Chronic lymphocytic leukemia is a chronic form of leukemia. One person’s CLL may be another’s small lymphocytic lymphoma (SLL). Leukemia and lymphoma are sister diseases. When the cancer cells are located mostly in the lymph nodes, the disease is called SLL. When most of the cancer cells are located in the bloodstream and the bone marrow, the disease is referred to as CLL, although the lymph nodes and spleen are often involved.
CLL tends to be an indolent (slow-growing) cancer, but it can progress to a more aggressive disease. About one-third of CLL patients will live for years or decades without symptoms. Another one-third will require therapy immediately or will be symptomatic within three to five years and require treatment. The final one-third will experience intermediate disease progression with waxing and waning disease that responds to treatment.
Surveillance or watchful waiting is a common approach. The chemotherapy regimens most commonly used for treatment of CLL are R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone); FR (fludarabine, rituximab); FCR (fludarabine, cyclophosphamide, rituximab); BR (bendamustine, rituximab); BCR (bendamustine, cyclophosphamide, rituximab); and PCR (pentostatin, cyclophosphamide, rituximab). Monoclonal antibodies used include alemtuzumab (Campath) approved for use in patients with advanced CLL who are no longer responding to other treatments; ofatumumab (Arzerra) approved for patients with CLL refractory to fludarabine (Fludara) and alemtuzumab (Campath); and rituximab (Rituxan) approved in combination with fludarabine and cyclophosphamide for patients with untreated or previously treated CD20-positive CLL.
Stem cell transplantation is a treatment option typically reserved for patients whose CLL does not respond to standard therapies. Patients whose disease has transformed into a more aggressive form potentially could benefit from a reduced intensity allogeneic transplant.
There have been several promising developments for CLL patients in recent years. For example, PCI-32765 is one of several drugs in clinical trials with the common theme that they all interfere with b-cell receptor signaling. When you ligate the b-cell receptor, you provide a very strong signal for survival and proliferation to the cell. There are a number of different downstream kinases in that pathway, and the drugs that have been in clinical trials inhibit the message that tells the cell to survive and proliferate, but those drugs target totally different kinases. CAL-101 is a PI3 Kinase inhibitor; PCI-32765 is a Bruton’s Tyrosine Kinase (BTK) inhibitor; and fostamatinib is a spleen tyrosine kinase inhibitor (SYK). One study showed a 67% response rate of patients with relapsed CLL. Also the drugs are oral, so they are easy to administer. PCI-32765 appears to have very minimal side effects. The most common side effect is diarrhea, which often tends to be self-limited. Also, the drugs are not myelosuppressive, which is particularly important to leukemic patients who, even when they are not myelosuppressed, do not have a normally functioning immune system, and, therefore, are prone to infections. Some believe that b-cell inhibitors will be a game-changer in CLL and b-cell lymphomas.
A recent study using bendamustine combined with rituximab (BR) in patients with relapsed and/or refractory CLL shows it to be effective and safe in patients with relapsed CLL and to have notable activity in fludarabine-refractory disease. Major but tolerable toxicities were myelosuppression and infections. Lenalidomide may be an option for elderly patients with chronic lymphocytic leukemia who may be unable to tolerate traditional chemoimmunotherapy such as FCR. Bendamustine (Treanda) is both more effective and less toxic than the standard CHOP regimen when both are combined with rituximab (Rituxan). According to Dr. Mathias Rummel of University Hospital in Germany, it should be “preferred as first-line therapy” in patients with follicular lymphoma and similar slow-moving diseases. It is important to have multiple agents and alternatives—choices of monoclonal antibodies, kinases inhibitors, etc. One study, for example, concluded that, patients with fludarabine-refractory chronic lymphocytic leukemia that was resistance to rituximab, responded to ofatumumab.