Multicenter phase II clinical trial of nilotinib for patients with imatinib-resistant or -intolerant chronic myeloid leukemia from the East Japan CML study group evaluation of molecular response and the efficacy and safety of nilotinib

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Abstract

Background

Nilotinib is a second-generation tyrosine kinase inhibitor that exhibits significant efficacy as first- or second-line treatment in patients with chronic myeloid leukemia (CML). We conducted a multicenter Phase II Clinical Trial to evaluate the safety and efficacy of nilotinib among Japanese patients with imatinib-resistant or -intolerant CML-chronic phase (CP) or accelerated phase (AP).

Results

We analyzed 49 patients (33 imatinib-resistant and 16 imatinib-intolerant) treated with nilotinib 400 mg twice daily. The major molecular response (MMR) rate was 47.8% at 12 months among 35 patients who did not demonstrate an MMR at study entry. Somatic BCR-ABL1 mutations (Y253H, I418V, and exon 8/9 35-bp insertion [35INS]) were detected in 3 patients at 12 months or upon discontinuation of nilotinib. Although 75.5% of patients were still being treated at 12 months, nilotinib treatment was discontinued because of progressing disease in 1 patient, insufficient effect in 2, and adverse events in 9. There was no statistically significant correlation between MMR and trough concentrations of nilotinib. Similarly, no correlation was observed between trough concentrations and adverse events, except for pruritus and hypokalemia. Hyperbilirubinemia was frequently observed (all grades, 51.0%; grades 2–4, 29%; grades 3–4, 4.1%). Hyperbilirubinemia higher than grade 2 was significantly associated with the uridine diphosphate glucuronosyltransferase ( UGT) 1A9 I399C/C genotype ( P = 0.0086; Odds Ratio, 21.2; 95% Confidence Interval 2.2–208.0).

Conclusions

Nilotinib was efficacious and well tolerated by patients with imatinib-resistant or -intolerant CML-CP/AP. Hyperbilirubinemia may be predicted before nilotinib treatment, and may be controlled by reducing the daily dose of nilotinib in patients with UGT1A9 polymorphisms.

Trial registration

clinicaltrials.gov: UMIN000002201

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Most cited references 26

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Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet.

Michele Baccarani, Jorge Cortés, Fabrizio Pane … (2009)

To review and update the European LeukemiaNet (ELN) recommendations for the management of chronic myeloid leukemia with imatinib and second-generation tyrosine kinase inhibitors (TKIs), including monitoring, response definition, and first- and second-line therapy. These recommendations are based on a critical and comprehensive review of the relevant papers up to February 2009 and the results of four consensus conferences held by the panel of experts appointed by ELN in 2008. Cytogenetic monitoring was required at 3, 6, 12, and 18 months. Molecular monitoring was required every 3 months. On the basis of the degree and the timing of hematologic, cytogenetic, and molecular results, the response to first-line imatinib was defined as optimal, suboptimal, or failure, and the response to second-generation TKIs was defined as suboptimal or failure. Initial treatment was confirmed as imatinib 400 mg daily. Imatinib should be continued indefinitely in optimal responders. Suboptimal responders may continue on imatinb, at the same or higher dose, or may be eligible for investigational therapy with second-generation TKIs. In instances of imatinib failure, second-generation TKIs are recommended, followed by allogeneic hematopoietic stem-cell transplantation only in instances of failure and, sometimes, suboptimal response, depending on transplantation risk.

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Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial.

Giuseppe Saglio, I Flinn, Gianantonio Rosti … (2011)

Nilotinib has shown greater efficacy than imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukaemia (CML) in chronic phase after a minimum follow-up of 12 months. We present data from the Evaluating Nilotinib Efficacy and Safety in clinical Trials-newly diagnosed patients (ENESTnd) study after a minimum follow-up of 24 months. ENESTnd was a phase 3, multicentre, open-label, randomised study. Adult patients were eligible if they had been diagnosed with chronic phase, Philadelphia chromosome-positive CML within the previous 6 months. Patients were randomly assigned (1:1:1) to receive nilotinib 300 mg twice a day, nilotinib 400 mg twice a day, or imatinib 400 mg once a day, all administered orally, by use of a computer-generated randomisation schedule, using permuted blocks, and stratified according to Sokal score. Efficacy results are reported for the intention-to-treat population. The primary endpoint was major molecular response at 12 months, defined as BCR-ABL transcript levels on the International Scale (BCR-ABL(IS)) of 0·1% or less by real-time quantitative PCR in peripheral blood. This study is registered with ClinicalTrials.gov, number NCT00471497. 282 patients were randomly assigned to receive nilotinib 300 mg twice daily, 281 to receive nilotinib 400 mg twice daily, and 283 to receive imatinib. By 24 months, significantly more patients had a major molecular response with nilotinib than with imatinib (201 [71%] with nilotinib 300 mg twice daily, 187 [67%] with nilotinib 400 mg twice daily, and 124 [44%] with imatinib; p<0·0001 for both comparisons). Significantly more patients in the nilotinib groups achieved a complete molecular response (defined as a reduction of BCR-ABL(IS) levels to ≤0·0032%) at any time than did those in the imatinib group (74 [26%] with nilotinib 300 mg twice daily, 59 [21%] with nilotinib 400 mg twice daily, and 29 [10%] with imatinib; p<0·0001 for nilotinib 300 mg twice daily vs imatinib, p=0·0004 for nilotinib 400 mg twice daily vs imatinib). There were fewer progressions to accelerated or blast phase on treatment, including clonal evolution, in the nilotinib groups than in the imatinib group (two with nilotinib 300 mg twice daily, five with nilotinib 400 mg twice daily, and 17 with imatinib; p=0·0003 for nilotinib 300 mg twice daily vs imatinib, p=0·0089 for nilotinib 400 mg twice daily vs imatinib). At 24 months, survival was comparable in all treatment groups, but fewer CML-related deaths had occurred in both the nilotinib groups than in the imatinib group (five with nilotinib 300 mg twice daily, three with nilotinib 400 mg twice daily, and ten with imatinib). Overall, the only grade 3 or 4 non-haematological adverse events that occurred in at least 2·5% of patients were headache (eight [3%] with nilotinib 300 mg twice daily, four [1%] with nilotinib 400 mg twice daily, and two [<1%] with imatinib) and rash (two [<1%], seven [3%], and five [2%], respectively). Grade 3 or 4 neutropenia was more common with imatinib than with either dose of nilotinib (33 [12%] with nilotinib 300 mg twice daily, 30 [11%] with nilotinib 400 mg twice daily, and 59 [21%] with imatinib). Serious adverse events were reported in eight additional patients in the second year of the study (four with nilotinib 300 mg twice daily, three with nilotinib 400 mg twice daily, and one with imatinib). Nilotinib continues to show better efficacy than imatinib for the treatment of patients with newly diagnosed CML in chronic phase. These results support nilotinib as a first-line treatment option for patients with newly diagnosed disease. Novartis. Copyright © 2011 Elsevier Ltd. All rights reserved.

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Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis.

Y. Hasegawa, M Ando, H Ueoka … (2000)

Irinotecan unexpectedly causes severe toxicity of leukopenia or diarrhea. Irinotecan is metabolized to form active SN-38, which is further conjugated and detoxified by UDP-glucuronosyltransferase (UGT) 1A1 enzyme. Genetic polymorphisms of the UGT1A1 would affect an interindividual variation of the toxicity by irinotecan via the alternation of bioavailability of SN-38. In this case-control study, retrospective review of clinical records and determination of UGT1A1 polymorphisms were performed to investigate whether a patient with the variant UGT1A1 genotypes would be at higher risk for severe toxicity by irinotecan. All patients previously received irinotecan against cancer in university hospitals, cancer centers, or large urban hospitals in Japan. We identified 26 patients who experienced severe toxicity and 92 patients who did not. The relationship was studied between the multiple variant genotypes (UGT1A1*28 in the promoter and UGT1A1*6, UGT1A1*27, UGT1A1*29, and UGT1A1*7 in the coding region) and the severe toxicity of grade 4 leukopenia (< or =0.9 x 10(9)/liter) and/or grade 3 (watery for 5 days or more) or grade 4 (hemorrhagic or dehydration) diarrhea. Of the 26 patients with the severe toxicity, the genotypes of UGT1A1*28 were homozygous in 4 (15%) and heterozygous in 8 (31%), whereas 3 (3%) homozygous and 10 (11%) heterozygous were found among the 92 patients without the severe toxicity. Multivariate analysis suggested that the genotype either heterozygous or homozygous for UGT1A1*28 would be a significant risk factor for severe toxicity by irinotecan (P < 0.001; odds ratio, 7.23; 95% confidence interval, 2.52-22.3). All 3 patients heterozygous for UGT1A1*27 encountered severe toxicity. No statistical association of UGT1A1*6 with the occurrence of severe toxicity was observed. None had UGT1A1*29 or UGT1A1*7. We suggest that determination of the UGT1A1 genotypes might be clinically useful for predicting severe toxicity by irinotecan in cancer patients. This research warrants a prospective trial to corroborate the usefulness of gene diagnosis of UGT1A1 polymorphisms prior tb irinotecan chemotherapy.

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Author and article information

Contributors

Naoto Takahashi

Masatomo Miura

Jun Kuroki

Kinuko Mitani

Atsushi Kitabayashi

Osamu Sasaki

Hideo Kimura

Kiyotoshi Imai

Norifumi Tsukamoto

Hideyoshi Noji

Takeshi Kondo

Mutsuhito Motegi

Yuichi Kato

Masayuki Mita

Hajime Saito

Chikashi Yoshida

Yoshihiro Torimoto

Tomofumi Kimura

Yuji Wano

Jun Nomura

Satoshi Yamamoto

Ko Mayama

Riko Honma

Tomohiro Sugawara

Shinji Sato

Atsushi Shinagawa

Maiko Abumiya

Takenori Niioka

Hideo Harigae

Kenichi Sawada

Journal

Journal ID (nlm-ta): Biomark Res

Journal ID (iso-abbrev): Biomark Res

Title: Biomarker Research

Publisher: BioMed Central

ISSN (Electronic): 2050-7771

Publication date Collection: 2014

Publication date (Electronic): 20 March 2014

Volume: 2

Page: 6

Affiliations

[1 ]Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, 1-1-1 Hondo, 010-8543 Akita, Japan

[2 ]Department of Pharmacology, Akita University Hospital, Akita, Japan

[3 ]Department of Internal Medicine, Yuri Kumiai General Hospital, Yurihonjo, Japan

[4 ]Department of Hematology and Oncology, Dokkyo Medical University School of Medicine, Mibu-machi, Japan

[5 ]Department of Internal Medicine, Akita Kumiai General Hospital, Akita, Japan

[6 ]Division of Hematology, Department of Internal Medicine, Miyagi Cancer Center, Natori, Japan

[7 ]Department of Hematology, Kita-Fukushima Medical Center, Date, Japan

[8 ]Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Japan

[9 ]Oncology Center, Gunma University Hospital, Maebashi, Japan

[10 ]Department of Cardiology and Hematology, Fukushima Medical University, Fukushima, Japan

[11 ]Stem Cell Transplantation Center, Hokkaido University Hospital, Sapporo, Japan

[12 ]Department of Internal Medicine, Senboku Kumiai General Hospital, Daisen, Japan

[13 ]Department of Neurology, Hematology, Metabolism, Endocrinology and Diabetology, Yamagata University Faculty of Medicine, Yamagata, Japan

[14 ]Department of Cardiology and Hematology, Shirakawa Kosei General Hospital, Shirakawa, Japan

[15 ]Department of Internal Medicine, Mito Chuo Hospital, Mito, Japan

[16 ]Department of Hematology, Mito Medical Center, Mito, Japan

[17 ]Oncology Center, Asahikawa Medical College Hospital, Asahikawa, Japan

[18 ]Division of Hematology, Department of Internal Medicine, Suifu Hospital, Mito, Japan

[19 ]Department of Hematology, Iwate Prefectural Central Hospital, Morioka, Japan

[20 ]Department of Internal Medicine, NTT East Japan Tohoku Hospital, Sendai, Japan

[21 ]Department of Hematology, Sapporo City General Hospital, Sapporo, Japan

[22 ]Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan

[23 ]Department of Hematology, Yamagata Prefectural Central Hospital, Yamagata, Japan

[24 ]Department of Internal Medicine, Osaki Citizen Hospital, Osaki, Japan

[25 ]Division of Hematology, Department of Internal Medicine, Okitama Public General Hospital, Higashi Okitama, Japan

[26 ]Division of Hematology, Department of Internal Medicine, Hitachi General Hospital, Hitachi, Japan

[27 ]Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan

Article

Publisher ID: 2050-7771-2-6

DOI: 10.1186/2050-7771-2-6

PMC ID: 3994575

PubMed ID: 24650752

SO-VID: ad9aa3b7-70f8-4273-9eb2-414db1a489c6

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 13 January 2014

Date accepted : 27 February 2014

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Multicenter phase II clinical trial of nilotinib for patients with imatinib-resistant or -intolerant chronic myeloid leukemia from the East Japan CML study group evaluation of molecular response and the efficacy and safety of nilotinib

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Abstract

Background

Results

Conclusions

Trial registration

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Efficacy of Communicating Science

Most cited references 26

Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet.

Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial.

Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis.

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