Abstract
Abstract 1378
Although the most rapidly growing portion of the United States population is the elderly (Yancik R and Ries L, Semin Oncol 2004), they are consistently underrepresented in cancer clinical trials (Hutchins L et al, N Engl J Med 1999). The incidence of chronic lymphocytic leukemia (CLL) is markedly increased in older people, with a median age at diagnosis of 72 years (Ries L et al, SEER Clinical Statistics Review 2008). In contrast, an age range of between 58 and 66 years has been noted in patients (pts) enrolled in key trials to evaluate the first-line treatment for CLL (Eichhorst B et al, Leuk Lymphoma 2009). Both fludarabine and chemoimmunotherapy with rituximab have not demonstrated much promise in the older subset of patients. Developing new therapeutics that have clinical benefit and also demonstrate feasibility of administration to this patient population is of great interest. Flavopiridol, is a pan-cyclin-dependent kinase inhibitor, that has demonstrated significant clinical activity in relapsed and refractory CLL pts including those with del(17p13.1)(Christian B et al, Clin Lymphoma Myeloma 2009). We sought to determine the feasibility and impact of treating patients over the age of 70 with flavopiridol by reviewing outcomes of two clinical trials using single-agent flavopiridol in patients with relapsed or refractory CLL at our institution (Byrd J et al, Blood 2007; Lin T et al, J Clin Oncol 2009). Pts were divided into categories based on age [≥70 years old (n = 21) and <70 years old (n = 95)]. Of the 21 pts aged 70 or older, all but one (95%) presented with Rai Stage III/IV compared with 76% of the younger pts (<70 years old; P = 0.07). Older age was also associated with complex karyotype (63% vs. 37%; P = 0.04). No significant difference was observed in response rates, with 43% of older pts achieving response vs. 47% of younger pts (P = 0.81). The estimated median progression free survival (PFS) for both age groups was 0.8 years (P = 0.9). In multivariable analyses, there remained no significant differences in response rates or PFS when controlling for treatment schedule, Rai stage and presence of complex karyotype (P = 0.76 and P = 0.89, respectively). Although overall survival tended to be worse in the older pts compared with the younger pts (estimated medians of 2.1 and 2.4 years, respectively), following adjustment for other variables in a multivariable analysis, this difference was no longer significant (P = 0.54, hazard ratio = 1.20 [95% CI: 0.7 – 2.1]). With respect to toxicities, no significant difference in occurrence of tumor lysis syndrome (TLS) or cytokine release syndrome (CRS) was observed between the two age groups, TLS occurred in 48% of older pts and 45% of younger pts (P = 1.00), while CRS occurred in 33% of older pts and 36% of younger pts (P = 1.00). As for infection, only 29% of older pts experienced this toxicity compared to 62% of younger pts (P = 0.007). In multivariable pharmacokinetic (PK) analyses of a patient subset (n=56), there were no significant associations observed between PK parameters and age when controlling for age, bilirubin level, alanine transaminase level, platelet count, white blood cell count, BUN, and 14 distinct single nucleotide polymorphisms. These data demonstrate that flavopiridol administration to older CLL patients is both feasible, acceptably tolerated, and has similar efficacy as compared to younger patients. Future development of treatment approaches with both single-agent and combination strategies of flavopiridol should be considered for older CLL patients.
Disclosures:
Off Label Use: The efficacy of the cyclin dependent kinase inhibitor, flavopiridol is under investigation in CLL. Jones:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbott Laboratories: Research Funding.
ER stress and autophagy: new discoveries in the mechanism of action and drug resistance of the cyclin-dependent kinase inhibitor flavopiridol