Chronic myeloid leukemia (CML) is a myeloproliferative disease characterized by the presence of BCR/ABL fusion gene in leukemic cells, which promotes uncontrolled cell proliferation. Up to 20% of CML patients show primary resistance or non-optimal response to tyrosine kinase inhibitor (TKI) therapy. We investigated the association between copy number variation (CNV) in glutathione S-transferases (GST) and cytochromes (CYP) and the response rate to TKI. We enrolled 47 patients with CML: 31 with an optimal response and 16 with failure at 6 months in accordance with European LeukemiaNet 2013 recommendations. CNV detection was performed using SALSA MLPA P128-C1 Cytochrome P450 probe mix. Patients with optimal response and with failure of TKI therapy showed different frequencies of wild type and mutated CYPs and GST (p<0.0013). Validation in the group of 15 patients proved high prognostic value (p = 0.02): positive and negative predictive value 83% and 78%; sensitivity and specificity 71% and 88%. Wild type genotypes of CYP and GST associate with a worse response to TKI treatment in CML patients. This test can be recommended for further clinical trials.
Кidney injury is a frequent and significant complication of cancer and cancer therapy. The kidneys are susceptible to injury from malignant infiltration, damage by metabolites of malignant cells, glomerular injury, nephrotoxic drugs including chemotherapeutic agents. Also bone marrow transplantation complications, infections with immune suppression (including septicemia), tumor lysis syndrome should be taken into account. Chemotherapeutic agents are a common cause of acute kidney injury but can potentially lead to chronic kidney disease development in cancer patients. This article summarizes risk factors of acute kidney injury in cancer patients. Risk factors are divided into two groups. The systemic are decrease of total circulating blood volume, infiltration of kidney tissue by tumor cells, dysproteinemia, electrolyte disturbances. The local (renal) risk factors are microcirculation disturbances, drugs biotransformation with formation of reactive oxygen intermediates, high concentration of nephrotoxic agents in proximal tubules and its sensitivity to ischemia. Drug-related risk factors include: drugs combination with cytotoxic effect high doses long term use necessity, direct cytotoxic effect of not only chemotherapeutic agents but also its metabolites, mean solubility forming intratubular precipitates. Early diagnosis, timely prevention and treatment of these complications provide significantly improve nononcologic results of treatment.
Chronic myeloid leukemia (CML) is characterized by the presence of the chimeric tyrosine kinase BCR-ABL in all leukemic cells. This non-specific enzyme promotes uncontrolled cell proliferation and genome instability. Tyrosine kinase inhibitors (TKI) help most of the people to achieve long standing remission, however up to 20% of patients develop slow response or even primary resistance to the therapy. In this work we focused on copy number variation (CNV) in glutathione transferases (GSTs) and cytochromes (CYPs) as possible predictors of the response rate to TKI. Thirty one CML patient with optimal response and 16 with therapy failure were enrolled in the study. Patient were grouped according to ELN2013 recommendations: BCR-ABL<1% and/or Ph+ 0% for optimal response and BCR-ABL>10% and/or Ph+ >35% at 6 months of TKI therapy for the failures. We found that these two groups of patients had differed frequencies of wild type and mutated genes: CYP1A2, CYP2A6, CYP2C19, CYP2C9, CYP2D6, CYP2E1, CYP3A4, CYP3A5, GSTM1, GSTP1, GSTT1 (p< 0.0013). Validation in the additional group of 15 CML patients showed that the test allows to predict failures and responders (p=0.02) with high accuracy: positive and negative predictive value 83% and 78%; sensitivity and specificity 71% and 88%. Disclosures Chelysheva: Novartis: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau. Shukhov:BMS: Honoraria; Novartis Pharma: Honoraria. Turkina:BMS: Honoraria; Novartis Pharma: Honoraria; Pfizer: Honoraria. Kutsev:Novartis: Speakers Bureau; Pfizer: Speakers Bureau.
Background: Paroxysmal nocturnal hemoglobinuria is a rare clonal hematopoietic stem cell disease that can lead to life-threatening complications including thrombotic events (TE), chronic kidney disease (CKD) and pulmonary hypertension. In 2011 the International PNH Registry was implemented in the Russian PNH cohort to assess the natural history of PNH and the effects of treatment with eculizumab. Aims:We aim to evaluate the change from baseline to last follow-up in physician-reported symptoms, LDH and hemoglobin concentration in treated and untreated PNH patients. Design and methods: The international PNH Registry is a non-interventional, prospective, multicenter observational study. The study population of this analysis comprised the Russian cohort of the Registry: all patients had a confirmed diagnosis of PNH according to international guidelines. As per local guidelines, blood transfusion dependency and a history of TE were the main indications for treatment with eculizumab. Data are presented as descriptive statistics only. The reporting period includes time from baseline until the earliest of: death; bone marrow transplant; discontinuation from the Registry; discontinuation from eculizumab; last follow-up in the Registry. Results: As of June 2014, the international PNH Registry has enrolled 479 patients from Russia, 75 patients were ever-treated with eculizumab (15.7%), among whom 60 had available data. The median (range) duration of follow-up of patients after eculizumab treatment was 0.8 (-0.7 – 1.9) years and the median years (range) from disease onset to the start of eculizumab treatment was 8.1 (1 – 30) years. One patient discontinued treatment due to the disappearance of PNH clones and disease manifestations. Fifteen deaths were reported during the reporting period; all in patients never treated with eculizumab. Table 1. History of medical events at baseline All patients (N = 464) Ever-treated with Eculizumab (N = 60) Never-treated patients (N = 404) History of BMD, n (%) 423* 313 (74) ongoing 39* 12 (31) ongoing 384* 301 (78) ongoing History of TE, n (%) 436* 30 (7) 39* 9 (23) 397* 21 (5) History of any RBC transfusion, n (%) 385* 300 (78) 39* 26 (67) 346* 274 (79) RBC transfusion in past 12 months, n (%) 419* 245 (59) 29* 22 (76) 390* 223 (57) History of CKD, n (%) 435* 24 (6) 39* 1 (3) 396* 23 (6) History of pulmonary hypertension, n (%) 435* 11 (3) 39* 4 (10) 396* 7 (2) *number of patients with available data Table 2. Change from baseline to last follow up for physician-reported symptoms All patients Ever-treated with eculizumab Never-treated patients Abdominal pain, n (%): Improved No change Worsened N=196 33 (17) 145 (74) 18 (9) N=29 15 (52) 10 (35) 4 (14) N=167 18 (11) 135 (81) 14 (8) Dysphagia, n (%): Improved No change Worsened N=195 17 (9) 162 (83) 16 (8) N=29 7 (24) 20 (69) 2 (7) N=166 10 (6) 142 (86) 14 (8) Dyspnea, n (%): Improved No change Worsened N=196 55 (28) 127 (65) 14 (7) N=29 15 (52) 12 (41) 2 (7) N=167 40 (24) 115 (69) 12 (7) Fatigue, n (%): Improved No change Worsened N=199 23 (12) 169 (85) 7 (4) N=29 4 (14) 25 (86) – N=170 19 (11) 144 (85) 7 (4) Hemoglobinuria, n (%): Improved No change Worsened N=196 29 (15) 156 (80) 11 (6) N=28 12 (43) 16 (57) – N=168 17 (10) 140 (83) 11 (7) Median (Q1, Q3) Hb concentrations at baseline in ever-treated and never-treated patients were 7.3 (6.3, 9.2) g/dL and 9.0 (7.2, 11.3) g/dL, respectively, and median (Q1, Q3) changes in Hb concentration from baseline to last follow up were 2.1 (1.2, 3.8) g/dL and 0.75 (-0.4, 2.5) g/dL, respectively. Median (Q1, Q3) LDH level at baseline in ever-treated and never-treated patients were 6.0 (3.6, 8.7) x the upper limit of normal (ULN) and 1.1 (0.8, 1.8) x ULN, respectively, and median (Q1, Q3) changes in LDH level from baseline to last follow up were -4.8 (-6.9, -1.9) and 0.0 (-0.2, 0.3) x ULN, respectively. Conclusion: This analysis represent the first report on longitudinal outcomes during eculizumab therapy in Russian patients included in the international PNH Registry and are considered essential for planning patients' follow-up, including monitoring of therapeutic effects and prophylaxis against break-through hemolysis. Overall, the data show an improvement in physician-reported symptoms and reduced hemolysis, as measured by plasma LDH level, in patients treated for a relatively short period of time. Disclosures Lisukov: Alexion: Honoraria. Kulagin:Alexion: Honoraria. Shilova:Alexion: Honoraria. Afanasyev:Alexion: Honoraria.
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