Changing Treatment Landscape in CLL

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The treatment landscape for individuals with chronic lymphocytic leukemia (CLL) has evolved dramatically over the past few years, states Richard Furman, MD. Just five years ago, treatments for patients with CLL generally caused severe adverse events, worsening of disease, or secondary malignancies, such as the development of myelodysplastic syndromes, acute myeloid leukemia, or transformation to large cell lymphoma. However, newer agents, such as anti-CD20 monoclonal antibodies, ibrutinib, and idelalisib are effective, well tolerated, and patients have a lower likelihood of developing resistance. With these novel agents, the disease can be controlled for long periods of time, says Furman.

Two of the most exciting drugs include ibrutinib and idelalisib, inhibitors of the B-cell receptor pathway, comments Jennifer R. Brown, MD, PhD. CLL is a B-cell malignancy that depends on chronic activation of the B-cell receptor pathway for cell growth, proliferation, and survival, allowing these agents to be highly effective.

Ibrutinib targets Bruton’s tyrosine kinase (BTK), a protein that signals downstream of the B-cell receptor in CLL and B-cells. Ibrutinib is approved for the treatment of CLL in individuals who have received at least one prior therapy and for the treatment of CLL with 17p deletion. The PCYC-1102 trial evaluated ibrutinib at 420 mg daily as a single agent given orally in patients over the age of 65 with CLL. Patients with low-risk cytogenetic characteristics (without 11q or 17p deletions) demonstrated a 3-year progression-free survival of 89%, states Brown.

Idelalisib, another B-cell receptor pathway inhibitor, targets the delta isoform of phosphoinositide 3-kinase (PI3K). Cell expression of the delta isoform is limited to hematopoietic cells, which allows for the avoidance of certain toxicities, such as hyperglycemia from effects on insulin secretion, says Brown. A placebo-controlled, phase III clinical trial evaluating the use of rituximab with or without idelalisib showed marked improvements in progression-free survival and overall survival in patients receiving the combination, leading to approval of idelalisib for relapsed and refractory CLL.