TY - JOUR
T1 - Switching to nilotinib versus imatinib dose escalation in patients with chronic myeloid leukaemia in chronic phase with suboptimal response to imatinib (LASOR)
T2 - a randomised, open-label trial
AU - Cortes, Jorge E.
AU - De Souza, Carmino Antonio
AU - Ayala, Manuel
AU - Lopez, Jose Luis
AU - Bullorsky, Eduardo
AU - Shah, Sandip
AU - Huang, Xiaojun
AU - Babu, K. Govind
AU - Abdulkadyrov, Kudrat
AU - de Oliveira, José Salvador Rodrigues
AU - Shen, Zhi Xiang
AU - Sacha, Tomasz
AU - Bendit, Israel
AU - Liang, Zhizhou
AU - Owugah, Tina
AU - Szczudlo, Tomasz
AU - Khanna, Sadhvi
AU - Fellague-Chebra, Rafik
AU - le Coutre, Philipp D.
N1 - Funding Information:
To our knowledge, LASOR was the first randomised, phase 3 trial comparing multiple treatment options in patients with suboptimal cytogenetic response as defined by ELN 2009 recommendations. 1 While the primary endpoint was not met, the response rate per the primary endpoint was affected by the crossover design. When accounting for crossover, higher rates of CCyR and major molecular response by 1 and 2 years were observed in patients assigned to switch to nilotinib 400 mg twice daily than in those assigned to dose-escalated imatinib. Suboptimal cytogenetic response per ELN 2009 recommendations might represent a heterogeneous patient population (eg, patients with no cytogenetic response might have greater disease severity than patients with PCyR but no CCyR at 12 months) with intermediate response, making it challenging both to identify the relevant patients and to define the most appropriate treatment strategies. Indeed, the high rate of screening failure in LASOR was due, in part, to many patients not meeting the highly specific criteria for suboptimal cytogenetic response required for enrolment. Additionally, as information on treatment adherence, dose reductions, or dose interruptions before enrolment was not available, it is unknown whether these factors might have contributed to patients' suboptimal cytogenetic responses at enrolment. Nonetheless, results from LASOR suggest that patients who fail to achieve ELN treatment milestones (ie, no cytogenetic response after 3 to 6 months, no PCyR after 6 to 12 months, or PCyR but no CCyR after 12 to 18 months) with front-line imatinib are more likely to achieve CCyR and major molecular response by switching to nilotinib than by receiving an increased imatinib dose. With the 2013 update of the ELN treatment recommendations, a greater emphasis was placed on achieving earlier, deeper treatment responses. 1,8 Per the 2013 ELN recommendations, patients enrolled in LASOR would be classified as having treatment failure. 8 This change reflects the earlier and higher rates of molecular responses observed in randomised clinical trials of second-generation tyrosine-kinase inhibitors, 9,10 and the associations between early molecular response (eg, BCR-ABL1 IS ≤10% at 3 months) and good long-term prognosis, including a reduced probability of loss of response or progression to accelerated phase or blast phase and improved overall survival. 2,11–14 The achievement of CCyR and major molecular response is likewise associated with improved long-term outcomes. 3,14–17 As a result, both CCyR and major molecular response are considered important milestones in the 2013 ELN treatment recommendations. 8 For patients receiving second-line treatment after failure of front-line imatinib, achievement of CCyR has similarly been associated with improved progression-free survival and overall survival. 18–21 In the pivotal trial 19 of second-line nilotinib for patients with resistance to or intolerance of imatinib, nilotinib-treated patients with CCyR at 12 months had a higher rate of progression-free survival at 4 years than did patients without CCyR at 12 months. Other reports have linked failure to achieve CCyR as early as 3 months after initiation of second-line therapy with increased risk of progression or death. 20,21 Although no differences were observed in progression-free survival or overall survival through 2 years of follow-up in LASOR, longer-term follow-up is needed to address any potential survival advantage from treatment switch. Although switching to nilotinib did not affect survival in LASOR, more patients achieved CCyR and major molecular response on nilotinib than on imatinib; it is possible that despite improved responses achieved following switch to nilotinib, patients might never achieve the benefit they would have if they had responded optimally to front-line therapy. The nilotinib dose used in this study (400 mg twice daily) is the dose approved for second-line therapy in patients with resistance to front-line imatinib. Although nilotinib 300 mg twice daily is now known to result in similar efficacy to 400 mg twice daily in the front-line setting, 9 it has not been established whether 300 mg twice daily would provide similar efficacy in patients with suboptimal response (or failure) on front-line therapy. Therefore, we deemed nilotinib 400 mg twice daily to be the most appropriate dose to investigate in this study as it is known to be effective in the second-line setting. In keeping with established best clinical practice and due to the uncertainty of the optimal treatment for patients enrolled in LASOR, patients were allowed to cross over to the alternative treatment group for intolerance or suboptimal response on study treatment. This confounded the analysis of some of the results, including the primary endpoint (CCyR at 6 months in the ITT population). Although the primary endpoint was not met, a higher proportion of patients achieved CCyR at 6 months with nilotinib 400 mg twice daily than with imatinib 600 mg daily when accounting for crossover. Overall, the rate of crossover was much higher in the imatinib group than in the nilotinib group (56 [59%] of 95 vs 13 [14%] of 96); thus, most patients received nilotinib during at least part of the study, including 16 patients in the imatinib group who crossed over by 6 months. By study end, only 33 patients were receiving imatinib. The safety profiles for nilotinib and imatinib were generally consistent with those seen in previous studies. 19,22–24 Before crossover, there were more adverse events and a higher rate of adverse event-related discontinuations in patients assigned to nilotinib than in patients assigned to imatinib dose escalation. This might be an expected outcome, considering that patients must have been tolerant of imatinib at study entry and most adverse events occur transiently with the introduction of treatment, decreasing in incidence over time. 19,25 Thus, a transient increase in adverse event incidence can be expected with TKI switch, regardless of second-line TKI choice. In LASOR, five patients in the nilotinib group and none in the imatinib group had cardiovascular events on study, in line with other reports showing higher rates of cardiovascular events with second-generation tyrosine-kinase inhibitors versus imatinib. 26,27 For patients on any tyrosine-kinase inhibitor, management of cardiovascular risk factors should be conducted in accordance with local guidelines. Overall, the proportion of patients with serious adverse events was similar between study groups. Taken together, these data suggest that both drugs were well tolerated, but as in all cases, the potential clinical benefits of switching to a more potent tyrosine-kinase inhibitor should be carefully balanced against the potential for adverse events on an individual basis. The results of LASOR are valuable for informing the clinical management of patients with chronic myeloid leukaemia in chronic phase, for whom responses that were considered suboptimal per 2009 ELN criteria are common and doctors have had, until now, no data-driven advice to inform their treatment selection. Although transient improvements might be seen in some patients after an increased dose of imatinib, a switch to nilotinib provided the most substantial benefit. While longer-term analyses are needed to establish whether the clinical benefits observed with switching to nilotinib are associated with improved long-term survival outcomes, the results from LASOR suggest that patients with suboptimal cytogenetic response per ELN 2009 recommendations 1 (considered to have treatment failure per ELN 2013 recommendations 8 ) are more likely to achieve improved cytogenetic and molecular responses with switching to nilotinib than with imatinib dose escalation. Contributors JEC, CADS, JLL, TO, TSz, and PDlC contributed to the study design; TO and TSz contributed to protocol writing; CADS, MA, JLL, XH, KGB, KA, Z-XS, TSa, ZL, SK, and PDlC collected data; MA and Z-XS performed research; JEC, CADS, JLL, EB, SS, XH, Z-XS, IB, ZL, TO, TSz, SK, and PDlC performed data analysis. RF-C was the director of the LASOR study at Novartis and oversaw all aspects of the study. PDlC served the senior investigator function of this trial. All authors drafted and approved the manuscript for submission. Declarations of interest CADS, JLL, EB, SS, XH, KGB, KA, JSRdO, Z-XS, IB, and ZL declare no competing interests. JEC has received consulting fees from Novartis, BMS, Ariad, and Pfizer outside of the submitted work. JEC has received a grant from Teva outside of the submitted work. MA has received grants and personal fees from Novartis and BMS during this study. MA has received grants and personal fees from Novartis and BMS outside of the submitted work. TSa has received personal fees from Novartis, BMS, Angellini, and Hematoonkologia.pl outside of the submitted work. TO is an employee of Novartis and owns Novartis stock. TSz is an employee of Novartis and has three patents issued broadly relevant to this work. SK and RF-C are employees of Novartis. PDlC has received speakers' honoraria from Novartis, BMS, ARIAD, and Pfizer. Acknowledgments Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. We thank Karen Kaluza and Jonathan Morgan of ArticulateScience LLC for medical editorial assistance with this manuscript.
Publisher Copyright:
© 2016 Elsevier Ltd
PY - 2016/12/1
Y1 - 2016/12/1
N2 - Background Optimal management of patients with chronic myeloid leukaemia in chronic phase with suboptimal cytogenetic response remains undetermined. This study aimed to investigate the safety and efficacy of switching to nilotinib vs imatinib dose escalation for patients with suboptimal cytogenetic response on imatinib. Methods We did a phase 3, open-label, randomised trial in patients with chronic myeloid leukaemia in chronic phase with suboptimal cytogenetic response to imatinib according to the 2009 European LeukemiaNet criteria, in Latin America, Europe, and Asia (59 hospitals and care centres in 12 countries). Eligible patients were aged 18 years or older with Philadelphia chromosome-positive chronic myeloid leukaemia in chronic phase and Eastern Cooperative Oncology Group performance status of 0–2. Before enrolment, all patients had received 3–18 months of imatinib 400 mg once daily and had a suboptimal cytogenetic response according to 2009 ELN recommendations, established through bone marrow cytogenetics. By use of an interactive response technology using fixed blocks, we randomly assigned patients (1:1) to switch to nilotinib 400 mg twice per day or an escalation of imatinib dose to 600 mg once per day (block size of 4). Investigators and participants were not blinded to study treatment. Crossover was allowed for loss of response or intolerance at any time, or for patients with no complete cytogenetic response at 6 months. The primary endpoint was complete cytogenetic response at 6 months in the intention-to-treat population. Efficacy endpoints were based on the intention-to-treat population, with all patients assessed according to the treatment group to which they were randomised (regardless of crossover); the effect of crossover was assessed in post-hoc analyses, in which responses achieved after crossover were excluded. We present the final results at 24 months' follow-up. This study is registered with ClinicalTrials.gov (NCT00802841). Findings Between July 7, 2009, and Aug 29, 2012, we enrolled 191 patients. 96 patients were randomly assigned to nilotinib and 95 patients were randomly assigned to imatinib. Complete cytogenetic response at 6 months was achieved by 48 of 96 patients in the nilotinib group (50%, 95·18% CI 40–61) and 40 of 95 in the imatinib group (42%, 32–53%; difference 7·9% in favour of nilotinib; 95% CI −6·2 to 22·0, p=0·31). Excluding responses achieved after crossover, 48 (50%) of 96 patients in the nilotinib group and 34 (36%) of 95 patients in the imatinib group achieved complete cytogenic response at 6 months (nominal p=0·058). Grade 3–4 non-haematological adverse events occurring in more than one patient were headache (nilotinib group, n=2 [2%, including 1 after crossover to imatinib]; imatinib group, n=1 [1%]), blast cell crisis (nilotinib group, n=1 [1%]; imatinib group, n=1 [1%]), and QT prolongation (nilotinib group, n=1 [1%]; imatinib group, n=1 [1%, after crossover to nilotinib]). Serious adverse events on assigned treatment were reported in 11 (11%) of 96 patients in the nilotinib group and nine (10%) of 93 patients in the imatinib group. Seven (7%) of 96 patients died in the nilotinib group and five (5%) of 93 patients died in the imatinib group; no deaths were treatment-related. Interpretation While longer-term analyses are needed to establish whether the clinical benefits observed with switching to nilotinib are associated with improved long-term survival outcomes, our results suggest that patients with suboptimal cytogenetic response are more likely to achieve improved cytogenetic and molecular responses with switching to nilotinib than with imatinib dose escalation, although the difference was not statistically significant when responses achieved after crossover were included. Funding Novartis Pharmaceuticals.
AB - Background Optimal management of patients with chronic myeloid leukaemia in chronic phase with suboptimal cytogenetic response remains undetermined. This study aimed to investigate the safety and efficacy of switching to nilotinib vs imatinib dose escalation for patients with suboptimal cytogenetic response on imatinib. Methods We did a phase 3, open-label, randomised trial in patients with chronic myeloid leukaemia in chronic phase with suboptimal cytogenetic response to imatinib according to the 2009 European LeukemiaNet criteria, in Latin America, Europe, and Asia (59 hospitals and care centres in 12 countries). Eligible patients were aged 18 years or older with Philadelphia chromosome-positive chronic myeloid leukaemia in chronic phase and Eastern Cooperative Oncology Group performance status of 0–2. Before enrolment, all patients had received 3–18 months of imatinib 400 mg once daily and had a suboptimal cytogenetic response according to 2009 ELN recommendations, established through bone marrow cytogenetics. By use of an interactive response technology using fixed blocks, we randomly assigned patients (1:1) to switch to nilotinib 400 mg twice per day or an escalation of imatinib dose to 600 mg once per day (block size of 4). Investigators and participants were not blinded to study treatment. Crossover was allowed for loss of response or intolerance at any time, or for patients with no complete cytogenetic response at 6 months. The primary endpoint was complete cytogenetic response at 6 months in the intention-to-treat population. Efficacy endpoints were based on the intention-to-treat population, with all patients assessed according to the treatment group to which they were randomised (regardless of crossover); the effect of crossover was assessed in post-hoc analyses, in which responses achieved after crossover were excluded. We present the final results at 24 months' follow-up. This study is registered with ClinicalTrials.gov (NCT00802841). Findings Between July 7, 2009, and Aug 29, 2012, we enrolled 191 patients. 96 patients were randomly assigned to nilotinib and 95 patients were randomly assigned to imatinib. Complete cytogenetic response at 6 months was achieved by 48 of 96 patients in the nilotinib group (50%, 95·18% CI 40–61) and 40 of 95 in the imatinib group (42%, 32–53%; difference 7·9% in favour of nilotinib; 95% CI −6·2 to 22·0, p=0·31). Excluding responses achieved after crossover, 48 (50%) of 96 patients in the nilotinib group and 34 (36%) of 95 patients in the imatinib group achieved complete cytogenic response at 6 months (nominal p=0·058). Grade 3–4 non-haematological adverse events occurring in more than one patient were headache (nilotinib group, n=2 [2%, including 1 after crossover to imatinib]; imatinib group, n=1 [1%]), blast cell crisis (nilotinib group, n=1 [1%]; imatinib group, n=1 [1%]), and QT prolongation (nilotinib group, n=1 [1%]; imatinib group, n=1 [1%, after crossover to nilotinib]). Serious adverse events on assigned treatment were reported in 11 (11%) of 96 patients in the nilotinib group and nine (10%) of 93 patients in the imatinib group. Seven (7%) of 96 patients died in the nilotinib group and five (5%) of 93 patients died in the imatinib group; no deaths were treatment-related. Interpretation While longer-term analyses are needed to establish whether the clinical benefits observed with switching to nilotinib are associated with improved long-term survival outcomes, our results suggest that patients with suboptimal cytogenetic response are more likely to achieve improved cytogenetic and molecular responses with switching to nilotinib than with imatinib dose escalation, although the difference was not statistically significant when responses achieved after crossover were included. Funding Novartis Pharmaceuticals.
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U2 - 10.1016/S2352-3026(16)30167-3
DO - 10.1016/S2352-3026(16)30167-3
M3 - Article
C2 - 27890073
AN - SCOPUS:84997634541
SN - 2352-3026
VL - 3
SP - e581-e591
JO - The Lancet Haematology
JF - The Lancet Haematology
IS - 12
ER -