Treatment Of Chronic Lymphatic Leukemia Research Articles

Covalent docking-driven virtual screening of extensive small-molecule libraries against Bruton tyrosine kinase for the identification of highly selective and potent novel therapeutic candidates

Bruton tyrosine kinases (BTKs) play critical roles in various diseases, including chronic lymphatic leukemia (CLL), Waldenström Macroglobulinemia, Marginal Zone Lymphoma, Mantle Cell Lymphoma (MCL), and Graft Versus Host diseases. BTKs are a family of tyrosine kinases involved in B lymphocyte signal transduction, development, and maturation. Their overexpression can lead to cancer as they are essential for the activation of the B Cell Receptor (BCR) signaling pathway. Blocking the activation of BTKs presents a promising approach for treating CLL. This study was centered around the identification of small-molecule therapeutics that have an impact on human BTK. The covalently bound Ibrutinib molecule, recognized for its ability to inhibit BTK, was used as the query molecule. IUPAC text files containing molecular fragments of Ibrutinib were employed to virtually screen five different libraries comprising small-molecules, resulting in the screening of over 2.4 million synthesized compounds. Covalent docking simulations were applied to the selected small-molecules obtained through text mining from databases. Potent hit molecules capable of inhibiting BTKs through virtual screening algorithms were identified, paving the way for novel therapeutic strategies in the treatment of CLL.

Radiolabeled PLGA Nanoparticles for Effective Targeting of Bendamustine in Tumor Bearing Mice.

Bendamustine is an important drug for the treatment of chronic lymphatic leukaemia (CLL), non-Hodgkin lymphoma (NHL). However, its delivery is challenging due to its instability. Current approach reports the development and characterization of bendamustine encapsulated PLGA nanoparticles for the effective targeting to leukemic cells. The prepared, bendamustine loaded PLGA nanoparticles (BLPNP) were developed and characterized for particle size, zeta potential and polydispersity index. The formed nanoparticles were further characterized with the help of electron microscopy for surface morphology. The formed nanoparticles were evaluated for cytotoxicity, cell uptake, ROS and cell apoptosis against THP-1 leukemic cells as a part of in vitro evaluation. In vivo organ bio-distribution and tumor regression studies were performed to track in vivo behaviour of BLPNP. The average particle size was 138.52 ± 3.25nm, with 0.192 ± 0.036 PDI and - 25.4 ± 1.38mV zeta potential. TEM images revealed the homogeneous particle size distribution with uniform shape. In vitro release exhibited a sustained drug-release behaviour up to 24h. Cytotoxicity against THP-1 cells through MTT assay observed IC50 value of 27.8 ± 2.1μM for BLPNP compared to pure drug, which was 50.42 ± 3.4μM. Moreover, in vitro studies like cell-uptake and cell apoptosis studies further confirmed the higher accumulation of BLPNP in comparison to the pure drug. Organ distribution and tumor regression studies were performed to track in vivo behaviour of bendamustine loaded nanoparticles. The overall study described a promising approach in terms of safety, least erythrocytic toxicity, better IC50 value with enhance tumor targeting and regression.

Targeting of B-cell receptor signalling in B-cell malignancies.

Pharmacological agents that inhibit enzymes of the B-cell receptor (BCR) pathway are of increasing importance in the treatment of B-cell malignancies. These include inhibitors of Bruton tyrosine kinase (BTK), phosphatidylinositol 3-kinase (PI3K), splenic tyrosine kinase and protein kinase Cβ. Two agents are already approved in the USA and Europe: ibrutinib, a BTK inhibitor, for the treatment of chronic lymphatic leukaemia (CLL), mantle cell lymphoma (MCL) and Waldenström's macroglobulinemia; and idelalisib, a PI3Kδ inhibitor, for the treatment of CLL and follicular lymphoma. In addition, the role of these drugs in diffuse large B-cell lymphoma and marginal zone lymphoma is under investigation, as single agents and in combination with chemotherapy. In CLL, both ibrutinib and idelalisib have an established role as first-line therapy in patients with del(17p), and in MCL, ibrutinib is a standard option for patients relapsing after chemoimmunotherapy. Unexpected toxicities have been encountered when combining these potent new agents with other drugs, including chemotherapy and lenalidomide, and based on this experience the risks and benefits of novel combinations must be evaluated carefully. In this review, we summarize the efficacy and safety results with these inhibitors and discuss novel combinations that are under study and the future role of BCR inhibitors in these disorders.

Innovative Antikörper-Therapien bei malignen Lymphomen

Non-Hodgkin s lymphoma (NHL) includes a group of malignant lymphoproliferative disorders, that particularly occur in the elderly and have an continuously increasing incidence. Because of the age distribution new treatment options with low toxicity and minor side effects - apart from "conventional" therapies like standard or high dose chemotherapy - are needed. Within these novel therapeutic modalities the use of the monoclonal antibody rituximab has been widely established. Other monoclonal antibodies, such as the anti-CD52-antibody alemtuzumab, are available for the treatment of chronic lymphatic leukemia (CLL) and T-cell-lymphomas and are being tested in clinical trials. Furthermore the option of combining targeted therapies, in which antibodies are used with radiotherapy, has led to the development of radio-immunotherapies that are now becoming available for clinical use. Current results in the treatment of advanced indolent lymphomas are promising, and their use in high-grade lymphoma and as first-line therapy is under investigation. This article summarizes the application of these novel immunotherapies and reviews the results of recent clinical trials, with particular emphasis on indications and practical aspects in everyday clinical life.

Fatal Thrombocytopaenia Temporally Related to the Administration of Alemtuzumab (MabCampath) for Refractory CLL Despite Early Discontinuation of Therapy

Alemtuzumab (Campath 1H -MabCampath), initially used for prophylaxis of graft versus host disease in allogenic transplantaion, is now increasingly used for refractory chronic lymphatic leukaemia (CLL). Its efficacy has been well documented in this--the commonest form of leukaemia. Alemtuzumab is associated with severe immunosuppression, allergic reactions and thrombocytopenia. Data sheet and information supplied by the manufacturer confirm the rare occurrence of serious immune thrombocytopenia, recommending discontinuation of therapy when platelet counts fall below 50×10 9 /l. We report a patient with refractory CLL in which relentless progressive cytopenia occurred despite the discontinuation of alemtuzumab therapy while the platelet count was over 97×10 9 /l. Marrow biopsy showed increased megakaryocytes, the patient bleed uncontrollably and died of cerebral haemorrhage with a platelet count <10×10 9 /l. Data on the predictive factors underlying this complication are few and deserve further study as this drug is increasingly used the treatment of CLL.

Unusual reaction to chlorambucil: a case report

In this brief report we describe, a case of cutaneous reaction during treatment of chronic lymphatic leukemia (CLL) with chlorambucil. The patient developed a confluent maculopapular erythema and large flaccid bullae of trunk, legs, feet and mucous membranes, with fever up to 38°C. Toxic epidermal necrolisis (TEN) was supposed and the diagnosis was confirmed by a skin patch test followed by cutaneous biopsy. TEN by chlorambucil is a rare syndrome that may be considered in presence of cutaneous reaction to this drug.

Expression of the multiple drug resistance gene (mdr‐1) and epitope masking in chronic lymphatic leukaemia

Resistance to cytotoxic agents is a common clinical problem in the treatment of chronic lymphatic leukaemia (CLL). The multidrug resistant (MDR) phenotype characterized by increased levels of a specific cell membrane p-glycoprotein, confers cross resistance to a wide range of structurally dissimilar antineoplastic drugs. We have studied the expression of this p-glycoprotein in chronic lymphatic leukaemia measured by immunofluorescence using a monoclonal antibody MRK 16 by flow cytometry. Initial results showed that only 12% of lymphocyte samples from CLL patients showed increased p-glycoprotein, conflicting with a previous observation that 53% of CLL patients had an increased level of mdr-1 mRNA. Treatment of the cells with neuraminidase to remove sialic acid residues increased the proportion of patients showing increased p-glycoprotein to 52%. This suggest that in a subset of CLL patients post translational modification of the protein occurs masking the epitope recognized by MRK 16. Abnormal sialylation patterns associated with malignancy are a well-recognized phenomenon.

Interferon α-2b bei chronischer lymphatischer Leukämie vom B-Zell-Typ*

In a clinical phase II study nine patients (five men and four women; mean age 48 [42-58] years) in an early stage of chronic lymphatic leukaemia (CLL) of the B-cell type were treated with recombinant alpha-2b interferon (IFN alpha-2b), initially at a dosage of 5 mega units subcutaneously three times weekly, but in some cases reduced to 2.5 or raised to 10 mega units. Duration of treatment has been 15-36 months. Through-flow cytometry in seven patients demonstrated a definite fall in circulating B1-positive lymphocytes. Lasting partial remission (duration of 106-134 weeks) was achieved in four patients, in a further four the condition remained stable. A recurrence was noted in the patient with the initially highest lymphocyte count (52,000/microliters) after 28 weeks, control being achieved only after 64 weeks of chemotherapy. Side effects were flu'-like symptoms and (in two instances) depression. In three patients there was a clear rise in serum immunoglobulin concentrations as sign of IFN alpha-2b-induced increased immune response, while in four HLA-DR expression on monocytes was doubled. It is concluded that early treatment of CLL with IFN alpha-2b may delay the onset of necessary chemotherapy, any antibody-deficiency may be improved and survival time may ultimately be lengthened.

Free light chains of immunoglobulins in serum from patients with leukaemias and multiple myeloma.

The serum concentration of free kappa and lambda light chains of immunoglobulins were measured in 114 patients with myelo- and lymphoproliferative disorders including multiple myeloma. Increased concentrations of a single light chain type, suggesting monoclonal origin, were found with high frequency in B-cell diseases only. Thus 6 out of 9 patients with chronic lymphatic leukaemia and 24 of 28 patients with multiple myeloma had increased concentrations of a single chain type. The highest values reported in chronic lymphatic leukaemia were approximately 10 and in multiple myeloma 1000 times normal mean. Cytostatic treatment of chronic lymphatic leukaemia was followed by a decrease in the light chain levels. The levels were, however, not correlated to the number of circulating lymphocytes, the lymphatic infiltration of tissue or clinical activity. Increased concentrations of both chain types, suggesting a polyclonal origin, were found in both of 2 patients with acute monocytic leukaemia, 6 of 7 with acute myelomonocytic leukaemia, 2 of 23 with acute myeloid leukaemia and 1 of 7 with acute lymphoblastic leukaemia. The highest levels of light chains in these groups were 5 times normal mean. All patients with myeloproliferative disorders revealed normal values of both light chain types.

Cutaneous Reaction to Chlorambucil

To the Editor.— Chlorambucil is an oral alkylating agent that has been used since early 1950, particularly for the treatment of chronic lymphatic leukemia. The side effects are gastrointestinal symptoms, such as nausea and vomiting, and bone marrow depression. Allergic skin reactions are extremely rare. This report refers to a patient with chronic lymphatic leukemia in whom a rash was produced when repeatedly challenged with a small dose of chlorambucil. The common features of the known three cases of skin reaction to chlorambucil are described. Report of a Case.— A 69-year-old man had breathlessness on exertion and on examination was found to have a firm liver, just palpable, and an enlarged spleen extending to the left iliac fossa. There was no lymphadenopathy. The results of the investigations done at the time of admission were as follows: hemoglobin level, 78%, 11.0 gm/100 ml; WBC count, 36,000/cu mm, 88% of which were

The role of endolymphatic radiotherapy in the treatment of chronic lymphatic leukaemia.

The role of endolymphatic radiotherapy in the treatment of chronic lymphatic leukaemia.

Remissions induced by chlorambucil in chronic granulocytic leukemia.

Elson1demonstrated that single doses of busulfan (1,4-dimethansulfonyloxybutane) (Myleran) produced a selective depression of granulocytes in the rat, whereas chlorambucil [p-(di-2-chloroethyl) aminophenylbutyric acid] was more specifically injurious to lymphocytes. He suggested that these two polyfunctional alkylating agents showed some specificity of action for these different cell types. For this reason, Galton and co-workers2employed busulfan in the treatment of chronic granulocytic leukemia and chlorambucil in treatment of chronic lymphatic leukemia and Hodgkin's disease with beneficial therapeutic results. Subsequent workers3have continued clinical trials of busulfan in chronic granulocytic leukemia and chlorambucil in chronic lymphatic leukemia and lymphomas, and their reports have served to support the view that these alkylating agents have separate and specific effects in these conditions. If correct, this is of extraordinary significance, since it would indicate that by chemical modifications polyfunctional alkylating agents could be designed to inhibit proliferation of specific tissues. This

Clinical Experience with CB 1348 (NN-DI(2-Chloroethyl,-P-Aminophenylbutyric ACID) in the Treatment of Chronic Lymphatic Leukaemia

Clinical Experience with CB 1348 (NN-DI(2-Chloroethyl,-P-Aminophenylbutyric ACID) in the Treatment of Chronic Lymphatic Leukaemia

Clinical experience with CB 1348 (NN-di(2-chloroethyl, -P-aminophenylbutyric acid) in the treatment of chronic lymphatic leukaemia.

Clinical experience with CB 1348 (NN-di(2-chloroethyl, -P-aminophenylbutyric acid) in the treatment of chronic lymphatic leukaemia.