Abstract and Introduction
In an optimized management algorithm of chronic lymphocytic leukemia (CLL), the early identification of high-risk patients, ideally prior to treatment, is a prerequisite for designing strategies tailored at overcoming therapy resistance. TP53 abnormalities play a central role in our current understanding of the poor prognosis of high-risk CLL patients, but fail to explain the molecular basis of 50% of high-risk CLL. Next-generation sequencing studies have revealed several novel genetic alterations in high-risk CLL, including NOTCH1, SF3B1 and BIRC3 mutations. Alterations of these genes occur in 5–10% of CLL at diagnosis, show a prevalence that increases in the more advanced phases of the disease, and confer poor prognosis in consecutive CLL series.
Although modern treatment strategies are highly effective in most cases of chronic lymphocytic leukemia (CLL), a challenging subgroup of patients show poor response to standard regimens.[1,2] The clinical importance of refractory CLL is based on the fact that unlike most CLL cases, patients belonging to this subgroup have a very poor prognosis (1–2 years of median overall survival [OS] in most studies) despite various salvage therapy strategies.[1,2] On these grounds, this patient subgroup is a prime candidate for investigational agents in clinical trials and/or allogeneic stem cell transplant.[1–3] In an optimized management algorithm of CLL, the early identification of high-risk patients, ideally prior to treatment, is a prerequisite for designing strategies tailored at overcoming therapy resistance. To this aim, it is desirable to have precise knowledge of molecular markers of chemorefractoriness, as well as a comprehensive biologic understanding of refractory CLL.
TP53 abnormalities play a central role in our current understanding of why CLL patients fail to respond to chemo-/chemoimmuno-therapy and, consequently, have short survival.[4–7] However, the observation that 17p13 deletion and TP53 mutation are found only in approximately 50% of refractory patients raises questions regarding the biologic basis of refractoriness in the remaining cases.[8,9] Major improvements in sequencing technologies offer a unique opportunity to examine the CLL genome for a comprehensive identification of genomic alterations. This approach has allowed the identification of a number of previously unrecognized mutated genes in chemorefractory CLL, including NOTCH1, SF3B1 and BIRC3.[10–17] In this review, the authors shall cover the main genetic lesions associated with high-risk and chemorefractory CLL.
Expert Rev Hematol. 2012;5(6):593-602. © 2012 Expert Reviews Ltd.