Advances in the Management of Chronic Lymphocytic Leukemia

Phoebe Starr

October 2011, Vol 2, No 6 - NCCN Hematology Congress


New York, NY—Several advances have been made in the diagnosis and treatment of chronic lymphocytic leukemia (CLL), according to Susan O’Brien, MD, Chief, Acute Leukemia Section at M.D. Anderson Cancer Center, Houston. Treatment selection can now be guided by fluorescence in situ hybridization (FISH) testing for genetic abnormalities, and 2 new treatments in early-stage development hold promise for patients with a poor prognostic cytogenetic profile.

FISH testing is used to identify 3 cytogenetic abnormalities of interest in CLL: 13q deletions—a predictor of good prognosis—and deletions of 11q and 17p, predictors of poor prognosis. The presence of these markers can guide treatment selection. The National Comprehensive Cancer Network (NCCN) guidelines are clear for CLL patients with 13q deletions but not with 11q and 17p deletions.

CLL with 11q deletions is associated with extensive lymphadenopathy, disease progression, and shorter median survival. Patients with CLL and these deletions, even if asymptomatic, will progress within 2 years. “Treatment [for 11q deletions] is needed, and the regimen should include an alkylating agent,” Dr O’Brien said.

Her preferred regimen is fludarabine (Fludara), cyclophosphamide (Cytoxan), and rituximab (Rituxan) (FCR), which was developed at M.D. Anderson. “FCR is the only regimen shown to improve survival in CLL,” Dr O’Brien said. A survival advantage for FCR over fludarabine and cyclophosphamide (FC), an older regimen, was demonstrated in the CLL8 trial: complete response rates were doubled with FCR versus FC, and 3-year survival was 87.2% with FCR versus 82.5% with FC. FCR is considered the standard of care for asymptomatic patients with CLL and 11q deletions, according to NCCN guidelines.

Reduced-dose FCR is also an option for elderly patients with good performance status; palliative care is recommended for elderly patients who are compromised.

The deletion of 17p predicts low response rates to treatment and poor prognosis in CLL. FCR is probably not going to be effective in this group of patients. “The NCCN guidelines list many choices for therapy, and whenever there are so many choices, it means that none of the therapies are particularly effective,” Dr O’Brien said.

Studies have failed to establish a good chemotherapy regimen for CLL characterized by 17p deletions. “Alemtuzumab [Campath] is not effective in patients with bulky disease, but it may be a good option for patients with nonbulky disease,” she said. Bendamustine (Treanda) plus rituximab is also not recommended for CLL with 17p deletions. The best choice for patients with 17p deletions is a clinical trial. Those who achieve a partial or complete remission with frontline therapy should be considered for allogeneic stem-cell transplant.

New Drugs

Dr O’Brien was enthusiastic about 2 new inhibitors of B-cell receptor signaling in early clinical trials that included patients with poor prognostic factors: PCI-32765 and CAL-101. “There is no question whether these 2 drugs will be approved. The question is when,” she said.

PCI-32765 is a small-molecule inhibitor of Bruton’s tyrosine kinase. Phase 1 trials showed promising results, especially in patients with a poor cytogenetic profile. The drug appears to be well tolerated and is associated with no cumulative toxicity. PCI-32765 is in phase 2 trials for CLL and non- Hodgkin lymphoma.

CAL-101, an orally available smallmolecule inhibitor of phosphoinositide- 3 kinase, achieved responses in the lymph nodes of CLL patients, including those with 17p deletions. The lymph nodes were reduced by 84% in volume, and hemoglobin and platelets were increased in studies of patients with refractory CLL.