Treatment of Elderly Patients With Chronic Lymphocytic Leukemia

An Unmet Clinical Need

Stefano Molica; Maura Brugiatelli; Fortunato Morabito; Felicetto Ferrara; Emilio Iannitto; Nicola Di Renzo; Silvana Capalbo; Pellegrino Musto; Francesco Di Raimondo


Expert Rev Hematol. 2013;6(4):441-449. 

In This Article

Utility of Assessing Prognosis of CLL in Younger & Older Patients

Generally, the clinical outcome of subjects with CLL is quite heterogeneous and the current dogma is that for every 100 patients with CLL, approximately one-third will not progress to treatment even over decades, one-third will eventually progress and one-third will need more urgent treatment than the rest.[5] Both Rai and Binet clinical staging systems that incorporate the most useful clinical features are still used for assessing CLL prognosis in either clinical trial or day-to-day practice.[6] To improve on these traditional predictors of outcome, a number of biological parameters have been assessed for their utility. Consequently, a plethora of prognostic parameters potentially able to predict survival or time to first treatment are now available.[7–8]

The newest biological variables of prognostic relevance are useful for understanding the clinical heterogeneity of disease, however, their value at the time of first diagnosis is limited.[6] Until large, prospective trials will demonstrate an advantage to treat earlier patients with asymptomatic CLL and high-risk biologic profile, the use of sophisticated tests of prognostic relevance should be limited to patients enrolled in clinical trials.

By contrast, prognostic information is very helpful at the time of initial treatment and should mainly rely on the standard FISH panel detecting deletions in the 13q, 11q and 17p locations, as well as trisomy 12.[6,9] At the time of initial treatment, about 7% of previously untreated patients with CLL have a deletion involving the short arm of chromosome 17 detected by FISH that covers the locus of the p53 gene. In addition, a small number of patients have mutations of the p53 gene without a 17p deletion.[10–11]

The European Research Initiative recently published recommendations on TP53 analysis in CLL. Conclusions were that in addition to the work-up recommended by the International Workshop on CLL guidelines in patients with treatment indications, TP53 mutations should be investigated.[12] Accordingly, alemtuzumab-based regimens should be considered for the treatment of this subset of patients.[13]

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 a very small number of CLL patients at diagnosis (i.e., 5–10%), although their prevalence increases in the more advanced phases of the disease.[14] Recently, Rossi et al. showed that an integrated mutational and cytogenetic model can classify CLL patients into more precise subgroups therefore providing significant advance in the understanding of the molecular heterogeneity of CLL and improving current prognostic algorithms.[15]

An unaddressed issue is represented by interactions between the age and the utility of prognostic tests. Shanafelt et al. published comprehensive data regarding the utility of prognostic tests for assessing risk of CLL patients across different ages.[16] Findings suggest that survival of CLL patients aged >75 years at diagnosis is no different than survival of age-matched healthy controls. In this subset of patients, we should look for newer integrated prognostic models that include the three major predictors of survival (age, parameters reflecting aggressiveness of disease and baseline comorbidities). Interestingly, the burden of comorbidities assessed by the Adult Comorbidity Evaluation-27 scale in association with the International Prognostic Scoring System, formed the basis of a recently proposed prognostic model in myelodysplastic syndrome.[17] Similar models should be developed in CLL.