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CLL pathogenesis and management
Figure 4. Evolutionary steps and growth dynamics of chronic lymphocytic leukemia. (Left) The progression of monoclonal B-cell lymphocytosis (MBL) to chronic lym- phocytic leukemia (CLL) is a linear process discriminated by the total number of lymphocytes. The presence of driver alterations is associated with rapid progression. Although a few alterations are enriched in CLL compared to MBL, both phases share a similar driver composition. (Middle) The main growth dynamics during the pre-treatment phase of the CLL are shown, including spontaneous regression, logistic growth and exponential growth. The main characteristics associated with each pattern are specified. WBC; peripheral white blood cell count. (Right) Richter transformation to diffuse large B-cell lymphoma (DLBCL) is associated with subset #8, NOTCH1 or TP53 mutations and complex karyotype. It follows a linear evolution from the CLL clone through the recurrent acquisition of CDKN2A and MYC alter- ations.
Clinical and prognostic implications of novel discoveries
The clinical course of CLL is rather heterogeneous, rang- ing from a fairly asymptomatic disease that may even regress spontaneously to a progressive disease that even- tually leads to the patient’s death, so there has always been remarkable interest in determining the prognosis of individual patients. Even though many prognostic mark- ers have been identified over the past decades, only a few prevail. For many years, the prognosis of patients with CLL was defined using purely clinical parameters, such as those included in the Rai and Binet staging systems,92,93 the IGHV mutational status,17,18 and numerical aberrations as determined by FISH.47 With the advent of next-generation sequencing, novel drivers were discovered (NOTCH1, SF3B1, BIRC3) and incorporated into these prognostic sys- tems, but none of these attempts succeeded in becoming standard of care.94–96 Indeed, the International Workshop on CLL (iwCLL) guidelines only recommend evaluating the IGHV status and presence/absence of TP53 aberra- tions in routine practice.86 The recent CLL International Prognostic Index (CLL-IPI) incorporates both clinical and cytogenetic/genomic data (age, clinical staging, β2- microglobulin serum concentration, IGHV mutation sta- tus and TP53 aberrations) into one prognostic score.97 The CLL-IPI was developed in cohorts of patients treated with CIT and has been validated in retrospective series.98–100 Among the five items, both TP53 and IGHV have the strongest impact on a patient’s outcome, and it is therefore not surprising that simplified versions of the CLL-IPI incorporating only these two markers have been pro- posed.101 A recent study has determined that a score based on the presence of unmutated IGHV, absolute lymphocyte count >15 x109/L, and palpable lymph nodes predicts for a shorter time to first treatment in patients with early, asymptomatic disease.102 On the other hand, several groups are advocating for the incorporation of novel markers, such as a complex karyotype55 or epigenetic sub- sets,27,28 into clinical practice. All these novel prognostic
and/or predictive models will need to be validated in cohorts of patients treated with targeted agents.
Treatment
Treatment for CLL has changed remarkably in the last decade (Figure 5). The mainstay of therapy used to be CIT - a combination of conventional chemotherapeutic agents plus a monoclonal antibody, such as rituximab or obinu- tuzumab, - although this is no longer the case, at least for most patients. Novel, targeted agents are now the pre- ferred option, and among them, the drugs currently approved by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) are the BTK inhibitor ibrutinib, the BCL2 inhibitor venetoclax and the PI3K inhibitor idelalisib, while the second-generation BTK inhibitor acalabrutinib and PI3K inhibitor duvelisib have already been approved by the FDA and are under evaluation by the EMA.
Frontline therapy
Not all patients with CLL require therapy. Despite all recent advances, the iwCLL still recommends watchful observation for patients with asymptomatic disease.86 This recommendation is based on at least two random- ized trials comparing observation to either chlorambucil monotherapy or fludarabine, cyclophosphamide and rit- uximab (FCR).103,104 Both trials concluded that early therapy in asymptomatic patients was not associated with a pro- longed overall survival. Very recently, preliminary results from a third trial comparing ibrutinib versus observation were presented.105 Patients receiving ibrutinib had a longer event-free survival, but no overall survival advantage, although the results were still immature. Moreover, although severe adverse events rates were comparable between groups, patients receiving ibrutinib had a higher incidence of some specific adverse events such as bleed- ing, hypertension and atrial fibrillation.
For patients with symptomatic disease requiring thera- py, ibrutinib is often recommended based on four phase III
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