Second-line B cell receptor-targeting agents, such as ibrutinib and idelalisib, as well as the B cell lymphoma-2 (BCL-2) inhibitor venetoclax are emerging as “new options” for some patients in the second-line treatment setting of relapsed and refractory chronic lymphocytic leukemia (CLL).

These options may be effective following chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR), according to a review published in the  Annals of Hematology.1

Progression-free survival (PFS) and overall survival (OS) have improved markedly among patients with relapsed/refractory CLL, particularly among patients with IGHV mutations, due to frontline anti-CD20 monoclonal antibody-based chemoimmunotherapy with FCR, the authors wrote.

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FCR is therefore the “frontline standard of care in a younger population with few comorbidities,” they reported. “A 10-year follow-up of 300 patients treated with FCR at MD Anderson Cancer Center indicated a sustained PFS in a subset of patients, with 42 patients experiencing no relapses beyond 10.4 years.”2

Even among patients with strong first-line chemoimmunotherapy responses, however, most will relapse and must undergo second-line treatment.

For patients with limited prior treatment lines and durable response to first-line FCR (eg, PFS longer than 24 months), FCR retreatment remains an option — but acquired genetic aberrations, impaired marrow reserve, and comorbidities “often made this suboptimal therapy for many patients.”

As with frontline therapy, second-line treatment decisions should be guided by patient age, comorbidities, and marrow reserve, the latter of which in some patients will be impaired by previous lines of treatment.

Repeat cytogenetic assessment should be performed to detect del (17p), the frequency of which increases with relapse.

“Ibrutinib, idelalisib, and venetoclax are all active in relapsed CLL with del (17p),” the authors noted. “An indirect comparison of ibrutinib monotherapy and idelalisib plus ofatumumab suggested a longer PFS and fewer discontinuations with ibrutinib, although a head-to-head trial is required for a true comparison.”

RELATED: CD49d Expression Associated With Lymphadenopathy in CLL

Combination therapies involving the newer agents are undergoing clinical study in patients with CLL.


  1. Shustik C, Bence-Bruckler I, Delage R, Owen CJ, Toze CL, Coutre S. Advances in the treatment of relapsed/refractory chronic lymphocytic leukemia. Ann Hematol. 2017 Apr 7. doi: 10.1007/s00277-017-2982-1 [Epub ahead of print]
  2. Thompson PA, Tam CS, O’Brien SM, et al. Fludarabine, cyclophosphamide and rituximab achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2016;127:303-9.