Plasma concentrations of dasatinib have a clinical impact on the frequency of dasatinib dose reduction and interruption in chronic myeloid leukemia: an analysis of the DARIA 01 study

Plasma concentrations of dasatinib have a clinical impact on the frequency of dasatinib dose... Background Dasatinib has shown promising anti-leukemic activity against chronic myeloid leukemia (CML). However, patients receiving dasatinib frequently require dose reductions and treatment interruptions (treatment alteration). Methods We prospectively analyzed the frequency and significance of treatment alteration during dasatinib therapy in patients with CML. In all patients, trough plasma concentrations of dasatinib (C ) at steady state were assessed on day 28 min of therapy. Results 28% of patients had their doses reduced at a median of 42 days, and 25% of patients had temporarily interrupted at a median of 54 days after treatment initiation. The overall dasatinib treatment alteration-free rate at 1 year was 66%. Age was significantly correlated with C on day 28 (p = 0.014), and the correlation remained significant after adjusting dasatinib min dose (g), body weight (kg) (C /D/W) (p = 0.026). In the univariate analysis, deep molecular response, advanced PS, higher min C /D/W were associated with a significantly higher risk of treatment alteration (HR 4.19, 95% CI: 1.06–16.60, p = 0.041; min HR 5.26, 95% CI: 1.33–20.80, p = 0.018; and HR 10.15, 95% CI: 2.55–40.48, p = 0.001, respectively). In the multivariate analysis, advanced PS and higher C /D/W were correlated with the incidence of treatment alteration (HR 4.78, 95% CI: min 1.01–22.70, p = 0.049; HR 6.17, 95% CI: 1.17–32.50, respectively). Conclusion Current data demonstrate that patients treated with dasatinib who displayed a high C /D/W value and/or min advanced PS were at a high risk for altered treatment. Keywords Dasatinib · Plasma concentration · Chronic myeloid leukemia · Treatment adherence · Individualized dasatinib therapy Introduction and overall survival (OS) at 5 years [6]. In the DASISION study, 39% of patients initially treated with dasatinib and Dasatinib is a novel tyrosine kinase inhibitor (TKI) of BCR- 37% of patients treated with imatinib are no longer receiv- ABL and SRC family kinases that has shown promising ther- ing their respective initial therapy, and this discontinuation apeutic effects in patients with chronic myeloid leukemia might have limited the potential benefits of treatment [6 ]. (CML) [1–6]. In the DASISION study, the cumulative rates With regard to the imatinib therapy, poor adherence seemed of major molecular response (MMR) and molecular response to be the predominant reason underlying the lack of adequate at 5 years were significantly greater in patients treated with clinical responses [7]. Larson et al. focused on the imatinib dasatinib compared with imatinib [4–6]. However, there pharmacokinetics and reported that plasma trough levels of were no significant differences in progression-free survival imatinib at steady state (day 29) was a significant prognos- tic indicator of midterm and long-term clinical responses in CML patients [8]. Then, we prospectively analyzed the frequency and significance of dose reductions and treatment * Shuichi Mizuta mizuta@spacelan.ne.jp interruptions during dasatinib therapy (treatment alteration) Extended author information available on the last page of the article Vol.:(0123456789) 1 3 International Journal of Clinical Oncology in patients with CML focusing on trough plasma concentra- patients were permitted to receive hydroxyurea to control tions of dasatinib at steady state. elevated WBC and/or platelets. Evaluations Materials and methods Patients were seen once-weekly for the first 4 weeks and Patients once-monthly for the following 11 months. Treatment effi- cacy was determined on the basis of hematologic assess- We conducted a phase 2 study to evaluate continuity of ments, bone marrow cytogenetics, and molecular responses dasatinib therapy in patients with chronic phase CML in peripheral blood as assessed every 3 months. Patients who (CML-CP) in the DARIA 01 study (UMIN000007345). achieved CCyR were not required to undergo bone mar- Patients enrolled in the study were at least 16 years of age, row cytogenetic analysis. AEs were continuously assessed and had Ph-positive CML-CP and primary or acquired throughout the study, and they were graded according to hematologic resistance or intolerance to prior TKI therapy National Cancer Institute Common Terminology Criteria (imatinib and/or nilotinib). CML-CP was defined as < 15% for Adverse Events (CTCAE), version 3.0. Safety assess- blasts, < 20% basophils, < 30% blasts and promyelocytes, ments included AEs, hematologic and cardiac enzyme lev- and platelets > 100 × 10 /L in peripheral blood samples, and els, biochemical parameters, urinalysis, electrocardiography, no extramedullary involvement. Patients were considered and physical examination. Chest X-rays were conducted at TKI-intolerant if they had previously only tolerated TKI baseline and once-weekly for the first 4 weeks. Following doses less than 400 mg/day or had discontinued TKI therapy the first 4 weeks of the study, chest X-rays were conducted due to toxicity potentially related to imatinib at a dose of as required for the detection or monitoring of pleural effu- 400 mg/day or less. Primary resistance to prior TKI ther- sion. All patients underwent BCR-ABL mutational analysis apy was defined as lack of complete hematologic response at baseline. mRNA from peripheral blood cells was collected (CHR) after 3 months, lack of major cytogenetic response and analyzed for BCR-ABL gene mutations using denatur- (MCyR) after 6 months, and lack of complete cytogenetic ing high-performance liquid chromatography and sequenc- response (CCyR) after 12 months. The present study was ing. BCR-ABL transcripts were analyzed by Biomedical approved by the Institutional Review Board of the Fujita Laboratories (BML) (Tokyo, Japan) according to the inter- Health University School of Medicine and conformed to the national scale (IS) [9]. A deep molecular response (DMR) provisions of the 1964 Declaration of Helsinki and its later was defined as less than 0.01% of the International Scale amendments or comparable ethical standards. All patients (BCR-ABL IS), corresponding to a 4-log reduction from a provided written, informed consent before participating in standardized baseline value. Progression was defined as a the study. doubling of white blood cell count, loss of CHR, increase in Ph-positive bone marrow metaphase cells, transformation to Study design and treatment accelerated phase/blast phase, or death from any cause. All patients were told that their status of dasatinib administra- The primary objective of this study was to identify factors tion would be monitored, and they were required to declare influencing the frequency and significance of treatment unused tablets to their physician. alteration during dasatinib therapy at 12 months. The sec- ondary objective was to evaluate the correlation between pharmacokinetic (PK) parameters and treatment alteration PK analysis of dasatinib therapy, adverse events (AEs). Dasatinib was administered at an initial dose of 100 mg once daily. Dose Trough plasma concentrations of dasatinib (C ) at steady min interruption or reduction was permitted in cases of non- state were assessed on day 28 of therapy. Blood samples hematologic toxicity grade 2 or greater, hematologic toxic- were collected in heparinized tubes and immediately centri- ity grade 3 or greater, or upon request from a patient. After fuged. The separated plasma samples were stored in poly- a dose interruption or reduction associated with toxicity, propylene tubes at − 30 °C until the PK analysis. Plasma dasatinib could be re-administrated at a dose of 50–100 mg/ concentration of dasatinib was measured using high-per- day if the toxicity recovered to Grade 1 or 0. Dasatinib dose formance liquid chromatography coupled with electrospray adjustment upon re-administration was determined by the mass spectrometry (HPLC–MS) as previously described, treating physician. Treatment was continued until disease with some modifications [10]. The lower limit of quantita- progression or intolerable toxicity. During the study, CML tion of dasatinib by this method was 0.1 ng/mL and intra- therapies other than dasatinib were prohibited; however, and inter-day variabilities were within 5.0%. 1 3 International Journal of Clinical Oncology Table 1 Patient demographics and characteristics at baseline Data analysis and statistical methods Median age, years (range) 51 (20–86) Dasatinib dose reduction-free and/or interruption (treat- Sex ment alteration) -free rates were estimated using the  Male/female 21/11 Kaplan–Meier product limit method. Differences between ECOG performance status groups were analyzed using the log-rank test, the Fisher  0 29 exact test was used to calculate p values for incidences of  1 3 responses and pleural effusion. Univariate and multivariate Disease history Cox regression analyses were used to evaluate the predic-  Newly diagnosed 23 tive value of various clinical variables on the risk of treat-  Resistant/Intolerant 9 ment alteration. The following variables were evaluated: Previous therapy for CML age range (< 60 or ≥ 60), CML status at dasatinib initia-  Imatinib 5 tion (CP, CCyR, or DMR), CML profile (newly diagnosed,  Nilotinib 3 prior TKI intolerance, or prior TKI resistance), performance  Other 1 status (PS) at diagnosis (0 or 1), C on day 28 (< 1.4 or min  None 23 ≥ 1.4 ng/mL), C on day 28 after adjusting dasatinib dose min Disease status (g), body weight (kg) (C /D/W). The relationship between min  CP 26 C , C /D/W, and age were evaluated using Pearson’s cor- min min  CCyR 2 relation coefficient. All of the statistical analyses were con-  DMR 4 ducted using STATA 12 software (STATA Corp., College BCR–ABL mutation status Station, TX, USA).  Positive/negative 0/32 CP chronic phase;  CCyR cytogenetic complete remission; DMR deep molecular remission Results patient (13%). Complete clinical and radiological resolution Patients of PE was achieved in 5 patients (62%), and clinical symp- toms resolved in the remaining 3 patients (38%). Between April 2012 and September 2013, 32 CML-CP Dasatinib interruption and dose reduction patients were enrolled in the study. Patient characteristics are summarized in Table 1. The median age was  51 years (range Figure 1 details the progress of all patients through the study. 20–86). Twenty-three patients (75.0%) were treatment-naïve, and the remaining 9 patients (25.0%) had been switched to The dose of dasatinib was reduced in 9 patients (28%) at a median of 42 days (range 7–123 days) after treatment ini- dasatinib from another TKI due to treatment intolerance or resistance. Dasatinib treatment was initiated a median of tiation. Treatment was temporarily interrupted in 8 patients (25%) at a median of 54 days (range 14–331 days) after treat- 1 month (range 0–109 months) after CML diagnosis. Upon the initiation of dasatinib, 26 patients were in the CP, 2 were ment initiation. Among 8 patients who had PE, 5 patients experienced treatment alteration (reduction in 2 patients, in CCyR, and 4 were in DMR. No patients had BCR-ABL mutations at baseline. reduction and interruption in 3 patients). Three patients (9%) discontinued treatment due to withdrawal of consent at 287 day, myelo-suppression at 236 days, or gastro-intestinal bleeding at 342 days. At the final observation, 25 patients Toxic effects were being treated with 100 mg of dasatinib, and 4 patients were being treated with a reduced dose (50 or 40 mg). The Grade 3 or 4 neutropenia and/or thrombocytopenia occurred in 9 (28%) and 5 patients (16%), respectively. Hematologi- overall treatment alteration-free rate was 66% (95% confi- dence interval [CI]: 47–79%) (Fig. 2). cal AEs requiring dasatinib dose reduction and/or treatment interruption occurred in 5 patients (16%), and these AEs Clinical response typically resolved within 3 months. Grade 1 pleural effusion (PE) occurred in 3 patients (9%), and grade 2 PE occurred in The rates of CCyR and DMR in the 22 treatment-naïve 5 patients (16%). PE was treated with diuretics in 3 patients (38%), steroid therapy and dasatinib dose reduction in 2 patients were 68% and 4% at 3 months, 91% and 32% at 6 months, and 91% and 55% at 12 months, respectively. In the patients (25%), diuretics and dasatinib dose reduction in 2 patients (25%), and dasatinib dose reduction alone in 1 10 patients who had been switched from other TKIs, 3 of 1 3 International Journal of Clinical Oncology Fig. 1 A flowchart of all patients entered into the DARIA 01 study Correlation of dasatinib trough levels with age PK data associated with dasatinib on day 28 were available for all of the study participants. On day 28, 27 patients were still being treated with the initial dose of 100 mg, and the remaining 5 were being treated with a lower dose (50 mg) due to an AE. The median C of dasatinib was 1.4 ng/ min mL (range 0.0–6.0 ng/mL). The median C after adjusting min for dasatinib dose (g) and body weight (kg) (C /D/W), on min day 28 was 0.19 (range 0.00–2.7). The inter-patient variabil- ity might reflect individual differences in drug metabolism and/or excretion. A linear regression analysis demonstrated that age was significantly correlated with C on day 28 min Fig. 2 Dasatinib dose reduction- and/or interruption-free  (alteration- (r = 0.431, p = 0.014; Fig. 3), and the correlation remained free) rate significant after adjusting for C /D/W (r = 0.394, p = 0.026; min Fig. 3). the 4 patients in CHR achieved CCyR, and 1 of 2 patients in CCyR achieved a DMR at 3 months. The rates of CCyR PE and dasatinib serum concentration and DMR were 90% and 60% at 3 months, 90% and 60% at 6 months, and 90% and 78% at 12 months, respectively. Among 16 patients who showed high C (≥ 1.4  ng/mL), min Twenty-nine of the 32 patients remained on dasatinib ther- five (31%) experienced PE. On the other hand, in 16 patients apy at 1 year. No patients experienced disease progression who showed low C (< 1.4 ng/mL), 3 (19%) experienced min while being treated with dasatinib. There was no significant PE. There was no significance in the incidence of PE difference in clinical responses in patients that underwent between two groups (p = 0.685). Among 16 patients who treatment alteration (p = 0.157) compared with patients that showed high C /D/W (≥ 0.19), six (38%) experienced PE. min did not undergo these adjustments. On the other hand, in 16 patients who showed low C /D/W min (< 0.19), 2 (13%) experienced PE. The difference between two groups did not reach statistical difference (p = 0.220). The incidence of PE by 12 months in high age (≥ 60) group was higher than that in low age (< 60) group, but did not 1 3 International Journal of Clinical Oncology Fig. 3 Relationship between age and dasatinib trough plasma concentrations reach statistical significance (40% vs. 18%, p = 0.1864). p = 0.0473) (Fig. 4). And also, the treatment alteration-free With regard to adverse events other than PE, there were no rate in low C /D/W group (88, 95% CI: 59–97%) was min significant correlation between AEs and dasatinib serum significantly greater than that in the high C /D/W group min concentration. (C , C /D/W) (Supplemental tables 1, 2). (44, 95% CI: 20–66%, p = 0.0047) (Fig. 4). Table 2 presents min min the results of the univariate and multivariate Cox regres- Risk factors for dasatinib treatment alteration sion analyses of risk factors for treatment alteration. In the univariate analysis, DMR, advanced PS, higher C /D/W min The treatment alteration-free rate was significantly greater were associated with a significantly higher risk of treatment in the low C group (< 1.4 ng/mL) (81, 95% CI: 52–94%) alteration (HR 4.19, 95% CI: 1.06–16.60, p = 0.041; HR min compared with the high C group (50, 95% CI: 25–71%, 5.26, 95% CI: 1.33–20.80, p = 0.018; and HR 10.15, 95% min Fig. 4 a 1-year dasatinib treatment alteration-free rate by dasatinib trough plasma concentrations (C ) (ng/ min mL) (1.4 ≧ vs. <1.4). b 1-year dasatinib treatment alteration- free rate by trough plasma concentrations of dasatinib after adjusting for dasatinib dose (g) and body weight (kg) (C /D/W min ratio) at day 28 (0.19 ≧ vs. < 0.19) 1 3 International Journal of Clinical Oncology Table 2 Relationship between Characteristic Univariate analysis Multivariate analysis the dasatinib interruption/ reduction of treatment and the HR (95% CI) p HR (95% CI) p remaining variables Age  > 60 1.00  ≥ 60 2.46 (0.75–8.14) 0.138 NA Sex  Female 1.00  Male 1.88 (0.57–6.17) 0.300 NA CML status at dasatinib initiation  CP 1.00  CyCR 2.52 (0.31–20.7) 0.388 1.26 (0.14–11.0) 0.834  DMR 4.19 (1.06–16.6) 0.041 1.21 (0.26–5.74) 0.809 Prior-therapy before dasatinib administration  No 1.00  Yes 2.60 (0.79–8.58) 0.116 NA PS at dasatinib treatment  0 1.00 0.018  1 5.26 (1.3–20.8) 4.78 (1.01–22.7) 0.049 C on day 28 (ng/mL) min  > 1.4 1.00  ≥ 1.4 3.53 (0.93–13.41) 0.063 NA C /D/W on day 28 min  > 0.19 1.00  ≥ 0.19 10.15 (2.55–40.48) 0.001 6.17 (1.17–32.5) 0.032 CP chronic phase; CyCR cytogenetical complete remission; DMR deep molecular remission; C plasma min concentrations of dasatinib at steady state;  C /D/W,  C after an adjustment in the dasatinib dose and min min body weight CI: 2.55–40.48, p = 0.001, respectively). In the multivari- patients experienced a dose reduction and 25% of patients ate analysis, advanced PS and higher C /D/W were still experienced temporarily interruption of treatment after ini- min correlated with the incidence of treatment alteration (HR tiating dasatinib therapy. The 1-year overall dasatinib treat- 4.78, 95% CI: 1.01–22.70, p = 0.049; HR 6.17, 95% CI: ment alteration-free rate was 66%. 9% of patients discon- 1.17–32.50, p = 0.032). tinued the treatment due to withdrawal of consent or an AE at 1-year from dasatinib therapy. No patients experienced disease progression while being treated with dasatinib. Discussion As it often necessitates treatment discontinuation, PE can limit the therapeutic efficacy of dasatinib [12– 14]. On the It is now recognized that discontinuation of dasatinib ther- other hand, several studies reported that the pleural effusion apy is a critical factor in the achievement and maintenance was common in elderly patients and did not affect any nega- of an optimal response to dasatinib therapy [11]. In the tive treatment results if that were clinically manageable [15, DASISION study, dasatinib treatment was interrupted in 16]. In the present study, the incidence of PE by 12 months in 63% of patients, the dose of dasatinib was reduced in 31% high age (≥ 60) group was higher than that in low age (< 60) of patients [5]. At the end of the 3-year observation period, group, but did not reach statistical significance (p = 0.1864). 29% patients discontinued dasatinib therapy for various Several studies have reported that a higher Cmax of dasat- reasons (AE: 10%, disease progression or treatment failure: inib was associated with greater clinical response rates, and 10%, unrelated AE: 2%, death: 2%, or other reason: 5%) [5]. lower trough concentrations were associated with a lower However, the detailed course leading to discontinuation in risk of PE [12, 17–19]. In the prospective OPTIM dasat- each case has not been reported. To the best of our knowl- inib trial, patients with a dasatinib trough concentration edge, there have been no previous reports regarding the tim- of − 3 nM (1.5 ng/mL) at day 15 were randomized to the ing of dasatinib reduction, interruption, and/or discontinu- non-dose adjustment group or the dose adjustment group ation in midterm observation. In the present study, 28% of to obtain a C0 of < 3 nM [20]. The overall rates of pleural 1 3 International Journal of Clinical Oncology effusion at 36 months were 49% and 11%, respectively, in diagnosis were risk factors for treatment alteration during the non-adjustment and adjustment groups, and the dis- the midterm point in the observation period of the DARIA continuation rates of dasatinib therapy were 27% and 13%, 01 study. Monitoring dasatinib PK parameters could help to respectively (p = 0.008) [20]. They concluded that monitor- predict the risk of treatment alteration of dasatinib therapy ing dasatinib PK parameters could help predict the risk of and optimize the efficacy of dasatinib therapy. side effects and prevent discontinuation of dasatinib therapy Acknowledgements This study was supported by a non-profit organi- [20]. In the present study, patients who had high C /D/W min zation Epidemiological and Clinical Research Information Network showed higher incidence of PE than that in low C /D/W min (ECRIN). The authors thank Yumi Miyashita at ECRIN for collecting group (38% vs. 13%, respectively), despite it did not reach the data. statistical significance (p = 0.220). Indeed, among 8 patients who had PE, 5 patients experienced treatment alteration. Author contributions SM: planning study design and conducting study, writing of the manuscript, and final approval of the manuscript. MS: However, pleural effusions were well managed effectively data collection, writing of the manuscript, and final approval of the through administration of diuretics or steroid therapy and/or manuscript. HT: data collection, writing of the manuscript, and final dasatinib dose modifications. After then, they could continue approval of the manuscript. KM: PK analysis, data interpretation and dasatinib therapy. Better management of PE might contrib- writing of the manuscript, and final approval of the manuscript. KM: data collection, writing of the manuscript, and final approval of the ute to prevent discontinuation of dasatinib therapy. In the manuscript. TH: data collection, writing of the manuscript, and final present study, age was significantly correlated with C min approval of the manuscript. TT: data collection, writing of the manu- (p = 0.012) (Fig. 2), and the correlation remained signifi- script, and final approval of the manuscript. RS: data collection, writing cant after adjusting for C /D/W (p = 0.026). The treatment of the manuscript, and final approval of the manuscript. HK: data col- min lection, writing of the manuscript, and final approval of the manuscript. alteration-free rate was significantly greater in the low C min AK: data collection, writing of the manuscript, and final approval of the group (< 1.4 ng/mL) compared with the high C group min manuscript. MSO: data interpretation and data review/approval, and (81% and 50%, respectively, p = 0.0473) (Fig. 4). And also, writing of the manuscript, and final approval of the manuscript. SM: the treatment alteration-free rate in low C /D/W group was planning study design, data interpretation and data review/approval, min and writing of the manuscript, and final approval of the manuscript. significantly greater than that in the high C /D/W group min JS: data interpretation and data review and writing of the manuscript, (88% and 44%, respectively, p = 0.0047) (Fig. 4). The higher and final approval of the manuscript. NE: conducting study and data C /D/W, instead of higher C , was significantly corre - min min interpretation and writing of the manuscript, and final approval of the lated with the incidence dasatinib treatment alteration rate manuscript. in the multivariate analysis. The C /D/W possibly could min Funding This study was supported by a non-profit organization Epi- reflect patient’s ability to metabolize and/or excretion dasat- demiological and Clinical Research Information Network (ECRIN). inib. A larger patient sample is needed to determine which would be better to predict the dasatinib treatment alteration Compliance with ethical standards and to prevent discontinuation of dasatinib therapy. To our knowledge, this is the first prospective study eval- Conflict of interest Masashi Sawa received honoraria from Bristol- uating prognostic factors that influence the treatment altera- Myers Squibb. Hiroshi Kojima received honoraria from Celgene. Sa- tion of dasatinib therapy in patients with CML. However, the toshi Morita received honoraria from Bristol-Myers Squibb. Junichi Sakamoto received honoraria from Tsumura and Chugai Pharmaceuti- limitations of our study need to be considered. Our study cal, and has received consultancy fees from Takeda. Nobuhiko Emi was limited by the presence of residual confounding factors, received honoraria from Kyowa Hakko Kirin and Chugai Pharmaceu- both known and unknown. tical. All other authors report no conflicts of interest relevant to this The present study focused on clinical outcomes of 32 article. patients at the midterm point (1 year) of the observation Ethical approval The present study was approved by the Institutional period of the DARIA 01 study; however, dasatinib therapy Review Board of the Fujita Health University School of Medicine and can be continued for much longer periods of time. A long- conformed to the provisions of the 1964 Declaration of Helsinki and term observation study including more large number of its later amendments or comparable ethical standards. All patients provided written, informed consent before participating in the study. patients is needed to clarify the risks for the treatment altera- tion of dasatinib therapy. 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De Francia S, D’Avolio A, De Martino F et al (2009) New HPLC- Association (EHA) MS method for the simultaneous quantification of the antileuke- mia drugs imatinib, dasatinib, and nilotinib in human plasma. J Chromatogr B Anal Technol Biomed Life Sci 877:1721–1726 Affiliations 1,11 2 3 4 2 3 Shuichi Mizuta  · Masashi Sawa  · Hisashi Tsurumi  · Kana Matsumoto  · Kotaro Miyao  · Takeshi Hara  · 5 2 6 7 8 9 Takeshi Takahashi  · Reona Sakemura  · Hiroshi Kojima  · Akio Kohno  · Mari S. Oba  · Satoshi Morita  · 10 1 Junichi Sakamoto  · Nobuhiko Emi Masashi Sawa Reona Sakemura msawa@wine.plala.or.jp r.sakemura@med.nagoya-u.ac.jp Hisashi Tsurumi Hiroshi Kojima htsuru@gifu-u.ac.jp kojima@daidohp.or.jp Kana Matsumoto Akio Kohno kmatsumo@dwc.doshisha.ac.jp akohno@wd5.so-net.ne.jp Mari S. Oba Kotaro Miyao mari.oba@med.toho-u.ac.jp koutarou380@yahoo.co.jp Satoshi Morita Takeshi Hara smorita@kuhp.kyoto-u.ac.jp haratake@muh.biglobe.ne.jp Takeshi Takahashi Junichi Sakamoto ttakahashi@gmhosp.gifu.gifu.jp sakamjun@med.nagoya-u.ac.jp 1 3 International Journal of Clinical Oncology Nobuhiko Emi Department of Hematology, Daido Hospital, Nagoya, Japan nemi@fujita-hu.ac.jp Department of Hematology and Oncology, JA Aichi Konan Kosei Hospital, Konan, Japan Department of Hematology, Fujita Health University School of Medicine, Toyoake, Japan Department of Medical Statistics, Faculty of Medicine, Toho University, Tokyo, Japan Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan Department of Hematology, Graduate School of Medicine, Gifu University, Gifu, Japan Tokai Central Hospital, Kagamigahara, Japan 4 11 Department of Clinical Pharmaceutics, Doshisha Women’s Hematology and Immunology, Kanazawa Medical College of Liberal Arts, Kyoto, Japan University, 1-1 Daigaku, Uchinada, Kahoku-gun, Ishikawa 920-0293, Japan Department of Hematology, Gifu Municipal Hospital, Gifu, Japan 1 3 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png International Journal of Clinical Oncology Springer Journals

Plasma concentrations of dasatinib have a clinical impact on the frequency of dasatinib dose reduction and interruption in chronic myeloid leukemia: an analysis of the DARIA 01 study

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Springer Japan
Copyright
Copyright © 2018 by The Author(s)
Subject
Medicine & Public Health; Oncology; Surgical Oncology; Cancer Research
ISSN
1341-9625
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1437-7772
D.O.I.
10.1007/s10147-018-1300-9
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Abstract

Background Dasatinib has shown promising anti-leukemic activity against chronic myeloid leukemia (CML). However, patients receiving dasatinib frequently require dose reductions and treatment interruptions (treatment alteration). Methods We prospectively analyzed the frequency and significance of treatment alteration during dasatinib therapy in patients with CML. In all patients, trough plasma concentrations of dasatinib (C ) at steady state were assessed on day 28 min of therapy. Results 28% of patients had their doses reduced at a median of 42 days, and 25% of patients had temporarily interrupted at a median of 54 days after treatment initiation. The overall dasatinib treatment alteration-free rate at 1 year was 66%. Age was significantly correlated with C on day 28 (p = 0.014), and the correlation remained significant after adjusting dasatinib min dose (g), body weight (kg) (C /D/W) (p = 0.026). In the univariate analysis, deep molecular response, advanced PS, higher min C /D/W were associated with a significantly higher risk of treatment alteration (HR 4.19, 95% CI: 1.06–16.60, p = 0.041; min HR 5.26, 95% CI: 1.33–20.80, p = 0.018; and HR 10.15, 95% CI: 2.55–40.48, p = 0.001, respectively). In the multivariate analysis, advanced PS and higher C /D/W were correlated with the incidence of treatment alteration (HR 4.78, 95% CI: min 1.01–22.70, p = 0.049; HR 6.17, 95% CI: 1.17–32.50, respectively). Conclusion Current data demonstrate that patients treated with dasatinib who displayed a high C /D/W value and/or min advanced PS were at a high risk for altered treatment. Keywords Dasatinib · Plasma concentration · Chronic myeloid leukemia · Treatment adherence · Individualized dasatinib therapy Introduction and overall survival (OS) at 5 years [6]. In the DASISION study, 39% of patients initially treated with dasatinib and Dasatinib is a novel tyrosine kinase inhibitor (TKI) of BCR- 37% of patients treated with imatinib are no longer receiv- ABL and SRC family kinases that has shown promising ther- ing their respective initial therapy, and this discontinuation apeutic effects in patients with chronic myeloid leukemia might have limited the potential benefits of treatment [6 ]. (CML) [1–6]. In the DASISION study, the cumulative rates With regard to the imatinib therapy, poor adherence seemed of major molecular response (MMR) and molecular response to be the predominant reason underlying the lack of adequate at 5 years were significantly greater in patients treated with clinical responses [7]. Larson et al. focused on the imatinib dasatinib compared with imatinib [4–6]. However, there pharmacokinetics and reported that plasma trough levels of were no significant differences in progression-free survival imatinib at steady state (day 29) was a significant prognos- tic indicator of midterm and long-term clinical responses in CML patients [8]. Then, we prospectively analyzed the frequency and significance of dose reductions and treatment * Shuichi Mizuta mizuta@spacelan.ne.jp interruptions during dasatinib therapy (treatment alteration) Extended author information available on the last page of the article Vol.:(0123456789) 1 3 International Journal of Clinical Oncology in patients with CML focusing on trough plasma concentra- patients were permitted to receive hydroxyurea to control tions of dasatinib at steady state. elevated WBC and/or platelets. Evaluations Materials and methods Patients were seen once-weekly for the first 4 weeks and Patients once-monthly for the following 11 months. Treatment effi- cacy was determined on the basis of hematologic assess- We conducted a phase 2 study to evaluate continuity of ments, bone marrow cytogenetics, and molecular responses dasatinib therapy in patients with chronic phase CML in peripheral blood as assessed every 3 months. Patients who (CML-CP) in the DARIA 01 study (UMIN000007345). achieved CCyR were not required to undergo bone mar- Patients enrolled in the study were at least 16 years of age, row cytogenetic analysis. AEs were continuously assessed and had Ph-positive CML-CP and primary or acquired throughout the study, and they were graded according to hematologic resistance or intolerance to prior TKI therapy National Cancer Institute Common Terminology Criteria (imatinib and/or nilotinib). CML-CP was defined as < 15% for Adverse Events (CTCAE), version 3.0. Safety assess- blasts, < 20% basophils, < 30% blasts and promyelocytes, ments included AEs, hematologic and cardiac enzyme lev- and platelets > 100 × 10 /L in peripheral blood samples, and els, biochemical parameters, urinalysis, electrocardiography, no extramedullary involvement. Patients were considered and physical examination. Chest X-rays were conducted at TKI-intolerant if they had previously only tolerated TKI baseline and once-weekly for the first 4 weeks. Following doses less than 400 mg/day or had discontinued TKI therapy the first 4 weeks of the study, chest X-rays were conducted due to toxicity potentially related to imatinib at a dose of as required for the detection or monitoring of pleural effu- 400 mg/day or less. Primary resistance to prior TKI ther- sion. All patients underwent BCR-ABL mutational analysis apy was defined as lack of complete hematologic response at baseline. mRNA from peripheral blood cells was collected (CHR) after 3 months, lack of major cytogenetic response and analyzed for BCR-ABL gene mutations using denatur- (MCyR) after 6 months, and lack of complete cytogenetic ing high-performance liquid chromatography and sequenc- response (CCyR) after 12 months. The present study was ing. BCR-ABL transcripts were analyzed by Biomedical approved by the Institutional Review Board of the Fujita Laboratories (BML) (Tokyo, Japan) according to the inter- Health University School of Medicine and conformed to the national scale (IS) [9]. A deep molecular response (DMR) provisions of the 1964 Declaration of Helsinki and its later was defined as less than 0.01% of the International Scale amendments or comparable ethical standards. All patients (BCR-ABL IS), corresponding to a 4-log reduction from a provided written, informed consent before participating in standardized baseline value. Progression was defined as a the study. doubling of white blood cell count, loss of CHR, increase in Ph-positive bone marrow metaphase cells, transformation to Study design and treatment accelerated phase/blast phase, or death from any cause. All patients were told that their status of dasatinib administra- The primary objective of this study was to identify factors tion would be monitored, and they were required to declare influencing the frequency and significance of treatment unused tablets to their physician. alteration during dasatinib therapy at 12 months. The sec- ondary objective was to evaluate the correlation between pharmacokinetic (PK) parameters and treatment alteration PK analysis of dasatinib therapy, adverse events (AEs). Dasatinib was administered at an initial dose of 100 mg once daily. Dose Trough plasma concentrations of dasatinib (C ) at steady min interruption or reduction was permitted in cases of non- state were assessed on day 28 of therapy. Blood samples hematologic toxicity grade 2 or greater, hematologic toxic- were collected in heparinized tubes and immediately centri- ity grade 3 or greater, or upon request from a patient. After fuged. The separated plasma samples were stored in poly- a dose interruption or reduction associated with toxicity, propylene tubes at − 30 °C until the PK analysis. Plasma dasatinib could be re-administrated at a dose of 50–100 mg/ concentration of dasatinib was measured using high-per- day if the toxicity recovered to Grade 1 or 0. Dasatinib dose formance liquid chromatography coupled with electrospray adjustment upon re-administration was determined by the mass spectrometry (HPLC–MS) as previously described, treating physician. Treatment was continued until disease with some modifications [10]. The lower limit of quantita- progression or intolerable toxicity. During the study, CML tion of dasatinib by this method was 0.1 ng/mL and intra- therapies other than dasatinib were prohibited; however, and inter-day variabilities were within 5.0%. 1 3 International Journal of Clinical Oncology Table 1 Patient demographics and characteristics at baseline Data analysis and statistical methods Median age, years (range) 51 (20–86) Dasatinib dose reduction-free and/or interruption (treat- Sex ment alteration) -free rates were estimated using the  Male/female 21/11 Kaplan–Meier product limit method. Differences between ECOG performance status groups were analyzed using the log-rank test, the Fisher  0 29 exact test was used to calculate p values for incidences of  1 3 responses and pleural effusion. Univariate and multivariate Disease history Cox regression analyses were used to evaluate the predic-  Newly diagnosed 23 tive value of various clinical variables on the risk of treat-  Resistant/Intolerant 9 ment alteration. The following variables were evaluated: Previous therapy for CML age range (< 60 or ≥ 60), CML status at dasatinib initia-  Imatinib 5 tion (CP, CCyR, or DMR), CML profile (newly diagnosed,  Nilotinib 3 prior TKI intolerance, or prior TKI resistance), performance  Other 1 status (PS) at diagnosis (0 or 1), C on day 28 (< 1.4 or min  None 23 ≥ 1.4 ng/mL), C on day 28 after adjusting dasatinib dose min Disease status (g), body weight (kg) (C /D/W). The relationship between min  CP 26 C , C /D/W, and age were evaluated using Pearson’s cor- min min  CCyR 2 relation coefficient. All of the statistical analyses were con-  DMR 4 ducted using STATA 12 software (STATA Corp., College BCR–ABL mutation status Station, TX, USA).  Positive/negative 0/32 CP chronic phase;  CCyR cytogenetic complete remission; DMR deep molecular remission Results patient (13%). Complete clinical and radiological resolution Patients of PE was achieved in 5 patients (62%), and clinical symp- toms resolved in the remaining 3 patients (38%). Between April 2012 and September 2013, 32 CML-CP Dasatinib interruption and dose reduction patients were enrolled in the study. Patient characteristics are summarized in Table 1. The median age was  51 years (range Figure 1 details the progress of all patients through the study. 20–86). Twenty-three patients (75.0%) were treatment-naïve, and the remaining 9 patients (25.0%) had been switched to The dose of dasatinib was reduced in 9 patients (28%) at a median of 42 days (range 7–123 days) after treatment ini- dasatinib from another TKI due to treatment intolerance or resistance. Dasatinib treatment was initiated a median of tiation. Treatment was temporarily interrupted in 8 patients (25%) at a median of 54 days (range 14–331 days) after treat- 1 month (range 0–109 months) after CML diagnosis. Upon the initiation of dasatinib, 26 patients were in the CP, 2 were ment initiation. Among 8 patients who had PE, 5 patients experienced treatment alteration (reduction in 2 patients, in CCyR, and 4 were in DMR. No patients had BCR-ABL mutations at baseline. reduction and interruption in 3 patients). Three patients (9%) discontinued treatment due to withdrawal of consent at 287 day, myelo-suppression at 236 days, or gastro-intestinal bleeding at 342 days. At the final observation, 25 patients Toxic effects were being treated with 100 mg of dasatinib, and 4 patients were being treated with a reduced dose (50 or 40 mg). The Grade 3 or 4 neutropenia and/or thrombocytopenia occurred in 9 (28%) and 5 patients (16%), respectively. Hematologi- overall treatment alteration-free rate was 66% (95% confi- dence interval [CI]: 47–79%) (Fig. 2). cal AEs requiring dasatinib dose reduction and/or treatment interruption occurred in 5 patients (16%), and these AEs Clinical response typically resolved within 3 months. Grade 1 pleural effusion (PE) occurred in 3 patients (9%), and grade 2 PE occurred in The rates of CCyR and DMR in the 22 treatment-naïve 5 patients (16%). PE was treated with diuretics in 3 patients (38%), steroid therapy and dasatinib dose reduction in 2 patients were 68% and 4% at 3 months, 91% and 32% at 6 months, and 91% and 55% at 12 months, respectively. In the patients (25%), diuretics and dasatinib dose reduction in 2 patients (25%), and dasatinib dose reduction alone in 1 10 patients who had been switched from other TKIs, 3 of 1 3 International Journal of Clinical Oncology Fig. 1 A flowchart of all patients entered into the DARIA 01 study Correlation of dasatinib trough levels with age PK data associated with dasatinib on day 28 were available for all of the study participants. On day 28, 27 patients were still being treated with the initial dose of 100 mg, and the remaining 5 were being treated with a lower dose (50 mg) due to an AE. The median C of dasatinib was 1.4 ng/ min mL (range 0.0–6.0 ng/mL). The median C after adjusting min for dasatinib dose (g) and body weight (kg) (C /D/W), on min day 28 was 0.19 (range 0.00–2.7). The inter-patient variabil- ity might reflect individual differences in drug metabolism and/or excretion. A linear regression analysis demonstrated that age was significantly correlated with C on day 28 min Fig. 2 Dasatinib dose reduction- and/or interruption-free  (alteration- (r = 0.431, p = 0.014; Fig. 3), and the correlation remained free) rate significant after adjusting for C /D/W (r = 0.394, p = 0.026; min Fig. 3). the 4 patients in CHR achieved CCyR, and 1 of 2 patients in CCyR achieved a DMR at 3 months. The rates of CCyR PE and dasatinib serum concentration and DMR were 90% and 60% at 3 months, 90% and 60% at 6 months, and 90% and 78% at 12 months, respectively. Among 16 patients who showed high C (≥ 1.4  ng/mL), min Twenty-nine of the 32 patients remained on dasatinib ther- five (31%) experienced PE. On the other hand, in 16 patients apy at 1 year. No patients experienced disease progression who showed low C (< 1.4 ng/mL), 3 (19%) experienced min while being treated with dasatinib. There was no significant PE. There was no significance in the incidence of PE difference in clinical responses in patients that underwent between two groups (p = 0.685). Among 16 patients who treatment alteration (p = 0.157) compared with patients that showed high C /D/W (≥ 0.19), six (38%) experienced PE. min did not undergo these adjustments. On the other hand, in 16 patients who showed low C /D/W min (< 0.19), 2 (13%) experienced PE. The difference between two groups did not reach statistical difference (p = 0.220). The incidence of PE by 12 months in high age (≥ 60) group was higher than that in low age (< 60) group, but did not 1 3 International Journal of Clinical Oncology Fig. 3 Relationship between age and dasatinib trough plasma concentrations reach statistical significance (40% vs. 18%, p = 0.1864). p = 0.0473) (Fig. 4). And also, the treatment alteration-free With regard to adverse events other than PE, there were no rate in low C /D/W group (88, 95% CI: 59–97%) was min significant correlation between AEs and dasatinib serum significantly greater than that in the high C /D/W group min concentration. (C , C /D/W) (Supplemental tables 1, 2). (44, 95% CI: 20–66%, p = 0.0047) (Fig. 4). Table 2 presents min min the results of the univariate and multivariate Cox regres- Risk factors for dasatinib treatment alteration sion analyses of risk factors for treatment alteration. In the univariate analysis, DMR, advanced PS, higher C /D/W min The treatment alteration-free rate was significantly greater were associated with a significantly higher risk of treatment in the low C group (< 1.4 ng/mL) (81, 95% CI: 52–94%) alteration (HR 4.19, 95% CI: 1.06–16.60, p = 0.041; HR min compared with the high C group (50, 95% CI: 25–71%, 5.26, 95% CI: 1.33–20.80, p = 0.018; and HR 10.15, 95% min Fig. 4 a 1-year dasatinib treatment alteration-free rate by dasatinib trough plasma concentrations (C ) (ng/ min mL) (1.4 ≧ vs. <1.4). b 1-year dasatinib treatment alteration- free rate by trough plasma concentrations of dasatinib after adjusting for dasatinib dose (g) and body weight (kg) (C /D/W min ratio) at day 28 (0.19 ≧ vs. < 0.19) 1 3 International Journal of Clinical Oncology Table 2 Relationship between Characteristic Univariate analysis Multivariate analysis the dasatinib interruption/ reduction of treatment and the HR (95% CI) p HR (95% CI) p remaining variables Age  > 60 1.00  ≥ 60 2.46 (0.75–8.14) 0.138 NA Sex  Female 1.00  Male 1.88 (0.57–6.17) 0.300 NA CML status at dasatinib initiation  CP 1.00  CyCR 2.52 (0.31–20.7) 0.388 1.26 (0.14–11.0) 0.834  DMR 4.19 (1.06–16.6) 0.041 1.21 (0.26–5.74) 0.809 Prior-therapy before dasatinib administration  No 1.00  Yes 2.60 (0.79–8.58) 0.116 NA PS at dasatinib treatment  0 1.00 0.018  1 5.26 (1.3–20.8) 4.78 (1.01–22.7) 0.049 C on day 28 (ng/mL) min  > 1.4 1.00  ≥ 1.4 3.53 (0.93–13.41) 0.063 NA C /D/W on day 28 min  > 0.19 1.00  ≥ 0.19 10.15 (2.55–40.48) 0.001 6.17 (1.17–32.5) 0.032 CP chronic phase; CyCR cytogenetical complete remission; DMR deep molecular remission; C plasma min concentrations of dasatinib at steady state;  C /D/W,  C after an adjustment in the dasatinib dose and min min body weight CI: 2.55–40.48, p = 0.001, respectively). In the multivari- patients experienced a dose reduction and 25% of patients ate analysis, advanced PS and higher C /D/W were still experienced temporarily interruption of treatment after ini- min correlated with the incidence of treatment alteration (HR tiating dasatinib therapy. The 1-year overall dasatinib treat- 4.78, 95% CI: 1.01–22.70, p = 0.049; HR 6.17, 95% CI: ment alteration-free rate was 66%. 9% of patients discon- 1.17–32.50, p = 0.032). tinued the treatment due to withdrawal of consent or an AE at 1-year from dasatinib therapy. No patients experienced disease progression while being treated with dasatinib. Discussion As it often necessitates treatment discontinuation, PE can limit the therapeutic efficacy of dasatinib [12– 14]. On the It is now recognized that discontinuation of dasatinib ther- other hand, several studies reported that the pleural effusion apy is a critical factor in the achievement and maintenance was common in elderly patients and did not affect any nega- of an optimal response to dasatinib therapy [11]. In the tive treatment results if that were clinically manageable [15, DASISION study, dasatinib treatment was interrupted in 16]. In the present study, the incidence of PE by 12 months in 63% of patients, the dose of dasatinib was reduced in 31% high age (≥ 60) group was higher than that in low age (< 60) of patients [5]. At the end of the 3-year observation period, group, but did not reach statistical significance (p = 0.1864). 29% patients discontinued dasatinib therapy for various Several studies have reported that a higher Cmax of dasat- reasons (AE: 10%, disease progression or treatment failure: inib was associated with greater clinical response rates, and 10%, unrelated AE: 2%, death: 2%, or other reason: 5%) [5]. lower trough concentrations were associated with a lower However, the detailed course leading to discontinuation in risk of PE [12, 17–19]. In the prospective OPTIM dasat- each case has not been reported. To the best of our knowl- inib trial, patients with a dasatinib trough concentration edge, there have been no previous reports regarding the tim- of − 3 nM (1.5 ng/mL) at day 15 were randomized to the ing of dasatinib reduction, interruption, and/or discontinu- non-dose adjustment group or the dose adjustment group ation in midterm observation. In the present study, 28% of to obtain a C0 of < 3 nM [20]. The overall rates of pleural 1 3 International Journal of Clinical Oncology effusion at 36 months were 49% and 11%, respectively, in diagnosis were risk factors for treatment alteration during the non-adjustment and adjustment groups, and the dis- the midterm point in the observation period of the DARIA continuation rates of dasatinib therapy were 27% and 13%, 01 study. Monitoring dasatinib PK parameters could help to respectively (p = 0.008) [20]. They concluded that monitor- predict the risk of treatment alteration of dasatinib therapy ing dasatinib PK parameters could help predict the risk of and optimize the efficacy of dasatinib therapy. side effects and prevent discontinuation of dasatinib therapy Acknowledgements This study was supported by a non-profit organi- [20]. In the present study, patients who had high C /D/W min zation Epidemiological and Clinical Research Information Network showed higher incidence of PE than that in low C /D/W min (ECRIN). The authors thank Yumi Miyashita at ECRIN for collecting group (38% vs. 13%, respectively), despite it did not reach the data. statistical significance (p = 0.220). Indeed, among 8 patients who had PE, 5 patients experienced treatment alteration. Author contributions SM: planning study design and conducting study, writing of the manuscript, and final approval of the manuscript. MS: However, pleural effusions were well managed effectively data collection, writing of the manuscript, and final approval of the through administration of diuretics or steroid therapy and/or manuscript. HT: data collection, writing of the manuscript, and final dasatinib dose modifications. After then, they could continue approval of the manuscript. KM: PK analysis, data interpretation and dasatinib therapy. Better management of PE might contrib- writing of the manuscript, and final approval of the manuscript. KM: data collection, writing of the manuscript, and final approval of the ute to prevent discontinuation of dasatinib therapy. In the manuscript. TH: data collection, writing of the manuscript, and final present study, age was significantly correlated with C min approval of the manuscript. TT: data collection, writing of the manu- (p = 0.012) (Fig. 2), and the correlation remained signifi- script, and final approval of the manuscript. RS: data collection, writing cant after adjusting for C /D/W (p = 0.026). The treatment of the manuscript, and final approval of the manuscript. HK: data col- min lection, writing of the manuscript, and final approval of the manuscript. alteration-free rate was significantly greater in the low C min AK: data collection, writing of the manuscript, and final approval of the group (< 1.4 ng/mL) compared with the high C group min manuscript. MSO: data interpretation and data review/approval, and (81% and 50%, respectively, p = 0.0473) (Fig. 4). And also, writing of the manuscript, and final approval of the manuscript. SM: the treatment alteration-free rate in low C /D/W group was planning study design, data interpretation and data review/approval, min and writing of the manuscript, and final approval of the manuscript. significantly greater than that in the high C /D/W group min JS: data interpretation and data review and writing of the manuscript, (88% and 44%, respectively, p = 0.0047) (Fig. 4). The higher and final approval of the manuscript. NE: conducting study and data C /D/W, instead of higher C , was significantly corre - min min interpretation and writing of the manuscript, and final approval of the lated with the incidence dasatinib treatment alteration rate manuscript. in the multivariate analysis. The C /D/W possibly could min Funding This study was supported by a non-profit organization Epi- reflect patient’s ability to metabolize and/or excretion dasat- demiological and Clinical Research Information Network (ECRIN). inib. A larger patient sample is needed to determine which would be better to predict the dasatinib treatment alteration Compliance with ethical standards and to prevent discontinuation of dasatinib therapy. To our knowledge, this is the first prospective study eval- Conflict of interest Masashi Sawa received honoraria from Bristol- uating prognostic factors that influence the treatment altera- Myers Squibb. Hiroshi Kojima received honoraria from Celgene. Sa- tion of dasatinib therapy in patients with CML. However, the toshi Morita received honoraria from Bristol-Myers Squibb. Junichi Sakamoto received honoraria from Tsumura and Chugai Pharmaceuti- limitations of our study need to be considered. Our study cal, and has received consultancy fees from Takeda. Nobuhiko Emi was limited by the presence of residual confounding factors, received honoraria from Kyowa Hakko Kirin and Chugai Pharmaceu- both known and unknown. tical. All other authors report no conflicts of interest relevant to this The present study focused on clinical outcomes of 32 article. patients at the midterm point (1 year) of the observation Ethical approval The present study was approved by the Institutional period of the DARIA 01 study; however, dasatinib therapy Review Board of the Fujita Health University School of Medicine and can be continued for much longer periods of time. A long- conformed to the provisions of the 1964 Declaration of Helsinki and term observation study including more large number of its later amendments or comparable ethical standards. All patients provided written, informed consent before participating in the study. patients is needed to clarify the risks for the treatment altera- tion of dasatinib therapy. Open Access This article is distributed under the terms of the Crea- tive Commons Attribution 4.0 International License (http://creat iveco mmons.or g/licenses/b y/4.0/), which permits unrestricted use, distribu- tion, and reproduction in any medium, provided you give appropriate Conclusion credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. We demonstrated that trough plasma concentrations of dasatinib after adjusting for dasatinib dose and body weight (C /D/W) at day 28 and performance status (PS) at min 1 3 International Journal of Clinical Oncology 11. Noens L, Hensen M, Kucmin-Bemelmans I et al (2014) Meas- References urement of adherence to BCR-ABL inhibitor therapy in chronic myeloid leukemia: current situation and future challenges. Hae- 1. Apperley JF (2015) Chronic myeloid leukaemia. Lancet matologica 99:437–447 385:1447–1459 12. Steegmann JL, Baccarani M, Breccia M et al (2016) European 2. 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De Francia S, D’Avolio A, De Martino F et al (2009) New HPLC- Association (EHA) MS method for the simultaneous quantification of the antileuke- mia drugs imatinib, dasatinib, and nilotinib in human plasma. J Chromatogr B Anal Technol Biomed Life Sci 877:1721–1726 Affiliations 1,11 2 3 4 2 3 Shuichi Mizuta  · Masashi Sawa  · Hisashi Tsurumi  · Kana Matsumoto  · Kotaro Miyao  · Takeshi Hara  · 5 2 6 7 8 9 Takeshi Takahashi  · Reona Sakemura  · Hiroshi Kojima  · Akio Kohno  · Mari S. Oba  · Satoshi Morita  · 10 1 Junichi Sakamoto  · Nobuhiko Emi Masashi Sawa Reona Sakemura msawa@wine.plala.or.jp r.sakemura@med.nagoya-u.ac.jp Hisashi Tsurumi Hiroshi Kojima htsuru@gifu-u.ac.jp kojima@daidohp.or.jp Kana Matsumoto Akio Kohno kmatsumo@dwc.doshisha.ac.jp akohno@wd5.so-net.ne.jp Mari S. Oba Kotaro Miyao mari.oba@med.toho-u.ac.jp koutarou380@yahoo.co.jp Satoshi Morita Takeshi Hara smorita@kuhp.kyoto-u.ac.jp haratake@muh.biglobe.ne.jp Takeshi Takahashi Junichi Sakamoto ttakahashi@gmhosp.gifu.gifu.jp sakamjun@med.nagoya-u.ac.jp 1 3 International Journal of Clinical Oncology Nobuhiko Emi Department of Hematology, Daido Hospital, Nagoya, Japan nemi@fujita-hu.ac.jp Department of Hematology and Oncology, JA Aichi Konan Kosei Hospital, Konan, Japan Department of Hematology, Fujita Health University School of Medicine, Toyoake, Japan Department of Medical Statistics, Faculty of Medicine, Toho University, Tokyo, Japan Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan Department of Hematology, Graduate School of Medicine, Gifu University, Gifu, Japan Tokai Central Hospital, Kagamigahara, Japan 4 11 Department of Clinical Pharmaceutics, Doshisha Women’s Hematology and Immunology, Kanazawa Medical College of Liberal Arts, Kyoto, Japan University, 1-1 Daigaku, Uchinada, Kahoku-gun, Ishikawa 920-0293, Japan Department of Hematology, Gifu Municipal Hospital, Gifu, Japan 1 3

Journal

International Journal of Clinical OncologySpringer Journals

Published: May 29, 2018

References

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