ASH News Daily 2013 - Day 2 - (Page A-13)

Sunday, December 8, 2013 TRANSPLANTATION To B or Not to B: Two Faces of the B Lymphocyte BY SHAJI KUMAR, MD the human body, playing a crucial role in health and disease. While the classic approach to the study of the immune system attempts to compartmentalize the cellular and humoral aspects, we are just starting to realize the intricate and complex relationship of the effector and regulator cells of the B- and Tcell compartments. In yesterday's Scientific Committee Session, Burgeoning Roles of B Cells in Transplant, attendees were well rewarded by three great speakers covering a lesser known aspect of B-cells - its active contribution to pathology and disease. In the first presentation of the session, Dr. Ann Marshak-Rothstein, University of Massachusetts, provided a compelling story on the active role played by wayward B cells in the development of autoimmune disorders. She elucidated the complex interplay between the B-cell receptors and the toll-like receptors in the development of auto-reactive B cells. In the context of knockout mouse models lacking specific TLRs, Dr. Marshak-Rothstein also highlighted the complex interac- T LEUKEMIA Taking a BiTE Out of Acute Lymphocytic Leukemia BY MARK M. UDDEN, MD record for the treatment of adults with acute lymphocytic leukemia (ALL). Pediatric hematologists can take pride in their superior long- N othing is more discouraging and downright depressing than the track term remission rate of 85 percent compared with only a 45 percent rate in most studies of adult ALL. Why is adult ALL so intractable? Is it the disease itself, the inability of adults to tolerate high-dose chemotherapy, or both? The answers to these questions and a glimpse of promising new treatment strategies ASH attendees traverse the lobby of the Ernest N. Morial Convention Center during the 55th ASH Annual Meeting and Exposition. that might override poor-risk factors for all patients was the topic of discussion in yesterday's session, Changing Paradigms in Acute Lymphocytic Leukemia: From the Genome to the Patient. According to Dr. Anjali Advani, Cleveland Clinic, Ohio, the session chair, there is hope that "our depression will be alleviated - for the following reasons: 1) the use of pediatric inspired regimens for younger adults will likely improve outcomes; 2) the addition of novel treatments to standard therapy; and 3) targeting specific pathways." If you were unable to attend this session, it will be repeated from 7:30 to 9:00 a.m. in La Nouvelle Ballroom C in the convention center. Dr. Christine Harrison, Newcastle University Leukemia Research Cytogenetics Group, United Kingdom, began by sorting out the bewildering array of genetic mayhem in ALL. She stated, "To achieve the goal of curing all patients with ALL and reducing toxicity there is a need for new therapies to target underlying molecular pathology of the disease, he immune system is arguably the most complex system of checks and balances in tion between the environment and the BCR/TLR-mediated generation of auto-reactive B cells, which in turn may play a crucial role in the development of autoimmune disorders such as lupus. This was followed by a very stimulating presentation by Dr. Thomas Tedder, Duke University, Durham, NC, on the regulatory role of B cells, a function commonly attributed to T-cell subsets. While the traditional concept is that of B cells regulating the immune function through production of antibodies, he presented convincing evidence of cytokine-mediated regulation of the immune response by the B cells. Work from his laboratory has identified a rare subset of B cells that secrete IL-10 and negatively regulate inflammation in autoimmune disease, as well as normal immune response. These cells introduce an antigen-specific aspect to the regulation of the immune response and interaction between these B cells and T cells further modulate the antigen-specific responses. From a therapeutic perspective, the ability of autologous IL-10 secreting B cells to blunt the immune response opens up an entirely new approach to therapy in patients with autoimmune disease as well as transplant rejection. An increasing wealth of data demonstrates that the donor B cells play an important role in maintaining the finely orchestrated balance between GVHD and GVL. The topic of allogeneic stem cell transplantation often conjures up images of T cells running amok and unleashing the terrible manifestations of GVHD, or of the benevolent T cells trying to mop up the tumor cells through a wide variety of immunologic mechanisms, depending on individual perspective. T-cellspecific agents such as the calcineurin inhibitors have remained the mainstay for transplanters trying to maintain the fine balance between GVHD and GVL. With all the attention given to reining in donor T cells, B cells have not been on most people's radar screen. An increasing wealth of data demonstrates that the donor B cells play an important role in maintaining the finely orchestrated balance between GVHD and GVL. In the third topic of yesterday's session, Dr. Jerome Ritz, Dana- ASH NEWS DAILY Page A-13 ® Farber Cancer Institute, Boston, MA, presented an overview of the current understanding of the less recognized but important role of B cells in the development of graftversus-host disease. It has been recognized that the donor B cells can mount an immune response and generate antibodies to minor histocompatibility antigens as well as tumor-specific antigens, and development of these antibodies is associated with reduced risk of relapse. Less well understood is the role of donor B cells in the development of GVHD. Unlike T cells, which clearly play a role in the development of acute GVHD, B cells seem to be contributing primarily to the chronic GVHD; this is understandable given the delayed reconstitution of the B-cell compartment post stem cell transplantation. Clearly, this is not another exotic finding restricted to animal models, as is evident from the beneficial effects of rituximab in the treatment as well as prevention of GVHD. Dr. Ritz's ended the session with a discussion of the importance of the B-cell activating factor (BAFF) in generating and maintaining this hitherto unanticipated activity of B cells. Dr. Kumar indicated no relevant conflicts of interest. which forms the crux of leukemia research at this time." In addition to reviewing established good and bad prognostic chromosomal and genetic predictors for pre B-cell ALL, Dr. Harrison delivered an update on newly recognized abnormalities in signaling pathways. These included iAMP21, CRLF2, IKZF1, MLL, JAK2, and the BCR-ABL-like ALL leukemias. According to Dr Harrison, "A subgroup of BCR-ABL1-like geneexpression signature accounts for 10 to 15 percent of childhood and 25 percent of adult B-cell precursor ALL, and there is evidence for sensitivity to TKI when incorporated into therapy." Next, Dr. Mary Relling, St. Jude Children's Hospital, Memphis, TN, focused on how pharmacogenomic variation affects efficacy and toxicity of ALL treatment. For example, there are ethnic differences that may affect responses to therapy and relapse rates of ALL. There are also differences in drug metabolism that may limit effect or enhance »» LEUKEMIA Page A-14

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ASH News Daily 2013 - Day 2

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