The results of our prospective study have revealed great diversity in the treatment regimens used to manage MM in real-life practice. This diversity was linked to factors such as novel agent accessibility and evolving treatment recommendations. Our results provide insight into associated clinical benefits.

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Chronic lymphocytic leukemia (CLL) mainly affects older people: the median age at diagnosis is > 70 years. Elderly patients with CLL are heterogeneous with regard both to the biology of their disease and aging. Following the diagnosis of CLL in an elderly individual, careful risk assessment is essential when treatment options are evaluated. This includes not only clinical staging and evaluation of disease-specific prognostic biomarkers such as 17p deletion and TP53 mutation, but also of comorbidities, physical capacity, nutritional status, cognitive capacity, ability to perform activities of daily living and social support. Comorbidity scoring and geriatric assessment tools are helpful in achieving such multidimensional evaluation in a systematic manner. The introduction of new drugs including novel monoclonal antibodies and kinase inhibitors offers enhanced opportunities for the treatment of elderly patients with CLL. This position paper of a Task Force of the International Society of Geriatric Oncology (SIOG) reviews currently available evidence relevant to such patients. All types of elderly patient (i.e. chronological age > 65-70 years) are considered, from robust (fit) to vulnerable (unfit) to the terminally ill. Among the topics covered are the following: (i) the relationship between chronological age, prognosis and survival, (ii) assessment of biological aging, (iii) biological age as a determinant of treatment feasibility and tolerance and (iv) tailoring of both first and further-line treatment to the circumstances of the individual patient.

Background The Wnt/β-catenin signalling is aberrantly activated in primary B cell chronic lymphocytic leukaemia (CLL). Epigenetic silencing of pathway inhibitor genes may be a mechanism for its activation. In this study, we investigated systematically and quantitatively the methylation status of 12 Wnt/β-catenin pathway inhibitor genes – CDH1, DACT1, DKK1, DKK2, DKK3, DKK4, SFRP1, SFRP2, SFRP3, SFRP4, SFRP5 and WIF1 – in the cell lines EHEB and MEC-1 as well as patient samples. Methods Quantification of DNA methylation was performed by means of bisulphite pyrosequencing and confirmed by bisulphite Sanger sequencing. Gene expression was analysed by qPCR using GAPDH as internal control. E-cadherin and β-catenin protein quantification was carried out by microsphere-based immunoassays. Methylation differences observed between the patient and control groups were tested using generalised least squares models. Results For 10 genes, a higher methylation level was observed in tumour material. Only DKK4 exhibited similarly high methylation levels in both tumour and normal specimens, while DACT1 was always essentially unmethylated. However, also for these inhibitors, treatment of cells with the demethylating agent 5-aza-2´-deoxycytidine resulted in an induction of their expression, as shown by quantitative PCR, suggesting an indirect epigenetic control of activity. While the degree of demethylation and its transcriptional consequences differed between the genes, there was an overall high correlation of demethylation and increased activity. Protein expression studies revealed that no constitutive Wnt/β-catenin signalling occurred in the cell lines, which is in discrepancy with results from primary CLL. However, treatment with 5-aza-2´-deoxycytidine caused accumulation of β-catenin. Simultaneously, E-cadherin expression was strongly induced, leading to the formation of a complex with β-catenin and thus demonstrating its epigenetically regulated inhibition effect. Conclusions The results suggest an epigenetic silencing mechanism of the Wnt/β-catenin pathway inhibitor genes in CLL. Hypermethylation and silencing of functionally related genes may not be completely stochastic but result from the tumour epigenome reprogramming orchestrated by Polycomb-group repressive complexes. The data are of interest in the context of epigenetic-based therapy.

BCD-020 is a proposed rituximab biosimilar, which has shown high similarity to rituximab in quality and nonclinical studies in vitro and in vivo.International multicenter clinical trial was conducted to compare efficacy and safety of BCD-020 and reference rituximab in adult (older than 18 years) patients with indolent lymphomas (follicular lymphoma grade 1-2, splenic marginal zone lymphoma, and nodal marginal zone lymphoma). Pharmacokinetics, pharmacodynamics, and immunogenicity were also studied.Patients with no previous biologic treatment for lymphoma were randomly assigned 1:1 to receive BCD-020 or comparator 375 mg/m 2 for 4 weeks.Primary study outcome was day 50 overall response rate defined as complete or partial remission. Equivalence range was −20% to 20% for 95% CI for overall response rates difference. Secondary outcomes included adverse events, pharmacokinetics, pharmacodynamics, and immunogenicity.One hundred seventy-four patients were enrolled, 89 in BCD-020 arm and 85 in comparator arm. The overall response rate was 44.71% in BCD-020 arm and 41.89% in comparator arm. Limits of 95% confidence interval (CI) for difference of overall response rates between arms were (−12.62%-18.24%) showing equivalent efficacy.Sixty-one (68.54%) and 59 (69.41%) patients had at least one adverse event in BCD-020 arm or comparator arm, respectively. No unexpected adverse reactions were reported.Antidrug antibodies with no neutralizing activity were detected in two patients in comparator arm on day 14 further declining below detection threshold.Rituximab concentrations had equivalent pattern after intravenous administration of both drugs. Both drugs caused depletion of B-cells without significant influence on other blood cell lineages.In this study, we showed equivalent efficacy of BCD-020 and reference rituximab when used in patients with CD20-positive indolent lymphomas. We also confirmed pharmacokinetic equivalence of BCD-020 and reference rituximab. Safety profile,

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.

T-cell acute lymphoblastic leukemia (T-ALL) is a rare disease usually treated with intensive, high-dose consolidation chemotherapy followed by an allotransplant in a substantial number of patients. The data of the RALL-2009 study on 125 adult T-ALL patients suggest that similar total chemotherapy doses given less intensively over a longer interval without interruptions and with an auto- rather than an allotransplant produce outcomes like current more intensive protocols and an allotransplant: 9-year cumulative incidence of relapse (CIR), leukemia-free survival (LFS), and survival were 24% (95% CI 16–33%), 70% (95% CI 59–79%) and 62% (95% CI 51–72%). In a landmark analysis, subjects achieving a complete remission and receiving an autotransplant had a lower 9-year CIR (9% [95% CI 2–22%] vs. 29% [95% CI 16–43%]; p = 0.0076) and better LFS (91% [95% CI 79–98%] vs. 58% [95% CI 41–74%]; p = 0.0009) and survival (92% [95% CI 77–99%] vs. 60% [95% CI 44–77%]; p = 0.001) compared with subjects not receiving an autotransplant. In a multivariate analysis, white blood cells ≥100 × 109/L at study entry were significantly associated with worse LFS (HR = 2.842 [95% CI 1.131–7.143]; p = 0.0263) and survival (HR = 6.085 [95% CI 1.918–19.3]; p = 0.0022) because of more early deaths (HR = 2.42 [95% CI 1.04–5.67]; p = 0.041). Receiving an autotransplant correlated with a lower CIR (HR = 0.23 [95% CI 0.07–0.73]; p = 0.0136) and better LFS (HR = 0.27 [95% CI 0.08–0.85]; p = 0.0256) and survival (HR = 0.158 [95% CI 0.045–0.550]; p = 0.0037).

A lower chemotherapeutic load and a small number of allogeneic BMTs did not affect total positive treatment results in adult patients with ALL, by complying with the principle achieving the continuity of cytostatic effects and by preserving the total cytostatic loading dose. The results of the Russian investigation casts some doubt on the necessity of using very intensive consolidation cycles and performing a large number of allogeneic BMTs in adult patients with ALL.