Biology and Treatment of Chronic Lymphocytic Leukemia

Abstract

Major advances have occurred in our understanding of the biology, immunology, and opportunities for treatment of chronic lymphocytic leukemia (CLL) in recent times. Surface antigen analysis has helped us define classical CLL and differentiate it from variants such as marginal zone leukemia, mantle cell leukemia, and prolymphocytic leukemia. An important observation has been that the B-cells in indolent types of CLL, which do not require therapy, have undergone somatic hypermutation and function as memory B-lymphocytes whereas those more likely to progress have not undergone this process.Section I by Dr. Nicholas Chiorazzi encompasses emerging elements of the new biology of CLL and will address the types of somatic hypermutation that occur in CLL cells and their correlation with other parameters such as telomere length and ZAP70 status. In addition he addresses the concept of which cells are proliferating in CLL and how we can quantitate the proliferative thrust using novel methods. The interaction between these parameters is also explored.Section II by Dr. Thomas Kipps focuses on immune biology and immunotherapy of CLL and discusses new animal models in CLL, which can be exploited to increase understanding of the disease and create new opportunities for testing the interaction of the CLL cells with a variety of elements of the immune system. It is obvious that immunotherapy is emerging as a major therapeutic modality in chronic lymphocytic leukemia. Dr. Kipps addresses the present understanding of the immune status of CLL and the role of passive immunotherapy with monoclonal antibodies such as rituximab, alemtuzumab, and emerging new antibodies. In addition the interaction between the CLL cells and the immune system, which has been exploited in gene therapy with transfection of CLL cells by CD40 ligand, is discussed.In Section III, Dr. Michael Keating examines the question "Do we have the tools to cure CLL?" and focuses on the fact that we now have three distinct modalities, which are able to achieve high quality remissions with polymerase chain reaction (PCR) negativity for the immunoglobulin heavy chain in CLL. These modalities include initial chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab, the use of alemtuzumab for marrow cytoreduction in minimal residual disease and allogeneic bone marrow transplants. The emergence of non-ablative marrow transplants in CLL has led to the broadening of the range of opportunities to treat older patients. The addition of rituximab to the chemotherapy preparative regimens appears to be a significant advance.The combination of our increased understanding of the biology, immune status, and therapy of CLL provides for the first time the opportunity for curative strategies. I. UNRAVELING THE BIOLOGY OF CHRONIC LYMPHOCYTIC LEUKEMIANicholas Chiorazzi, MD,* Bradley Messmer, PhD, Rajendra N. Damle, PhD, Steven L. Allen, MD, Kanti R. Rai,MB,BS, and Manlio Ferrarini, MD In recent years, our view of the biological features classically ascribed to the leukemic B ...

Dichotomy in NF-κB signaling and chemoresistance in immunoglobulin variable heavy-chain-mutated versus unmutated CLL cells upon CD40/TLR9 triggering

“…The clinical course of chronic lymphocytic leukemia (CLL) is highly variable (Keating et al, 2003) and prognosis is strongly associated with mutation status of the immunoglobulin variable heavy-chain genes (Fais et al, 1998;Damle et al, 1999;Oscier et al, 2002). Patients with unmutated CLL have a rapidly progressive disease compared with patients with mutated CLL.…”

Effective elimination of fludarabine-resistant CLL cells by PEITC through a redox-mediated mechanism

“…A hallmark of CLL cells is their resistance to apoptosis, leading to prolonged cell survival and development of drug resistance. 1 The use of fludarabine-based therapies and, more recently, the availability of therapeutic antibodies have improved treatment outcomes. 1 However, CLL remains incurable.…”

“…1 The use of fludarabine-based therapies and, more recently, the availability of therapeutic antibodies have improved treatment outcomes. 1 However, CLL remains incurable. Although currently available agents such as fludarabine, cyclophosphamide, and rituximab are effective in inducing complete remission, many patients eventually develop drug resistance leading to disease relapse.…”

Patogênese da leucemia linfóide crônica

“…Quando se analisam os subtipos com e sem mutação somática, estes últimos apresentam telômeros mais curtos do que os primeiros e maior atividade de telomerase. 15 Portanto, as células sem mutações somáticas passam por um número maior de divisões celulares possivelmente após múl-tiplas exposições a estimulação antigênica. Este cenário prediz que as células não mutadas têm uma gama muito maior de oportunidade para adquirir aberrações cromossômicas, e, portanto, de apresentar um curso clínico mais agressivo.…”