Efficacy of nilotinib in chronic myeloid leukemia patients resistant to or intolerant of imatinib: Results after 2 years

Imatinib has been the first-line option for chronic myeloid leukemia (CML) and provides excellent outcomes for many. However, a number of patients were resistant to or intolerant of imatinib. This study aims to evaluate the 2-year results of treatment with nilotinib in these resistant or intolerant patients.

JOURNAL OF MEDICAL RESEARCH EFFICACY OF NILOTINIB IN CHRONIC MYELOID LEUKEMIA PATIENTS RESISTANT TO OR INTOLERANT OF IMATINIB: RESULTS AFTER YEARS Phu Chi Dung¹, Nguyen Tan Binh², Pham Quang Vinh³ ¹Blood Transfusion Hematology Hospital, Hochiminh City ²Department of Health, Hochiminh city ³Department of Hematology, Hanoi Medical University Imatinib has been the first-line option for chronic myeloid leukemia (CML) and provides excellent outcomes for many However, a number of patients were resistant to or intolerant of imatinib This study aims to evaluate the 2-year results of treatment with nilotinib in these resistant or intolerant patients A case series study was conducted in 72 resistant or intolerant CML patients at Ho Chi Minh City (HCMC) Blood Transfusion Hematology hospital who received nilotinib between January 2015 and December 2017 Overall, there were 60/72 patients who were resistant to imatinib Mutations were observed in 30.6% of patients Approximately two-thirds of cases had the duration of greater than year from imatinib resistance/ intolerance to nilotinib therapy After 24 months of nilotinib, complete cytogenetic response (CCyR) and major molecular response (MMR) were achieved in 51.3% and 44.8% of patients, respectively Complete hematologic response (CHR) was rapidly obtained (97.2% after months) Two-year overall survival (OS) and progression-free survival (PFS) were 98.5% and 91.4%, respectively In conclusion, nilotinib is an effective therapeutic option for CML patients who were resistant to or intolerant of imatinib in Vietnam condition Keywords: chronic myeloid leukemia, resistant, intolerant, imatinib, nilotinib I INTRODUCTION Chronic myeloid leukemia (CML) is a common malignant hematologic disease Its pathogenic mechanism involves a reciprocal translocation between chromosomes and 22 which is known as Philadelphia chromosome (Ph) This cytogenetic abnormality causes the BCR-ABL fusion gene which then encodes the BCR-ABL oncoprotein The augmented tyrosine kinase activity of BCR-ABL protein induces the activation of multiple signaling pathways Corresponding author: Phu Chi Dung, Blood Transfusion Hematology Hospital, Hochiminh City Email: chidungyk85@gmail.com Received: 27/11/2018 Accepted: 12/03/2019 28 Therefore, it leads to the proliferation of mature granulocytes, reduced stromal adherence and inhibited apoptosis Imatinib is the first-generation tyrosine kinase inhibitor (TKI) which made extraordinary progress in treating CML A recent result of IRIS study showed that 10-year overall survival (OS) rate was 83.3% and the rate of progression decreased dramatically (6.9%) [1] However, approximately 36% of patients had to discontinue their treatment due to unexpected responses or adverse events These findings were also seen in Vietnam’s studies [2; 3] Management of CML patients who were resistant to or intolerant of imatinib has been a challenge, especially in countries with limited JMR 118 E4 (2) - 2019 JOURNAL OF MEDICAL RESEARCH resources like Vietnam In general, three methods have been mentioned, including highdose imatinib, switching to second or thirdgeneration TKIs or allogeneic hematopoietic stem cell transplantation (HSCT) Actually, switching to another TKI (such as nilotinib, dasatinib, bosutinib or ponatinib) is a preferred option because they have greater effectiveness and lower toxicities than allogeneic HSCT Since 2015, in Vietnam, several hospitals have utilized nilotinib as salvage therapy for resistant or intolerant CML A few studies were conducted to prove the efficacy of nilotinib but sample size and follow-up duration were inadequate Thus, the main aim of this study to determine the efficacy of nilotinib in imatinib-resistant or intolerant CML patients between January 2015 and December 2017 at Hochiminh city Blood Transfusion Hematology Hospital This was a retrospective, case series study which was conducted at HCMC Blood Transfusion Hematology Hospital from From January 2015 to December 2017 Seventytwo patients who were resistant to or intolerant of imatinib were recruited Inclusive criteria required individuals to be in chronic or accelerated phase with ECOG performance status score under Patients did not carry mutations which were insensitive to nilotinib and had normal liver / renal function The patients who used other TKIs (not imatinib or nilotinib) previously or had increased risks of severe toxicities of nilotinib (such as pregnancy, breastfeeding, history of acute pancreatitis) were excluded The patients with high cardiovascular risks after nilotinib or had the unmanageable comorbidities were not allowed to participate in the study Study process Figure is the diagram which showed the process of study: II METHODS Study design Figure Flow chart of study Assessment of response to nilotinib Responses were evaluated according to the criteria of European LeukemiaNet (ELN) [4], JMR 118 E4 (2) - 2019 29 JOURNAL OF MEDICAL RESEARCH including types: - Complete hematologic response (CHR) was characterized by platelet count from 150 to 450 x 109/L, white blood cell count from to 10 x109/L without blasts in peripheral blood smear and splenohepatomegaly - Cytogenetic response (CyR): there were different levels + Partial cytogenetic response (PCyR) was defined as # 35% Ph+ cells + Complete cytogenetic response (CCyR) was defined as absence of Ph+ cell + Major cytogenetic response (MCyR) included both PCyR and CCyR - Molecular responses were divided into levels: Major molecular response (MMR) if BCR/ABL # 0.1% and complete molecular response (CMR) if BCR/ABL fusion gene was undetected Statistical analysis Data were analyzed using SPSS software Survival probability was estimated by KaplanMeier and compared with the log-rank test Overall survival (OS) was defined from the start of nilotinib to the date of death or last follow-up Progression-free survival (PFS) was calculated from the date of starting nilotinib to the date of death or last follow-up or documented disease progression to accelerated/blastic phase 30 III RESULTS Patient characteristics From January 2015 to December 2017, 72 patients who matched inclusive criteria were recruited for this study Median age at nilotinib start was 48 years At diagnosis, the majority of patients were categorized into a high-risk group according to Sokal and Eutos index (63,9% and 76,4%, respectively) Almost all patients with treatment failure were resistant to imatinib The proportion of primary resistance was more than 60% Mutation screening detected 30.6% of patients carrying resistant mutations and among them, 26.4% of cases had at least mutations Distribution of mutations in our study was diverse, such as Q252H, G250, M244V (P loop); L298V, M388L (SH3 domain); E355A, E355G, M351T (SH2 domain); L387M (activation loop); E450V, E453K, S438C (catalytic loop) There were 47.2% of patients receiving high-dose imatinib but only 11/34 (32.4%) achieved PCyR or better (Table 1) Most of the patients were in chronic phase at baseline Before starting nilotinib, approximately 60% of cases attained CHR and one-third had less than 35% Ph+ cells In our study, about two-thirds of participants had duration from diagnosis of resistance/ intolerance to nilotinib over year (Table 1) JMR 118 E4 (2) - 2019 JOURNAL OF MEDICAL RESEARCH Table Patient characteristics Characteristic Median age at nilotinib start (range) Gender, n (%) Best response to standard-dose imatinib (400mg/day) Imatinib resistance or intolerance n = 72 48 (16-77) Male 45 (62.5%) Female 27 (37.5%) Complete hematologic response (CHR) 40 (55.6%) Complete cytogenetic response (CCyR) (8.3%) Partial cytogenetic response (PCyR) 13 (18.1%) Major molecular response (MMR) (9.7%) No response (8.3%) Imatinib resistance 60 (83.3%) Imatinib intolerance 12 (16.7%) Mutations associated with imatinib resistance 22 (30.6%) Receiving high-dose imatinib before starting nilotinib 34 (47.2%) Phases of CML at baseline Chronic phase Accelerated phase Duration from diagnosis of resistance/ ≤ year intolerance to nilotinib > year 67 (93.1%) (6.9%) 28 (38.9%) 44 (61.1%) Response assessment after nilotinib In our study, at months, there were 97.2% of patients achieving CHR The 24-month rate of CCyR and MCyR were 51,3% and 80.3%, respectively We found that 44.8% of patients attaining MMR, of whom 12 cases had CMR (12.7%) (Figure 2) Figure Cumulative incidence of responses after nilotinib JMR 118 E4 (2) - 2019 31 JOURNAL OF MEDICAL RESEARCH There was a significant correlation between the rate of CCyR and age at nilotinib start, deep responses to high-dose imatinib, Ph+ # 35% before nilotinib or duration from diagnosis of resistance/intolerance to nilotinib (Table 2) of mutations, Ph+ # 35% before nilotinib or duration from diagnosis of resistance/ intolerance to nilotinib (Table 2) A multivariate analysis demonstrated that the patients who had Ph+ # 35% before nilotinib or duration from diagnosis of resistance/intolerance to nilotinib # year achieved better CCyR and MMR (p < 0.05) On the other hand, achievement of MMR was significantly related to deep responses to high-dose imatinib, the presence Table Univariate Cox regression analyses of patients’ characteristics and 24-month CCyR, MMR n 24-month CCyR ≤ 40 30 64.4% > 40 42 31.7% Reponse to highdose imatinib Not achieve MCyR 24 17.9% Achieve MCyR 11 89.4% Mutation of BCR/ ABL No Yes 22 58.9% Ph+ ≤ 35% before nilotinib No 46 30.8% Yes 26 84.3% 28 70.0% 44 38.3% Variable Age Durarion from ≤ year diagnosis of resistance/intolerance to > year nilotinib 50 47.9% p 0.029 0.003 0.165 0.000 24-month MMR 57.9% 38.3% 15.4% 69.3% 38.9% 57.8% 21.2% 79.7% p 0.099 0.002 0.019 0.000 60.2% 0.005 34.9% 0.030 Survival rates After years of nilotinib, overall survival (OS) was 98.5% and progression-free survival (PFS) was 91.4% (Figure 3) Subgroup analysis showed that chronic-phase patients had better survival (2-year OS 100% and PFS 93.8%) than those in accelerated phase (2year OS 75.5% and PFS 40.0%) (p = 0.000) 32 In addition, the groups achieving CCyR and MCyR after nilotinib had greater PFS (2-year PFS was 100% and 97.8%, respectively) than those without these responses (2-year PFS was 82.8% and 75.6%, respectively) (p = 0.010 and 0.001) However, two factors did not affect OS (p= 0.264 and 0.751) JMR 118 E4 (2) - 2019 JOURNAL OF MEDICAL RESEARCH Figure Overall survival (OS) and progression-free survival (PFS) after nilotinib IV DISCUSSION In our study, more than 80% of patients were resistant to imatinib Several mechanisms were involved in imatinib resistance, such as BCR/ABL overexpression, abnormalities of drug pumps or alternative pathways…[5] However, point mutations of BCR/ABL still played an important role so that structural changes affected drug binding The incidence of resistant mutations in this study was 30.6% higher than the rates in the reports of Takahashi [6] and Kuo [7] In our insufficient conditions, late switching from imatinib to other second-generation TKIs after imatinib resistance/intolerance was confirmed may result in reproliferation of cancer cells and the rapid emergence of mutations in BCR-ABL This can explain our relatively higher rate of mutations than others in some countries We found that 6-month CHR was 97.2% Our 24-month CCyR, MCyR and MMR were 51.3%, 80.3% and 44.8%, respectively These results were similar to those of other reports which demonstrated the good efficacy of using nilotinib in Vietnam (Table 3) Table Compare the rates of response to other studies Reference CHR CCyR Kantarjian H.M (n = 321) [8] NR 44% (24 months) Kuo C.Y (n = 85) [7] 80.0% 75.3% (6 months) (24 months) Takahashi N (n = 49) [6] 73.9% (12 months) Our study (n = 72) 97.2% 51.3% (6 months) (24 months) MCyR MMR OS PFS 59% 28% 87% 64% (24 months) (24 months) (24 months) (24 months) 85.6% 56.8% (24 months) (24 months) NR 87% 47.8% 95% (12 months) (12 months) (36 months) NR NR 80.3% 44.8% 98.5% 91.4% (24 months) (24 months) (24 months) (24 months) According to our analysis, there was a significant correlation between age and achievement of 24-month CCyR This finding was also recognized in studies of Lipton [9] and Giles [10] Therefore, elder patients should receive a different treatment strategy in order to optimize responses but reduce toxicities as much as possible JMR 118 E4 (2) - 2019 33 JOURNAL OF MEDICAL RESEARCH Interestingly, our patients with imatinibresistant mutations more likely attained MMR than those without mutations All of the mutations occurring in this study had low IC50 Although Jabbour and his colleagues just paid attention to CCyR, they realized that the patients who carried low-IC50 mutations achieved better responses than those without mutations [11] Thus, screening mutations before starting second- or thirdgeneration TKIs is an important component which helps physicians not only choose the suitable medications but also predict long-term responses of CML patients [12] Previous deep responses to imatinib were associated with the likelihood of achieving responses to nilotinib This finding was clearly demonstrated in the study of Koren-Michowitz [13] The good responses to imatinib were identified as the percentage of Ph+ cells before starting nilotinib The study of Jabbour indicated that patients who had the lower percentage of Ph+ cells attained better CyR rate [14] Our study also determined this significant relationship We provided strong evidence that late switching to nilotinib after confirming imatinib resistance/intolerance dramatically affected the achievement of CCyR and MMR The data of TIDEL-II study demonstrated that early switching to nilotinib had more benefits [15] There are several possible explanations for this prolonged waiting time for using nilotinib, but commonly it might be related to inaccessibility to second- or third-generation TKIs in Vietnam This may lead to the uncontrollable proliferation of malignant cells which is accompanied by genetic instability Consequently, it is possible to emerge new mutations which impact the outcome of other TKIs At 24 months of nilotinib, the probability 34 of OS and PFS were comparable to those in other studies (Table 3) Again, these results indicate that nilotinib was effective in resistant or intolerant patients of Vietnam Subgroup analysis revealed that phases of the disease had an important correlation with both OS and PFS This finding was also consistent with several previous studies of Kuo, Rossi and Jabbour [7; 14; 16] Patients with accelerated phase had intrinsic resistant mechanisms, such as stronger BCR-ABL overexpression, greater genetic instability and high risk of acquiring new mutations Although nilotinib was still beneficial for patients with accelerated phase, an intensive therapy should be required to well manage the disease, such as hematopoietic stem cell transplantation Achievement of CCyR after TKIs is usually a good indicator of the superior outcome Our study provided additional evidence that attaining MCyR or CCyR reduced the risk of disease progression This relationship was enhanced in the study of Jabbour [14] Generally, careful monitoring of cytogenetic tests should be maintained regularly in order to early identify and manage the patients with treatment failure and prevent disease progression The major limitation of this study lies in the fact that the sample size was small and lack of random assigment However it showed some benefits of nilotinib in treating resistant or intolerant CML patients in Vietnam V CONCLUSION Taken together, our study contributed some evidence about the efficacy of nilotinib for CML patients who were resistant to or intolerant of imatinib in Vietnam To improve further responses to nilotinib, switching to second- or third-generation TKIs should be implemented as soon as possible when patients are JMR 118 E4 (2) - 2019 JOURNAL OF MEDICAL RESEARCH diagnosed as resistant/intolerant CML, especially for those who maintain cytogenetic responses MAIN RESEARCH Evaluating the efficacy of nilotinib in chronicphase chronic myeloid leukemia patients who were resistant to or intolerant of imatinib ACKNOWLEDGMENTS We would like to thank all patients who participated in our study; HCMC Blood Transfusion Hematology Hospital; and our colleagues for their assistance in the study REFERENCES Hochhaus A., Larson R A., Guilhot F., et al (2017) Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia N Engl J Med, 376 (10), 917-927 Nguyen Quoc Thanh, Nguyen Thi My Hoa and Phu Chi Dung (2015) Evaluation of 10-year imatinib’s treatment effects of chronic myeloid leukemia patients in chronic phase The Medical Journal of Hochiminh city, 19 (4), 225-236 Nguyen Thi My Hoa and Nguyen Tan Binh (2010) Evaluating efficacy and safety of imatinib mesylate on the treatment of chronic myeloid leukemia in chronic phase at Blood Transfusion and Hematology Hospital, Hochiminh city Vietnam Journal of Medicine, 373 (2), 143-152 Baccarani M., Cortes J., Pane F., et al (2009) Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet J Clin Oncol, 27 (35), 6041-6051 Milojkovic D and Apperley J (2009) Mechanisms of Resistance to Imatinib and Second-Generation Tyrosine Inhibitors in JMR 118 E4 (2) - 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2019 ... before nilotinib or duration from diagnosis of resistance/intolerance to nilotinib (Table 2) of mutations, Ph+ # 35% before nilotinib or duration from diagnosis of resistance/ intolerance to nilotinib. .. Outcome of 82 chronic myeloid leukemia patients treated with nilotinib or dasatinib after failure of two prior tyrosine kinase inhibitors Haematologica, 98 (3), 399-403 JMR 118 E4 (2) - 20 19 ... main aim of this study to determine the efficacy of nilotinib in imatinib -resistant or intolerant CML patients between January 20 15 and December 20 17 at Hochiminh city Blood Transfusion Hematology