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If you have recently been diagnosed with CLL, you probably have questions. 

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FEATURED VIDEO

Dr. Michael Keating was the key-note speaker at the CLL Live Conference recently held in Canada. Here he discusses new treatment and research strategies.    

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May 2012 

Greetings!

Thanks for joining us for another issue of Tidbits. Dr. Keating is ambitious to get rid of chemotherapy. This month he takes us on a magical mystery tour of new, non-chemotherapeutic strategies. We also clarify what the microenvironment is and its relation to the success of non-chemotherapies. The series on clinical trials continues with the ins and outs of Phase II trials.        

Getting Rid of Chemotherapy in CLL:   

a magical mystery tour 

Dr. Michael Keating President and CEO  of CLL Global

Chemotherapy has played a pivotal role in cancer treatment for many decades. My mentor, Dr. Emil J Freireich, led the first clinical trials using multiple types of chemotherapy as treatment in the 1960s. The success of these experiments led to the cure for 80-90% of patients suffering from childhood acute lymphoblastic leukemia, opening the door to combination chemotherapy as a standard option for most cancers.

Twelve years ago, we combined two chemotherapy drugs, fludarabine (Fludara) and cyclophosphamide (Cytoxan), with the monoclonal antibody, rituximab (Rituxan). This combination, known as FCR, changed the way CLL is treated and has had a significant impact for CLL patients. It has become the standard treatment option for patients who can tolerate it, and has been described as "the gold standard for CLL". While this sounds good, concerns have persisted.

Fludarabine and cyclophosphamide, and all chemotherapies, cause suppression of the immune system, a depression in normal blood counts and DNA damage which may contribute to the causation of second cancers. Additionally, FCR and other current treatments are not benefiting every CLL patient. Thus, a major goal regarding treatment is to replace chemotherapeutic agents with more personalized options. 

The anti-chemotherapy era in which we are about to embark has been decades in the making. One of the biggest challenges to date with treating CLL is that it has a very comfortable relationship with other cells in the body and the immune system. Even though CLL is an invader, the body thinks it is not. CLL cells manipulate other cells in order to stay alive and thrive. Previously, researchers could not figure out why some drugs worked well when tested in a petri dish in the laboratory, but were significantly less effective once given to patients. Once this mystery was partially solved, the playing field changed.

The CLL Microenvironment

A microenvironment is a habitat in the body made up of a structural network of cells within individual organs. Teamwork and communication between cells in the microenvironment allow the cells and organs to survive. CLL cells reside in a few microenvironments within the body: the lymph nodes, spleen and bone marrow. These microenvironments provide protective surroundings for the CLL cells to dwell which makes this an optimal area to target with therapy.

Researchers have known for many years that CLL cells infiltrate the lymph nodes, spleen and bone marrow. However, it was not until recently that a working concept of the microenvironment was suggested. Researchers were previously perplexed that drugs were successful at eliminating CLL cells when tested in the laboratory, but not as successful when given to patients. Also, CLL cells are notorious for resisting cell death (called apoptosis) which is a normal part of the cell cycle. But, researchers could not figure out why CLL cells would die so quickly when taken out of a patient's body for research. The extent to which CLL cells rely on other cells in the body is now understood.

This image is a model of the bone marrow microenvironment. Here the CLL cells (in green) interact with the stromal cells (in red).  http://bloodjournal.hematologylibrary.org

CLL cells are known for freely floating throughout the blood

stream. It is now thought that the microenvironments may serve as "refueling" stations. One hypothesis is that CLL cells travel around the body and dock in a lymphatic tissue to reenergize. The CLL microenvironments consist of populations of different types of cells. Some of the major players are stromal cells which make up the connective tissue, accessory cells that aid in communication, nurselike cells that attract CLL cells to the microenvironment and protect them from apoptosis, and T-cells which promote growth and drug resistance.

The discovery of the microenvironment has had a large impact on CLL treatment. As discussed in the President's Corner article above, new drugs like ibrutinib (formerly PCI-32765) and lenalidomide (Revlimid) are already being used to target the communication between CLL cells and their microenvironments. The full effectiveness of these drugs is to be determined. In the interim, researchers will continue to unveil the connection between CLL cells and the protection provided by the microenvironment to consider new ways to exploit this relationship.  

Phase II Clinical Trials

Last month's issue of Tidbits introduced Phase I trials as studies conducted to ensure a new drug or treatment is safe in humans and to determine the optimal dosage. (Click here to read the article.) The optimal dose is then used in Phase II trials which look at a drug's efficacy in people with a specific type of cancer or related cancer. Phase II studies relevant for CLL patients may incorporate other hematologic malignancies such as B-cell Non-Hodgkin Lymphoma and Waldenstrom's Macroglobulinemia. Another important objective of Phase II studies is to continue to look at the safety of the treatment.

Phase II trials enroll more patients than Phase I studies and are often conducted at more institutions. In general, Phase II studies usually have less than 100 participants. Having a larger cohort of patients gives researchers a better idea of potential side effects and may expose some less common side effects.

Regardless of the phase of study, all clinical trials are subject to an extensive review of safety. An Institutional Review Board can stop a trial at any time if patients are experiencing unexpected harm. During clinical trials, there is a constant evaluation of the risk-benefit ratio.

Depending on the particular Phase II study, patients may or may not be able to receive prior treatment for their disease. The eligibility criteria for the protocol of the study details whether or not prior treatments are acceptable and if so, what type and amount of prior treatments are permitted.

Phase II trials are intended to provide an indication as to whether a treatment is effective. After a Phase I or Phase II trial, the researchers may decide not to move on to the next phase of development or to stop testing if the treatment is not safe or effective. Sometimes clinical trial phases may be combined (for example Phase I/II or Phase II/III trials). In this case the goal may be to allow for quicker development of a new treatment. Next month's Tidbits will explore Phase III trials.

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