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

Takahashi, Naoto; Miura, Masatomo; Kuroki, Jun; Mitani, Kinuko; Kitabayashi, Atsushi; Sasaki, Osamu; Kimura, Hideo; Imai, Kiyotoshi; Tsukamoto, Norifumi; Noji, Hideyoshi; Kondo, Takeshi; Motegi, Mutsuhito; Kato, Yuichi; Mita, Masayuki; Saito, Hajime; Yoshida, Chikashi; Torimoto, Yoshihiro; Kimura, Toshihide; Wano, Yuji; Nomura, Jun; Yamamoto, Satoshi; Mayama, Ko; Honma, Riko; Sugawara, Tomohiro; Sato, Shinji; Shinagawa, Atsushi; Abumiya, Maiko; Niioka, Takenori; Harigae, Hideo; Sawada, Kenichi

doi:10.1186/2050-7771-2-6

Cited by 22 publications

(11 citation statements)

References 32 publications

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“…Several reports have demonstrated that BCR-ABL Ins35bp is detected mainly in patients who have achieved hematological/cytogenetic response, but not DMR, despite long-term TKI treatment. (6,12,15,43) In contrast, extremely low amounts of BCR-ABL Ins35bp were detected in patients with newly-diagnosed, previously untreated CML (data not shown). We found that TKI treatment inhibits recruitment of RNA polymerase a toward genomic BCR-ABL, which positively regulates both transcription and pre-mRNA intron splicing, resulting in a relative increase in the amount of BCR-ABL Ins35bp with a decrease of total BCR-ABL transcript level.…”

Section: Discussionmentioning

confidence: 88%

“…It has remained unclear how alternatively spliced BCR‐ABL Ins35bp variants can be acquired in CML cells under TKI treatment, and why mis‐splicing reproducibly occurs at the specific sites of intronic 35 bp in ABL intron 8. Several reports have demonstrated that BCR‐ABL Ins35bp is detected mainly in patients who have achieved hematological/cytogenetic response, but not DMR, despite long‐term TKI treatment . In contrast, extremely low amounts of BCR‐ABL Ins35bp were detected in patients with newly‐diagnosed, previously untreated CML (data not shown).…”

Section: Discussionmentioning

confidence: 89%

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Persistent detection of alternatively spliced BCR‐ABL variant results in a failure to achieve deep molecular response

Yuda

Miyamoto

Odawara³

et al. 2017

Cancer Science

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Treatment with tyrosine kinase inhibitors (TKI) may sequentially induce TKI‐resistant BCR‐ABL mutants in chronic myeloid leukemia (CML). Conventional PCR monitoring of BCR‐ABL is an important indicator to determine therapeutic intervention for preventing disease progression. However, PCR cannot separately quantify amounts of BCR‐ABL and its mutants, including alternatively spliced BCR‐ABL with an insertion of 35 intronic nucleotides (BCR‐ ABLI ns35bp) between ABL exons 8 and 9, which introduces the premature termination and loss of kinase activity. To assess the clinical impact of BCR‐ABL mutants, we performed deep sequencing analysis of BCR‐ABL transcripts of 409 samples from 37 patients with suboptimal response to frontline imatinib who were switched to nilotinib. At baseline, TKI‐resistant mutations were documented in 3 patients, whereas BCR‐ ABLI ns35bp was detected in all patients. After switching to nilotinib, both BCR‐ABL and BCR‐ ABLI ns35bp became undetectable in 3 patients who attained complete molecular response (CMR), whereas in the remaining all 34 patients, BCR‐ ABLI ns35bp was persistently detected, and minimal residual disease (MRD) fluctuated at low but detectable levels. PCR monitoring underestimated molecular response in 5 patients whose BCR‐ ABLI ns35bp was persisted, although BCR‐ ABLI ns35bp does not definitively mark TKI resistance. Therefore, quantification of BCR‐ ABLI ns35bp is useful for evaluating “functional” MRD and determining the effectiveness of TKI with accuracy.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 89%

Persistent detection of alternatively spliced BCR‐ABL variant results in a failure to achieve deep molecular response

Yuda

Miyamoto

Odawara³

et al. 2017

Cancer Science

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“…The threshold for nilotinib C 0 should be set above 761 ng/mL on a receiver operating characteristic (ROC) curve with a sensitivity of 76.2% and specificity of 77.8%. 60) Afterwards, however, 10 patients during the first 12 months discontinued nilotinib treatment because of severe adverse events such as thrombocytopenia and hyperbilirubinemia. 61) Consequently, in the final analysis of the EJCML study, the nilotinib C 0 tended to increase in patients who achieved MMR at 12 months, but this result was not statistically significant; the median C 0 were 774 ng/mL and 490 ng/mL (less than 500 ng/mL), respectively (p=0.261).…”

Section: Nilotinib Tdmmentioning

confidence: 99%

“…On the other hand, in UGT1A1 EM patients who achieved MMR at 12 months, the steady-state mean nilotinib C 0 was 934 ng/ mL. 59) Based on the EJCML study and the steady-state mean nilotinib C 0 , 59,61) a target C 0 of 800 ng/mL is recommended for TDM after administration of the initial 600 mg/d dose of nilotinib (Fig. 4).…”

Section: Nilotinib Tdmmentioning

confidence: 99%

Therapeutic Drug Monitoring of Imatinib, Nilotinib, and Dasatinib for Patients with Chronic Myeloid Leukemia

Miura

2015

Biological & Pharmaceutical Bulletin

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139

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Imatinib, nilotinib, and dasatinib are tyrosine kinase inhibitors (TKIs) that have become first-line treatments for Philadelphia chromosome-positive chronic myeloid leukemia (CML). According to European LeukemiaNet recommendations, the clinical response of CML patients receiving TKI therapy should be evaluated after 3, 6, and 12 months. For patients not achieving a satisfactory response within 3 months, the mean plasma concentration for the three months of TKI administration must be considered. In TKI therapy for CML patients, therapeutic drug monitoring is a new strategy for dosage optimization to obtain a faster and more effective clinical response. The imatinib plasma trough concentration (C 0 ) should be set above 1000 ng/mL to obtain a response and below 3000 ng/mL to avoid serious adverse events such as neutropenia. For patients with a UGT1A1*6/*6, *6/*28, or *28/*28 genotype initially administered 300-400 mg/d, a target nilotinib C 0 of 500 ng/mL is recommended to prevent elevation of bilirubin levels, whereas for patients with the UGT1A1*1 allele initially administered 600 mg/d, a target nilotinib C 0 of 800 ng/mL is recommended. For dasatinib, it is recommended that a higher C max or C 2 (above 50 ng/mL) to obtain a clinical response and a lower C 0 (less than 2.5 ng/mL) to avoid pleural effusion be maintained by once daily administration of dasatinib. Although at present clinicians consider the next pharmacotherapy from clinical responses (efficacy/ toxicity) obtained by a fixed dosage of TKI, the TKI dosage should be adjusted based on target plasma concentrations to maximize the efficacy and to minimize the incidence of adverse events.

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“…A target C trough of 761 ng/mL is recommended for nilotinib TDM. 108 Pazopanib. Clinical studies [109][110][111][112] have established a target C trough of 20 000 ng/mL for pazopanib.…”

Section: Additional Tkis Potentially Feasible For Tdmmentioning

confidence: 99%

Pharmacokinetic‐Guided Dosing of New Oral Cancer Agents

Lucas

Martin

2017

The Journal of Clinical Pharma

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Generally, licensed drug-dosing recommendations for chemotherapy are based on results from clinical trials in which subjects are usually of relatively normal body size, middle-aged, and are relatively racially homogeneous, with minimal comorbidity and specific tumor characteristics. Very few nontrial patients meet these characteristics, resulting in clinical practice having to extrapolate dosing recommendations to the specific patient. There is insufficient research on the impact of obesity-associated physiological changes prevalent in patients with common cancers on standard pharmacokinetic and pharmacodynamic parameters. Yet quantifying the influence of obesity on the pharmacology of chemotherapy is vital, as dosing inappropriate for body composition (ie, flat dosing or mg/kg based on total body weight) may increase the risk of adverse events and reduce clinical effectiveness. Unfortunately, there are few cancer guidelines to aid clinicians in selecting the optimal dose in the obese-even recent guidelines are based predominantly on clinical opinion/current practice in treating obese patients, rather than evidence. Data in many other vulnerable groups, for example, those with significant comorbidity and older patients, are also scarce. Because of the known limitations of body surface area-guided dosing, therapeutic drug monitoring or pharmacokinetic-guided dosing, which predicts an individual's exposure, has increasingly been shown to be a powerful tool in cancer therapy. Used appropriately, it can adjust for differences in pharmacokinetic parameters not considered when body size-based dosing or "one dose fits all" is used. This review will focus predominantly on the rationale for pharmacokinetic-guided dosing of the newer oral molecularly targeted antineoplastics in people whose drug exposure is not predicted by their physiology or body composition.

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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

Cited by 22 publications

References 32 publications

Persistent detection of alternatively spliced BCR‐ABL variant results in a failure to achieve deep molecular response

Persistent detection of alternatively spliced BCR‐ABL variant results in a failure to achieve deep molecular response

Therapeutic Drug Monitoring of Imatinib, Nilotinib, and Dasatinib for Patients with Chronic Myeloid Leukemia

Pharmacokinetic‐Guided Dosing of New Oral Cancer Agents

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