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Latest Research and Promising DevelopmentsOverview
OverviewMany drugs are approved by the United States Food and Drug Administration (FDA) for very specific and often restricted indications. This section will focus exclusively on those drugs that are not currently FDA approved for CLL and may represent major advances in our efforts to cure or manage cancer better. Therefore, patients may find that these drugs are only available in clinical trials. This section will forego detailed discussions about presently approved agents in CLL and efforts to expand their indications in specific subtypes of the disease. Refer to treatment section of the website for already approved agents in CLL. It is critical to remember that today’s science is moving very fast. Therefore, the information below may not be entirely comprehensive or accurate depending on when this information is being read. Please check with the Lymphoma Research Foundation or your physician for additional information and recent updates.
Monoclonal AntibodiesA monoclonal antibody (MAb) targets a specific antigen, which is like a beacon that attracts antibodies and immune cells. Large amounts of antibodies can now be directed to a single antigen on the cell’s surface In addition to the two monoclonal antibodies approved for CLL, alemtuzumab (Campath) and ofatumumab (Arzerra), many other monoclonal antibodies are currently under investigation. These include MAbs targeting antigens such as CD19, CD20, CD23, CD25, CD37 and CD40.
Immunomodulatory Drugs (IMids) Immunomodulatory agents, referred to as IMids, may not only impact the nourishing environment of the cancer cells, but may also inhibit the formation of new blood vessels (angiogenesis). They may also induce both apoptosis (programmed cell death) and growth arrest in resistant cancer cells. These drugs have also been shown to increase the numbers of tumor fighting natural killer (NK) cells in patients’ blood. These NK cells then mount a cellular response against the lymphoma. Thalidomide (Thalomid) and lenalidomide (Revlimid) are oral agents that have been approved by FDA for other blood disorders. Recent studies have shown that they work well in patients with CLL. Particularly impressive is their efficacy in patients with certain adverse prognostic factors where conventional therapies do not seem to work well. Side effects include lowering of platelet counts, neuropathy and increased risk of blood clots. There are several ongoing studies looking into the most effective use of these agents in CLL.
Proteasome InhibitorsNearly all cells in the body continually break down their own protein components to remove improperly made or damaged proteins and to control cell growth and other vital processes. The “cellular disposal” system which handles these proteins is called the “proteasome.” In this form of cellular housekeeping, the proteasome cuts up protein molecules that are no longer needed by the cell. Recently, physicians and scientists have learned that certain cancer cells are particularly vulnerable to a new class of molecules called proteasome inhibitors. Bortezomib (Velcade), a therapy first approved for a type of blood cancer called multiple myeloma, was the first drug of this type approved to treat cancer. This drug has been approved for relapsed mantle cell lymphoma and is currently being tested as a therapy for follicular lymphoma and relapsed/refractory CLL.
Purine AnalogsPurine analogs belong to a class of drugs called antimetabolites. These drugs enter the cell and are transformed into an active form of the drug that is incorporated into cellular DNA, interfering with its function and its ability to repair itself. This effect results in cell death.
Bcl-2 Directed TherapiesPerhaps one of the most exciting new areas in cancer drug discovery over the last decade has revolved around the discovery and development of new small molecules which appear to be able to “teach” cancer cells how to die. One intrinsic feature of every tumor cell is its ability to divide when it should not and to resist dying when it should die. This “cell death thermostat” is established by the expression of a variety of proteins in the cell known as pro- and anti-apoptotic modulators. Pro-apoptotic proteins induce cell death while anti-apoptotic proteins resist cell death. Clearly, tumor cells contain an overabundance of those anti-apoptotic proteins which help the tumor cells survive even despite very toxic environments including those imposed by chemotherapy. One of the first of these drugs is called oblimersen (Genasense). Since the development of oblimersen (Genasense), a variety of new small molecules, many of which are orally available, have been developed (e.g., ABT-263 and AT-101). These drugs appear to inhibit the anti-apoptotic influence of many different proteins within the tumor cell, thereby increasing the sensitivity of the tumor cell to the induction of cell death by chemotherapy. Though these agents are now in very early development, they have so far demonstrated very promisingactivity in early phase clinical trials across a whole range of lymphoma. The future development of these agents will be oriented toward studying them in combination and lowering the threshold required to induce cell death when given in combination with other drugs known to be active in lymphoma. These agents have the value that they target biology that is selectively overrepresented in tumor cells and therefore are not associated with the same toxicity seen with combination chemotherapy and to date have been found to be very tolerable in early phase I and II clinical trials in patients with lymphoma.
Other AgentsNumerous other small molecules are under investigation in CLL.
Subscribe to the related discussion group where frequent and interesting discussions do take place. Richard Furman, MD, a CLL expert from Weill Medical College of Cornell University and New York-Presbyterian, is active on this discussion group, so we have an important medical advisor on board. |
