Understanding the Challenges, Best Treatment Approach for CLL

^{By Julie Gould}

Chris Fausel, PharmD, MHA, BCOP, clinical manager at Indiana University Simon Cancer Center, highlights the challenges in treating chronic lymphocytic leukemia, and explains some of the benefits of using ibrutinib compared to chemotherapy.  

What are the most significant challenges in treating chronic lymphocytic leukemia?

Chronic lymphocytic leukemia (CLL) is primarily a disease of patients older than 60 years characterized by monoclonal lymphocytosis, lymphadenopathy and cytopenias.  Constitutional symptoms such as weight loss, fatigue, fevers and night sweats coupled with infectious complications are hallmark disease features of CLL.  CLL may often respond well to treatment, however, it will eventually relapse and become less responsive to subsequent treatment modalities.  Specific patient groups, such as those with deletion of chromosome 17p have a more aggressive disease course and respond less well to treatment. 

Can you explain some of the benefits of using ibrutinib compared to chemotherapy?

Historical treatment approaches to CLL have involved the combination of alkylating agents with corticosteroids (e.g. chlorambucil with prednisone) and evolved over the years to combine these drug classes and/or purine antimetabolites with anti-CD20 monoclonal antibodies such as rituximab (e.g. fludarabine, cyclophosphamide, with rituximab).  The introduction of the Bruton’s tyrosine kinase inhibitor drug ibrutinib provided patients with a novel treatment option for the treatment of CLL which can be taken orally.  Ibrutinib demonstrated first-line activity in patients older than 65 years in a Phase III trial compared to chlorambucil with improvement in both progression-free survival (PFS) at 24 months (89% vs. 34%) and 24 month overall survival (OS) 95% vs 84%.  (Burger JA, et al. N Engl J Med. 2015;373(25):2425-37.)  A second Phase III trial in patients 65 and older tested whether ibrutinib +/- rituximab was superior to bendamustine with rituximab in previously untreated CLL.  The 2 year PFS was approximately 88% in the ibrutinib-containing arms and was 74% in the bendamustine/rituximab arm.  No difference in OS was observed at a median follow-up of 38 months. (Woyach JA, et al. N Engl J Med. 2018;379(26):2517-28 ) 

Ibrutinib has also been evaluated in a Phase III trial compared to FCR chemoimmunotherapy in patients 70 years and younger.  The three year PFS favored the ibrutinib and rituximab compared to FCR (89.4% vs. 72.9%) and the 3 year OS also favored the ibrutinib and rituximab arm (98,8% vs 91.5%).  (Shanafelt TD, et al. N Engl J Med. 2019;381(5):432-43.)