Cytogenetic abnormalities are quite frequent in patients with CLL. Older methods used to perform conventional cytogenetic analysis reported cytogenetic abnormalities in 56% of patients, but these techniques required cell culture and the use of B-cell mitogens to prompt cell division in order to count metaphases. With the advent of fluorescence in situ hybridization (FISH), the ability to detect chromosomal abnormalities is enhanced, since both cells undergoing mitosis and cells in interphase can be examined. In addition, the results obtained using bone marrow and serum specimens are equivalent. Using FISH, Dohner et al found that 82% of patients had abnormal cytogenetics. The cytogenetic profile can change over time; Shanafelt et al examined untreated early-stage patients and found that clonal evolution occurred in 18 of 159 patients (11%); 17 of these changes were found after 5 years of follow up.
Deletion of the short arm of chromosome 17 (del[17p]) is associated with a very aggressive clinical course and is predictive of decreased progression-free survival (PFS), lack of response to therapy, short response duration, and short OS (Figure).[31,33,34] Del(17p) has been described in as few as 7% of patients naïve to treatment and in as many as 33% of patients with advanced, relapsed disease.[31,35,36] Most patients with del(17p) have other associated chromosomal abnormalities. However, there is some variability in prognosis among patients who carry a 17p deletion, and not all patients with this deletion are destined to have rapidly advancing disease.
Tumor protein 53 (p53 or TP53) is a tumor-suppressor protein encoded by the TP53 gene, which is located on the short arm of chromosome 17. TP53 mutations have been described in 8.5% to 15% of patients, with the majority seen in patients with del(17p).[39-44] However, there is a small subset of patients (3.1% to 4.5% of patients) who have TP53 mutations in the absence of del(17p). [41,43] TP53 mutations are more prevalent in progressive and refractory CLL. A TP53 mutation is an independent predictor of poor prognosis and confers even shorter OS than del(17p) in the absence of a TP53 mutation.
Chromosome 11q is deleted in 18% to 20% of patients with CLL.[31,35,36] Patients with 11q deletions (del[11q]) have more aggressive disease, shorter intervals between diagnosis and first treatment (9 months vs 43 months), more prevalent B symptoms, and more extensive lymphadenopathy. In the same study, in younger patients (< 55 years), those with 11q deletions had significantly shorter median survival (64 months vs 111 months)..
Similar to the case of del(17p) and TP53 mutations, mutations of the ataxia telangiectasia mutated (ATM) gene may have prognostic implications independent of those associated with the deletion of chromosome 11q, where it is located. ATM gene mutations have been described in approximately 12% of patients, and compared with ATM/TP53 wild-type, are associated with decreased treatment-free survival (40 months vs 130 months) and OS (85 months vs 217 months). In another study by Austen et al, 36% of patients with the 11q deletion also had ATM mutations in the remaining allele, and these patients had a more aggressive course and were more resistant to traditional chemotherapeutic agents. Germ-line mutations in the ATM gene in patients with CLL have also been described; it has been suggested that patients with a mutation in the ATM gene may be predisposed to the development of CLL.
Another common chromosomal aberration is trisomy 12, which is seen in 13% to 16% of patients.[31,35,36] The OS for these patients has been reported to be approximately the same as that in patients with normal genetics, which means that these deletions should thus be classified as intermediate risk. Deletion of the long arm of chromosome 6 is a rarer cytogenetic abnormality seen in patients with CLL (6% to 7% of patients).[31,48] It is generally considered an intermediate-risk feature, since it is associated with more prominent lymphocytosis with atypical morphology, splenomegaly, higher rates of CD38 positivity, and no association with IgVH mutation status.
Although there are cytogenetic abnormalities that are associated with poor outcomes, several cytogenetic patterns predict a more indolent disease course. Patients with normal cytogenetics, who comprise 18% of all patients, have a median survival of 111 months. A deletion on the long arm of chromosome 13 (del[13q]) is seen as the sole abnormality in 18% to 36% of patients[31,36] and is combined with other cytogenetic abnormalities in 19%. When it is the only cytogenetic abnormality, del(13q) confers a better prognosis; in one study, median survival was 17 years, compared with 13.2 years for patients with normal cytogenetics.
Cases of patients with infrequent cytogenetic abnormalities have also been described. Two cases of patients with a deletion of the long arm of chromosome 5 (5q-) but no other cytogenetic abnormalities have been reported; these patients were still Binet stage A at 18 and 28 months after diagnosis, which suggests that this abnormality portends a more indolent course. Other rare cytogenetic abnormalities have been described, including involvement of chromosome 8,[50,51] but more research is needed to determine their prognostic significance, if any.
The presence or absence of cytogenetic defects can also be used to guide treatment strategy and to predict response to treatment, distinguishing those patients who will benefit from standard treatment from those who will likely be treatment-refractory.
Patients with 17p deletions are known to be refractory to purine analogs and to have markedly worse outcome with front-line standard-of-care treatment with FCR; the subset of patients with 17p deletions receiving FCR had a PFS of 11.3 months, compared with 51.8 months in the entire cohort receiving FCR. Treatment with alemtuzumab (Campath) is effective in patients with 17p deletions, although they still have shorter survival than patients with better-risk cytogenetics. In a front-line randomized trial comparing alemtuzumab to chlorambucil, patients with del(17p) who received alemtuzumab had a longer PFS (10.7 months vs 2.2 months); in that study, patients with normal cytogenetics had a median PFS of 19.9 months and 14.3 months with alemtuzumab and chlorambucil, respectively. In another study of alemtuzumab, in patients who had received prior treatment, OS in patients with del(17p) was 19.1 months, compared with 27.5 months for patients with normal cytogenetics. Although alemtuzumab may somewhat mitigate the poor prognosis associated with del(17p), the PFS and OS of these patients are still inferior to those in patients with good-risk cytogenetics. These patients are therefore candidates for investigational therapies in the front-line setting, and if otherwise healthy, for stem cell transplant in first remission. Stem cell transplantation can produce durable PFS and OS in as many as 50% of patients.[54,55]
The 11q deletion also has important implications for treatment. Alkylating agents such as cyclophosphamide have been shown to improve response in patients with the 11q deletion. In US Intergroup Trial E2997, in which patients received fludarabine plus cyclophosphamide (FC) or fludarabine alone (F), patients with del(11q) who received FC had similar PFS to those patients with trisomy 12 or normal cytogenetics who received the same regimen. The addition of rituximab does not abrogate the poor prognosis associated with del(11q); in one study, patients with poor-risk cytogenetics (83% of whom had del[11q]) had significantly inferior PFS and OS. In the ongoing intergroup trial (Cancer and Leukemia Group B [CALGB] 10404), a four-arm study comparing fludarabine and rituxumab (FR) to FCR with and without 4 months of lenalidamide (Revlimid) maintenance, all patients with 11q22 deletions who were originally randomly assigned to treatment with FR are re-assigned to treatment with FCR followed by lenalidamide once FISH results are available. Another study suggests that del(11q) may respond better to immunochemotherapy with FCR; the 11q22 deletion was undetectable in 25 of 27 patients after treatment. Furthermore, treatment with pentostatin (Nipent), cyclophosphamide, and rituximab (PCR) resulted in no difference in PFS between patients with 11q22 deletions and those with other abnormalities (excluding 17p-).
Patients with trisomy 12 have high rates of response with rituximab-containing therapy, possibly because of their higher levels of expression of surface CD20. 
Our ability to stratify patients with CLL into high-risk and low-risk categories has advanced dramatically over the past two decades. However, which test or tests are most reliable remains to be seen. Overall, treatment outcomes have improved with the advent of chemoimmunotherapy regimens. Cytogenetic and molecular characterization of neoplastic cells in CLL is becoming increasingly important in predicting clinical course and determining best first-line treatment. Additional research into investigational therapies to target different cytogenetic and molecular profiles is necessary.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.