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Activity and tolerability of nilotinib
A retrospective multicenter analysis of chronic myeloid leukemia patients who are imatinib resistant or intolerant
Article first published online: 19 AUG 2010
Copyright © 2010 American Cancer Society
Volume 116, Issue 19, pages 4564–4572, 1 October 2010
How to Cite
Koren-Michowitz, M., le Coutre, P., Duyster, J., Scheid, C., Panayiotidis, P., Prejzner, W., Rowe, J. M., Schwarz, M., Goldschmidt, N. and Nagler, A. (2010), Activity and tolerability of nilotinib. Cancer, 116: 4564–4572. doi: 10.1002/cncr.25351
- Issue published online: 22 JUN 2010
- Article first published online: 19 AUG 2010
- Manuscript Accepted: 4 FEB 2010
- Manuscript Revised: 2 JAN 2010
- Manuscript Received: 9 OCT 2009
Vol. 117, Issue 1, 230, Article first published online: 27 AUG 2010
- chronic myeloid leukemia;
- tyrosine kinase inhibitors;
- response prediction
Nilotinib is active in imatinib-resistant and -intolerant chronic myeloid leukemia patients and was recently approved for these indications.
Data on the efficacy and safety of nilotinib treatment were collected from 2 phase 2 expanded access clinical trials with similar designs (CAMN107AIL01 and ENACT).
Of 88 study patients (58 chronic, 11 accelerated, 19 blast crisis), the best responses to nilotinib were complete hematologic response (CHR) in 27%, partial cytogenetic response in 12%, complete cytogenetic response in 14%, and major molecular response in 19%. Patients achieving at least a CHR during imatinib therapy were more likely to respond to nilotinib, and failure to achieve at least a CHR on imatinib therapy was predictive of progression or lack of response to nilotinib (P = .0021). Responses were not statistically different in subgroup analysis, including that of imatinib intolerance compared with imatinib resistance, presence of ABL kinase domain mutations compared with absence of mutations, and previous treatment with another second-generation tyrosine kinase inhibitor compared no prior treatment. The overall survival and progression-free survival rates at 1 year were 83% and 48% for the entire cohort, 93% and 66% in chronic phase, and 64% and 19% in advanced phase. Adverse hematological events included thrombocytopenia (all events, 27%; grade 3-4, 13%) and leukopenia (all events, 18%; grade 3-4, 10%). The majority of the nonhematological events were mild, the most common being rash, infection, bone pain, headache, nausea, and vomiting.
Nilotinib treatment is an efficient and safe therapy for imatinib-resistant or -intolerant patients. Prior response to imatinib therapy is a predictor for the response to nilotinib. Cancer 2010. © 2010 American Cancer Society.
Chronic myeloid leukemia (CML) is a chronic myeloproliferative disorder characterized by an underlying balanced chromosomal translocation, t(9;22)—the Philadelphia chromosome, which generates the BCR-ABL fusion protein—a tyrosine kinase with enhanced activity. Although treatment with imatinib has changed the current management of CML drastically, discontinuation of treatment may occur in 14% of chronic phase patients because of resistance and in 5% because of toxicity.1 Discontinuation of therapy is even more frequent in the advanced phases of the disease. A variety of mechanisms underlying treatment resistance were identified in the past, including mutations of the BCR-ABL kinase domain, amplification of the Philadelphia chromosome, and clonal evolution.2 This has led to the design of more potent second generation tyrosine kinase inhibitor intended to overcome resistance. The second generation tyrosine kinase inhibitor nilotinib (Novartis, East Hanover, NJ) is an aminopyrimidine derivative of imatinib with an increased binding affinity to the chimeric p210 BCR-ABL. Nilotinib is active in Philadelphia-positive CML both in vitro3, 4 and in clinical studies of imatinib-resistant or -intolerant patients in chronic phase, accelerated phase (AP), and blast crisis (BC) CML.5-8 It was recently approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of imatinib-resistant or -intolerant CML patients9 in chronic and accelerated phases. Additional information regarding the efficacy and safety of nilotinib can be gained from expanded access trials that incorporate in their design aspects learned from the initial phase 2 trials, and are aimed at treating broader populations. Here we report data from a combined cohort of 2 expanded access clinical trials of therapy with nilotinib in imatinib-resistant or -intolerant CML patients in all clinical disease phases, ENACT (Expanding Nilotinib Access in Clinical Trials) and CAMN107AIL01 (ClinicalTrials.gov numbers NCT00302016 and NCT00264160, respectively).
MATERIALS AND METHODS
CML patients ≥18 years old with resistance or intolerance to imatinib therapy were included in the study. Resistance or intolerance to a second generation tyrosine kinase inhibitor was an additional inclusion criterion in the CAMN107AIL01 protocol. To define imatinib resistance, patients had to be treated with at least 600 mg imatinib daily or with the highest tolerated dose. Patients developing an ABL kinase domain mutation during imatinib therapy with an intermediate imatinib sensitivity (L248, G250, Q252, F317, and H396) or with an in vitro insensitivity to imatinib (Y253, E255, and T315)10 were eligible for the trial even if treated with an imatinib dose of <600 mg/d.
Imatinib resistance in chronic phase was defined as a failure to obtain a complete hematologic response (CHR) after 3 months of imatinib therapy or a loss of a CHR, a failure to achieve a minimal cytogenetic response after 6 months of imatinib therapy or a loss of a minimal cytogenetic response, a failure to achieve a major cytogenetic response after 12 months of imatinib therapy or a loss of a major cytogenetic response, cytogenetic progression defined as an increase of ≥30% in bone marrow Philadelphia+ metaphases, or a clonal evolution during therapy with imatinib.
Imatinib resistance in AP and BC was defined as disease progression from chronic phase to an AP or BC or from AP to BC during imatinib therapy, persistent disease for ≥2 weeks during imatinib therapy for BC, disease progression during imatinib therapy (an increase of ≥50% in peripheral white blood cell, basophil, blast, or platelet count), or a lack of a bone marrow response after 4 weeks of imatinib therapy.
Imatinib intolerance was defined as the development of grade 3 or 4 adverse events of any duration or grade 2 adverse events persisting for ≥1 month despite optimal supportive care.
Patients had to have adequate liver, kidney, and cardiac function and a World Health Organization performance status of ≤2. Patients with active central nervous system (CNS) disease were excluded from the study.
The study was approved by the local institutional review board committees according to the declaration of Helsinki, and all patients gave their informed consent.
ABL Kinase Domain Mutation Analysis
Screening for ABL kinase domain mutation was required at entry to CAMN107AIL01 and optional for patients included in the ENACT trial, and was done by direct sequencing or using a chip-based matrix-assisted laser desorption-time-of-flight mass spectrometer with specific primers designed for each mutation site.11
Our analysis includes data from 2 cohorts of patients with similar study designs. Patients from the ENACT trial, a multicenter international trial conducted in Europe, were recruited from Germany (3 centers), Poland, and Greece between November 2006 and March 2008. CAMN107AIL01 patients were recruited in Israel from 3 participating centers between June 2006 and December 2007. The Data reported in this article were collected into a common datasheet and analyzed together.
Study Design and Treatment
Nilotinib was administered at a dose of 400 mg twice daily for a treatment duration of 12 months or until study withdrawal. The dose was reduced to 400 mg daily in patients experiencing a grade ≥3 nonhematological toxicity or grade ≥3 hematological toxicity recovering between 14 and 42 days. Patients with recurring grade ≥3 nonhematological toxicities or a grade ≥3 hematological toxicity recovering after ≥42 days were withdrawn from the study. Other reasons for study discontinuation included unsatisfactory therapeutic response, intolerable toxicity, protocol violation, withdrawal of consent, and death. Responding patients were maintained on therapy after the end of the study until the approval of nilotinib in their respective countries. Follow-up of patients who were withdrawn from the trial was done until 30 days after the last nilotinib dose; extended follow-up data for the patients continuing therapy with nilotinib are included in this report. Dose escalation was not allowed.
The study objectives were safety (ENACT) and both safety and efficacy in the CAMN107AIL01 trial as assessed by the rates of hematological, cytogenetic and molecular responses within the study period.
Response rates were calculated as percentages from the respective populations of patients. Rates of CHR, partial cytogenetic response, complete cytogenetic response, major cytogenetic response (partial cytogenetic response + complete cytogenetic response), and major molecular response were compared between subgroups using a chisquare analysis. Survival curves were done using the Kaplan-Meier method.
A total of 88 patients from 8 centers (ENACT, 54; CAMN107AIL01, 34) are included in this analysis; their baseline features are shown in Table 1. The median follow-up duration was 445 days (range, 34-1000 days), and the mean treatment duration was 273 days (range, 1-954 days).
|Median age, y (range)||60 (23-85)|
|Sex, women/men, %||62/38|
|Median disease duration, mo (range)||44 (2-200)|
|Prior therapies other than imatinib, % (No. with data)|
|Other TKIsb||18 (87)|
|Disease phase at study entry, No. (%)|
|Blast [myeloid/lymphoid]||19 [15/4] (17)|
|Additional cytogenetic abnormalities % (No. with data)c||31 (74)|
|ABL KD mutation, % (No. with data)||26 (78)|
|Imatinib resistance, No. (%)||66 (75)|
|Imatinib intolerance, No. (%)||22 (25)|
|Imatinib dose ≥600 mg prior to study, % (No. with data)||60 (71)|
|Median prior imatinib duration, mo (range)||23.7 (1-95)|
|Prior imatinib best response, % (No. with data)|
Fifty-eight (66%) patients were included in the study in chronic phase, 11 (12%) in AP, and 19 (22%) in BC. Imatinib resistance was the reason for inclusion for 66 (75%) patients and intolerance for 22 (25%). At the time of data analysis, 28 patients had completed the study, and 21 were on therapy within the study. Thirty-nine patients had discontinued therapy because of disease progression/lack of response (n = 20), side effects (n = 11), stem cell transplantation (SCT) (n = 3), and other reasons (n = 5).
Response rates are shown in Figure 1 for the whole group, and Table 2 shows the responses to nilotinib according to the disease phase at study inclusion. The best responses to nilotinib were CHR in 23 (27%), partial cytogenetic response in 10 (12%), complete cytogenetic response in 12 (14%), and major molecular response in 16 (19%) patients. An additional 15 (18%) patients had stable disease during treatment with imatinib, and 1 advanced phase patient returned to chronic phase. CHR was newly achieved in 40 (66%), major cytogenetic response in 30 (43%), and major molecular response in 16 (20%) patients not having those responses at study entry (Fig. 1A). The median time to achieve a major cytogenetic response in the responding patients was 150 days (range, 20-421 days).
|Study Subgroup||Response/Evaluable, No. (%)|
|CP||25/35 (71)||14/32 (44)||14/37 (38)||21/40 (53)||8/41 (20)|
|AP||6/10 (60)||3/9 (33)||1/7 (14)||2/7 (29)||0/10 (0)|
|BP||9/16a (56)||4/14 (29)||6/14 (43)||8/15 (53)||2/16 (13)|
|Myeloid||7/12a (58)||4/12 (33)||4/10 (40)||6/10 (60)||2/12 (17)|
|Lymphoid||2/3 (67)||0/2 (0)||2/3 (67)||2/3 (67)||0/4 (0)|
|Prior TKI therapy||.71||.72||1.0||1.0|
|Yes||5/9 (55)||3/10 (30)||3/9 (33)||1/11 (9)|
|No||34/52 (65)||18/45 (40)||12/22 (55)||9/55 (16)|
|ABL KD mutation||.39||.54||.38||.48|
|Yes||10/19 (53)||6/19 (32)||5/20 (25)||2/20 (10)|
|No||23/35 (66)||13/30 (43)||16/40 (40)||10/49 (20)|
|ABL KD mutation with an IC50 >150||.001||.008||.02||.02||.19|
|Yes||1/9 (11)||0/9 (0)||0/9 (0)||0/9 (0)||0/9 (0)|
|No||32/44 (73)||19/40 (48)||20/51 (39)||26/61 (43)||13/60 (22)|
|Additional cytogenetic abnormalities||.22||1.0||.45||.7|
|Yes||9/17 (53)||6/17 (35)||2/14 (14)||2/18 (11)|
|No||27/38 (71)||12/32 (38)||9/30 (30)||7/38 (18)|
Response rates were lower in imatinib-resistant compared with imatinib-intolerant patients, and were 61% and 75% for a CHR, 36% and 50% for a partial cytogenetic response, 29% and 47% for a complete cytogenetic response, and 16% and 33% for a major molecular response in imatinib-resistant and -intolerant patients, respectively. These differences, however, were not statistically different (P = .54, .48, .22, and .18, respectively), presumably because of the small number of patients in each subgroup (Fig. 1B). There was no difference in response rates between patients with and without additional cytogenetic abnormalities at study entry (Table 2).
The achievement of at least a CHR during imatinib therapy was predictive of a subsequent response to nilotinib, whereas a failure to achieve at least a CHR on imatinib therapy was predictive of progression or lack of response to nilotinib therapy. Seventy percent of patients whose best response to imatinib was a CHR achieved at least a CHR to nilotinib, whereas 60% of patients without a CHR on imatinib did not achieve at least a CHR on nilotinib (P = .0021). Of patients with a CHR as best response to imatinib, 40% had a CHR as their best response to nilotinib, whereas 15% maintained a previously achieved CHR, and 30% achieved at least a major cytogenetic response. The remaining 15% of patients either did not respond to therapy or their response is not known. Furthermore, of the patients with a prior major cytogenetic response to imatinib, 70% have achieved a major cytogenetic response or better to nilotinib, and 10% have maintained their previously achieved response, whereas only 17% have achieved only a CHR during nilotinib therapy, and 3% of patients progressed.
For the purpose of survival analysis, the data for patients in AP and BC were analyzed together as advanced phase disease. The median overall survival was 914 days in chronic phase and 727 days in advanced phase disease (Fig. 2A), and has not yet been reached for patients with imatinib intolerance compared with 914 days for imatinib-resistant patients (P = .15) (Fig. 2B). The median progression-free survival was not reached in chronic phase and was 120 days in advanced phase disease (Fig. 2C), and was significantly better in imatinib-intolerant compared with imatinib-resistant patients (not reached compared with 319 days; P = .028; 95% confidence interval, 1.102-5.380) (Fig. 2D). The overall survival rates at 1 year were 83% for the entire cohort, 93% for chronic phase patients, and 64% for patients in advanced phase, and the progression-free survival rates at 1 year were 48%, 66%, and 19%, respectively.
Prior Tyrosine Kinase Inhibitor Therapy
Nilotinib therapy was commenced in 16 (18%) patients after failure or intolerance in response to another second generation tyrosine kinase inhibitor in 6 and 8 patients, respectively, and for an unknown reason in 2. The prior tyrosine kinase inhibitor was dasatinib in 14 patients, bosutinib in 1 (this patient was also treated with dasatinib), and INNO 406 in 1. Response rates in this subgroup were not significantly different compared with responses in patients without prior therapy with another tyrosine kinase inhibitor (Table 2). There was no significant difference in responses between patients with a prior second generation tyrosine kinase inhibitor failure compared with patients showing prior tyrosine kinase inhibitor intolerance (P = .28, data not shown).
Baseline ABL Kinase Domain Mutations
Twenty (26%) patients had 22 ABL kinase domain mutations at study entry; their best responses are shown in Table 3. ABL kinase domain mutations were found at baseline only in patients with imatinib resistance and not in patients with imatinib intolerance (20 of 65 compared with 0 of 22, P = .002). Mutations were found more often in patients with an advanced phase CML (8 of 41 in chronic phase, 5 of 9 in AP, 7 of 18 in BP; P = .0187). Interestingly, patients previously treated with another second generation tyrosine kinase inhibitor had a borderline lower frequency of ABL kinase domain mutations (1 of 15 compared with 19 of 60; P = .057). The frequency of ABL kinase domain mutations was not significantly different in patients with various baseline treatment histories, including prior treatment with interferon α (7 of 27 in treated compared with 10 of 48 in nontreated patients; P = .57), chemotherapy (8 of 29 in treated compared with 9 of 45 in nontreated patients; P = .57), and SCT (2 of 7 in treated compared with 21 of 77 in nontreated patients; P = 1.0). Similarly, there was no difference in the frequency of mutations between patients with additional cytogenetic abnormalities at study entry (7 of 21) compared with those with no cytogenetic abnormalities (11 of 53; P = .36). There was no statistically significant difference in the rate of responses to nilotinib between patients with and without ABL kinase domain mutations at baseline. CHR was newly achieved in 53% compared with 66%, partial cytogenetic response in 32% compared with 43%, complete cytogenetic response in 25% compared with 40%, and major molecular response in 10% compared with 20% in patients with ABL kinase domain mutations and patients with no mutations, respectively (Table 2). Hughes et al15 has recently reported that the clinical responses to nilotinib in patients with chronic phase CML were similar in patients without baseline ABL kinase domain mutations and those with mutations having a relatively low concentration that inhibits 50% (IC50) value to nilotinib, with a cutoff value of ≤150 nM, or with unknown IC50 values. We have therefore reanalyzed our data and compared the responses achieved in patients harboring mutations with an IC50 >150 nM (Y253H, E255K, T315I, and F359V) to the responses in patients without mutations or with mutations and an IC50 ≤150 nM or an unknown IC50 (combined group). In the group of patients harboring mutations with a high IC50, CHR was newly achieved in 11%, and none of the patients achieved a cytogenetic or molecular response compared with newly achieved rates of CHR in 73%, partial cytogenetic response in 48%, CCR in 39%, and major molecular response in 22% in the combined group (P = .001, .008, .02, and .19, respectively) (Table 2).
|Mutation||IC50 Values for Nilotinib, nM10, 24||No.||Best Response|
Seven patients had both kinase domain mutations and additional cytogenetic abnormalities at study entry. In this subgroup, CHR was newly achieved in 57%, partial cytogenetic response in 29%, complete cytogenetic response in 17%, and major molecular response in 0%. These rates were not significantly different from the rates of responses in patients with neither kinase domain mutations nor other cytogenetic abnormalities (CHR, 80%; partial cytogenetic response, 50%, 56%; major molecular response, 19%; P = .79). Among the patients who were previously treated with a second generation tyrosine kinase inhibitor, 1 patient had 2 ABL kinase domain mutations before starting therapy with nilotinib (L387M and E255K). This patient's best response was a CHR.
New ABL kinase domain mutations were acquired in 7 patients during nilotinib therapy (2 patients had 2 mutations each), including F311L, E255K (n = 3), T315I (n = 3), Y253H, and F359V. All patients have discontinued nilotinib because of disease progression (n = 6) and SCT (1 patient).
The average daily nilotinib dose at the time of data collection in the 73 evaluable patients was 715 mg (range, 200-800 mg). Hematological toxicities occurred in 36 (40%) patients on nilotinib therapy and were of grade 3 to 4 in 31%. The most common toxicities were thrombocytopenia in 24 (27%) and leucopenia in 16 (18%) patients, and were of grade 3 to 4 in 11 (13%) and 9 (10%) patients, respectively. Nonhematological and biochemical adverse events appearing in ≥2 patients are summarized in Table 4. Overall, 55% of patients experienced at least 1 nonhematological adverse event, with 1% being grade 3 to 4, and 34% of patients had at least 1 biochemical abnormality during therapy, including a 7% rate of grade 3 to 4 abnormalities. The most common nonhematological adverse events were skin rash, infections, headache, and bone pain. Infections occurred in 7 (9%) patients and were viral in 2 (herpes simplex and herpes zoster), bacterial in 2 (recurring pneumonia and cellulites), and fungal in 1 (perianal mycosis). The nature of infection was not defined in 2 patients. Of the 7 patients who entered the study because of an intolerable skin rash and/or edema during imatinib therapy, 4 had recurrence of skin rash during nilotinib therapy, with 1 patient experiencing a grade 3 to 4 skin rash. There was no recurrence of edema. Of the patients previously treated with another second generation tyrosine kinase inhibitor, 4 have discontinued treatment because of intolerance; all were treated with dasatinib and suffered from dyspnea that was because of a pleural effusion in 2 and an exacerbation of underlying chronic obstructive pulmonary disease in 1 patient. The nature of dyspnea in the fourth patient was not known, and he had normal cardiac and lung functions and normal chest computed tomography. None of the patients had a recurrence of lung toxicity. The most common biochemical abnormalities were hyperbilirubinemia, an elevation of liver enzymes, hyperglycemia, and an elevation of amylase and/or lipase levels. Interestingly, 3 of the 5 patients with abnormal pancreatic enzyme levels were reported from the same center in Europe. There were no episodes of clinical pancreatitis. There were 5 patients who had liver toxicities during therapy with imatinib. None of these patients had a recurrence of liver abnormalities during nilotinib therapy. Rare adverse events during nilotinib therapy, occurring in 1 patient each, included a low-grade QT prolongation and grade 3 to 4 pneumonitis. One patient suffered a grade 4 polyneuropathy but was found to have a CNS relapse of lymphoid BC after the end of the study.
|Adverse Event||All, No. (%)||Grade 3-4, No. (%)|
|Rash||14 (18)||1 (1)|
|Infection||7 (9)||1 (1)|
|Bone pain||5 (6)||1 (1)|
|Dyspnea||3 (4)||1 (1)|
|Fever||3 (4)||2 (3)|
|Muscle cramps||3 (4)||0|
|Edema||3 (4)||1 (1)|
|Abdominal pain||2 (3)||0|
|Hyperbilrubinemia||15 (17)||2 (2)|
|Elevated liver enzymes||12 (14)||1 (1)|
|Elevated amylase/lipase||5 (6)||0|
|Elevated CPK||3 (3)||0|
The optimal selection and use of a second tyrosine kinase inhibitor in CML patients who are imatinib intolerant or resistant is of great importance and needs to be finely tuned. Our results reinforce the efficacy and safety of nilotinib shown in previous reports5-8 and recent updates.8, 16-18 CHR was newly achieved in 66% and major cytogenetic response in 43%. The rates of CHR (71%) and major cytogenetic response (53%) in chronic phase are comparable to the reported rates of 74% and 48%, respectively.5 Similarly, the response rates in AP are equivalent to those previously reported, with a CHR rate of 60% compared with 47% and a major cytogenetic response rate of 29% compared with 29%.6 The results of nilotinib therapy in BC patients in our cohort are better than the recently reported rates,8 with a CHR rate of 56% compared with 11% and a major cytogenetic response rate of 53% compared with 40%. The relatively small number of BC patients analyzed in our study may explain these differences. The overall survival rate at 1 year for chronic phase patients in our study is also in accordance with the previously published rate,5 and the rate in advanced phase of 64% is compatible with the published overall rate of 78% in AP6 and 42% in BC.8 With currently 2 approved second generation tyrosine kinase inhibitors (ie, nilotinib and dasatinib), and extensive research on other novel kinase inhibitors, the identification of factors that may predict the response to second line therapy can assist in treatment decisions. For patients in chronic phase, Branford et al19 have recently demonstrated that the initial molecular response to a second generation tyrosine kinase inhibitor was predictive of subsequent responses. In advanced phase patients, it was shown that the failure to achieve a CHR at the time of achievement of a major cytogenetic response with a second generation tyrosine kinase inhibitor is associated with a poor prognosis.20 In the current study, we have found that a previous good response to imatinib was predictive of a good response to nilotinib. In addition, the depth of response to imatinib was predictive of the depth of response to nilotinib. This suggests that patients who are considered for second line therapy with nilotinib because of imatinib intolerance or those with secondary resistance after achieving at least a CHR on imatinib are more likely to respond to nilotinib. Conversely, patients who did not achieve at least a CHR during therapy with imatinib are less likely to respond to nilotinib and may do better with another tyrosine kinase inhibitor or other treatment modalities.
Our findings regarding ABL kinase domain mutations are quite intriguing; kinase domain mutations in our cohort were only found in imatinib resistant patients and were less frequent in patients who were previously treated with another second generation tyrosine kinase inhibitor. This may suggest that the mechanism of resistance in patients treated sequentially with 2 tyrosine kinase inhibitors is less likely to involve ABL kinase domain mutations. Another possible explanation for the lower frequency of kinase domain mutations observed may involve the study inclusion criteria, allowing recruitment of patients with intolerance to a second generation tyrosine kinase inhibitor. These patients are probably less likely to have ABL kinase domain mutations. In accordance with the recently reported clinical results in chronic phase patients,21 and with a cutoff of IC50 ≤150 nM for mutations with a higher chance of clinical responses to nilotinib recently described by Hughes et al,15 we found that patients harboring mutations with an in vitro moderate or high resistance to nilotinib, including E255K, Y253H, and F359V,22-25 were less likely to respond to nilotinib, and none of the 3 T315I-positive patients responded. These mutations were also the most commonly newly acquired mutations in patients who did not respond to nilotinib or progressed during therapy.
Therapy with nilotinib was well tolerated. We did observe a recurrence of skin rash in patients who were intolerant to imatinib because of skin rashes; however, none of the other imatinib-related toxicities recurred during nilotinib therapy. Importantly, none of the patients who experienced pulmonary toxicities during dasatinib therapy had a recurrent toxicity during therapy with nilotinib, making this agent applicable for dasatinib-intolerant patients.
In conclusion, our results support the efficacy and good tolerability of nilotinib treatment in patients who are unable to continue imatinib therapy for CML in both chronic phase and advanced phases. The relation between responses to nilotinib and the previous response to imatinib therapy found in this study may assist in future decisions regarding the choice of a new generation tyrosine kinase inhibitor as well as timing of therapeutic changes.
CONFLICT OF INTEREST DISCLOSURES
The data included in this article are extracted from clinical trials supported by Novartis. Dr. le Coutre has received honoraria from Novartis, and Dr. Nagler has received consultancy, honoraria, and research funding from Novartis.
- 5Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007; 110: 3540-3546., , , et al.
- 8Nilotinib in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in blast crisis (CML-BC) who are resistant or intolerant to imatinib. J Clin Oncol. 2008; 26: 7017., , , et al.
- 16Nilotinib in chronic myeloid leukemia patients in accelerated phase (CML-AP) with imatinib resistance or intolerance: 2-year follow-up results of a phase 2 study [abstract]. ASH Annual Meeting Abstracts. 2008; 112: 3229., , , et al.
- 17Nilotinib in chronic myeloid leukemia patients in chronic phase (CMLCP) with imatinib resistance or intolerance: 2-year follow-up results of a phase 2 study [abstract]. ASH Annual Meeting Abstracts. 2008; 112: 3238., , , et al.
- 18Efficacy and tolerability of nilotinib in chronic myeloid leukemia patients in chronic phase (CML-chronic phase) who failed prior imatinib and dasatinib therapy: updated results of a phase 2 study [abstract]. ASH Annual Meeting Abstracts. 2008; 112: 3234., , , et al.
- 19The initial molecular response of chronic phase CML patients treated with second generation ABL inhibitor therapy after imatinib failure can predict inadequate response and provide indications for rational mutation screening [abstract]. ASH Annual Meeting Abstracts. 2008; 112: 331., , , , , .
- 20Failure to achieve a complete hematologic response at the time of achievement of a major cytogenetic response with second generation tyrosine kinase inhibitors is associated with a poor prognosis among patients with chronic myeloid leukemia in accelerated or blast phase. Blood. 2009; 13: 5058-5063., , , et al.
- 21Nilotinib efficacy according to baseline BCR-ABL mutations in patients with imatinib-resistant chronic myeloid leukemia in chronic phase (CML-CP) [abstract]. ASH Annual Meeting Abstracts. 2008; 112: 3216., , , et al.