Retrospective analysis of nilotinib and dasatinib efficacy in second line treatment of chronic myeloid leukemia in Polish hematological centers

Until now, there has been no randomized study directly comparing the activity of second-generation BCR-ABL tyrosine kinase inhibitors (TKI-2G) nilotinib and dasatinib in chronic myeloid leukemia (CML). The aim of our study was to retrospectively analyze efficacy of nilotinib and dasatinib in the real life setting of CML with resistance or intolerance of imatinib. Of 108 included patients treated in polish hematology centers, 75 received dasatinib and 33 patients received nilotinib. Rates of complete cytogenetic response (CCyR) did not differ between the two groups of patients. After six months of therapy, CCyR was achieved in 34.7% of patients treated with dasatinib and 38.7% treated with nilotinib (p=0.86), while after 12 months, the CCyR rates were 60.0% and 77.0% in dasatinib and nilotinib groups, respectively (p=0.11). Moreover, we have not observed any significant difference in the probability of progression-free survival (p=0.89) or overall survival (p=0.99) between patients treated with these two TKI-2G. In conclusion, the results of our analysis indicate that nilotinib and dasatinib have comparable and satisfactory efficacy in the treatment of CML patients refractory or intolerant to imatinib. Our findings support current strategy of choice of IKT-2G according to drug toxicity profile and risk of specific adverse events in an individual patient

STRATEGY OF VISUAL PROPRIOCEPTIVE CONTROL IN PATIENTS WITH INJURY TO THE ANTERIOR CRUCIATE LIGAMENT OF THE KNEE AND HEALTHY INDIVIDUALS (SOCCER PLAYERS)

Objective: Knee joint dysfunction resulting from injury to the anterior crucial ligament (ACL) is associated not only with mechanical joint instability but also with damage of ligamentous receptors responsible for the joint proprioception. It was found that disturbances of signals from the damaged joint produce disorders in movement perception and position of the analogous joint in the normal limb. This study is aimed at evaluating the control strategy in patients with an injury to the anterior crucial ligament.Design: Cohort study; Level of evidence, 3. Subjects/Patients- 84 men, aged 15 to 55 years (mean age 27 years) were included in this study. Methods- Patients were divided into two groups: those with unilateral injury to the ACL (33 patients) and a control group of healthy volunteers (soccer players; 51 men). Anterior crucial ligament damage was confirmed with arthroscopic knee joint examination in every patient. The way of visual proprioceptive control was assessed with both dynamic (DRT) and static (SRT) Riva tests standing on one leg. Tests were performed with the Delos Postural Proprioceptive System (Delos s.r.l., Corso Lecce, Torino, Italy) in the biomechanical evaluation laboratory at Rehasport Clinic in Poznań. Results: A statistically significant difference for deviations from the averaged axis in SRT (static Riva test) with closed eyes was found between the limb with a damaged ACL and the normal limb in the group of patients with injury to the ACL (p=0.006) and between the limb with a damaged ACL and normal limbs in healthy volunteers (p=0.022). A statistically significant difference for deviations from the averaged axis in SRT with closed eyes was also found between the dominant and non-dominant limb in healthy volunteers (p=0.013). No significant differences in the results of tests with open eyes were noted. Conclusions: The results of systems and their contribution to the visual proprioceptive control suggest an important role of the visual system in compensation of archeproprioceptive system disorders resulting from injury to the ACL. Clinical Relevance: Neurological deficits of proprioceptive perception, associated with injury to the ACL and affecting the balance, may be noted only in the results of tests performed with closed eyes

Impact of genetic polymorphisms of drug transporters ABCB1 and ABCG2 and regulators of xenobiotic transport and metabolism PXR and CAR on clinical efficacy of dasatinib in chronic myeloid leukemia

INTRODUCTION: Functional single-nucleotide polymorphisms (SNPs) in genes regulating cellular uptake, elimination, and metabolism of xenobiotics may potentially influence the outcome of chronic myeloid leukemia (CML) patients treated with BCR-ABL1 tyrosine kinase inhibitors (TKI). Dasatinib, a second-generation TKI, is a substrate of the ABC-superfamily xenobiotic transporters ABCB1 (MDR1, Pg-P) and ABCG2 (BCRP). Pregnane X receptor (PXR, NR1I2) and constitutive androstane receptor (CAR, NR1I3) are involved in the control of expression of ABCB1 and ABCG2. AIM OF THE STUDY: In this study, we assessed the impact of inherited variants in ABCB1, ABCG2, PXR, and CAR genes on dasatinib efficacy and toxicity in CML. MATERIALS AND METHODS: Sixty-one tagging SNPs in ABCB1, ABCG2, PXR, and CAR genes were analyzed by real-time quantitative PCR with specific probes in 86 CML patients who failed imatinib therapy. RESULTS: We found the associations between SNPs rs7787082 (ABCB1, OR = 0.2; 95% CI = 0.06-0.66, p = 0.008), rs12505410 (ABCG2, OR = 3.82; 95% CI = 1.38-10.55; p = 0.010), and rs3114018 (ABCG2, OR = 0.24; 95% CI = 0.08-0.71; p = 0.010) and the probability of achieving CCyR. Furthermore, progression-free survival (PFS) was significantly influenced by SNPs rs3732357 (HR = 0.2, 95% CI = 0.26-0.70; p = 0.001), rs3732360 (HR = 0.59; 95% CI = 0.38-0.93; p = 0.020), rs11917714 (HR = 0.58; 95% CI = 0.36-0.92; p = 0.020), and rs3732359 (HR = 0.57; 95% CI = 0.36-0.91; p = 0.024) in PXR; rs2307418 (HR = 2.02; 95% CI = 1.19-3.43; p = 0.048) in CAR; and rs2235023 (HR = 2.49; 95% CI = 1.13-5.50; p = 0.011) and rs22114102 (HR = 1.90; 95% CI = 1.00-3.63; p = 0.028) in ABCB1. Moreover, overall survival (OS) was impacted by rs3842 (HR = 1.84; 95% CI = 1.01-3.33; p = 0.012) and rs2235023 (HR = 2.28; 95% CI = 1.03 = 5.02; p = 0.027) in ABCB1, rs11265571 (HR = 1.59; 95% CI = 0.82-3.08; p = 0.037) and rs2307418 (HR = 73.68; 95% CI = 4.47-1215.31; p = 0.003) in CAR, and rs3732360 (HR = 0.64; 95% CI = 0.40 = 1.04; p = 0.049) in PXR. Taking into account the influence of the tested SNPs on treatment toxicity, we found a significant relationship between allele G of polymorphism in the ABCB1 rs7787082 (OR = 4.46; 95% CI = 1.38-14.39 p = 0.012) and hematological complications assuming the codominant gene inheritance model as well as a significant correlation between the presence of minor allele (G) of SNP rs2725256 in the ABCG2 gene (OR = 4.71; 95% CI = 1.20-18.47; p = 0.026) and the occurrence of non-hematological complications assuming a recessive gene inheritance model. CONCLUSION: Our data suggest that inherited variants in the genes encoding for proteins involved in the transport of xenobiotics may modify the toxicity and efficacy of dasatinib therapy in CML patients