A Higher Dose of Dasatinib May Increase the Possibility of Crossing the Blood–Brain Barrier in the Treatment of Patients With Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia
Xiaoyuan Gong, M.D.; Le Li, M.D.; Hui Wei, M.D.; Bingcheng Liu, M.D.; Chunlin Zhou, M.D.; Guangji Zhang, M.D.; Kaiqi Liu, M.D.; Dong Lin, M.D.; Benfa Gong, M.D.; Shuning Wei, M.D.; Yan Li, M.D.; Yingchang Mi, M.D.; Ying Wang, M.D.∗; and Jianxiang Wang, M.D.∗
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
ABSTRACT
Purpose: Dasatinib is a second-generation tyrosine kinase inhibitor with higher central nervous system (CNS) penetration compared with imatinib and nilotinib in in vitro studies. However, limited clinical data are available regarding the dosage and CNS penetration of dasatinib. The purpose of this study was to investigate the actual ability of dasatinib to cross the blood–brain barrier in patients with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL).
Methods: Plasma and cerebrospinal fluid (CSF) samples collected from Ph+ ALL patients treated with dasatinib were analyzed by using an LC-MS/MS assay. Findings: Orally administered dasatinib 100 mg once daily was well absorbed by the patient but penetrated poorly into the CSF. The use of a higher drug dosage (140 mg/d) may increase systemic drug exposure and enhance the penetration of dasatinib into the CSF.
Implications: Based on this study, the use of a higher dosage of dasatinib (140 mg/d) is recommended in patients at high risk of CNS relapse or patients who need treatment for CNS leukemia.
Key words: Cerebrospinal fluid concentration, Dasatinib, Philadelphia chromosome–positive acute lymphoblastic leukemia.
INTRODUCTION
The introduction of BCR-ABL1 tyrosine kinase in- hibitors (TKIs) has greatly improved the prognosis of Philadelphia chromosome–positive acute lymphoblas- tic leukemia (Ph+ ALL).1–3 At present, the main TKIs available are imatinib of the first generation; dasatinib, nilotinib, and bosutinib of the second generation; and ponatinib of the third generation.4 Due to the limited central nervous system (CNS) penetration of most TKIs, prophylactic intrathecal therapy is an indispensable part of treatment for patients with Ph+ ALL.5 Dasatinib can penetrate the blood–brain barrier (BBB) and holds promising therapeutic potential in managing CNS leukemic disease compared with other TKIs.6,7 However, cases in which dasatinib has failed to prevent CNS leukemia due to insufficient penetrance of the drug in the CNS have been reported.8 Pharmacokinetic studies have shown that the maximum plasma concentration of dasatinib appeared at 0.25 to 2 hours after administration; however, studies on the concentrations of dasatinib in cerebrospinal fluid (CSF) were limited to case reports.7,9–11
To date, there are few clinical data on the relation- ship between human plasma and CSF concentration of dasatinib. The optimal dose of dasatinib in the treatment of CNS diseases has yet to be determined. To address this issue, LC-MS/MS was used to measure the plasma and CSF concentrations of dasatinib in a prospective, single-arm clinical study in the treatment of adult patients with Ph+ ALL.
PATIENTS AND METHODS
A total of 31 adults with newly diagnosed Ph+ ALL between January 2016 and April 2018 at our center were registered. Our institution is a 92-bed center for leukemia chemotherapy in a Chinese tertiary hospital. Patients with a history of chronic myeloid leukemia were excluded from the study. One patient failed in screening due to organ dysfunction, and thus 30 patients were included in this prospective, single-arm study (ClinicalTrials.gov identifier: NCT02523976).
All patients received a combination treatment of dasatinib (Yinishu, CTTQ) and pediatric-inspired chemotherapy. For CNS leukemia prophylaxis, routine triple intrathecal injection (methotrexate 10 mg, dexamethasone 10 mg, and cytarabine 50 mg) was performed after peripheral blood cell count recovery in the induction and consolidation cycles, which was not different from patients with Ph– ALL. The patients who proceeded for transplantation received prophylactic triple intrathecal injection 8 times, and the patients who underwent continuous chemotherapy received intrathecal injection up to 12 to 14 times.
Dasatinib was administered 100 mg once daily for all patients during induction and early consolidation courses. The dosage of dasatinib was escalated to 70 mg BID (140 mg/d) in 5 patients due to poor molecular response during later consolidation courses. Dasatinib was administered on the condition that clinical benefit was preserved, and it was continued until relapsed disease, unacceptable adverse events, physician decision, or before stem cell transplantation. During patient screening, we checked whether patients were taking any drugs that affect the absorption or metabolism of dasatinib according to drug instruction. Fortunately, none of the 30 patients had a combination of drugs that might affect dasatinib absorption before enrollment. The use of comedication with drugs known to reduce the plasma dasatinib concentration should be avoided during the treatment stage. For example, antacid should be avoided within 2 hours before or after taking dasatinib.
Dasatinib concentrations were measured in both plasma and CSF by using an LC-MS/MS method. The LC column was a Shim-pack XR-ODSⅡ column (2.0 mm × 50 mm, 2.2 μm particles; Shimadzu Corporation, Tokyo, Japan) maintained at 40°C with a flow rate of 0.35 mL/min. A gradient elution method was used with a mobile phase consisting of 0.1% formic acid in a mix of water/acetonitrile. The LC was interfaced to an advantage ion-trap mass spectrometer operated in the positive ion electrospray, multiple reaction monitoring mode. For dasatinib, fragmentation of m/z 488 yielded daughter ions for quantitation at m/z 401. For the internal standard, m/z 496 was fragmented to yield daughters at m/z 406. The standard curve was fitted with a quadratic regression weighted by reciprocal concentration (1/x). For this method, the limit of quantification (LQ) was 1 ng/mL and 0.5 ng/mL in plasma and CSF, respectively.
Based on previous study results11 that peak concentrations of dasatinib in blood occurred 0.5 to 2 hours after administration, several blood sampling points were set for plasma concentration detections. Plasma dasatinib concentrations at 0.5, 6, and 8 hours after administration were measured on the first day of the induction course; plasma dasatinib concentrations before and 2 and 6 hours after administration were measured on day 15 of the induction course; and plasma dasatinib concentrations before and 0.5 and 2 hours after administration were measured on day 29 of the induction course. After the detection of plasma dasatinib concentrations during induction treatment, maximum plasma concentration was observed 2 hours after a single oral administration. We therefore decided to collect CSF samples before and 2 hours after taking dasatinib during consolidation courses to explore the relationship between human plasma and CSF concentration. In addition to routine CSF tests, CSF samples of at least 1 mL were collected in sterile tubes for drug concentration analysis before intrathecal chemotherapy. To prevent the influence of CSF mixed with blood, if red blood cells were observed in a CSF cytology test sample, the sample would then not be measured for drug concentration; the sample would be taken at the next lumbar puncture. Finally, 27 and 25 paired samples of plasma and CSF were collected before and 2 hours after administration of the total dosage of dasatinib (100 mg/d) during consolidation courses, respectively. The paired concentrations of plasma and CSF 2 hours after administration of dasatinib in the 5 patients received 140 mg/d were also measured. The flowchart of screening and sample collection is shown in the Supplemental Figure (see the online version at doi:10.1016/j.clinthera.2021.05. 009).
The study protocol was approved by the Ethics Committee of Blood Diseases Hospital. Written informed consent from all patients was obtained in accordance with the Declaration of Helsinki.
RESULTS
The median age for the study cohort (N = 30) was 37.0 years (range, 19–50 years), and 56.7% of the patients were male. The demographic and clinical characteristics of the patients are summarized in Table I. The median plasma concentrations 0.5, 6, and 8 hours after administration on day 1 were 16.90 (standard deviation, SD 44.80), 32.58 (SD 17.90), and 19.07 (SD 10.69) ng/mL, respectively. The median plasma concentrations before therapy and 2 and 6 hours after administration on day 15 were 1.78 (SD 0.84), 45.13 (SD 37.63), and 29.25 (SD 21.71) ng/mL.
The median plasma concentrations before therapy and 0.5 and 2 hours after administration on day 29 were 1.71 (SD 0.70), 65.35 (SD 97.59), and 80.11 (SD 49.02) ng/mL.
The plasma concentration–time profiles of dasa- tinib on days 1, 15, and 29 during the induction course are shown in Figure 1. Maximum plasma concentration was observed 2 hours after a single oral administration (Figure 2), and extremely variable plasma concentrations were noticed between different individuals, as shown in Figure 1. In the study of the relationship between plasma concentration and CSF concentration, the plasma samples revealed that the median plasma concentration before administration of dasatinib was 2.1 (SD 2.08) ng/mL. The paired dasatinib concentration in CSF was found in only 1 of the 27 patients (ie, 0.194 ng/mL), which was detectable but below the LQ level. The median plasma concentration 2 hours after administration was 87.14 (SD 63.01) ng/mL. The paired detectable dasatinib concentrations in CSF were found in 4 of the 25 patients: 0.231, 0.297, 0.410, and 0.679 ng/mL (but only one above the LQ). Five patients had a dose escalation of dasatinib to 70 mg BID; detectable levels of dasatinib in CSF were found in all patients, 2 of them above the LQ (1.010 and 0.845 ng/mL), one approached the LQ (0.489 ng/mL), and the remaining 2 below the LQ (0.104 and 0.274 ng/mL). The plasma and CSF concentrations of the 5 patients treated with different doses of dasatinib are listed in Table II. During the monitoring of plasma and CSF concentrations, no patient discontinued dasatinib for any reason.
DISCUSSION
In the era of TKIs, CNS relapse is still a challenge for Ph+ ALL patients.12 According to the literature, the incidence of CNS relapse in patients with Ph+ ALL is 8% to 17%. Once CNS involvement occurs, the prognosis of patients is dismal even after active treatment.12,13 In addition to systemic chemotherapy, intrathecal therapy, and craniocerebral radiotherapy, TKIs with effective CSF penetration are essential for patients with CNS involvement. The first-generation imatinib has been proven to have limited ability to cross the BBB.14 Among the second- and third-generation drugs, nilotinib, bosutinib, and ponatinib combined with systemic and intrathecal chemotherapy have been successfully used in the treatment of CNS leukemia, including Ph+ ALL and chronic myeloid leukemia lymphoid blast crisis. However, the reports were all from individual cases, and the data regarding concentrations of the aforementioned TKIs in human CSF are limited.15–19 The potential of these TKIs in crossing the BBB, however, is not definite and warrants further study.
Dasatinib has been considered as the most promising TKI for the prevention and treatment of CNS leukemia due to its CNS penetration potential.6,7 However, using dasatinib as frontline therapy for Ph+ ALL patients did not reduce leukemia recurrence in the CNS
compared with imatinib in some clinical trials,12,14 which raised questions about the ability of dasatinib to cross the BBB. It should be noted that dasatinib was administered at a dose of 100 mg/d in these studies. In vitro studies have shown that dasatinib is a substrate of human P-glycoprotein and breast cancer resistance protein (BCRP), which limits access of dasatinib to the CNS by transmembrane transporting.11 Even though dasatinib can be transferred across the BBB, low concentration of the drug might be inadequate to eliminate all leukemia cells in the CNS sanctuary.
At present, there is no standard dose recommenda- tion of dasatinib for the treatment of adult Ph+ ALL, and the dosage in clinical studies ranges from 70 mg/d to 140 mg/d.4 Almost all cases reported to be effective in the treatment of CNS leukemia with dasatinib were prescribed 140 mg/d.6,9 The dosage of dasatinib in the treatment of pediatric Ph+ ALL has also been discussed. For dasatinib administered at a daily dosage of 80 mg/m2 in pediatric Ph+ ALL patients, a significantly low incidence of isolated CNS relapse was reported (1
SUPPLEMENTARY MATERIALS
Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j. clinthera.2021.05.009. of 92 cases) compared with the 2 other studies that used a lower dosage (60 mg/m2 once daily).20–22
Our data showed that oral administration of dasatinib 100 mg once daily was well absorbed by the patient but penetrated poorly into the CSF. Therefore, the low incidence of CNS relapse to a great extent should be attributed to stringent enforcement of lumbar puncture and triple intrathecal injection. The use of a higher drug dosage (140 mg/d) could increase systemic drug exposure and enhance the penetration of dasatinib into the CSF. Based on our study, we recommend the use of a higher dosage of dasatinib in patients at high risk of CNS relapse or patients who need treatment for CNS leukemia. Whether a higher dosage of dasatinib could potentially reduce the occurrence of CNS leukemia requires further research. To the best of our knowledge, the present study is the largest on the relationship between human plasma and CSF concentration of dasatinib in adult patients with Ph+ ALL. Due to the limited number of patients, there is no conclusion about the relationship between plasma concentration and molecular response. The benefit of increasing the dasatinib dose in adult patients needs to be investigated in a larger patient cohort.
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