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Combination of arsenic trioxide and Dasatinib: a new strategy to treat Philadelphia chromosome-positive acute lymphoblastic leukaemia.

ABSTRACT: Tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL), one of the most common and aggressive forms of haematological malignancies. However, TKI resistance has remained an unsolved issue. In this study, we investigate the impact of adding arsenic trioxide (ATO) on the action of Dasatinib, a second-generation TKI, in Ph+ ALL. We show that ATO cooperates with Dasatinib in both TKI-sensitive and resistant Ph+ ALL cell lines to increase apoptosis and we unravel the underlying mechanisms. Indeed, combining ATO and Dasatinib leads to severe cell apoptosis by activating the UPR apoptotic IRE1/JNK/PUMA axis, while neutralizing the UPR ATF4-dependent anti-apoptotic axis, activated by ATO alone. Additionally, ATO and Dasatinib in combination repress the expression of several genes, which we previously showed to be associated with shorter survival probability in ALL patients. Overall these data support the use of ATO in combination with Dasatinib as a novel therapeutic regimen for Ph+ ALL patients.

SUBMITTER: Wang T

PROVIDER: S-EPMC5824394 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Combination of arsenic trioxide and Dasatinib: a new strategy to treat Philadelphia chromosome-positive acute lymphoblastic leukaemia.

Wang Tao T Cheng Chunyan C Peng Lijun L Gao Mengqing M Xi Mengping M Rousseaux Sophie S Khochbin Saadi S Wang Jin J Mi Jianqing J

Journal of cellular and molecular medicine 20171220 3

Tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph<sup>+</sup> ALL), one of the most common and aggressive forms of haematological malignancies. However, TKI resistance has remained an unsolved issue. In this study, we investigate the impact of adding arsenic trioxide (ATO) on the action of Dasatinib, a second-generation TKI, in Ph<sup>+</sup> ALL. We show that ATO cooperates with Dasatinib in both TKI ...[more]

PMID: 29266867

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Project description:BACKGROUND:Combination of chemotherapy with a tyrosine-kinase inhibitor is effective in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukaemia. Ponatinib is a more potent BCR-ABL1 inhibitor than all other tyrosine-kinase inhibitors and selectively suppresses the resistant T315I clones. We examined the activity and safety of combining chemotherapy with ponatinib for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia in this continuing phase 2 trial. METHODS:In this single-centre, phase 2, single-arm trial, adult patients with previously untreated Philadelphia chromosome-positive acute lymphoblastic leukaemia were sequentially enrolled. Patients who had received fewer than two courses of previous chemotherapy with or without tyrosine-kinase inhibitors were also eligible. Patients had to be aged 18 years or older, have an Eastern Cooperative Oncology Group performance status of 2 or less, have normal cardiac function (defined by ejection fraction above 50%), and have adequate organ function (serum bilirubin ?3·0 mg/dL and serum creatinine ?3·0 mg/dL, unless higher concentrations were believed to be due to a tumour). Patients received eight cycles of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) alternating with high-dose methotrexate and cytarabine every 21 days. Ponatinib 45 mg was given daily for the first 14 days of cycle 1 then continuously for the subsequent cycles. Patients in complete remission received maintenance with ponatinib 45 mg daily with vincristine and prednisone monthly for 2 years followed by ponatinib indefinitely. The primary endpoint for this study was event-free survival. The trial is registered at ClinicalTrials.gov, number NCT01424982. FINDINGS:37 patients were enrolled and treated from Nov 1, 2011, to Sept 1, 2013. 2-year event-free survival rate was 81% (95% CI 64-90). Grade 3 or more toxic effects included infections during induction (20 [54%] patients), increased aspartate aminotransferase and alanine aminotransferase concentration (14 [38%] patients), thrombotic events (three [8%]), myocardial infarction (three [8%]), hypertension (six [16%]), skin rash (eight [22%]), and pancreatitis (six [16%] patients). Two patients died from from myocardial infarction potentially related to treatment; another patient also died from myocardial infarction related to sepsis. Two further patients died, one from bleeding and another from infection, both deemed unrelated to treatment. INTERPRETATION:The first results of this ongoing trial indicate that the combination of chemotherapy with ponatinib is effective in achieving early sustained remissions in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia. New strategies, including dosing titration of ponatinib and optimised control of vascular risk factors, might further improve outcomes. FUNDING:ARIAD Pharmaceuticals Inc.

Project description:ImportanceA randomized clinical trial is needed to determine whether the second-generation Abl-tyrosine kinase inhibitor dasatinib is more effective than the first-generation inhibitor imatinib mesylate for childhood Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL).ObjectiveTo determine whether dasatinib given at a daily dosage of 80 mg/m2 is more effective than imatinib mesylate at a daily dosage of 300 mg/m2 to improve event-free survival of children with Philadelphia chromosome-positive ALL in the context of intensive chemotherapy without prophylactic cranial irradiation.Design, setting, and participantsThis open-label, phase 3 randomized clinical trial was conducted at 20 hospitals in China. Enrollment occurred from January 1, 2015, through September 18, 2018, and randomization was stopped on October 4, 2018, when the early stopping criterion of the trial was met. Patients aged 0 to 18 years were recruited. Of the 225 patients with the diagnosis, 35 declined participation and 1 died before treatment, leaving 189 patients available for analysis. Data were analyzed from January 1 through August 4, 2019.InterventionsPatients were randomized to receive daily dasatinib (n = 92) or imatinib (n = 97) continuously for the entire duration of ALL therapy from the time of diagnosis made during remission induction to the end of continuation therapy.Main outcomes and measuresThe primary outcome was event-free survival, analyzed based on intention to treat. The secondary outcomes were relapse, death due to toxic effects, and overall survival.ResultsAmong the 189 participants (136 male [72.0%]; median age, 7.8 [interquartile range (IQR), 5.2-11.3] years) and a median follow-up of 26.4 (IQR, 16.3-34.1) months, the 4-year event-free survival and overall survival rates were 71.0% (95% CI, 56.2%-89.6%) and 88.4% (95% CI, 81.3%-96.1%), respectively, in the dasatinib group and 48.9% (95% CI, 32.0%-74.5%; P = .005, log-rank test) and 69.2% (95% CI, 55.6%-86.2%; P = .04, log-rank test), respectively, in the imatinib group. The 4-year cumulative risk of any relapse was 19.8% (95% CI, 4.2%-35.4%) in the dasatinib group and 34.4% (95% CI, 15.6%-53.2%) in the imatinib group (P = .01, Gray test), whereas the 4-year cumulative risk of an isolated central nervous system relapse was 2.7% (95% CI, 0.0%-8.1%) in the dasatinib group and 8.4% (95% CI, 1.2%-15.6%) in the imatinib group (P = .06, Gray test). There were no significant differences in the frequency of severe toxic effects between the 2 treatment groups.Conclusions and relevanceIntensive chemotherapy including dasatinib at a dosage of 80 mg/m2 per day yielded superior results in the treatment of Philadelphia chromosome-positive ALL compared with imatinib mesylate at a dosage of 300 mg/m2 per day and provided excellent control of central nervous system leukemia without the use of prophylactic cranial irradiation.Trial registrationChinese Clinical Trial Registry: ChiCTR-IPR-14005706.

Project description:ObjectivesTo investigate the effectiveness and safety of tyrosine kinase inhibitors (TKIs) in the management of paediatric Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ALL).DesignA systematic review and meta-analysis.Data sourcesElectronic searches were conducted on CENTRAL, MEDLINE, EMBASE, SIOP, ASPHO, ASCO, ASH and four Chinese databases from inception to 8 March 2020. Language of publications was restricted in English and Chinese.Eligibility criteriaProspective and retrospective comparative studies were included.Data extraction and synthesisTwo authors independently assessed and extracted data. Quality of studies was assessed by the Cochrane Collaboration's tool and Newcastle-Ottawa Scale. Subgroup analysis was performed by comparing different types of TKIs. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation approach.ResultsTwo randomised controlled trials (RCTs) and four cohort studies enrolling 536 patients were included. For RCTs, the pooled HR was 0.68 (95% CI 0.26 to 1.78) in overall survival (OS), 0.63 (95% CI 0.28 to 1.42) in event-free survival (EFS), respectively, comparing TKI arm with non-TKI arm for treatment of paediatric Ph+ALL. There was significant difference in OS and EFS between imatinib arm and dasatinib arm (HR 2.26, 95% CI 1.02 to 5.01; HR 2.36; 95% CI 1.27 to 4.39, respectively). For cohort studies, the pooled HR was 0.25 (95% CI 0.14 to 0.47) in OS, 0.25 (95% CI 0.12 to 0.56) in EFS, respectively, comparing TKI arm with non-TKI arm. There was no significance difference in adverse drug reaction between TKI group and without TKI group (risk ratio (RR) 0.82, 95% CI 0.63 to 1.08 in RCT; RR 1.01, 95% CI 0.64 to 1.59 in cohort studies; respectively), and imatinib versus dasatinib (RR 0.97, 95% CI 0.77 to 1.23). The quality of evidence was rated as low for OS, EFS and adverse drug reaction (ADR).ConclusionsThe combination of TKIs with chemotherapy is likely to improve the OS and EFS rates in paediatric Ph+ALL, and dasatinib is superior than imatinib. Large sample size and prospective controlled studies are warranted.Prospero registration numberCRD42018104107.

Dataset Information

Combination of arsenic trioxide and Dasatinib: a new strategy to treat Philadelphia chromosome-positive acute lymphoblastic leukaemia.

Publications

Combination of arsenic trioxide and Dasatinib: a new strategy to treat Philadelphia chromosome-positive acute lymphoblastic leukaemia.

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