Application of New Drugs in Chronic Lymphocytic Leukemia

Over the last few years, several new agents have been under evaluation in preclinical studies as well as in early clinical trials, and have shown promise in treating CLL. These treatments include new monoclonal antibodies (mAbs), immunomodulating agents, novel purine nucleoside analogs, Bcl-2 inhibitors and other agents. The most promising are a new mAbs targeted CD20 molecule or CD23, anti-CD40 mAbs and anti-CD37 antibody. Oblimersen, flavopiridol, and lenalidomide are also being evaluated both in pre-clinical studies and in early clinical trials. However, available therapies are only partially efficient and there is an obvious need to develop better strategies and new, more specific and active drugs

Vascular endothelial growth factor and its soluble receptors VEGFR-1 and VEGFR-2 in the serum of patients with systemic lupus erythematosus.

We investigated the serum concentration of vascular endothelial growth factor (VEGF) and its two soluble receptors, sVEGFR-1 and sVEGFR-2, in a group of 60 patients with systemic lupus erythematosus (SLE), and 20 healthy controls, using an enzyme-linked immunosorbent assay. We examined a possible association between serum levels of these proteins and certain clinical and laboratory parameters as well as SLE activity. VEGF, sVEGFR-1 and sVEGFR-2 were detectable in all patients with SLE and in all normal individuals. The VEGF level was higher in active SLE (mean, 300.8 pg/ml) than in inactive SLE (mean, 165.9 pg/ml) (p < 0.05) or in the control group (mean, 124.7 pg/ml) (p < 0.04). The highest sVEGFR-1 concentrations were also detected in active SLE patients (mean, 42.2 pg/ml) and the lowest in inactive disease (mean, 32.0 pg/ml) (p < 0.01). In contrast, the levels of sVEGFR-2 were lower in SLE (mean, 12557.6 pg/ml) than in the control group (mean, 15025.3 pg/ml) (p < 0.05). We found a positive correlation between sVEGFR-1 concentration and the SLE activity score p = 0.375 (p < 0.004) and a negative, but statistically insignificant correlation between sVEGFR-2 and SLE activity (p = -0.190, p > 0.05). Treatment with steroids and cytotoxic agents did not influence VEGF or its soluble receptors levels. In conclusion, in SLE patients the levels of VEGF and sVEGFR-1 are higher in patients with active SLE than in inactive disease or healthy persons. In contrast, the level of sVEGFR-2 is lower in active SLE than in inactive disease. The imbalance between VEGF and its soluble receptors may be important in SLE pathogenesis

High serum level of endostatin in multiple myeloma at diagnosis but not in the plateau phase after treatment.

We investigated the serum concentration of endostatin in 84 patients with multiple myeloma (MM) and in 13 healthy controls. The level of measured anti-angiogenic agent was correlated with the phase and stage of the disease, and most importantly with clinical and laboratory parameters depicting the disease activity (haemoglobin, creatinine, albumins, calcium, M-component, C-reactive protein, beta2-microglobulin, lactate dehydrogenase, stage of bone disease) as well as serum levels of pro-angiogenic cytokines such as vascular endothelial growth factor, hepatocyte growth factor, fibroblast growth factor and transforming growth factor-beta. The median serum level of endostatin in MM patients was 58 ng/ml and was statistically significantly higher than in the control group (median, 40 ng/ml; p=0.015). MM patients in phase I (at diagnosis) had higher levels of endostatin (median, 69 ng/ml) than those in phase II (plateau phase after treatment) (median, 49 pg/ml; p=0.044). We did not find any statistical correlation between the level of endostatin and stage of MM according to the Durie and Salmon system. The serum concentration of endostatin in MM patients with a normal level of albumins was significantly higher than in others with hypoalbuminaemia (median, 62 ng/ml versus 39 ng/ml; p=0.033). Also, patients with a normal value of lactate dehydrogenase had a higher concentration of endostatin than those with values >425 U/l (median, 70 ng/ml versus 39 ng/ml; p=0.019). We did not show any statistical correlation between the concentration of endostatin and level of haemoglobin, creatinine, calcium, C-reactive protein, beta2-microglobulin and stage of bone disease. We failed to find positive or negative correlations between the level of endostatin and vascular endothelial growth factor, hepatocyte growth factor, fibroblast growth factor and transforming growth factor-beta. The concentration of endostatin did not influence the probability of survival in MM patients in our study. In conclusion, our data indicate that endostatin has a higher level in MM patients than in healthy controls. Highest values were stated in active phases of the disease (at presentation and in progression). Different clinical and laboratory parameters generally do not influence the concentration of endostatin (except albumins and lactate dehydrogenase)

Nowe horyzonty w leczeniu przewlekłej białaczki limfocytowej

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western world, accounting for approximately 30% of all leukemias in Europe and North America. Recently, significant progress in the characterization and understanding of the biology and prognosis of CLL has provided new opportunities for the development of innovative, more effective therapies. Several new anti-CD20 monoclonal antibodies directed against lymphoid cells have been developed and are under investigation in preclinical studies and clinical trials. Currently, the most promising is obinutuzumab, a novel third generation anti-CD20 monoclonal antibody that exhibits superior caspase-independent apoptosis and antibody-dependent cellular cytotoxicity than rituximab. The antibody has shown a safety profile similar to that of rituximab and promising efficacy in patients with CLL. The CD37 antigen may be advantageous over CD20 in diseases in which the level of CD37 expression is higher than that of CD20. The results of recent preclinical and early clinical studies suggest that anti-CD37 antibodies and related agents can be useful in the treatment of CLL, and many small molecule inhibitors targeting B-cell antigen receptor (BCR) signaling pathways have recently been under investigation in patients. Promising clinical results have been observed with a Btk inhibitor, ibrutinib, and a selective inhibitor of PI3Kδ, idelalisib. Several other agents including immunomodulating agents and those targeting the antiapoptotic bcl-2 family of proteins also show promise in treating CLL. Moreover, immune-based treatment strategies intended to augment the cytotoxic potential of T cells offer exciting new treatment options for patients with CLL

B-cell chronic lymphocytic leukemia-associated nuclear antigens

One- and two-dimensional polyacrylamide gel electrophoresis were used to compare the composition of nuclear polypeptides from normal and В-cell chronic lymphocytic leukemia mononuclear cells. Against two electrophoretically-specific nuclear proteins with molecular weight of 38/39 and 44/46 kD a from leukemic cells rabbit sera were obtained. As it was analyzed by Western blot technique the available antisera recognized the 38/39 kDa antigen in 53 of the 56 (94.6%), while the 44/46 kDa in 46 of the 49 (93.9%) of examined В-CLL nuclear fraction preparations, but not in normal ones. The pi values of described leukaemia-specific antigens were determined; p38/39 had pi in the range of pH 6.55 -7.00 and p44/46 - in the range of pH 6.2-6.4.Zadanie pt. „Digitalizacja i udostępnienie w Cyfrowym Repozytorium Uniwersytetu Łódzkiego kolekcji czasopism naukowych wydawanych przez Uniwersytet Łódzki” nr 885/P-DUN/2014 dofinansowane zostało ze środków MNiSW w ramach działalności upowszechniającej naukę

Monoclonal antibodies for the treatment of chronic lymphocytic leukemia

Przeciwciała monoklonalne przyczyniły się do znacznego postępu w leczeniu przewlekłej białaczki limfocytowej (CLL). Największe znaczenie kliniczne mają obecnie alemtuzumab i rytuksymab. Rytuksymab jest hybrydowym ludzkim/mysim przeciwciałem, reagującym z antygenem CD20. Jest on obecnie stosowany głównie w terapii skojarzonej, najczęściej łącznie z analogami puryn i cyklofosfamidem, zarówno w pierwszej, jak i w kolejnych liniach leczenia. alemtuzumab jest humanizowanym, szczurzym przeciwciałem monoklonalnym reagującym z antygenem CD52. alemtuzumab jest stosowany u chorych opornych na analogi puryn. Może być również bardzo cennym lekiem w CLL z mutacją genu p53 lub delecją 17p. Ofatumumab (HuMax, Arzerra) jest ludzką immunoglobuliną (Ig)G1K. reaguje on z antygenem CD20, lecz rozpoznaje inny epitop tego antygenu niż rytuksymab. obecnie ofatumumab jest zarejestrowany do leczenia chorych na CLL, opornych na fludarabinę i alemtuzumab. ponadto, wiele nowych przeciwciał monoklonalnych jest ocenianych u chorych na CLL w badaniach przedklinicznych i klinicznych. Należą do nich lumiliksymab, obinutuzumab (GA-101), TRU-016, moxetumomab pasudotox i inne leki.Monoclonal antibodies (mAbs) have changed the natural course of chronic lymphocytic leukemia (CLL). The most important clinical value in the patients with CLL have at present two mAbs – rituximab and alemtuzumab. The first one is a human mouse antibody, rituximab (IDEC C2B8, Rituxan, Mabthera) that targets CD20 antigen. The second is alemtuzumab (Campath-1H), a humanized form of a rat antibody active against CD52. Over the last few years, several new monoclonal antibodies have been investigated in preclinical studies and clinical trials for patients affected by CLL. The most promising are mAbs directed against CD20, CD22, CD23, CD37 and CD40. New generations of anti-CD20 mAbs were engineered to have augmented antitumor activity by increasing complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity and increased Fc binding affinity. New mAbs directed against CD20 include human mAb ofatumumab (Arzerra, HuMax CD20) and obinutuzumab (GA-101), a novel third – generation fully humanized and optimized mAb. These agents are highly cytotoxic against B-cell lymphoid cells and are evaluated in CLL. Some other new mAbs are also active in indolent NHL. These treatments include epratuzumab, apolizumab, galiximab, anti-TRAIL receptors mAbs, anti-CD37 and anti-CD40 mAbs. Small modular immunopharmaceuticals (SMIP) that retain Fc mediated effector functions have been also developed and investigated in preclinical studies and clinical trials. The SMIP molecules include TRU-015 (anti-CD20) and TRU-016 (anti-CD37). Further studies are needed to elucidate the role of these agents in CLL