, NY, USA Nilotinib (AMN 107) ABL, PDGFR, c-KIT, ARG, EPHB4 Oral Approved Novartis, San Carlos, CA, USA Bosutinib (SKI-606) ABL, FGR, LYN, SRC Oral Phase II Wyeth, Madison, NJ, USA INNO-406 (NS-187) ABL, LYN, PDGFR, c-KIT Oral Phase I Innovive Pharmaceuticals, New York, NY, USA AZD0530 Src family kinases Oral Phase II AstraZeneca, Washington, DC, (solid tumors) USA MK-0457 (VX-680) Aurora kinases, FLTE, JAK2, ABL, T315I ABL Intravenous Phase II Merck & Co., Inc., Whitehouse Station, NJ, USA PHA-739358 Aurora A, B and C Oral Phase II Nerviano Medical Sciences, Nerviano, Italy Abbreviation: CML, chronic myeloid leukemia. Adapted from Weisberg et al.106

Leukemia Class effects of TKIs in the treatment of CML FJ Giles et al 1700 SPOTLIGHT

Figure 2 ABL signaling and inhibition in cardiomyocytes.101 In cardiomyocytes, imatinib induces ER stress, leading to the activation of the PKR- like ER kinase (PERK) and IRE1 pathways, and to the overexpression of kinase Cd (PKCd). PERK phosphorylates the eukaryotic translation initiation factor 2a (EIF2a) as part of a protective response, and on sustained ER stress, IRE1 activates Jun N-terminal kinases (JNKs), leading to the of 14-3-3 and release of BAX followed by mitochondrial depolarization, ATP depletion, cytochrome c (Cyt c) release, and features of necrotic and apoptotic cell death. Adapted from Force et al.107

release of cytochrome c into the cytosol, reduction in cellular Src kinase inhibition: myelosuppression ATP content and .29 However, serious cardiac events Nilotinib does not inhibit the Src family of kinases at therapeutic associated with imatinib therapy are rare. In fact, a retrospective doses. However, owing to its less selective binding capacity, analysis of six imatinib monotherapy trials, comprising 2327 dasatinib strongly inhibits Src and related kinases. These kinases patients with 5595 years of patient exposure (median exposure are key signaling members in normal hematopoiesis. Five Src duration, 2.4 years), revealed a congestive heart failure family members, HCK, LYN, FGR, LCK and BLK, are expressed incidence of 0.2%.30 Furthermore, retrospective analysis of the only in hematopoietic cells.37 HCK is critical for the develop- International Randomized Study of Interferon and STI571 (IRIS) ment and survival of myeloid cells and B . LYN is in Chronic Myeloid Leukemia trial, which compared expressed in all blood cell lineages except T cells and is IFN þ cytarabine (Ara-C) with imatinib in 1106 newly diagnosed required for B-cell development.38–40 LYN is also an important patients with CML in chronic phase (CP), found that the incident modulator of erythropoiesis, as it positively modulates erythroid cases of cardiac failure and left ventricular dysfunction possibly progenitor cell expansion to promote erythrocyte survival.41 In or probably related to study medication exposure was 0.04% fact, LYN knockout mice are anemic.42 Although there is no per year (1 case in 2309 years of patient exposure) for patients clear clinical link between Src inhibition by dasatinib and receiving imatinib vs 0.75% per year (4 cases in 536 years of myelosuppression, nilotinib, which does not inhibit the Src patient exposure) in patients receiving IFN þ Ara-C.30 More family of kinases, has a more favorable myelosuppression recently, a retrospective analysis of 219 patients with gastro- profile. Further, a review of clinical trial data reveals that rates intestinal stromal tumors or other receiving imatinib of grade 3/4 hematologic AEs for dasatinib treatment were therapy showed rare occurrence of congestive heart failure, higher than those seen with nilotinib in both CML-CP and observed in only one elderly patient with known prior cardiac CML-advanced phase (AP) patients.16,43 Specifically, CML-CP disease.31 Taken together, it appears that imatinib has little patients displayed grade 3/4 neutropenia and thrombocytopenia clinical impact on cardiac function. at respective rates of 50 and 49% with dasatinib therapy, and Cardiac adverse events (AEs), including congestive heart 30 and 28% with nilotinib therapy.44,45 Overall, rates of failure, left ventricular dysfunction and QT prolongation, have myelosuppression are higher in CML-AP patients with both all been reported with dasatinib and nilotinib, with the rates of agents. However, rates of grade 3/4 , neutropenia and left ventricular dysfunction highest with dasatinib.32,33 Further, thrombocytopenia were still higher in CML-AP patients receiv- 2% of patients in dasatinib clinical trials developed congestive ing dasatinib: 70, 74 and 83%, respectively, compared with heart failure or cardiac dysfunction. Of these cases, half were CML-AP patients receiving nilotinib: 27, 41 and 36%, respec- grade 3/4.34 A systematic literature review of clinical trials tively.43 It should be noted that rates of hematologic AEs on using nilotinib 400 mg twice daily or dasatinib 70 mg twice dasatinib therapy improved with 100 mg once-daily dosing. In daily revealed that grade 3/4 nonhematologic AEs, including the dasatinib phase II dose optimization study, 100 mg once- arrhythmia, were more than 2–7 times higher for dasatinib daily dosing significantly reduced the incidence of grade 3/4 compared with nilotinib, though the events occurred in o5% thrombocytopenia (22 vs 37%; P ¼ 0.004) and reduced the rates of the study population.16 Despite the cardiac concerns of grade 3/4 anemia (10 vs 16%; P ¼ NS) and neutropenia (33 vs for nilotinib and dasatinib, overall rates of QTcF interval 42%; P ¼ NS).46 It is unclear what effects could develop because changes4500 ms were low for both agents (o1%).33,35 More- of the long-term inhibition of Src in patients treated with over, although cardiac events were present, albeit uncommon, dasatinib for extended periods of time. in both dasatinib and nilotinib clinical trials, sudden death on nilotinib or dasatinib because of cardiac events has rarely been reported and can be further safeguarded against by performing PDGF inhibition: altered bone metabolism and fluid baseline electrocardiogram.36 Still, at this time, there is insuffi- retention cient evidence to exclude a relationship between the rare Altered bone metabolism. Hypophosphatemia can occur occurrence of sudden death in patients treated with either with imatinib and nilotinib therapy. Memorial Sloan-Kettering nilotinib or dasatinib and cardiac AEs. investigators observed hypophosphatemia among a small

Leukemia Class effects of TKIs in the treatment of CML FJ Giles et al 1701 percentage of their CML patients enrolled in the IRIS trial CML-CP and 3% of CML-blast phase (BP) patients.61 Nilotinib (described in detail above).47 In a subsequent case–control inhibits PDGFR with a potency similar to that of imatinib and study, 16 of 24 (67%) CML patients developed hypophos- the incidence of edema in nilotinib-treated patients is also phatemia on imatinib. Grade 3/4 hypophosphatemia rates of rare.33 An 11% rate of grade 1/2 peripheral edema was observed 10% have been reported for patients receiving nilotinib.33 in CML-CP patients enrolled in nilotinib phase II trials and Patients with hypophosphatemia had elevated parathyroid no patients had grade 3/4 peripheral edema. Occurrence of hormone levels, low-to-normal serum levels, high anasarca, pleural or pericardial effusion and ascites was also levels of phosphate excreted in the urine and decreased serum extremely rare. Serosal inflammation, specifically, pleural levels of osteocalcin and N-telopeptide of cross-links, effusion, is more common in CML patients treated with dasatinib both of which are markers of bone resorption. It is hypothesized therapy, with rates of any grade pleural effusion ranging that inhibition of bone turnover by imatinib leads to low serum between 14 and 35%. Rates of pleural effusion can be especially calcium and phosphate levels, which in turn causes increased high among patients with advanced CML. In patients who have parathyroid secretion and phosphate excretion in an attempt to failed imatinib and received dasatinib therapy, rates of grade 3/4 maintain calcium homeostasis. pleural effusion were found to be as high as 19% in CML-CP Platelet-derived growth factor receptor-a, a factor that patients and 28% in CML-myeloid blast crisis patients.62–64 All decreases osteoblast development and activity and may alter of the aforementioned data are from dasatinib dosing at 70 mg bone metabolism, is known to be inhibited by imatinib and twice daily and it should be noted that the incidence of grade nilotinib. PDGFRa is highly expressed in cultured osteoprogeni- 3/4 pleural effusions, but not the overall incidence, was tors and osteoblasts, and plays a critical role in the development significantly decreased with the widely used 100 mg once-daily of rat skeleton.48 The PDGF isoforms, PDGF-AA and PDGF-BB, dosing of dasatinib (16 vs 7%; P ¼ 0.024).46 The high rates stimulate replication49 and migration50 of rat osteoblasts of pleural effusion with dasatinib therapy may be related to its 65,66 in vitro. PDGF-BB also increases the number of rat osteoblasts potent inhibition of PDGFRb (IC50, 28 nmol/l). The lesser in vivo.51 In human and murine cells, osteoblast survival is degree of PDGFRb inhibition by imatinib and nilotinib may thought be stimulated by PDGF-BB through the phosphorylation explain the significantly lower incidence of pleural effusion with of Akt.52 these agents compared with dasatinib.67,68 Therefore, a decrease in osteoclast development and activity Recent evidence suggests that the peripheral edema seen with may also result from imatinib and nilotinib therapy. In humans, imatinib and the pulmonary edema associated with dasatinib mature osteoclasts are derived from the monocyte–macrophage may be because of distinct mechanisms. In a recent cohort study lineage.53 The maturation of macrophages into osteoclasts of 43 CML-CP patients, generalized fluid retention was not a requires the activity of macrophage colony-stimulating factor significant predictor of pulmonary edema.69 The only variables secreted by stromal cells and osteoblasts, which binds to the found to be predictive of pulmonary edema in a multivariate colony-stimulating factor 1 receptor on macrophages.54 In vitro analysis were a history of autoimmune disease (relative risk, 13; studies show that macrophage colony-stimulating factor activa- 95% confidence interval, 1.6–103) and dasatinib dose (relative tion of colony-stimulating factor 1 receptor is inhibited by risk 7.4; 95% confidence interval, 1.2–44.3). These results imatinib.55 Although data are limited, and no mechanistic suggest that dasatinib-induced pulmonary edema does not studies with nilotinib have been performed at this time, there correlate with generalized fluid retention and may instead be is some evidence that PDGF-BB stimulates bone resorption mediated by an immune mechanism. The findings also suggest by osteoclasts in humans directly through PDGFRb.56 Thus, that the inhibition of PDGFR alone may not be sufficient to the inhibition of PRGFRb by imatinib may interfere with cause serosal inflammation, but that the combined inhibition of osteoclast-stimulated bone resorption. In addition to the effects Src (affecting vascular permeability) and PDGFR (affecting of imatinib therapy described above, hypophosphatemia has interstitial fluid pressure and vascular permeability) could be a been observed in patients with renal cell carcinoma on contributing factor to the high incidence of pleural effusions sunitinib47 and in approximately 11% of CML-CP patients in with dasatinib. Notably, bosutinib, a dual Src and ABL inhibitor clinical trials with dasatinib (Figure 3).16 Therefore, abnormal- with little activity against PDGFR, has not been associated with ities in bone metabolism may be a general class effect of TKIs pleural effusion.70,71 Src inhibition may also mediate fluid that inhibit PDGFR. retention. Vascular permeability mediated by vascular endo- thelial growth factor is directly dependent on Src kinases that are widely expressed in lung tissues.72,73 Src also regulates focal SPOTLIGHT Fluid retention. Platelet-derived growth factor receptor adhesions and adherens junctions, which may be involved in inhibition also affects fluid retention and serosal inflammation the stability of the pleural epithelium and pleural space (pleural effusions). PDGFRb is expressed in pericytes57 and lung homeostasis.74,75 As Src kinases are inhibited by dasatinib with 58 tissue, and is involved in the regulation of . an IC50 of 0.5 nM, it is reasonable to hypothesize that Src kinase Inhibition of PDGFR has been well documented to induce inhibition by dasatinib may contribute to fluid retention changes in intratumoral interstitial pressures and fluid homeo- observed in treated patients.37,65,66 Other risk factors for stasis among the tumor compartment, vascular compartment pulmonary edema on dasatinib include prior cardiac history, and extracellular space.59 These changes may explain why hypertension and twice-daily administration of dasatinib.62 patients who receive PDGFR inhibitors develop edema and third Other risk factors include advanced disease (BP4AP4CP), spacing of fluid (mobilization of fluid to a location within the previous lung problems (smoking and infections) and in those body, rendering it unavailable to the ). By maintained on starting doses of dasatinib.76 contributing to edema and volume increase in patients, PDGFR inhibition may also tax the cardiovascular system and induce cardiotoxicity by indirectly straining the heart. Imatinib-asso- c-KIT inhibition: dermatologic toxicity, ciated peripheral edema is primarily superficial.60 Serosal myelosuppression and other adverse events inflammation resulting in anasarca, pleural or pericardial The c-KIT receptor is an important target in the treatment of effusion or ascites is rare with imatinib, occurring in 1% of various solid tumor types and hematologic malignancies. In

Leukemia Class effects of TKIs in the treatment of CML FJ Giles et al 1702 SPOTLIGHT

Figure 3 Molecular determinants of hypophosphatemia in patients treated with PDGFR inhibitors.41 M-CSF, macrophage colony-stimulating factor; PDGF, platelet-derived growth factor; RANK, receptor activator of NF-kB; RANKL, receptor activator of NF-kB . Adapted from Berman et al.47

these , high levels of c-KIT result from overexpression of skin basal cells, , epithelial cells of the breast, tissue the protein or mutations in the KIT gene. In most gastrointestinal mast cells and other cells.80 Recent data suggest that c-KIT has a stromal tumor cases, c-KIT is constitutively activated.77 major role in melanogenesis, homeostasis and Activated forms of c-KIT have also been found in a number of ultraviolet B-induced pigmentation.81 other malignancies, including disorders, and acute myelogenous leukemia.78 Myelosuppression. c-KIT is essential for the development of normal blood cells, melanocytes and mast cells.82,83 The degree Dermatologic toxicity. Cutaneous reactions, including of c-KIT inhibition by imatinib, nilotinib and dasatinib seems to superficial edema and skin rash, are the most common correlate with the rates of myelosuppression seen with each nonhematologic side effects found with imatinib therapy.5 In a agent. With the identification of c-KIT as a potential target for study of 118 CML patients on imatinib therapy, superficial anticancer therapy, there were concerns that AEs might preclude edema and rash were observed in 48 and 12.7% of patients, their utility in the anticancer armamentarium. Although it is still respectively.79 There was also a high prevalence of pigmentary unclear whether the inhibition of c-KIT plays a direct role in changes, which included 40.9% depigmentation (localized or some of the clinical AEs observed with c-KIT inhibitors, several generalized) and 3.6% hyperpigmentation. Pigmentary changes, AEs reported with imatinib, nilotinib and dasatinib are skin rash and related events are most likely due to imatinib consistent with c-KIT inhibition, including myelosuppression. inhibition of c-KIT in the skin. c-KIT is normally expressed in Despite these safety concerns, the clinical activity of imatinib

Leukemia Class effects of TKIs in the treatment of CML FJ Giles et al 1703 Table 3 Incidence of nonhematologic adverse events reported for Table 4 Incidence of hematologic adverse events reported for nilotinib and dasatinib in STUDY 2101 and START-C trials, nilotinib and dasatinib in STUDY 2101 and START-C trials, respectively respectively

Nonhematologic AEs Nilotinib107 (n ¼ 321)a Dasatinib62 (n ¼ 186)b Grade 3/4 hematologic AEs Nilotinib107 Dasatinib62 (n ¼ 321)a (n ¼ 186)b Drug related (%) Any grade Grade 3/4 Any grade Grade 3/4 Neutropenia 30 49 Rash 30 2 22 0.5 Thrombocytopenia 28 47 Pruritus 25 o 1NRNR Anemia 10 22 Nausea 24 o 1191 Fatigue 20 1 28 1 Abbreviations: AEs, adverse events; START-C, SRC/ABL Tyrosine Headache 18 2 34 1 Kinase Inhibitor Activity Research Trial. aSTUDY 2101, 14 months of follow-up. Diarrhea 12 2 30 2 b Dyspnea NR NR 27 3 START-C, 8 months of follow-up.

Biochemical abnormalities (%) Elevated total bilirubin 71 7 14 0 twice-daily dasatinib-treated patients compared with that in Hyperglycemia 70 12 NR NR 400–600 mg twice-daily nilotinib (18 vs 6%, respectively). Elevated ALT 67 4 52 2 Elevated AST 54 2 60 2 Pleural effusions were also more frequently noted with dasatinib Hypophosphatemia 52 15 NR NR treatment (19%) compared with nilotinib (1.2%) treatment. Elevated 45 16 NR NR Finally, hematologic AEs were more frequent in dasatinib- treated patients, with nearly half the patients receiving 70 mg Fluid retention (%) twice-daily dasatinib experiencing grade 3/4 neutropenia and Peripheral edema 19 (6) 0 33 (18) 0 thrombocytopenia. Dasatinib treatment was also associated Pleural effusion 4 (1.2) 2 (0.6) 35 (19) 6 (3) with bleeding events, reported in 16% of all patients and in 4% Abbreviations: AEs, adverse events; ALT, alanine aminotransferase; experiencing grade 3/4 AEs.44,88 In a separate study, 81% of all AST, aspartate aminotransferase; NR, not reported; START-C, SRC/ bleeding episodes occurred in the , with a ABL Tyrosine Kinase Inhibitor Activity Research Trial. median time of 6 weeks to development of bleeding.89 aSTUDY 2101, 14 months of follow-up. bSTART-C, 8 months of follow-up. Dasatinib treatment has also been shown to induce platelet- aggregation effects when compared with imatinib, nilotinib or bosutinib treatment.90 The low frequency of bleeding events and nilotinib in gastrointestinal stromal tumor has been observed with nilotinib makes it a good choice for patients attributed to their inhibitory effects on the c-KIT receptor.84,85 with risk factors for bleeding complications. Overall, it is important to consider that much of the current literature on dasatinib-related AEs focuses on the 70 mg twice-daily dose, but Clinical implications of differential target kinase profiles it is important to keep in mind that the 100 mg once-daily dose of imatinib, nilotinib and dasatinib is now widely used and significantly reduces the number Imatinib has a favorable safety profile with an overall low of several AEs, including grade 3/4 pleural effusion and incidence of grade 3/4 AEs in newly diagnosed CML-CP thrombocytopenia.46 patients. Rash, fatigue, headache, nausea, diarrhea, and muscle A major therapeutic advantage of nilotinib is the absence and joint pain are the most frequently reported drug-related of any significant cross-intolerance with imatinib.91,92 Nilotinib events. Less than 3% of patients report grade 3/4 events.5 Grade as subsequent treatment is very well tolerated by the majority 3/4 superficial edema is also infrequent and occurs in less than of patients with imatinib intolerance (Table 5). Recurrence 1% of patients. Imatinib treatment does result in myelo- of similar grade 3/4 AEs during nilotinib therapy was observed suppression, including grade 3/4 neutropenia (14.3%), thrombo- in less than 1% (1/71) and 18%, 7 of 38 patients with non- cytopenia (7.8%) and anemia (3.1%). A longer-term follow-up hematologic and hematologic imatinib intolerance, respec- of the IRIS study (described above in detail) has not significantly tively. All the patients who experienced nonhematologic changed the safety profile of imatinib.86 Imatinib is overall well imatinib intolerance were CML-CP patients experiencing tolerated. However, some patients require further treatment with thrombocytopenia.91,92 During secondary dasatinib therapy, SPOTLIGHT a second-generation TKI because of resistance to, or intolerance approximately 4%, 9 of 225 patients with nonhematologic, and of, imatinib. 13%, 6 of 46 patients with hematologic imatinib intolerance Nilotinib and dasatinib are both highly active in CML-CP experienced recurrence of similar grade 3/4 AEs.93,94 In this patients who have failed imatinib because of resistance or study, reoccurrence of grade 3/4 hematologic toxicity was intolerance.44,45,64,87 However, their safety profiles differ sub- observed in 86%, 37 of 43 patients. Cross-intolerance of stantially (Tables 3 and 4). The most common nonhematologic dasatinib treatment is most typically a result of neutro- grade 3/4 adverse events for patients with CML-CP treated with penia and/or thrombocytopenia.95–100 Patients who switched nilotinib include lipase elevation (16%), bilirubin elevation (7%) to dasatinib because of imatinib intolerance subsequently and hyperglycemia (12%). The increases in serum glucose were discontinued dasatinib due to intolerance at similar levels to not clinically significant and no patient discontinued study drug nilotinib. because of hyperglycemia. Lipase elevations were transient and Taken together, nilotinib appears to have a greater overall asymptomatic; however, patients with an earlier history of favorable safety profile with regard to fluid retention, myelo- pancreatitis should have lipase checked periodically. Conver- suppression and bleeding events, and shows little cross- sely, headache and diarrhea related to study drug appear to be intolerance with imatinib in imatinib-intolerant patients. When more frequent in dasatinib-treated patients. Importantly, more selecting a second-generation TKI for patients with imatinib patients treated with dasatinib experience fluid retention. The resistance or intolerance, the safety of the therapy should incidence of peripheral edema is threefold greater in 70 mg help guide the treatment decision for each individual patient.

Leukemia Class effects of TKIs in the treatment of CML FJ Giles et al 1704 Table 5 Comparison of nonhematologic adverse events observed in imatinib-intolerant patients treated with nilotinib90,91

Reason for imatinib Imatinib Grade 3/4 AE or persistent Grade 3/4 AE AE that led to dose D/C nilotinib intolerance intolerant grade 2 AE on nilotinib on nilotinib reduction of nilotinib due to AE

Nonhematologic 57 4 1 0 0 Rash/skin 26 0 0 0 0 Fluid retention 17 0 0 0 0 GI 17 3 1 0 0 Diarrhea 12 3 1 0 0 Liver toxicity 9 1 0 0 0 ALT 3 1 0 0 0 AST 4 0 0 0 0 Myalgia/arthralgia 10 0 0 0 0

SPOTLIGHT Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; D/C, discontinued; GI, gastrointestinal.

However, other considerations are also important and must as well as the most favorable safety profiles, and are excellent be accounted for in the decision-making process, including the therapeutic options for patients with CML. Future studies will patient’s status, the differential pharmacokinetic determine how the emerging therapies with varied target kinase profile and dosing schedule of the therapy, concomitant profiles will also fit into the CML treatment paradigm. medications and likely adherence to therapy, among others.

Conflict of interest Emerging agents in the treatment of CML Bosutinib (SKI-606) is an oral dual Src/Abl TKI capable of FG received research support from Bristol-Myers Squibb, Merck, 200-fold greater BCR-ABL inhibition compared with imatinib Novartis and Wyeth; MO’D received an honoraria from (Table 2). Unlike imatinib, bosutinib does not show any Novartis; and RS has nothing to disclose. appreciable activity against c-KIT or PDGFR.71 As bosutinib is also an inhibitor of Src kinase, it may have a safety profile Acknowledgements similar to dasatinib. Interestingly, no patients in a phase I/II bosutinib study experienced pleural effusion or pulmonary Financial support for medical editorial assistance was provided by edema.70 This could be because of the fact that bosutinib is a 71 Novartis Pharmaceuticals. We thank Michael Mandola, PhD weaker inhibitor of PDGFR. At the moment, the greatest safety (Health Interactions), for medical editorial assistance with this challenge with bosutinib appears to be the high level of grade manuscript. 3/4 diarrhea that must be managed appropriately to ensure treatment continuation. MK-0457 is a moderate-to-strong inhibitor of ABL and JAK2, and a robust inhibitor of aurora References kinase and FLT3.101 Notably, MK-0457 is the only second- generation TKI to show efficacy against the BCR-ABL T315I 1 Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM 102 mutation in vitro. In November 2007, patient enrollment into et al. Efficacy and safety of a specific inhibitor of the BCR-ABL phase I and II MK-0457 trials was suspended, pending a full tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001; analysis of all efficacy and safety data after one patient displayed 344: 1031–1037. QTc prolongation. INNO-406, which is structurally related to 2 Melo JV, Deininger MW. Biology of chronic myelogenous imatinib and nilotinib, strongly inhibits both BCR-ABL and LYN. leukemia–signaling pathways of initiation and transformation. Hematol Oncol Clin North Am 2004; 18: 545–568. This dual inhibition may be significant as acquired imatinib 3 Ren R. Mechanisms of BCR-ABL in the pathogenesis of chronic resistance is thought to be mediated in part through LYN myelogenous leukaemia. Nat Rev Cancer 2005; 5: 172–183. overexpression. In vitro analysis of INNO-406 showed 20-fold 4 Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, greater potency than imatinib and inhibited several imatinib- Gattermann N et al. Five-year follow-up of patients receiving resistant BCR-ABL mutants, but not T315I. In addition to imatinib for chronic myeloid leukemia. N Engl J Med 2006; 355: BCR-ABL, INNO-406 also inhibits PDGFR and c-KIT to a 2408–2417. 24,103 5 O’Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, similar degree as imatinib. INNO-406 has no effect on Src, Cervantes F et al. Imatinib compared with interferon and low- and as a result, may have a safety advantage over dasatinib. dose cytarabine for newly diagnosed chronic-phase chronic INNO-406 was well tolerated in phase I trials of heavily myeloid leukemia. N Engl J Med 2003; 348: 994–1004. pre-treated CML-AP patients who failed prior therapy, including 6 NCCN Clinical Practice Guidelines in Oncology. Chronic imatinib, because of resistance and intolerance.104–106 More Myelogenous Leukemia. v.2. 2009. clinical data are needed to determine if INNO-406 will 7 Baccarani M, Saglio G, Goldman J, Hochhaus A, Simonsson B, Appelbaum F et al. Evolving concepts in the management of benefit CML patients. Overall, the prospects of combining chronic myeloid leukemia: recommendations from an expert currently approved TKIs with emerging therapies that are active panel on behalf of the European LeukemiaNet. Blood 2006; 108: against the T315I mutation are of particular interest, given 1809–1820. the potential for combination therapy of CML treatment in the 8 Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN future. et al. Clinical resistance to STI-571 cancer therapy caused by Overall, there appears to be an emerging pattern of TKI kinase BCR-ABL gene mutation or amplification. Science 2001; 293: 876–880. selectivity profiles in the treatment of CML being closely linked 9 Branford S, Rudzki Z, Walsh S, Parkinson I, Grigg A, Szer J et al. to their respective safety profiles. Currently, nilotinib and Detection of BCR-ABL mutations in patients with CML treated imatinib exhibit the most selective kinase inhibition profiles, with imatinib is virtually always accompanied by clinical

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Leukemia