Second-generation BCR-ABL inhibitors for frontline treatment of chronic myeloid leukemia in chronic phase

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1 Critical Reviews in Oncology/Hematology 82 (2012) Second-generation BCR-ABL inhibitors for frontline treatment of chronic myeloid leukemia in chronic phase Gianantonio Rosti, Fausto Castagnetti, Gabriele Gugliotta, Francesca Palandri, Michele Baccarani Department of Hematology and Oncology L. and A. Seràgnoli, University of Bologna, Italy Accepted 7 April 2011 Contents 1. Introduction Impact of time to response on long-term outcome: imatinib data Importance of tolerability Development of second-generation BCR-ABL inhibitors Phase 2 trial of frontline dasatinib in CML-CP Phase 2 trials of frontline nilotinib in CML-CP Phase 3 randomized trial of frontline dasatinib vs imatinib in CML-CP Phase 3 randomized trial of frontline nilotinib vs imatinib in CML-CP Potential application of dasatinib and nilotinib in the frontline setting Conclusions Conflict of interest statement Reviewers Acknowledgments References Biographies Abstract Results from several trials in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) of dasatinib and nilotinib, two BCR-ABL inhibitors with higher in vitro potency compared with imatinib, have recently been reported. In this review, the rationale for assessing dasatinib and nilotinib in the frontline setting is discussed and data from clinical trials performed to date are summarized, including single-arm studies and randomized trials compared with imatinib. Overall, both dasatinib and nilotinib have shown superior efficacy compared with imatinib during the first year of treatment and longer-term follow-up is needed to confirm that this superiority is maintained over time. Both agents have also shown favorable tolerability profiles, although distinct patterns of adverse events are seen with each agent. Clinicians now have several effective options to treat patients newly diagnosed with CML-CP and available data suggest that dasatinib and nilotinib represent improved therapeutic options compared with imatinib Elsevier Ireland Ltd. All rights reserved. Keywords: Chronic myeloid leukemia; Imatinib; Dasatinib; Nilotinib; Phase 2 clinical trials; Randomized controlled trials 1. Introduction Corresponding author at: Department of Hematology and Oncology L. and A. Seràgnoli, St Orsola-Malpighi Hospital, University of Bologna, Via Massarenti, Bologna, Italy. Tel.: ; fax: address: gianantonio.rosti@unibo.it (G. Rosti). For almost a decade, imatinib was unrivalled as the agent of choice for frontline treatment of newly diagnosed chronic myeloid leukemia (CML). This situation occurred following the IRIS trial (International Randomized study of Interferon /$ see front matter 2011 Elsevier Ireland Ltd. All rights reserved. doi: /j.critrevonc

2 160 G. Rosti et al. / Critical Reviews in Oncology/Hematology 82 (2012) [IFN] vs STI571), which showed that in patients diagnosed with CML in chronic phase (CP), life expectancy at 5 years improved from approximately 50% with previous IFN-based regimens to approximately 90% with imatinib [1 3]. With 8 years follow-up, the cumulative rate of complete cytogenetic response (CCyR) was 83%, estimated event-free survival (EFS; survival without loss of response or progression to accelerated or blast phase [AP/BP]) was 81%, and estimated overall survival (OS) was 85% [4]. Among all patients in the imatinib arm, rates of events (loss of response, progression to AP/BP, or death) were highest in years 1 3 (3.3%, 7.5%, and 4.8% in years 1, 2, and 3, respectively) and lower during subsequent follow up ( % per year in years 4 8). A similar pattern was seen for rates of progression to AP/BP (1.5%, 2.8%, and 1.8% in years 1, 2, and 3, respectively; 0 0.9% per year in years 4 8). Of the 457 patients who achieved a CCyR in the imatinib arm, 82 (18%) had loss of CCyR during treatment, including 15 (3%) who progressed to AP/BP [4]. A separate assessment of the efficacy of imatinib was reported in an intention-to-treat (ITT) analysis of patients newly diagnosed CML-CP treated with frontline imatinib at a single UK center. Of 204 patients, approximately one-third failed to achieve or maintain what the authors considered to be a minimum level of response (partial cytogenetic response; PCyR) [5]. It is well established that outcomes during imatinib therapy are significantly worse in patients with CML-CP who are identified as having high-risk disease based on prognostic scoring methods devised by Sokal [6] and Hasford [7] and colleagues. In the IRIS trial, 52%, 29%, and 19% of patients had low, intermediate, or high scores using Sokal risk [8], and rates of CCyR by 5 years were 89%, 82%, and 69%, respectively (P < 0.001) [1]. However, increasing the imatinib starting dose does not improve response rates in patients with high-risk disease. In a randomized study comparing frontline treatment with standard-dose imatinib (400 mg/d) or high-dose imatinib (800 mg/d) in patients with newly diagnosed CML-CP and high Sokal risk scores, no significant differences in rates of CCyR or major molecular response (MMR) were seen at any time [9]. Thus, based on an idealized objective of 100% of patients deriving long-term benefit from BCR-ABL inhibitor therapy, currently approximately 20 25% of patients fail to reach and/or maintain this objective, and among all patients, those with high-risk disease have a significantly worse outcome. Since 2007, two newer BCR-ABL inhibitors dasatinib and nilotinib have been available for treating patients who developed resistance or intolerance to frontline imatinib. Both agents were shown to induce a CCyR in approximately half of patients with CML-CP who had failed or become intolerant to prior imatinib therapy [10,11]. Recently, data have been reported from randomized trials of dasatinib or nilotinib compared with imatinib for frontline treatment of newly diagnosed CML-CP [12,13]. In this review, we will discuss the rationale for assessing newer agents in the frontline setting and summarize emerging data for dasatinib and nilotinib. 2. Impact of time to response on long-term outcome: imatinib data Considerable efforts have been directed at identifying those patients who will have better or worse long-term outcomes on imatinib treatment and one of the most powerful predictors is lack of early response. Achieving a CCyR and major molecular response (MMR) during early treatment with frontline imatinib is associated with a better long-term survival without progression to AP/BP (termed transformation-free survival; TFS). In the IRIS trial, no patient who had achieved both a CCyR and MMR by 12 months had progressed to AP/BP at 8 years [4]. Analyses from IRIS and other sources have also found that patients with a CCyR who had also achieved a MMR by 12 and 18 months of first-line imatinib therapy had a lower probability of losing their CCyR compared with patients in CCyR who had not achieved a MMR at the specified time point [14,15]. Based on these data, it has been suggested that attaining a MMR may be a safe haven associated with optimal long-term outcomes in patients with CML [14]. Conversely, it is also known that failure to respond within a defined timeframe is associated with an increased probability of loss of response, progression, or death. Patients with CML-CP who had achieved a CCyR at 3, 6, 12, and 18 months in the IRIS trial always had more favorable long-term outcomes than patients who had achieved lesser degrees of cytogenetic response at these time points. In particular, in patients who had achieved a CCyR at 12 months, the probability of stable CCyR and EFS at 8 years was 87% and 94%, respectively, compared with 57% and 80% in patients who had achieved only a PCyR at 12 months, and 14% and 38% in patients who had a lower or no cytogenetic response at 12 months [4]. Similarly, in the single-center ITT analysis discussed earlier, TFS and OS were both higher in the 121 patients who achieved CCyR by 12 months compared with the 72 patients who failed to reach CCyR by 12 months (5-year TFS was 96% vs 74%, P = 0.007; 5-year OS was 98% vs 74%, P = 0.03) [5]. In a separate single-center analysis, patients who achieved a stable CCyR or MMR (lasting 12 months or more) had improved EFS compared with patients who responded but did not have a stable response [16]. The association between a stable MMR and long-term durability of CCyR was also identified in studies of patients treated with imatinib after prior IFN failure [17]. In addition, it has been shown that a delayed CCyR during frontline imatinib treatment for CML-CP is associated with a decreasing probability of ever achieving a CCyR and an increasing risk of event. Of 208 patients who received standard-dose or high-dose imatinib, the probability of eventually achieving a CCyR in nonresponding patients decreased from 75% at 3 months, to 57% at 6 months, and 42% at 12 months (P = 0.002). Patients without CCyR at these time points also had a similar decrease in the probability of ever achieving a MMR (62%, 43%, 31%; P = 0.004), whereas the risk of event progressively increased (23%, 34%, 38%; P = 0.16) [18].

3 G. Rosti et al. / Critical Reviews in Oncology/Hematology 82 (2012) Table 1 European LeukemiaNet definitions of optimal response, suboptimal response, and failure during frontline imatinib treatment [19]. Response Optimal Suboptimal Failure Warning Baseline Not applicable Not applicable Not applicable High risk; CCA/Ph+ 3 months CHR and at least minor CyR (Ph+ 65%) No CyR (Ph+ >95%) Less than CHR Not applicable 6 months At least PCyR (Ph+ 35%) Less than PCyR (Ph+ >35%) No CyR (Ph+ >95%) Not applicable 12 months CCyR PCyR (Ph+ 1 35%) Less than PCyR (Ph+ >35%) Less than MMR 18 months MMR Less than MMR Less than CCyR Not applicable Any time Stable or improving MMR Loss of MMR; mutations Loss of CHR; loss of CCyR; mutations; CCA/Ph+ Increase in transcript levels; CCA/Ph Abbreviations: CCA, clonal chromosome abnormalities; CHR, complete hematologic response; CyR, cytogenetic response; CCyR, complete CyR; MMR, major molecular response; PCyR, partial CyR; Ph+, Philadelphia chromosome positive; Ph Philadelphia chromosome negative. The principle of achieving a specific level of response within a defined time frame has served as the basis for CML treatment recommendations, such as those published by the European LeukemiaNet (ELN) that define an optimal response, suboptimal response, and treatment failure during imatinib treatment (Table 1) [19]. According to these recommendations, an optimal response includes achievement of CCyR by 12 months and MMR by 18 months. Independent studies have confirmed that patients classified as having failure or suboptimal response on imatinib according to ELN recommendations have significantly worse outcomes than optimally responding patients [15,20,21]. These data suggest that increasing the proportion of patients with newly diagnosed CML-CP who achieve an optimal response to frontline therapy has the potential to decrease the occurrence of progression to AP/BP and other negative outcomes. 3. Importance of tolerability In the IRIS trial, imatinib was shown to have superior tolerability compared with IFN-based treatment. However, several characteristic adverse events (AEs) of imatinib were identified, including cytopenia, edema, gastrointestinal (GI) disturbances, musculoskeletal pain, and skin complaints, which can each be problematic despite the low occurrence of grade 3/4 AEs [1]. After 5 years of follow-up in the IRIS trial, 5% of patients in the imatinib arm had discontinued treatment or crossed over to the IFN arm because of AEs [1]. A recent trial comparing standard-dose imatinib with high-dose imatinib illustrates the importance of treatment tolerability. In the phase 3 TOPS (Tyrosine Kinase Inhibitor OPtimization and Selectivity) trial, 476 patients with newly diagnosed CML-CP were randomized 2:1 to receive frontline treatment with imatinib 800 mg/d or 400 mg/d [22]. After 12 months, rates of CCyR (70% vs 66%; P = ) and MMR (46% vs 40%; P = ) were similar in both arms. In safety monitoring, several assessments indicated that imatinib 800 mg/d dosing was poorly tolerated relative to standard 400 mg/d dosing. These included a higher overall rate of grade 3/4 AEs (64% vs 33%), lower average dose intensity compared with starting dose (83% vs 97%), greater requirement for dose interruptions lasting >5 days (67% vs 38%), and greater requirement for dose reductions (61% vs 18%). Furthermore, more patients discontinued treatment in the imatinib 800 mg/d arm vs 400 mg/d arm (20% vs 16%), predominantly because of more patients discontinuing due to AEs (9% vs 4%). Interestingly, of patients in the 800 mg/d arm who remained on therapy and were evaluable at 12 months, the subset of patients in the 800 mg/d arm who were able to tolerate and maintain a higher average dose intensity ( 600 mg/d; 69% of evaluable patients) achieved higher response rates (MMR in 62 63%) than patients who had an average dose intensity of <600 mg/d (MMR in 21 38%). However, the effect was counteracted by the worse tolerability of high-dose treatment, resulting in no overall efficacy advantage for the 800 mg/d arm [22]. In a recent study investigating the occurrence of intolerance to standard-dose imatinib in patients with CML-CP in a clinical practice setting in France, 197/627 (31%) imatinib-treated patients experienced an AE requiring treatment modification or discontinuation and 6% discontinued imatinib due to toxicity [23]. In addition, prospective observational studies have shown that decreased adherence to imatinib treatment results in significantly worse treatment responses [24,25]. In one of these studies, adherence rates were found to be significantly lower in patients who had specified AEs (asthenia, nausea, muscle cramps, and bone or joint pains) [24]. Together, these data illustrate that treatment tolerability is an important consideration for CML treatment that has the potential to affect efficacy. 4. Development of second-generation BCR-ABL inhibitors Following the development of imatinib, several novel agents with inhibitory activity against the BCR-ABL fusion kinase have been developed, of which dasatinib and nilotinib have been most extensively assessed. Dasatinib was developed independently from imatinib and has a distinct chemical structure. Dasatinib has 325-fold higher in vitro potency compared with imatinib against BCR-ABL-expressing cells and binds to BCR-ABL with a distinct, although overlapping,

4 162 G. Rosti et al. / Critical Reviews in Oncology/Hematology 82 (2012) binding site [26,27]. Nilotinib was developed by modifying the chemical structure of imatinib and has fold higher in vitro potency against BCR-ABL expressing cells. The higher potency of nilotinib is presumed to result from an improved fit within the ATP-binding site of BCR-ABL compared with imatinib [26,28]. Although all three agents inhibit kinases other than BCR-ABL (including KIT and platelet-derived growth factor receptor), dasatinib has activity against a wider range of additional targets, most notably SRC-family kinases, whereas nilotinib has a similar target range to imatinib [29]. During imatinib treatment, mutations of BCR-ABL are a known cause of resistance, particularly acquired resistance [30,31]. Among patients with CML-CP treated with frontline imatinib, BCR-ABL mutations were detected in 6 14%, whereas higher rates ( 50 80%) have been reported in patients with advanced phases of CML [30,31]. In vitro studies have shown that both dasatinib and nilotinib have a narrower spectrum of mutations associated with resistance than imatinib. In one study, mutants emerging in BCR-ABL-expressing cells following exposure to N-ethyl- N-nitrosourea (a potent mutagen) and selected by imatinib, dasatinib, or nilotinib treatment were compared. At low drug concentrations, 20 different resistance mutations were selected with imatinib, ten with nilotinib, and nine with dasatinib. At intermediate drug levels, the spectrum narrowed to two affected amino acids for dasatinib (T315 and F317) and three for nilotinib (Y253, E255, and T315), compared with six for imatinib (G250, Q252, Y253, E255, T315, H396) [32]. Similar findings were identified in a separate in vitro study comparing nilotinib and imatinib [33]. Resistance mutations increase the concentration of drug needed to inhibit cells expressing BCR-ABL, typically expressed as the median inhibitory concentration (IC 50 ) [26,28,34]. In imatinib-treated patients, response rates to dasatinib or nilotinib among patients with a specific BCR-ABL mutation show broad correlation with IC 50 values for the second-line agent for the specific mutation [35,36]. However, the fact that patients with the same mutation may derive different levels of benefit from the same drug indicates that factors other than mutations contribute to resistance. In a recent analysis, attempts to adjust in vitro IC 50 values for different mutations to take account of peak plasma drug concentrations failed to improve the prediction of clinical response rates to secondline dasatinib or nilotinib, and the authors acknowledged that responses would be affected by additional factors such as plasma protein binding and cell influx/efflux [37]. Across multiple studies, fewer mutations have been associated with clinical resistance to dasatinib or nilotinib compared with imatinib. More than 50 amino acid residues of BCR-ABL have been associated with different levels of resistance to imatinib in patients with CML [38], whereas in the second-line clinical setting, mutational resistance has predominantly been associated with mutations in three amino acids for dasatinib (V299, T315, and F317) and four amino acids for nilotinib (Y253, E255, T315I, and F359) [35,36,39 43]. In general, mutations associated with clinical resistance to dasatinib and nilotinib have the largest fold increases in IC 50 compared with unmutated BCR-ABL. Clinical studies have shown that responses to imatinib are lower in patients whose cells express low levels of OCT-1, a transporter protein that imports imatinib into cells [44 46]. In vitro, however, neither dasatinib nor nilotinib require OCT-1 for cell entry, suggesting that responses to the newer agents should not be affected by OCT-1 expression [44,47]. In CML cell lines treated with imatinib, overexpression of the P-glycoprotein efflux protein (encoded by the MDR1 gene) leads to reduced intracellular concentrations of imatinib and resistance [48 50]. In patients with CML, single nucleotide polymorphisms in MDR1 are associated with significantly different MMR rates, supporting the hypothesis that P-glycoprotein may have clinical relevance [51,52]. Dasatinib and nilotinib are both substrates of P-glycoprotein; however, in vitro studies have reported conflicting conclusions on whether either agent can overcome resistance mediated by P-glycoprotein overexpression or whether dasatinib and nilotinib remain susceptible to this mechanism of resistance [47,53 57]. Overall, these data indicate that the modified chemistry of dasatinib and nilotinib compared with imatinib provide mechanisms for improved treatment responses and decreased resistance, illustrating the rationale for clinical assessment in the frontline setting Phase 2 trial of frontline dasatinib in CML-CP In a phase 2 trial performed at M D Anderson Cancer Center, Houston, 62 patients with newly diagnosed CML- CP received dasatinib 100 mg randomly assigned as either 100 mg once-daily (QD; n = 31) or 50 mg twice daily (BID; n = 31). Median age was 47 years and the Sokal risk score was low in 81%, intermediate in 13%, and high in 6% patients. Nineteen patients had received imatinib for a median of 17 days (range 3 30 days). At the time of reporting, 50 patients had been observed for 3 months and were evaluable for response (median follow-up 24 months). CCyR and MMR rates were 98% and 82% respectively, including 10% who achieved a complete molecular response (CMR). Efficacy was similar in the QD and BID arms (CCyR in 100% vs 96%; MMR in 79% vs 85%, respectively). Responses were achieved rapidly, with median times to CCyR of 3 months and to MMR of 6 months. At 3 and 6 months, CCyR had been achieved by 82% and 94%, respectively. The estimated 24-month EFS rate was 88% and no deaths or progression to AP/BP had occurred by last follow-up [58]. Dasatinib treatment was well tolerated overall. Muscle and joint aches, fatigue, dermatologic complaints, headaches, and diarrhea were the most common nonhematologic AEs. There was a low incidence of grade 3 nonhematologic AEs, of which fatigue (6%), joint/muscle pain (6%), peripheral

5 G. Rosti et al. / Critical Reviews in Oncology/Hematology 82 (2012) neuropathy (5%), dyspnea (5%), and memory impairment (5%) were most common. Pleural effusion, a noted AE of dasatinib seen in trials in the second-line setting, occurred 13% of patients overall, of which 11% were grade 1/2 and 2% were grade 3. A trend was seen for a lower occurrence of pleural effusion with dasatinib 100 mg QD (2/31 patients) vs 50 mg BID (6/31 patients) [58], consistent with findings from a dose-optimization study performed with dasatinib in patients with CML-CP and prior imatinib therapy [10]. In the frontline study, grade 3/4 neutropenia, thrombocytopenia, and anemia were reported in 21%, 10%, and 6% of patients, respectively. Of five instances of grade 4 cytopenia, all were reported in the BID arm. Treatment adjustments included interruptions in 48% (most commonly for pleural effusion, dyspnea, and headache) and dose reduction in 35%. Three patients discontinued following toxicity (two for pleural effusion and one for prolonged cytopenia) [58] Phase 2 trials of frontline nilotinib in CML-CP Two single-arm phase 2 trials of nilotinib 400 mg BID in patients with newly diagnosed CML-CP have been reported. In the phase 2 trial of nilotinib performed by the GIMEMA (Gruppo Italiano Malattie EMatologiche dell Adulto) CML working party, 73 patients received nilotinib 400 mg BID. Median age was 51 years and Sokal risk score was low in 45%, intermediate in 41%, and high in 14% of patients. Based on the ITT principle, the rate of CCyR at 12 months was 96% and MMR at 12 months was 85%. Similar to the frontline dasatinib study discussed above, responses were achieved rapidly, including 3-month rates of CCyR and MMR of 78% and 52%, respectively [59]. After 3 years of follow-up, only one patient had confirmed loss of CCyR and all but three patients (96%) had achieved MMR. Of 51% of patients who had achieved CMR at least once, 25% were in stable CMR. Only one patient experienced disease progression (to CML-BP after 6 months) or developed a BCR-ABL mutation (T315I in the same patient) [60]. Nilotinib was also well tolerated and most AEs occurred during the first 12 months of therapy. Dermatologic complaints, musculoskeletal pain, headache, dry eye/conjunctivitis, and fatigue were the most common nonhematologic AEs. Only rash (5%), musculoskeletal pain (4%), and pruritis (4%) were reported at grade 3, with no grade 4 nonhematologic AEs reported. Biochemical abnormalities have been noted in trials of nilotinib in patients with prior imatinib therapy [11]. In the GIMEMA trial, markers of liver or pancreatic toxicity were observed, including elevated bilirubin in 53% (grade 3 in 16%), alanine aminotransferase (ALT) in 42% (grade 3 in 8%), -glutamyl transferase in 38% (grade 3 in 7%), aspartate aminotransferase (AST) in 26% (grade 3 in 3%), lipase in 30% (grade 3 in 4%, grade 4 in 4%), amylase in 19% (grade 3 in 5%), and glucose in 14% (grade 3 in 4%). Grade 3/4 cytopenia was rare, with grade 3 or 4 neutropenia reported in 3% and 1% of patients, and grade 3 or 4 thrombocytopenia reported in 1% each. No grade 3/4 anemia occurred. Based on previous reports of QT prolongation with nilotinib, all patients were monitored by electrocardiogram. Transient and clinically irrelevant abnormalities were seen in 26% of patients, including QT interval prolongation to greater than 450 ms in 3%. Treatment interruption was required by 45% of patients during months 1 6 (mainly for biochemical abnormalities and less frequently for nonhematologic AEs), decreasing to 7 8% from months 13 to 30. Throughout all periods of follow-up, median daily dose was mg/d in 62 67% of patients (starting dose was 800 mg/d). Four patients discontinued nilotinib following toxicity (lipase elevation in three patients, atrial fibrillation in one patient) [59,60]. A phase 2 trial of frontline nilotinib 400 mg BID was also performed by M D Anderson Cancer Center. In a recent report, of 61 patients enrolled, 51 had been observed for 3 months and were evaluable for response (median follow-up 17 months) [61]. Median age was 46 years and Sokal risk scores were low, intermediate, or high in 70%, 23%, and 7% of patients, respectively. Twelve patients had received imatinib for a median of 22 days (range 2 28 days). Overall, 98% and 76% of patients achieved CCyR and MMR, respectively, and 24% achieved a CMR. Again, responses were rapidly achieved, as shown by median times to CCyR or MMR of 3 months, and rates of CCyR at 3 months (90%) and 6 months (98%). The estimated rate of EFS at 24 months was 90%, with one patient progressing to BP who had a new E255K mutation detected, and no deaths occurred by last follow-up. Rates of AEs were generally higher in the M D Anderson trial of nilotinib compared with the GIMEMA trial. The most commonly observed nonhematologic AEs were fatigue, rash, headache, nausea, abdominal pain, and dyspnea. Grade 3/4 AEs were infrequent and included nonneutropenic fever (5%), fatigue (3%), and joint pain (3%). Similar to the GIMEMA study, biochemical abnormalities were noted. The most common were elevated ALT or AST in 46 48% (no grade 3/4), hyperglycemia in 44% (grade 3/4 in 5%), elevated bilirubin in 39% (grade 3/4 in 7%), hypophosphatemia in 15% (no grade 3/4), and lipase elevation in 10% (grade 3/4 in 5%). Grade 3 or 4 cytopenia consisted of neutropenia in 12%, thrombocytopenia in 11%, and anemia in 5%. Cardiac toxicity was rare and comprised two cases each of hypertension and QT interval prolongation (none grade 3/4). Treatment interruptions were needed by 37% of patients (most commonly for elevated liver enzymes, cytopenia, or unrelated procedures/surgeries), dose reduction was needed by 17% of patients, and four patients discontinued therapy following toxicity (AE not specified) [61]. Overall, phase 2 data for dasatinib and nilotinib suggested that both agents induced higher rates of CCyR and MMR and more rapid responses in patients with newly diagnosed CML-CP compared with historic data for imatinib, and each agent had encouraging tolerability. Randomized trials were needed for further assessment.

6 164 G. Rosti et al. / Critical Reviews in Oncology/Hematology 82 (2012) Phase 3 randomized trial of frontline dasatinib vs imatinib in CML-CP The DASatinib vs Imatinib Study In Treatment-Naïve CML patients (DASISION, CA ) evaluated the efficacy and safety of frontline dasatinib 100 mg QD (n = 259) or imatinib 400 mg QD (n = 260) in patients with CML- CP [12]. Patients were stratified by Hasford risk score, an alternative prognostic indicator to the Sokal score that incorporates two further baseline parameters (percentage of basophils and eosinophils in peripheral blood) in addition to those utilized by the Sokal method (age, spleen size, platelet count, percentage of blast cells). Recent ELN recommendations have confirmed that both the Sokal and Hasford scores are valid prognostic indicators for patients with CML-CP receiving frontline imatinib therapy [19], although within a given patient population, the Hasford method categorizes fewer patients as high risk compared with the Sokal method. For example, in the GIMEMA study of frontline nilotinib, the proportions of patients with low, intermediate, or high risk scores were 45%, 41%, 14%, respectively, using the Sokal method and 40%, 59%, and 1%, respectively, using the Hasford method [59]. The primary endpoint for the DASISION study was the rate of confirmed CCyR by 12 months (defined as CCyR documented on two consecutive assessments). Secondary endpoints included rates of CCyR (standard definition) or MMR, time to response, progression-free survival (PFS), and OS. Patient characteristics were well balanced between both arms, median age was years, and 19% of patients in both arms had high Hasford risk scores [12]. After median treatment duration of 18 months, 81% vs 80% of patients remained on dasatinib or imatinib treatment, respectively. Reasons for discontinuation in dasatinib vs imatinib arms included treatment failure in 2.3% vs 4.3%, progressive disease (including loss of response) in 3.5% vs 5.0%, and death in 1.6% vs 0.4% [62]. Dasatinib had superior efficacy over imatinib, including a higher 12-month rates of confirmed CCyR (77% vs 66%; P = 0.007), standard CCyR (83% vs 72%; P = 0.001), and MMR (46% vs 28%; P < ). By 18 months, response rates for dasatinib vs imatinib were confirmed CCyR in 78% vs 70% (P = ), CCyR in 85% vs 80%, and MMR in 57% vs 41% (P = ), respectively. In patients from all Hasford risk categories, the highest response rates were consistently seen in the dasatinib arm (Table 2). Responses were achieved more rapidly with dasatinib vs imatinib, as shown by significantly shorter times to confirmed CCyR and CCyR (hazard ratios [HR] 1.5; P < for both comparisons) and to MMR (HR 2.0; P < ). At 3 months, CCyR had been achieved by 54% vs 31%, and at 6 months, MMR had been achieved by 27% vs 8%, respectively. Progression to AP/BP occurred in 6 (2.3%) dasatinib-treated patients and 9 (3.5%) imatinib-treated patients (P-value not reported). No patient who achieved a MMR progressed to AP/BP [12,62]. Dasatinib and imatinib treatment resulted in different patterns of AEs, which were mostly grade 1/2 and manageable with dose reductions and transient interruptions. Of drugrelated nonhematologic AEs occurring in 10% of either arm, several types of AE occurred less frequently with dasatinib compared with imatinib, including nausea, vomiting, myalgia, rash, and superficial edema. Only pleural effusion was more common with dasatinib than with imatinib (12% vs 0% by 18 months; 0.4% grade 3 or above). However, the occurrence of pleural effusion did not affect the efficacy of dasatinib, as shown by the MMR rate of 65% in patients who had a pleural effusion. For all nonhematologic AEs occurring in 10% of patients, rates of grade 3/4 events were 1% or less in both arms (Table 3). Rates of grade 3/4 cytopenia in dasatinib and imatinib arms were neutropenia in 22% vs 20%, thrombocytopenia in 19% vs 10%, and anemia in 11% vs 7%, respectively. Rates of grade 3/4 laboratory abnormalities were low and similar in both arms, including elevations in ALT (<1% vs 1%), AST (<1% vs 1%), and bilirubin (1% vs 0%). No grade 3/4 elevations in lipase, amylase, or glu- Table 2 Response rates during treatment with frontline dasatinib or imatinib in the DASISION trial [12,62]. % of patients (95% CI) P-value Dasatinib 100 mg QD (N= 259) Imatinib 400 mg QD (N= 260) Confirmed CCyR By 12 months 77 (71 82) 66 (60 72) By 18 months CCyR by 12 months 83 (78 88) 72 (66 77) Low Hasford risk score Intermediate Hasford risk score High Hasford risk score CCyR rate overall (18-month follow-up) MMR by 12 months 46 (40 52) 28 (23 34) < Low Hasford risk score Intermediate Hasford risk score High Hasford risk score MMR rate overall (18-month follow-up) Abbreviations: CCyR, complete cytogenetic response; CI, confidence interval; MMR, major molecular response; QD, once daily.

7 G. Rosti et al. / Critical Reviews in Oncology/Hematology 82 (2012) Table 3 Hematologic AEs and drug-related nonhematologic adverse events (AEs) that occurred in at least 10% of patients in patients treated with either frontline dasatinib or imatinib in the DASISION trial after 18 months of follow-up [62]. Dasatinib 100 mg QD (N = 258) Imatinib 400 mg QD (N = 258) All grades Grade 3/4 All grades Grade 3/4 % of patients Hematologic AEs Neutropenia NR 22 NR 20 Thrombocytopenia NR 19 NR 10 Anemia NR 11 NR 7 Nonhematologic AEs Fluid retention Superficial edema <1 Pleural effusion 12 <1 0 0 Diarrhea 18 < Nausea Vomiting Myalgia Rash Headache Fatigue 8 < Abbreviation: NR, not reported. cose occurred in either arm. QT intervals were monitored during the trial. With dasatinib and imatinib, QT intervals of ms occurred in 2% vs 4%, respectively, and QT intervals >500 ms occurred in 0.4% in each arm. Median changes in QT interval from baseline were 3.0 ms with dasatinib and 8.2 ms with imatinib [12,62]. Discontinuation following drug-related toxicity occurred in 6.2% with dasatinib vs 4.3% with imatinib, which was due to cytopenia in 2.7% vs 1.2% and nonhematologic side effects in 3.5% vs 3.1%, respectively. Four patients (1.6%) discontinued dasatinib due to pleural effusion [12,62]. The total number of deaths (including deaths after study discontinuation) was 11 for dasatinib (due to disease progression in four patients, infection in four patients, myocardial infarction in two patients, and bladder cancer in one patient) and six for imatinib (due to disease progression in four patients, clinical deterioration in one patient, and myocardial infarction in one patient) [63]. One death in each group was attributed to study treatment (both due to myocardial infarction). Median daily doses were 99 mg/d for dasatinib and 400 mg/d for imatinib and rates of dose reduction or interruption were not reported [12,62] 4.4. Phase 3 randomized trial of frontline nilotinib vs imatinib in CML-CP Outcomes with nilotinib vs imatinib were compared in the Evaluating Nilotinib Efficacy and Safety in Clinical Trials of Newly Diagnosed Ph+ CML patients (ENESTnd) trial, a randomized trial of nilotinib 300 mg BID (n = 282) vs nilotinib 400 mg BID (n = 281) vs imatinib 400 mg QD (n = 283). In this trial, patients were stratified according to Sokal risk score [13]. The primary endpoint for the ENESTnd study was the rate of MMR at 12 months. The main secondary endpoints were the rate of durable MMR at 24 months and the rate of CCyR by 12 months. Patient baseline characteristics were well balanced between all arms; median age was years and 28% of patients in each arm had high Sokal risk scores [13]. After a median treatment duration of months, the proportions of patients remaining on study treatment were 74% in the nilotinib 300 mg arm, 78% in the nilotinib 400 mg arm, and 67% in the imatinib arm. Reasons for discontinuation included suboptimal response/treatment failure in 9% vs 2% vs 13%, progression in <1% vs 1% vs 4%, and death in 1% vs <1% vs 0%, respectively [64]. Both nilotinib arms (300 and 400 mg) had superior efficacy over imatinib, including higher rates of CCyR by 12 months (80% vs 78% vs 65%; P < for both comparisons) and MMR at 12 months (44% vs 43% vs 22%; P < for both comparisons). By 24 months, CCyR rates had reached 87% vs 85% vs 77% (P = and P = for nilotinib 300 mg or 400 mg vs imatinib, respectively); MMR rates at 24 months were 62% vs 59% vs 37% (P < for both comparisons). MMR rates were higher for both doses of nilotinib vs imatinib across all Sokal risk groups (Table 4) [13,65]. Responses were achieved more rapidly with nilotinib vs imatinib, as shown by shorter median times to MMR (8.6 months for nilotinib 300 mg, 11.0 months for nilotinib 400 mg, and median not reached for imatinib). At 6 months, MMR had been achieved by 33% vs 30% vs 12%, respectively. Progression to AP/BP occurred in two patients (0.7%) receiving nilotinib 300 mg, three patients (1.1%) receiving nilotinib 400 mg, and 12 patients (4.2%) receiving imatinib. Time to progression to AP/BP was significantly longer for nilotinib vs imatinib (P = with 300 mg and P = with 400 mg nilotinib). No patient who achieved a MMR progressed to AP/BP [13,64]. After 24 months, BCR-ABL mutations were detected in ten (4%) and eight (3%) patients in the nilotinib 300 and 400 mg arms, respectively, compared with 20 (7%) patients in the imatinib arm, and the number of

8 166 G. Rosti et al. / Critical Reviews in Oncology/Hematology 82 (2012) Table 4 Response rates during treatment with frontline nilotinib (300 mg or 400 mg BID) or imatinib in the ENESTnd trial [13,64,65]. Nilotinib 300 mg BID (N = 282) % of patients Nilotinib 400 mg BID (N = 281) Imatinib 400 mg QD (N = 283) P-value (nilotinib arms vs imatinib) CCyR by 12 months <0.001/<0.001 High Sokal risk score CCyR by 24 months / MMR at 12 months <0.0001/< Low Sokal risk score Intermediate Sokal risk score High Sokal risk score MMR at 24 months <0.0001/< Abbreviations: BID, twice daily; CCyR, complete cytogenetic response; MMR, major molecular response; QD, once daily. different amino acid changes detected was eight across both nilotinib arms compared with 13 in the imatinib arm [66]. Similar to the DASISION trial, nilotinib and imatinib were associated with different patterns of AEs, which were mostly grade 1/2 and manageable with dose reductions and transient interruptions. Of drug-related nonhematologic AEs occurring in 10% of any arm, rates of nausea, diarrhea, vomiting, muscle spasm, and edema were lower in the nilotinib arms compared with the imatinib arm, whereas rates of rash, alopecia, pruritus, and headache were higher in both nilotinib arms than in the imatinib arm. Except for grade 3/4 rash (3% with nilotinib 400 mg, 2% with imatinib), rates of grade 3/4 events were 1% or less. The incidence of grade 3/4 cytopenia for nilotinib arms vs imatinib were neutropenia in 11 12% vs 21%, thrombocytopenia in 10 12% vs 9%, and anemia in 4% vs 5%, respectively. Among biochemical abnormalities, elevations in ALT, AST, bilirubin, lipase, and glucose of any grade were more common with nilotinib vs imatinib, whereas elevated creatinine was less common with nilotinib vs imatinib (Table 5) [64]. In QT monitoring, a QT interval >480 ms occurred in <1% of patients in the nilotinib 400 mg arm and 0% in other arms. No patient had a QT interval >500 ms [65]. Discontinuation because of AEs or laboratory abnormalities occurred in 6% and 2% with nilotinib 300 mg, 10% and 3% with nilotinib 400 mg, and 9% and 1% with imatinib. Total deaths (including after study discontinuation) were nine Table 5 Hematologic adverse events (AEs), drug-related nonhematologic adverse events AEs that occurred in at least 10% patients, and selected biochemical abnormalities in patients treated with either frontline nilotinib (300 or 400 mg BID) or imatinib in the ENESTnd trial after 24 months of follow-up [13,64]. Nilotinib 300 mg BID (N = 279) Nilotinib 400 mg BID (N = 277) Imatinib 400 mg QD (N = 280) All grades Grade 3/4 All grades Grade 3/4 All grades Grade 3/4 % of patients Hematologic AEs Neutropenia NR 12 NR 11 NR 21 Thrombocytopenia NR 10 NR 12 NR 9 Anemia NR 4 NR 4 NR 5 Nonhematologic AEs Diarrhea 8 < Nausea 14 < Vomiting Rash 32 < Pruritus 16 <1 13 <1 6 0 Alopecia Headache <1 Fatigue <1 10 <1 Myalgia 10 < Muscle spasm <1 27 <1 Peripheral edema Facial edema < <1 Eyelid edema <1 0 2 <1 16 <1 Periorbital edema < Selected biochemical abnormalities Increased total bilirubin NR 4 NR 8 NR <1 Increased glucose NR 6 NR 5 NR 0 Increased lipase NR 7 NR 8 NR 3 Increased ALT NR 4 NR 9 NR 3 Abbreviations: ALT, alanine aminotransferase; BID, twice daily; NR, not reported; QD, once daily.

9 G. Rosti et al. / Critical Reviews in Oncology/Hematology 82 (2012) patients in the nilotinib 300 mg arm (five related to CML), six patients in the nilotinib 400 mg arm (three related to CML), and 11 patients in the imatinib arm (ten related to CML). Median daily doses were 594 mg/d for nilotinib 300 mg BID, 776 mg/d for nilotinib 400 mg BID, and 400 mg/d for imatinib 400 mg QD [64]. Dose reductions or interruptions were required in the first 12 months by 59%, 66%, 52% of patients, respectively [13]. 5. Potential application of dasatinib and nilotinib in the frontline setting Primary data for dasatinib and nilotinib compared with imatinib are very encouraging and show superior rates of response over imatinib combined with favorable tolerability. However, although the overall trends relative to imatinib can be compared, available data do not allow an accurate comparison of dasatinib and nilotinib because no head-to-head trial has been performed. For both dasatinib and nilotinib, additional follow-up is needed to confirm that initial efficacy benefits and long-term tolerability are maintained. Based on long-term follow-up from IRIS showing that the majority of events on imatinib occurred during the first 3 years of therapy, analyses such as EFS or TFS at 3 years will be highly informative. In addition, because earlier responses on imatinib are predictive for improved long-term outcomes (as discussed earlier), it will be interesting to see if the superior responses observed at early time points with the newer agents compared with imatinib will have similar predictive power. Available data suggest that nilotinib treatment is associated with a lower incidence of BCR-ABL mutations compared with imatinib [60,66], although longer follow-up is needed to confirm this observation, and similar data are needed for dasatinib. The new data suggest that the treatment paradigm for patients with newly diagnosed CML needs to be reconsidered, although the implications are open to debate. One option might be that the newer agents should be reserved only for patients who have inadequate responses to imatinib, such as those with suboptimal response or treatment failure after frontline treatment. However, given that the new trials assessed frontline treatment, and no trial has been performed to compare outcomes of patients who have received the newer agents frontline or second-line after imatinib, there is currently no evidence to support this approach. An alternative suggestion is that dasatinib and nilotinib treatment might be most appropriate for patients who have high-risk (Sokal/Hasford) disease, based on the inferior outcomes of this patient subgroup. However, in the DASISION and ENESTnd trials, efficacy improvements were apparent across all risk groups (Tables 2 and 4). Choosing between dasatinib and nilotinib is an additional consideration. Existing data show that dasatinib and nilotinib are both superior to imatinib in the frontline setting. However, different patterns of AEs were seen, suggesting that it is appropriate to consider comorbidity when prescribing these agents. With dasatinib, nausea, vomiting, musculoskeletal disorders, rash, and edema occur less frequently with dasatinib compared with imatinib, whereas pleural effusion and thrombocytopenia occur more frequently compared with imatinib. For nilotinib, dermatologic toxicity (rash, alopecia, pruritus), headache, and biochemical abnormalities associated with liver or pancreatic occur more commonly compared imatinib, whereas gastrointestinal disturbances (nausea, diarrhea, vomiting), muscle spasm, edema, and neutropenia occur less commonly with nilotinib compared with imatinib. With both dasatinib and nilotinib, similar to imatinib, AEs tended to occur early during treatment, were manageable in most cases with dose interruption/reduction and/or standard medical intervention, and rarely resulted in discontinuation. The difference in dosing schedule required for dasatinib (QD with or without food) and nilotinib (BID with no food 2 h before and 1 h after each dose) is a further consideration. In addition to clinical factors, treatment decisions will need to be made in the context of the local regulatory and economic environment. 6. Conclusions Several effective treatment options now exist for patients newly diagnosed with CML-CP. Recent data from phase 2 and phase 3 trials show that both dasatinib and nilotinib are associated with higher response rates during initial treatment and more rapid responses than imatinib, with available data also suggesting a reduced occurrence of disease progression. Both agents have also shown favorable tolerability in the frontline setting, although each is associated with distinct patterns of AEs. For all available BCR-ABL inhibitors, AEs rarely result in treatment discontinuation. Although these data may be sufficient to persuade many prescribers to utilize these agents in preference to imatinib, others may prefer to wait for data on long-term outcomes to become available, such as duration of response, EFS, and OS, before abandoning imatinib as the preferred frontline option. Similar to previous data in the second-line setting, choosing between frontline dasatinib and nilotinib remains difficult and may require consideration on a patient-to-patient basis. Conflict of interest statement Gianantonio Rosti has been a member of advisory boards for Novartis and Bristol-Myers Squibb (BMS), has acted as a speaker for Novartis, BMS, and Roche, and has received research funding from Novartis. Fausto Castagnetti has received honoraria from Novartis and BMS. Gabriele Gugliotta has received honoraria from Novartis. Michele Baccarani has been a member of advisory boards and acted as a consultant and speaker for Novartis and BMS, has been a member of advisory boards for Ariad and Pfizer,

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