Therapeutic Combinations and Sequences for CLL

The optimal combination and sequence of therapies used in chronic lymphocytic leukemia (CLL) remains unclear, states Jennifer Brown, MD, PhD. Some evidence suggests benefis for initiating a B-cell receptor (BCR) inhibitor, such as ibrutinib (Imbruvica) or idelalisib (Zydelig), before the administration of a monoclonal antibody, since the BCR inhibitors may reduce the incidence of infusion reactions typically associated with monoclonal antibodies, explains Javier Pinilla-Ibarz, MD, PhD. It is unknown if the sequencing of novel agents and antibodies affects clinical efficacy, notes Brown.

Many patients with CLL are receiving ibrutinib first, with the assumption that they may be rescued later, in the event of a relapse, with one of the other novel agents, such as the PI3-kinase inhibitor idelalisib or chemo-immunotherapy. At the moment, there are no data to support the effectiveness of chemo-immunotherapy after novel agents or a PI3 kinase inhibition after ibrutinib, says Brown. Other studies have shown that these patients respond poorly to any type of additional therapy, have relatively short survival, and have a high rate of Richter’s transformation.

Evidence has demonstrated improved outcomes when idelalisib is used in combination with an anti-CD20 antibody, such as rituximab (Rituxan) or ofatumumab (Arzerra), says William Wierda, MD, PhD. This answer is less clear with regard to ibrutinib, he adds.

Other clinical trials have evaluated the use of chemo-immunotherapy regimens and the use of anti-CD20 antibodies. The COMPLEMENT-1 study assessed chlorambucil in combination with ofatumumab versus chlorambucil monotherapy and showed benefit in progression-free survival in the combination arm. These data led to an FDA approval for ofatumumab as a treatment for previously untreated patients with CLL who were ineligible for fludarabine-based therapy in April 2014.