Alemtuzumab in the up-front setting

Alemtuzumab is a humanized chimeric monoclonal antibody targeting CD52. Although this agent already has an important role in the treatment of chronic lymphocytic leukemia (CLL), many of its uses are still being defined. Early trials showed alemtuzumab’s value in refractory disease and helped to define its excellent activity in the bone marrow, spleen and 17p deleted patients. The CAM307 trial has demonstrated alemtuzumab’s efficacy as monotherapy in the front-line setting, and ultimately led to its FDA approval as frontline therapy. Especially promising is the trend toward improved response in patients with high risk cytogenic abnormalities (17p del, 11q del, trisomy 12). The various consolidation trials have also provided promising results of achieving eradication of minimal residual disease (MRD). Although the ultimate benefit of achieving MRD negativity remains under investigation, alemtuzumab’s potent activity on the bone marrow will likely make it an important part of combination therapy

Augmenting NF-kappaB in poor-risk CLL: A general paradigm for other cancers?

Chronic lymphocytic leukemia (CLL) is a chronic lymphoproliferative disorder of B lymphocytes. It has an extremely variable clinical course. Some patients have a rather indolent course, whereas others are known to have a rapidly progressive disease. Most patients die from causes related to CLL that can be due to bone marrow failure, infection, or transformation to a high-grade lymphoma. Clinical stratification of CLL has revealed that a subset of patients with poor prognosis harbor cytogenetic alterations and lack mutations at the immunoglobulin locus. Therefore, the development of additional molecular biomarkers for patients at high risk for early lethality from CLL could help direct their care toward enrollment in clinical trials of promising experimental approaches such as inhibitors of BCL2 or BCR signaling or CD19 chimeric antigen receptor T cells (which have been shown to eradicate CLL in patients who have failed other approaches). In this issue, Mansouri et al. report that somatic mutations in the NFKBIE gene occur in 7% of poor prognosis patients, and this may be a common mechanism contributing to disease progression by sustaining the survival of malignant CLL cells

Combinations of idelalisib with rituximab and/or bendamustine in patients with recurrent indolent non-Hodgkin lymphoma

Key Points Combining phosphatidylinositol-3-kinase δ inhibition with rituximab, bendamustine, or both is feasible and active in relapsed iNHL. The safety of novel combinations should be proven in phase 3 trials before adoption in clinical practice.</jats:p

Chronic Lymphocytic Leukemia B Cells Can Undergo Somatic Hypermutation and Intraclonal Immunoglobulin VHDJH Gene Diversification

Chronic lymphocytic leukemia (CLL) arises from the clonal expansion of a CD5+ B lymphocyte that is thought not to undergo intraclonal diversification. Using VHDJH cDNA single strand conformation polymorphism analyses, we detected intraclonal mobility variants in 11 of 18 CLL cases. cDNA sequence analyses indicated that these variants represented unique point-mutations (1–35/patient). In nine cases, these mutations were unique to individual submembers of the CLL clone, although in two cases they occurred in a large percentage of the clonal submembers and genealogical trees could be identified. The diversification process responsible for these changes led to single nucleotide changes that favored transitions over transversions, but did not target A nucleotides and did not have the replacement/silent nucleotide change characteristics of antigen-selected B cells. Intraclonal diversification did not correlate with the original mutational load of an individual CLL case in that diversification was as frequent in CLL cells with little or no somatic mutations as in those with considerable mutations. Finally, CLL B cells that did not exhibit intraclonal diversification in vivo could be induced to mutate their VHDJH genes in vitro after stimulation. These data indicate that a somatic mutation mechanism remains functional in CLL cells and could play a role in the evolution of the clone

Unitarity constraints on the stabilized Randall-Sundrum scenario

Recently proposed stabilization mechanism of the Randall-Sundrum metric gives rise to a scalar radion, which couples universally to matter with a weak interaction ($\simeq 1$ TeV) scale. Demanding that gauge boson scattering as described by the effective low enerrgy theory be unitary upto a given scale leads to significant constraints on the mass of such a radion.Comment: 10 page Latex 2e file including 4 postscript figures. Accepted in Journal of Physics

Multiple Distinct Sets of Stereotyped Antigen Receptors Indicate a Role for Antigen in Promoting Chronic Lymphocytic Leukemia

Previous studies suggest that the diversity of the expressed variable (V) region repertoire of the immunoglobulin (Ig)H chain of B-CLL cells is restricted. Although limited examples of marked constraint in the primary structure of the H and L chain V regions exist, the possibility that this level of restriction is a general principle in this disease has not been accepted. This report describes five sets of patients, mostly with unmutated or minimally mutated IgV genes, with strikingly similar B cell antigen receptors (BCRs) arising from the use of common H and L chain V region gene segments that share CDR3 structural features such as length, amino acid composition, and unique amino acid residues at recombination junctions. Thus, a much more striking degree of structural restriction of the entire BCR and a much higher frequency of receptor sharing exists among patients than appreciated previously. The data imply that either a significant fraction of B-CLL cells was selected by a limited set of antigenic epitopes at some point in their development and/or that they derive from a distinct B cell subpopulation with limited Ig V region diversity. These shared, stereotyped Ig molecules may be valuable probes for antigen identification and important targets for cross-reactive idiotypic therapy

Inhomogeneous Bulk Viscous Fluid Universe with Electromagnetic Field and Variable Λ\Lambda-Term

Cylindrically symmetric inhomogeneous cosmological model for bulk viscous fluid distribution with electromagnetic field is obtained. The source of the magnetic field is due to an electric current produced along the z-axis. $F_{12}$ is the non-vanishing component of electromagnetic field tensor. To get the deterministic solution, it has been assumed that the expansion $\theta$ in the model is proportional to the shear $\sigma$. The values of cosmological constant for these models are found to be small and positive at late time, which are consistent with the results from recent supernovae Ia observations. Physical and geometric aspects of the models are also discussed in presence and absence of magnetic field.Comment: 21 pages, 8 figure

In Support of a Patient-Driven Initiative and Petition to Lower the High Price of Cancer Drugs

Comment in Lowering the High Cost of Cancer Drugs--III. [Mayo Clin Proc. 2016] Lowering the High Cost of Cancer Drugs--I. [Mayo Clin Proc. 2016] Lowering the High Cost of Cancer Drugs--IV. [Mayo Clin Proc. 2016] In Reply--Lowering the High Cost of Cancer Drugs. [Mayo Clin Proc. 2016] US oncologists call for government regulation to curb drug price rises. [BMJ. 2015