FISH Testing Guides Treatment of CLL: New Drugs on Horizon

Susan O'Brien, MD

Fluorescence in situ hybridization (FISH) testing for genetic abnormalities is the key to appropriate treatment selection for patients with chronic lymphocytic leukemia (CLL), according to Susan M. O’Brien, MD, professor of Medicine and chief of the Section of Acute Leukemia at MD Anderson Cancer Center in Houston, Texas, who spoke at the NCCN 6th Annual Congress: Hematologic Malignancies.

Three genetic markers are of particular interest, she said: 13q deletions (predict good prognosis) and deletions of 11q and 17p (predict poor prognosis). O’Brien focused her remarks on the latter 2 markers since the NCCN guidelines are clear for CLL characterized by 13q deletions.

Deletion of 11q is associated with extensive lymphadenopathy, disease progression, and shorter median survival. “Newly diagnosed patients with 11q deletions, even though asymptomatic, will progress within 2 years, and treatment is needed,” O’Brien said.

“These patients should receive an alkylating agent. My choice is fludarabine, cyclophosphamide, and rituximab [FCR, a regimen developed at MD Anderson], which is the only regimen shown to improve survival in CLL,” she stated.

FCR is now the standard of care for asymptomatic, healthy patients with CLL and 11q deletions. The CLL8 trial found that FCR versus FC doubled complete response rates and improved 3-year overall survival from 82.5% with FC versus 87.2% with FCR (P = .012).

Although FCR is the recommended front-line therapy for CLL in the NCCN guidelines, O’Brien noted that cyclophosphamide may not be necessary for patients without the 11q deletion. That issue is being addressed in an international randomized trial, she said.

Deletion of 17p is a harbinger of low response rates. “The 17p deletion is the mother of all poor prognostic factors for CLL,” O’Brien said.

For patients with 17p deletions, the choice of therapy is not clear. “The NCCN guidelines list many choices for therapy, so this tells you that no therapy works well,” she said. “FCR is probably not a good regimen for patients with 17p deletions.”

Studies of chemotherapy have been disappointing in patients with 17p deletions, but alemtuzumab may have a role in patients with non-bulky CLL. “Alemtuzumab was approved for refractory patients, so it had a bad reputation. It is a good option for patients with non-bulky disease, but it is not effective in patients with bulky lymph nodes.” She added that bendamustine and rituximab “will not be a solution for CLL with 17p deletions.”

Patients with 17p deletions should be enrolled in a clinical trial. Patients who achieve a partial or complete remission with front-line therapy should be considered for allogeneic stem cell transplant, O’Brien said.

CLL is primarily a disease of the elderly, and treatment strategies need to be individualized based on factors in addition to age, such as general performance status and comorbidities. For older patients who are compromised, palliative care is recommended. For those with good performance status, O’Brien recommended reduced-dose FCR or a clinical trial.

Two promising agents—both inhibitors of B-cell receptor signaling—are in early clinical trials for patients with poor prognostic factors: PCI-32765 and CAL-101.

PCI-32765 (Pharmacyclics, Inc) is a smallmolecule inhibitor of Bruton’s tyrosine kinase that has had promising phase I results in inhibiting CLL cell migration and adhesion, including patients with poor cytogenetic characteristics. This drug appears to be extremely well-tolerated in patients, with no cumulative toxicity. Phase II trials are now underway in CLL and in diffuse large B-cell lymphoma and mantle cell lymphoma.

CAL-101 (Gilead Sciences) is an orally available small-molecule inhibitor of phosphoinositide-3 kinase (PI3K). Phase I trials showed responses in lymph nodes, including patients with 17p deletions. In refractory CLL patients, 84% shrinkage in lymph nodes was observed, as well as an increase in hemoglobin and platelets.

“There is no question of whether these two drugs will be approved [for CLL]. The question is when they will be approved,” said O’Brien.