SummaryThe broaden application of adoptive T-cell transfer has been constrained by the technical abilities to isolate and expand antigen-specific T cells potent to selectively kill tumor cells. With the recent progress in the design and manufacturing of cellular products, T cells used in the treatment of malignant diseases may be regarded as anticancer biopharmaceuticals. Genetical manipulation of T cells has given T cells desired specificity but also enable to tailor their activation and proliferation potential. Here, we summarize the recent developments in genetic engineering of T-cell-based biopharmaceuticals, covering criteria for their clinical application in regard to safety and efficacy.

Chronic myeloid leukemia (CML) is a myeloproliferative disorder associated with a characteristic chromosomal translocation called the Philadelphia chromosome. This oncogene is generated by the fusion of breakpoint cluster region (BCR) and Abelson leukemia virus (ABL) genes and encodes a novel fusion gene translating into a protein with constitutive tyrosine kinase activity. The discovery and introduction of tyrosine kinase inhibitors (TKIs) irreversibly changed the landscape of CML treatment, leading to dramatic improvement in long-term survival rates. The majority of patients with CML in the chronic phase have a life expectancy comparable with that of healthy age-matched individuals. Although an enormous therapeutic improvement has been accomplished, there are still some unresolved issues in the treatment of patients with CML. One of the most important problems is based on the fact that TKIs can efficiently target proliferating mature cells but do not eradicate leukemic stem cells, allowing persistence of the malignant clone. Owing to the resistance mechanisms arising during the course of the disease, treatment with most of the approved BCR-ABL1 TKIs may become ineffective in a proportion of patients. This article highlights the different molecular mechanisms of acquired resistance being developed during treatment with TKIs as well as the pharmacological strategies to overcome it. Moreover, it gives an overview of novel drugs and therapies that are aiming in overcoming drug resistance, loss of response, and kinase domain mutations.

No abstract

e18552 Background: Multiple myeloma is a plasma cell dyscrasia that primarily involves bone marrow but also occurs in the soft tissues. While observing striking differences in clinical courses of patients with extramedullary plasmacytoma (EMP), solitary bone plasmacytoma (SBP), multifocal form of multiple myeloma (MFM) and multiple myeloma (MM), we wanted to assess prognostic factors and outcomes in those groups. This retrospective analysis was performed to evaluate response rate and overall survival (OS) of patients with extramedullary manifestations. Methods: We evaluated the data from 54 patients with MM (n=17), MFM (n=19), EMP (n=12) and SBP (n=6) treated at our institution from 1994-2012 and initially selected based on provided tissue samples. The MM control cohort was matched with regard to age, gender and prior treatment regimens. In 3 of 19 cases of MFM extramedullary locations were found at initial diagnosis. Two patients with EMP converted into MFM during the treatment. All EMP lesions arised in the upper aerodigestive tract. However extramedullary involvement in MFM was found in the head and neck (37%), chest (53%), abdomen (21%) and extremities (31%). Results: The 5-year OS rate was 92% in the patients with EMP. Whereas, 5-year OS rates of MM patients achieved 70.6%. MFM patients reached only 58% 5-year OS. The 5-year probability of progression was significantly higher in the group with MFM than EMP (89.5% vs 33%, p=0.0076, log rank test). Median progression free survival was 34 months for MM and 20 months for MFM (p=0.18). Conclusions: The 5-year progression free survival could be reached in 10 out of 12 patients with EMP. Two of the patients with primary EMP developed MFM. Moreover, the secondary development of extramedullary manifestation was associated with worse prognosis. Since the differences in the disease development cannot be easily predicted, there is an need of additional predictors that take into account different genetically determined risk status. Our retrospective analysis of genetic variations in this cohort of patients indicates the need of additional predictors in future randomized studies in these rare subtypes of MM.

No abstract