Therapeutic potential of new B cell-targeted agents in the treatment of elderly and unfit patients with chronic lymphocytic leukemia

Abstract

Chronic lymphocytic leukemia (CLL), the most common adult leukemia in the Western world, is primarily a disease of the elderly, with most patients ≥65 years of age and having at least one major comorbidity. Aggressive chemoimmunotherapy regimens recommended to achieve remission and improve survival in young, fit patients are often poorly tolerated in elderly and/or less physiologically fit ("unfit") patients, necessitating alternative treatment options. Although patient age, fitness, and comorbidities are key considerations in the selection of a treatment regimen, historically, clinical trials have been limited to young, fit patients by virtue of the ethical concerns associated with potential end organ toxic effects that could worsen comorbidities. However, the availability of new therapies promises a shift to a research paradigm that encompasses the identification of optimal treatments for elderly and unfit patients. Anti-CD20 monoclonal antibody therapy, which overall has improved response rates and survival in patients with CLL, has only recently been evaluated elderly and unfit patients. B cell-targeted agents such as the Bruton's tyrosine kinase inhibitor ibrutinib and the phosphatidylinositol 3-kinase inhibitor idelalisib are the first of a new generation of oral agents for CLL. Available clinical data suggest that these therapies have the potential to address the unmet need in elderly and unfit patients with CLL and result in clinical remission, and not merely symptom palliation and improved quality of life, which, by themselves, are also a reasonable goal.

Fig. 1

Age-related CLL statistics in the USA. a Percentage of US patients by age at CLL diagnosis, 2009 [6]. b Age-specific incidence rates of CLL, 2007–2011 [7]. CLL chronic lymphocytic leukemia

Fig. 2

Comorbidities in patients with CLL [8]. Major comorbidities include cardiac disease, diabetes mellitus, respiratory disease, and other malignancy. CLL chronic lymphocytic leukemia

Fig. 3

BCR signaling cascades in the a absence and b presence of antigen. Protein kinases are shown in red and the lipid kinase PI3Kδ in blue [38]. BCR B-cell receptor, BTK Bruton’s tyrosine kinase, Ig immunoglobulin, IKK I kappa B kinase, NF nuclear factor, NFAT nuclear factor of activated T cells P phosphorylation, PI3Kδ phosphatidylinositol 3-kinase, PKC protein kinase C, PLC phospholipase C, SYK spleen tyrosine kinase. From [38]

Fig. 4

Phase 1b/2 trial of ibrutinib monotherapy in elderly patients with CLL/SLL [61]. a Progression-free survival. b Overall survival. + = censored. CLL chronic lymphocytic leukemia, SLL small lymphocytic lymphoma. Reproduced with permission from [61]

Fig. 5

Phase 3 trial of idelalisib + rituximab versus rituximab monotherapy in patients with relapsed CLL and clinically significant coexisting medical conditions [62]. a Progression-free survival. b Overall survival. CLL chronic lymphocytic leukemia. Reproduced with permission from [62]