The Impact of Smoking on Relapse and Survival in Patients with Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Treated with the Combination of Intensive Therapy with Tyrosine Kinase Inhibitor

2019 ◽  
Vol 19 ◽  
pp. S180
Author(s):  
Koji Sasaki ◽  
Hagop Kantarjian ◽  
Guillaume Richard-Carpentier ◽  
Farhad Ravandi ◽  
Nicholas Short ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Intensive Therapy ◽  
Philadelphia Chromosome ◽  
Newly Diagnosed ◽  
The Impact ◽  
Philadelphia Chromosome Positive

scholarly journals Tyrosine kinase inhibitor prophylaxis after transplant for Philadelphia chromosome‐positive acute lymphoblastic leukemia

2019 ◽  
Vol 110 (10) ◽  
pp. 3255-3266 ◽  
Author(s):  
Yu Akahoshi ◽  
Satoshi Nishiwaki ◽  
Shuichi Mizuta ◽  
Kazuteru Ohashi ◽  
Naoyuki Uchida ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Philadelphia Chromosome Positive

Further Analytical, Pharmacokinetic, and Clinical Observations on Low-Dose Ponatinib in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Chemotherapy ◽  
2020 ◽  
Vol 65 (1-2) ◽  
pp. 35-41
Author(s):  
Pierantonio Menna ◽  
Ugo De Grazia ◽  
Francesco Marchesi ◽  
Giorgio Minotti ◽  
Emanuela Salvatorelli
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Human Plasma ◽  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Plasma Exposure ◽  
Dose Reductions ◽  
Philadelphia Chromosome Positive

Introduction: Ponatinib (PNT) is a tyrosine kinase inhibitor approved for treating patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL), or chronic myeloid leukemia, resistant or intolerant to other tyrosine kinase inhibitor or showing T315I mutation of BCR-ABL. Unfortunately, the clinical use of PNT is limited by the possible occurrence of vascular occlusive events. The incidence of vascular events seems to correlate with PNT dose intensity and plasma exposure. Dose reductions from 45 mg to 30 or 15 mg/day are increasingly considered to improve PNT safety but a plasma threshold of ∼40 nM must be achieved to ensure that antileukemic activity is preserved. Therapeutic drug monitoring (TDM) would be appropriate for patients treated by PNT. We, therefore, developed and validated a liquid chromatography tandem mass spectrometry (HPLC-MS/MS) assay to measure PNT plasma levels. Methods: PNT and its deuterated internal standard were extracted from human plasma by one-step protein precipitation. PNT was separated and quantified by HPLC-MS/MS operating in the multiple reaction monitoring acquisition mode. Results: The method was linear from 9.4 to 940 nM PNT. Limits of detection and lower limits of quantification (LLOQ) were, respectively, 1 and 9.4 nM. Selectivity, sensitivity, matrix effect, short-, and long-term stability met criteria of international guidelines for bioanalytical method validation. Intra- and inter-day accuracy and precision were calculated on 4 different concentrations (QCLow, QCMedium, QCHigh, and LLOQ), with all values being <15%. The method was successfully probed in leukemia Ph + ALL patients to show that PNT doses <45 mg/day caused lower plasma exposure but still achieved PNT levels at or above the 40 nM threshold. Conclusions: We developed a highly sensitive and selective HPLC-MS/MS method to quantify PNT in human plasma. This method might be used for TDM and to guide dose reductions if unnecessary high PNT levels are detected in a patient.

scholarly journals Combination of Dasatinib and Pediatric-Inspired Regimens in Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Single-Center Prospective Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2583-2583
Author(s):  
Zhang Guang ji ◽  
Jianxiang Wang ◽  
Ying Wang ◽  
Hui Wei ◽  
Yingchang Mi
Keyword(s):  
Overall Survival ◽  
Acute Lymphoblastic Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Free Survival

Background: Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is a rare subtype of acute lymphoblastic leukemia with a poor long-term prognosis. Recent studies suggested that the addition of tyrosine kinase inhibitor (TKI) to the traditional chemotherapy treatment has significantly improved Ph+ ALL patients response rates, disease-free survival, and overall survival (OS). Dasatinib, a second-generation tyrosine kinase inhibitor, can pass the blood-brain barrier and possesses a stronger inhibitory effect on both SRC kinase and BCR-ABL. In theory, it might be beneficial in Ph+ ALL treatment. This prospective, single-arm study assesses the efficacy of a combination of dasatinib and pediatric-inspired regimens in Ph+ ALL patients. Methods: 30 patients from the Institute of Hematology and Blood Diseases Hospital were enrolled in this study from January 2016 to April 2018. Eligible subjects were newly diagnosed Ph+ ALL adult patients. Chemotherapy regimens were initiated after the pediatric-inspired regimens, and standard induction chemotherapy was given for four weeks. Seven courses of consolidation or hematopoietic cell transplantation (HCT) were given to those who have achieved hematological complete remission (HCR). The primary objectives of this study were the HCR and molecular complete response (MCR), the major molecular response (MMR), the overall survival (OS), and the hematologic relapse-free survival (HRFS). The median follow-up time was 28 months. The trial registration number is NCT02523976. Results : 30 subjects were enrolled in this study with a median age of 37.5 years (range 19-50 years). All patients achieved HCR after four weeks of induction therapy with a cumulative MCR rate of 87.5%(21/24). The median HRFS and median OS were 19.5 (range 2-40 months) and 21 (range 7-41 months), respectively. The molecular response, assessed through monitoring of BCR-ABL transcript expression, revealed that 61.3% of the patients reached MMR and MCR after three months of treatment. Additionally, the results indicated that patients who achieved MCR in the first three months had a better HRFS (p=0.038). Fifteen of the patients (50%) proceeded to stem cell transplantation (SCT) within the first HCR period (SCT in HCR1). Only 13.3% (2/15) of the SCT cohort relapsed, and 20% (3/15) died. It is worth mentioning that the SCT in HCR1 cohort had better HRFS (P=0.03). Most adverse events were reversible, and none of the subjects had pulmonary hypertension. Conclusion: These findings indicate that an early MCR (3 months) has a positive impact on patients survival and that Dasatinib, combined with pediatric-inspired regimens, is effective and leads to a high MCR in patients with newly diagnosed Ph+ALL. Disclosures No relevant conflicts of interest to declare.

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