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Background. The treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKI) have diminished death probability and have changed the disease course. Achievement of complete cytogenetic response (CCyR) and major molecular response (MMR) are serve as warranties for freedom of progression and death from CML. There are many of CML patients are needed to change of initial TKI therapy with choice of the most efficient and safe drug for continuous life-long therapy to reach the optimal results of CML treatment. The newest of registered TKI drug in Russia is Bosutinib which has dual BCR-ABL and SRC kinase inhibitory activity and had showed good tolerability and efficacy in case of other TKIs resistance or intolerance. Aim. To analyze of own Bosutinib experience in patients with chronic myeloid leukemia with other TKIs resistance or intolerance and to make comparison with clinical trial results. Materials and methods. Clinical trials results from peer-reviewed journals. Outpatients charts of 51 patients (25 male and 26 females) with CML. Disease phase at the moment of Bosutinib therapy initiation was as follows: chronic - 37; acceleration - 8, blastic - 6. Bosutinib was used in the next lines of TKI therapy: second - 10; third - 18; fourth - 23. The indications for Bosutinib therapy were: intolerance to previous TKI - 21; resistance to previous TKI - 30. Results. Median of therapy duration was 6 months (1-50 months). The adverse events and tolerability of Bosutinib were similar with clinical trials data. The treatment was withdrawn by the adverse event only in 5 (10%) patients. The rates of the responses in the whole group of patients were as follows: CHR - 88%, stable in 76%; CCyR - 39%, stable in 37%, MMR - 31% and was 25% at the last follow-up. The Bosutinib efficacy in real life settings was slightly higher than clinical trials data. The factors influencing treatment responses were: disease phase, cause of switching to Bosutinib, line of therapy and presence and kind of BCR-ABL mutations, Therapy was continued in 22 (43%) patients, most them achieved stable optimal treatment response (CCyR and MMR). Conclusions. Bosutinib is a real alternative to other tyrosine kinase inhibitors and has its own mechanism of action and adverse events profile. The use of Bosutinib in real life clinical practice settings showed its efficacy and tolerability and could serve as base for recommendation to apply Bosutinib in hematology practice in Russia. Disclosures No relevant conflicts of interest to declare.

Background: Thrombosis in Primary Myelofibrosis (PMF) is one of the main but not fully covered problem. Thrombotic complications in PMF occur more frequently than in general population and could result to morbidity and lethality of patients. Several previous studies have demonstrated different thrombotic rates related to type molecular driver mutation (JAK2V617F, CALR, MPL) in myeloproliferative neoplasms, but this fact now is not fully understood. The standard clotting tests cover only initial stages of coagulation and could not evaluate anticoagulant system. Its results are not varied in PMF patients with different mutations. We have interested and initiated study of the coagulation system in PMF patients with integral hemostasis test - Calibrated Automated Thrombography (CAT). Here we present the results of pilot study group assessment. Aim: to investigate of the coagulation system in PMF patients with different molecular driver mutations (JAK2V617F, CALR, MPL) using thrombin generation test. Methods: The study included 13 MF patients (26 - 71 years, median = 40). There were 11 females and 2 males. Nine patients were JAK2V617F positive, 3 had CALR mutations and one patient was MPL-mutated. Thrombin generation was assessed by calibrated automated thrombinography (CAT) according to Hemker et al. Assessments were conducted in platelet poor plasma (PPP) with or without presence of thrombomodulin (PPP reagent +/- TM) as an activator of protein C system. The following parameters were evaluated: endogenous thrombin potential (ETP, nM*min), peak thrombin (Peak, nM), lag-time (Lag, min), and time to peak (TTP, min). Sensitivity ETP and Peak for TM were calculated as percent of decreasing of these parameters after adding to assay of TM (S ETP, % and S Peak, % respectively). STATISTICA 6.0 package was used in data analysis. Results were presented as median (Me) with 95% confidence intervals (CI). Results: ETP was highest in JAK2V617F patients (1213.57; min 781.60-max 1781.26 nM*min), intermediate in CALR (1058.47; min 933.14-max 1190.79 nM*min) and lowest in MPL group (972.49 nM*min). However, the Peak was higher in CALR (207.57; min 165.63-max 235.36 nM) than in JAK2V617F (160.9; (min 94.38-max 317.11 nM) and MPL (136.19 nM). We have observed disruption of protein C functioning in JAK2V617F (S-ETP 34%, min 8.65%-max 68.73%; S-Peak 20%, min 0.01%-max 44.64%) and MPL (S-ETP 46%; S-Peak 24%) groups compared to CALR patients (S-ETP 6.4%, min 2.5%-max 9.2%; S-Peak 1.8%, min 0.87%-max 1.8%). Conclusion: The results of thrombin production were differed in relation to driver mutation type. JAK2V617F-patients produced more thrombin and have protein C system dysfunction. It could be serve as an explanation of higher risk of thrombosis in MF patients with JAK2V617F mutation. The yielded results force us to continue research to confirm our findings on representative sample of PMF patients. Disclosures No relevant conflicts of interest to declare.

Introduction. A generic drug is a pharmaceutical drug considered to be equivalent to a brand-name product. A generic drug has to contain the same active ingredients as those of the original formulation. Regulatory agencies used to require that generics be identical to their brand-name counterparts with regards to pharmacokinetic properties. In most cases, generic products are available after the patent protection given to a drug's original developer expires. In Russia, a patent protection lasts for a 10-year period from registration of the original drug. To this day, twelve Imatinib generics have been registered in Russia. Aim. To assess the safety and efficacy of Imatinib generics for treatment of newly diagnosed Chronic myelogenous leukemia patients that have been in our center since August 2012. Materials and methods. 30 newly diagnosed CML patients were started on generics. The drugs: 1) GenericPh 100 mg, in capsules (Ph-Syntez, Russia); 2) GenericG 100 mg, in tablets (Laboratorio TUTEUR S.A.C.I.F.I.A., Argentina); 3) GenericIm 100 mg, in tablets (Sandoz d.d. (Slovenia). Switching from one generic to another was done due to intolerance. We analyzed the range and frequencies of adverse events (AE), cumulative incidences of complete hematologic (CHR), major cytogenetic (MCyR), complete cytogenetic (CCyR), and early molecular responses (BCR-ABL Results. Duration of the treatment with generics was 7-45 months, with a median of 13 months (GenericPh (27) + GenericG (2) + GenericIm (1)). No unexpected adverse events were observed during the Imatinib generics treatment. The generics tolerance did not differ from that of the original brand-name drug. Six patients were switched to second-generation tyrosine kinase inhibitors (TKI2) due to Imatinib intolerance. One patient progressed to blastic phase at 3 months after diagnosis. Three deaths were registered (1 - due to CML and 2 due to concomitant diseases). Overall survival rate was 90% and CML-related mortality - 3%. CHR at 3 months of the treatment was achieved in 93% of the patients. Cumulative response rates for cytogenetic and molecular responses are presented in Table 1. MR4.0 was registered in 23% of patients during overall treatment. Seven patients were switched to TKI2 due to insufficient efficacy of Imatinib. At the time of analysis 13 patients remained on Imatinib generics treatment: 12 patients with CCyR and 1 with PCyR, including 10 patients with MMR. Conclusion. Use of generics demands evaluation of its equivalency and control during its adoption into clinical practice. In terms of efficacy or tolerance no significant differences between the Imatinib generics studied and the original brand-name drug in newly diagnosed CML patients were found. Disclosures Shuvaev: Pfizer: Honoraria; BMS: Honoraria; Novartis pharma: Honoraria. Fominykh:BMS: Honoraria; Novartis Pharma: Honoraria.

Introduction. The substitution of brand-name drugs with cheaper generics is a modern tendency in health-care to decrease the burden on government budget and improve access to efficient treatment. Worldwide, generics have to be identical to the original drug in terms of pharmaceutical (active ingredients) and biological (pharmacokinetic) properties. Unfortunately, in Russia, as in most countries, there are no government regulations of equivalency to a brand-name product regarding dosage, strength, route of administration, quality, performance, and intended use. In Russia, since August 2012 the original Imatinib has almost fully been substituted with generics for the treatment of chronic myelogenous leukemia (CML). Aim. To assess tolerance and efficacy of Imatinib generics in terms of response durability by comparing it with that achieved previously in CML patients, who had received treatment with original Imatinib before switching to the generics. Materials and methods. Seventy-nine CML patients treated initially with original Imatinib (Novartis AG) with median treatment duration of 6.5 years (range, 0.5-11 years) were switched to generic drugs. The drugs: 1) GenericPh 100 mg, in capsules (Ph-Syntez, Russia) - 54 patients (44 with complete cytogenetic response (CCyR), including 32 with major molecular response (MMR); 2) GenericG 100 mg, in tablets (Laboratorio TUTEUR S.A.C.I.F.I.A., Argentina) - 25 patients (22 with CCyR, including 19 with MMR). In case of loss of response, besides non-compliance, we changed treatment to second-generation tyrosine kinase inhibitors (TKI2). Switching from one generic to another was made due to intolerance. We analyzed the range and frequency of adverse events (AE) and durability of responses achieved previously (hematologic, cytogenetic and molecular). IRIS data1 was used as a comparator for AE frequency during long-term Imatinib treatment. Statistical analysis included the Fisher exact test. Results. Tolerance of Imatinib generics was good with few exceptions. One patient in the GenericPh group suffered severe edema and was switched to Nilotinib with AE resolution. In the GenericG group 4/25 (16%) patients had severe gastroenterological toxicity (nausea, vomiting, abdominal distension, diarrhea) and were successfully switched to GenericPh. This might have been caused by the tablet filler (lactose) and related to concomitant lactose insufficiency in these patients. One patient had frequent infectious complications. Having stable deep molecular response, she entered the treatment free remission phase and had successful molecular response for more than two years. The frequency of other AEs is presented in Table 1. No significant differences were revealed between the generics and the original Imatinib in comparison with IRIS results. However, only 25% (20) of patients were free of any AE. No progression to AP/BC during the generics treatment was observed. Three deaths were registered (CML-related 1, blastic phase on Dasatinib treatment, the patient had only partial cytogenetic response to Imatinib and was switched to Dasatinib, with progression after 2 years on Dasatinib; cancer -1, cardiovascular disease -1). The patients who had inadequate responses to Imatinib before and after switching on generics were subsequently switched to TKI2: GenericPh - 11 patients (Nilotinib - 9 (CCyR - 8, MMR-7), Dasatinib - 2 (no CCyR with progression - 1, complete hematologic response -1)); GenericG - 3 patients (Nilotinib - 2, both with CCyR and MMR, Dasatinib - 1 -hematologic response with non-compliance). Durability of previousresponses was as follows: 4 patients lost their MMR: 3/54 (5.6%) while taking GenericPh and 1/25 (4%) - GenericG; 3 patients lost their CCyR: 2/54 (3.7%) while taking GenericPh and 1/25 (4%) - GenericG. All those patients were subsequently switched to TKI2 (3 re-achieving previous MMR and 1 demonstrating non-compliance). At the time of analysis there were still 58 (73%) patients on the generics treatment. 57 patients had CCyR and MMR, and one was not cytogenetically evaluated due to non-compliance (BCR-ABL 0.102%). Conclusion. No significant differences between the generics studied and the original Imatinib were observed in terms of their efficacy or tolerability in CML patients who were previously treated with a brand-name drug and subsequently switched to generics. Disclosures Shuvaev: Novartis pharma: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Fominykh:Novartis Pharma: Honoraria; BMS: Honoraria.

Introduction. The characteristics of pathological clone cells in the Primary Myelofibrosis (PMF) strongly influence on the variability of the clinical course and prognosis. The main of them are type of driver mutation in JAK2, MPL or CALR genes ("clonal markers" (CM)), cytogenetic and epigenetic alterations. It is very important to provide the physicians necessary and sufficient information about the molecular profile of the disease to select the appropriate therapy for the patient. The aim of our study was to investigate mutational diversity in PMF patients from the North-West region of the Russian Federation and to estimate overall survival (OS) depending on the type of CM, cytogenetic and epigenetic features. Materials and methods. We examined 115 patients with PMF (45 male, 70 female). Median age was 59 years (range 19-82). The detection of V617F mutation of JAK2 was carried out for all the patients. JAK2(-) samples were tested for MPL gene 515 codon mutations and 9th exon mutations in the CALR gene. All patients underwent the analysis of mutations in EZH2, ASXL1 and IDH1 genes. Karyotype research was done for 47 patients with suitable bone marrow samples. Differences of mutation/karyotype occurrence in groups were assessed using the χ2 test. Survival curves were estimated by the method of Kaplan-Meier. Differences were considered as statistically significant with p-value Results. CM were detected in 87 patients: JAK2(+) 47% (54/115), CALR(+) 23% (26/115), MPL(+) 6% (7/115) cases. No CM were found in 24% (28/115) patients, who considered as triple-negative (TN). The median survival of TN patients was significantly shorter than in the group of patients with any CM: 4 years vs 14.5 years, p=0.005. Five-year OS in TN patients was 30.6%, JAK2(+) - 83.8% and CALR(+) - 93.5% (p=0.046) (Figure 1). Median survival in JAK2(+) patients was 14.7 years, CALR(+) - 9.8 years. In MPL(+) patients with follow-up of 4 years median survival has not been reached. Patients were divided into 2 groups based on the results of cytogenetic analysis: low-risk group (LR) included 27 patients with normal karyotype (NK) and 5 patients - with del(13)(q22), del(20)(q12), add(6)(p25), del(6)(q15) single features; high risk group (HR) consisted of 15 patients with complex abnormalities and unfavorable aberrations (+8, -7/7q-, i(17q), inv(3), -5/5q-, 12p-). Median survival in the LR group was 7.5 years, in the HR group - less than 1.5 years (p=0.025). Unfavorable karyotype frequency was distinct in groups with different CM: CALR(+) - 9.1% (1/11), JAK2(+) - 35% (7/20), TN - 54% (7/14), MPL(+) - 0% (0/2) cases but these differences were not significant (p=0.107). We detected 28 mutations of the ASXL1 gene in 26/115 patients (22.6%): 24 patients had single mutation and two patients harbored two ASXL1 mutations at once. Mutation frequency was 13% (7/54) in JAK2(+) patients, 27% (7/26) in CALR(+), 32% in TN, 29% in MPL(+) (2/7). Differences in OS depending on the ASXL1-status were statistically significant in the TN group: median survival of the ASXL1(-) patients was 3.5 years, ASXL1(+) - 1.5 years (p=0.013). Two mutations in the EZH2 gene (1.7%) were observed - each one in TN and ASXL1(+) patients. Both cases were characterized by rapid disease progression. The first patient (a 61-year-old male, complex karyotype) progressed rapidly to the blast phase from diagnosis and died after 8 months. The second patient (a 75-year-old male, NK) had severe thrombocytopenia and died from a hemorrhagic stroke 5 months from diagnosis. We also detected 8 (7%) mutations in the IDH1 gene: 5 in CALR(+), 2 in TN, 1 in JAK2(+) patients. In seven cases it was a synonymous substitution G105 and in one case it was missense mutation R132C. The patient with the R132C mutation (a 74-year-old female, CALR(+), NK) had an unfavorable disease course: progression to blast phase was observed after 9 months from diagnosis. The patient died 13 months after disease progression. Conclusion. CM and epigenetic mutations frequencies in our PMF patients is consistent with international data. Type of CM, cytogenetic aberrations and epigenetic changes can be correlated with different prognosis of PMF. The absence of any CM, unfavorable karyotype and ASXL1-status in TN patient are associated with reduced OS. The impact of ASXL1-status in patients with CM as well as EZH2 and IDH1-status on the prognosis in PMF patients requires further studies. Figure OS in different groups of PMF patients. Figure. OS in different groups of PMF patients. Disclosures Shuvaev: Novartis pharma: Honoraria; BMS: Honoraria; Pfizer: Honoraria. Fominykh:BMS: Honoraria; Novartis Pharma: Honoraria.