BCD-020 (Acellbia, rituximab biosimilar candidate) was shown to be highly similar to innovator rituximab (MabThera®/Rituxan®) in terms of its quality characteristics, in vitro biological activity, as well as toxicology and PK/PD characteristics in non-human primates. International multicenter comparative randomized open-label clinical study was carried out in a period from 2011 to 2013 and involved over 30 centers in Russia, Ukraine and India. Its methodology and design complies with current EMA guidelines on similar biological products containing monoclonal antibodies (EMA/CHMP/BMWP/403543/2010). 92 patients with follicular non-Hodgkin’s lymphoma, stage I-IV by Ann Arbor, or marginal zone lymphoma, stage I-IV by Ann Arbor, ECOG 0-2, who had at least 1 measurable lesion were enrolled. According to study protocol patients with secondary transformed B-cell lymphomas or with highly aggressive types of tumor, bulky disease, severe concomitant somatic disorders and some other conditions were excluded. If a patient had previous story of chemotherapy or radiation he could be included after at least 3 weeks post-treatment. Participation of patients who were previously treated with any kind of monoclonal antibodies was prohibited. After signing standard informed consent form and completion of 28-days screening period eligible patients underwent stratification in accordance to their prognostic risk (FLIPI or IPI) and previous treatment (naïve or pretreated). Subsequently patients were randomized (1:1) into 2 groups: 46 patients were included in the main group where Acellbia (rituximab biosimilar) was administered at a dose of 375 mg/m2 as a slow IV infusion on day 1, 8, 15 and 22; 46 patients were included in the reference group where MabThera was used at the same regimen. Use of any other medicines for the treatment of lymphoma was strictly prohibited. Efficacy was assessed on the basis of computed tomography and bone marrow evaluation which were performed 1 month after the completion of treatment. Median age of patients in each group was 57.5 years (main group [50.0-64.0], reference group [47.0-65.0]). Manageable comorbidities were reported in 50% of patients in the main group and 34.78% of patients in the reference group, p=0.2053. Comparative analysis of the prognostic risk factors confirmed the equivalence of study groups. The number of pretreated patients in both groups was equal – 8 individuals per group. Statistical analysis didn’t find any difference in overall response rate in general population of patients (39.52% patients in the main group vs. 36.57% patients in the reference group, p=0.8250), as well as in population of pretreated patients (28.6% vs 37.5% respectively, p=1.00) and in population of naïve patients (42.8% vs 39.4% respectively, p=1.00). The lower limit of the two-tailed 95% CI for difference in proportions of ORR was equal to -0.17 and exceeded the predefined non-inferiority margin -0.2, which confirmed non-inferiority of Acellbia to MabThera in terms of efficacy. Treatment-associated AE of any grade were reported in 21.74% patients in both arms, in the absence of statistically or clinically significant difference (p = 0.8005). There were 2 cases of CTCAE 4.03 grade 3-4 AEs in each group. PK and PD parameters were shown to be equivalent in both study groups. Thus, study results suggest that Acellbia has same efficacy and safety in patients with B-cell non-Hodgkin’s lymphoma. Disclosures Chernyaeva: JCS BIOCAD: Employment. Ivanov:JCS BIOCAD: Employment. Isaev:JCS BIOCAD: Employment.

for the RESUME trialists (2020). Spliceosome mutations are common in persons with myeloproliferative neoplasm-associated myelofibrosis with RBC-transfusion-dependence and correlate with response to pomalidomide. Leukemia.

Background. Wt1 expression is thoroughly studied in acute myeloblastic leukemia and widely used for disease response monitoring.Its role in MPN is less known. Aim. The aim of the study was to reveal the incidence of elevated Wt1 expression in PMF and secondary MF, as well as to find out clinical significance during ruxolitinib therapy. Patients and methods. 38 pts were included ( Primary Mf-31, post PV- and post ET Mf- 8, males - 12, females- 26). Wt1 expression in peripheral blood was studied by qPCR at diagnosis and during ruxolitinib treatment using Quiagen kit. Dynamics of Wt1 expression was studied in 20 pts treated by ruxolininib. Spleen size was measured in cm below costal margin. Results. Wt1 increased expression was found in 35/38 pts. Correlation of Wt1 expression and DIPSS was not found. The relation between blast cell and Wt1 expression was studied by dividing pts in 3 subgroups according to the number of blast cells in peripheral blood- 0, 1-2, >2. Wt1 expression was lowest in the 1st group, and the highest in the 3rd group((p<.05). Ruxolitinib treatment resulted in the decrease of spleen size and parallel decrease of Wt1 level( p<.05 -Fig1).Pts with transformation to acute leukemia(5) had higher level of Wt1 than before transformation. Conclusion. Wt1 expression is elevated in the majority of pts with PMF as well as in secondary MF. Correlation was found with blast level and spleen size. Wt1 could be used for monitoring efficacy of ruxolitinib therapy Disclosures Konopleva: Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding.

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.

Introduction Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematopoietic stem cell disease that can lead to life-threatening complications including thrombotic events (TE), chronic kidney disease (CKD) and pulmonary hypertension. An international PNH Registry was implemented in 2008 to enhance understanding of the natural history of PNH, to describe treatment outcomes, and to evaluate the long term safety of eculizumab in treated patients. Methods This Registry is a non-interventional, prospective, multicenter, observational study. All patients with a diagnosis of PNH (confirmed in accordance with international diagnostic guidelines) or a detected PNH clone are enrolled irrespective of age or therapy. Data on patient demographics, medical histories, disease characteristics and treatment are collected at enrollment, every 6 months thereafter and/or at discontinuation. Descriptive statistics are used to describe the data; n, median and range (min–max) for continuous variables and percentages for categorical parameters. Results As of May 1, 2013, the Registry has enrolled 248 patients from Russia, over 50% of whom have a history of aplastic anemia or other bone marrow disorder (BMD) (Table 1). Disease characteristics for the overall population and by clone size or LDH level are presented in table1.A total of 25 patients have received eculizumab and have available follow-up data after starting treatment; median (range) follow-up time 4.4 (0.3–8.3) months. Among the 11 patients treated with eculizumab and with available LDH levels, the median LDH ratio was 5.7 X ULN before treatment and 1.0 X ULN at last follow-up assessment. Conclusion Russian patients included in the International PNH Registry show broad ranges of age, clone size, and degrees of hemolysis. History of TE, impaired renal function, and signs of chronic hemolysis are present among these patients regardless of PNH clone size. History of TE was recorded more frequently in patients with PNH clone sizes ≥20%, and was also more frequent among patients with LDH levels ≥1.5 x ULN. Among patients treated with eculizumab there was a marked decrease in hemolysis (as measured by LDH levels). Disclosures: Lisukov: Alexion: Honoraria. Kulagin:Alexion: Honoraria. Shilova:Alexion: Honoraria. Afanasyev:Alexion: Honoraria.

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In present research the comparative analysis of donor chimerism (DC) using different tests was performed to improve the diagnostic tool in patients with malignant hematological disorders after allo-HSCT. The RBC antigen typing, identification of ABO blood type and quantitative analysis of InDel-, STR-, Y-polymorphisms were carried out for detection of DC. In addition, the expression of well-known oncogenes and CD-markers for monitoring MRD was evaluated to predict relapse and clinical outcome. According to our research, the analysis of InDel polymorphism using AlleleSEQR-PCR is more sensitive test for estimation of DC as compared with other assays. Moreover, the sensitivity of AlleleSEQR-PCR may be increased after isolation of the CD34 cell population in bone marrow. Nevertheless, observation of high levels in DC (³95%) in some leukemia patients (ALL, Ph+, bcr-abl/p190+) during first 6 months after HSCT cannot exclude the possibility of relapse. Thus, the combined monitoring of both DC (InDel) and MRD (oncogenes, WT1 and CD-markers) is a more advisable and useful test in managing hematologic malignancies and predicting relapse risk after allo-HSCT.

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