Chronic Lymphocytic Leukemia PDF

Preface

With this book we have endeavored to develop a comprehensive and up-to-date picture of chronic lymphocytic leukemia. The authors represented herein are some of the leading experts in the field, and the focus is on how new developments in the molecular pathogenesis of this disease impact how we approach and treat patients with CLL. Our introduction to this disease is written by arguably the most famous CLL expert in the United States, Kanti Rai. The initial chapters focus on the origin and nature of the CLL cell and discuss this in relationship to gene expression profiling and molecular abnormalities. Sequencing of immunoglobulin heavy chain genes has shown that patients can be divided into two groups, those with mutated and those with unmutated VH genes (which has significant prognostic import). However, examination of gene expression profiles shows that mutated and unmutated samples are much more similar than different, all having a phenotype of an activated B cell. Thus, these conflicting perspectives on the disease are still being worked out. Another aspect of CLL is the familial clustering that is seen, and the search for genes predisposing to such familial cases is an active area of research. The fascinating finding that a percentage of "normal" people have a small clone of CD5+ B cells provides insight into possible development of the disease, but at the same time raises many questions. Dysregulation of apoptosis is a ubiquitous element in CLL and overexpression of multiple BCL-2 family members can potentially be targeted therapeutically with new molecules that are in clinical trials.

For the past 30 years both the Rai-staging system and the Binet-staging system (which are very similar) have been used to evaluate patients with newly diagnosed CLL. These staging systems are simple, relying only on a physical exam and a complete blood count. Yet they provide significant prognostic information as more advanced stages are associated with shorter survival. However, one limitation of these staging systems is that they are static. That is, in patients presenting with early-stage disease it is difficult to predict which patient is likely to progress and require treatment within a few years and which patient may live 20 years with indolent disease and die of other causes. In the last few years there has been a proliferation of factors, partly derived from research into signaling pathways in CLL, which can provide prognostic information within early-stage disease. Some of these include β2 microglobulin, mutation status of the VH gene, presence of CD38 or ZAP70, and molecular abnormalities detected by fluorescent in situ hybridization (FISH). However, this proliferation of important prognostic factors has also raised the question of correlation between factors, and when discordant, which ones are most important. This is an area under active investigation.

Another potential use of these prognostic factors is identifying a subset of patients who might benefit from early treatment. The approach to CLL has always been a watchand- wait approach based on a number of features, including the fact that patients tend to be older, with an average age of 70 years, may have very indolent disease and be asymptomatic, and the fact that there is no curative therapy for this disease. Thus, the medical axiom "first do no harm" spares patients who are asymptomatic and have indolent disease from the consequences of therapy that may be unnecessary. However, once a patient requires treatment for CLL their median survival averages seven years. Thus, most patients who require treatment for CLL will eventually die of complications of the disease. These patients can be thought of as "ticking time bombs," where the approach of just watching and waiting (or watching and worrying) does not appear very attractive. The presence of these newer prognostic factors can now clearly identify a population of patients who are not going to survive 10 to 20 years without treatment. However, an important question that is not yet answered is: Does early treatment benefit these patients? It is certainly possible that the same factors that predict for more aggressive disease predict for suboptimal response to the current regimens.

Treatment of CLL has evolved significantly over the past 10 years. Historically, chlorambucil, an oral alkylating agent, was the mainstay of therapy and was an effective palliative treatment with an inability to produce complete remission. Fludarabine, a nucleoside analog, proved to be an effective drug for this disease, and in a randomized trial of fludarabine versus chlorambucil it was shown that fludarabine produced higher complete and overall response rates and significantly longer time to progression. However, overall survival was not impacted. There are several potential reasons for this including the crossover design of the trial, the fact that subsequent therapies may also impact survival, and that the complete remission rate with fludarabine was only 20%. Given that this was the most effective single agent and that upfront treatment is the time when the best response is likely to be obtained, the fact that 80% of patients did not achieve a complete remission is certainly one possibility for lack of impact on survival. This has led to the development of new agents as well as combination regimens, which on early analysis appear to be improving survival in this disease, particular combinations including both fludarabine and the monoclonal antibody rituximab. Another monoclonal antibody, alemtuzumab, was approved for the treatment of fludarabine refractory CLL but may, in fact, be better utilized as a consolidation regimen after debulking by chemotherapy, given that it is exquisitely effective in eradicating marrow disease. Combinations of alemtuzumab and fludarabine are also being investigated.

There are a number of exciting agents in clinical trials, including BCL-2 family member inhibitors, new monoclonal antibodies, HSP-90 inhibitors, cyclin D1 inhibitors, and immunomodulatory drugs. Data relevant to all of these are also discussed in chapter 9.

The advent of nonmyeloablative stem cell transplant has made this modality available for the first time to the majority of patients with CLL. The use of myeloablative transplants typically involved high-dose cyclophosphamide and total-body radiation, which were too toxic for older patients, and so most patients with CLL were not candidates for transplant. Recent trials suggest that long-term survival in CLL can be affected in a proportion of patients who undergo stem cell transplant, and improvements in HLA typing also make this feasible for patients without related donors.

The diagnosis of CLL is accompanied by a number of management issues, including the interesting phenomenon of autoimmunity, the potential for development of Richter's transformation to large-cell lymphoma, and treatment of infections related to disease parameters (cytopenias, hypogammaglobulin), as well as parameters induced by treatment including T-cell deficiencies. All of these are discussed and addressed within the textbook.

We hope that readers will find this book enjoyable to read, highly informative, and at the same time clinically relevant in addressing some of the important questions that are being asked by physicians who have the responsibility of taking care of these patients.