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Treatment for CLL Will Incorporate More Targeted Therapies in the Near Future

TOP - August 2015, Vol 8, No 3

Hollywood, FL—Watch and wait re­mains the standard of care for patients with asymptomatic early-stage chronic lymphocytic leukemia (CLL), even for high-risk patients, but once therapy is indicated, targeted agents may supplant chemotherapy in the first-line treatment setting, said William G. Wierda, MD, PhD, Center Medical Director, Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX, at the 2015 National Comprehensive Cancer Network (NCCN) annual conference.

In his NCCN update of the CLL guideline, Dr Wierda noted that the Bruton’s tyrosine kinase (BTK) inhibitor­ ibrutinib (Imbruvica) could soon replace conventional chemotherapy with the combination of fludarabine (Fludara), cyclophosphamide (Cytoxan), and rituximab (Rituxan) as first-line therapy.

Age, comorbidities, and cytogenetics on fluorescence in situ hybridization are important considerations in selecting first-line therapy (with chemotherapy under the current guideline) once patients show disease progression symptoms, said Dr Wierda.

High-risk features include chromosome 17p deletion (del[17p]), 11q deletion, or unmutated IgVH genes. “We do watch those patients more closely,” he said. “If I have a patient with 17p deletion who doesn’t have an indication to start treatment, I’ll watch him more closely than I would a patient who has a 13p deletion as his sole abnormality and/or an unmutated IgVH. But we don’t start early treatment for those patients.”

The current standard frontline therapy for a fit younger patient with CLL is the combination of fludarabine, cyclophosphamide, and rituximab. This combination regimen was shown superior to bendamustine (Treanda) plus ri­­tuximab as first-line therapy in a recent study of patients aged ≤65 years with active untreated CLL without del(17p).

The updated version of the NCCN guideline states that patients who are free of minimal residual disease in the peripheral blood have better progression-free survival if residual splenomegaly is not clinically significant. The goal in fit, younger patients with IgVH mutations, therefore, should be minimal residual disease–negative complete remission with minimal chemotherapy.

In the elderly population or in patients with comorbidities, “We have less intensive chemotherapy regimens that are currently the standard of care,” Dr Wierda said. Chlorambucil plus a CD20 monoclonal antibody, either obinutuzumab (Gazyva) or ofatumumab (Arzerra), is currently preferred for this group in the guideline.

The randomized clinical trial RESONATE 2 that is in progress is comparing chlorambucil with ibrutinib as frontline therapy in elderly patients. “We all expect that trial to be a positive trial and show superior outcomes for those patients who receive ibrutinib in the frontline setting,” Dr Wierda said.

In high-risk patients, such as those with an unmutated IgVH, “We’re working on a non–chemotherapy-based regimen, because we know that even if we can get those patients into a good remission, they’re going to relapse, and most likely the benefit to them in delaying exposure to chemotherapy,” said Dr Wierda.

“So strategies that include ibrutinib and some of the new molecules are where we’re moving with the younger patients with an unmutated VH gene,” Dr Wierda said.

Ibrutinib was recently approved as frontline therapy in patients with CLL and del(17p); it previously received an indication for the treatment of patients with CLL who have received ≥1 previous therapies.

In the salvage setting, 2 drugs have been approved over the past year—ibrutinib and the oral PI3 kinase (PI3K) inhibitor idelalisib (Zydelig), which is given with rituximab. Most responses with idelalisib in this setting are partial responses, and its median progression-free survival is 19.4 months. Idela­lisib has shown efficacy in patients with relapsed CLL and del(17p).

Several other BTK inhibitors are in development, as well as several PI3K inhibitors, most targeting the delta isoform or the gamma and delta isoforms of PI3K. Spleen tyrosine kinase inhibitors are also in early-phase study, although the data with them “are less compelling” than the early data with ibrutinib, said Dr Wierda.

Another class of promising agents is the BCL-2 inhibitors. Venetoclax, the first in this class, is in registration phase 3 trials. It has produced complete responses in patients with relapsed or refractory CLL, and it has activity in patients with very high-risk CLL, such as patients with relapsed or refractory CLL and del(17p).

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