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CLL pathogenesis and management
response rate and progression-free survival, and had a comparable safety profile. In this trial VO was adminis- tered for a definite period of time (2 years), which is quite appealing for older/unfit patients. Moreover, many well established adverse prognostic markers, including U-CLL, ATM aberrations or NOTCH1/BIRC3 mutations, lost their negative effect in patients treated with VO. The only fac- tor that remained predictive of a shorter progression-free survival in this cohort of patients was TP53 aberrations.112 Finally, the alternative BTK inhibitor acalabrutinib was recently approved by the FDA (not by the EMA yet) as frontline therapy in view of the results of a phase III trial comparing acalabrutinib versus ClbO.114
Relapsed/refractory disease
Treatment for relapsed/refractory disease must be decided depending on prior therapy and also the reason why the original treatment was no longer appropriate (e.g., refractoriness vs. intolerance). Ibrutinib is the current gold standard therapy for patients with relapsed/refracto- ry disease, based on the results of several phase I-III tri- als,115–119 but this is also changing for two main reasons: (i) an increasing proportion of patients currently receive ibru- tinib as frontline therapy; and (ii) a few serious contenders have appeared in the last year.
Venetoclax is one of the best alternatives in this situa- tion, including patients with high-risk genomic aberra- tions. The drug was already proven effective and safe in several phase I-II trials, in patients who had previously received either CIT or BTK/PI3K inhibitors.120–123 The for- mal confirmation of this promising activity came with a phase III trial in which venetoclax combined with ritux- imab was superior to bendamustine plus rituximab in terms of response rate, progression-free survival and over- all survival, leading to its full approval for patients with relapsed/refractory CLL.124 Other possibilities are PI3K inhibitors and alternative BTK inhibitors. Idelalisib, in combination with rituximab, was the first PI3K inhibitor approved for the treatment of relapsed/refractory CLL based on the results of a phase III trial,125,126 and yet it is infrequently used because of its less favorable adverse- event profile. It may have a role in patients with complex karyotypes,127 who have a higher risk of progression and/or transformation when treated with ibrutinib or veneto- clax,90,128 or in older patients who also tend not to tolerate ibrutinib well,129 but there are no randomized data to sub- stantiate this potential superiority. Duvelisib was the sec- ond PI3K inhibitor approved by the FDA, also based on a phase III randomized trial.130 The efficacy and safety profile of the drug appear comparable with those of idelalisib, if not slightly advantageous. Regarding alternative BTK inhibitors, there are several products in development, but only acalabrutinib is approved by the FDA for the treat- ment of relapsed/refractory CLL. This is based on a phase III trial in which acalabrutinib was superior to either ben- damustine plus rituximab or idelalisib plus rituximab.131 In this trial, prior ibrutinib therapy was not allowed, but a separate trial has shown that 85% of patients who were intolerant to ibrutinib were subsequently able to take acal- abrutinib, with a 76% response rate.132
Despite all recent therapeutic advances, a proportion of patients will still fail to respond and should be considered for curative therapy. Currently, only allogeneic hematopoietic cell transplantation can be considered potentially curative, but it is also associated with consid-
erable morbidity and mortality. Over the past decades, the number of patients referred for allogeneic hematopoietic cell transplantation has dropped significantly,133 but the procedure should be recommended to young/fit patients in whom BCR/BCL2 inhibitor treatment fails, particularly in those with TP53 aberrations, or in the case of Richter transformation.134,135 Moreover, although chimeric antigen receptor T cells could also be appropriate in this situation and the results are promising,136 none of the commercially available products is yet approved for this indication.
Disease transformation
Richter transformation remains an ominous event for patients with CLL, particularly when it is clonally related to the original CLL, because none of the recently approved novel agents is truly effective. Indeed, disease transformation is a relatively common cause of failure to benefit from these drugs.90,128,129 Histological confirmation is always recommended since it can guide prognosis (i.e., Hodgkin lymphoma and clonally unrelated tumors have more favorable prognosis). Patients with transformed disease should be offered conventional CIT (e.g., R- CHOP: rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone) followed by allogeneic hematopoietic cell transplantation in the case of response. Autologous hematopoietic cell transplantation remains an option if allogeneic transplantation is consid- ered inappropriate.134 Chimeric antigen receptor T cells may also be effective but, unfortunately, none of the approved products is current available for patients with Richter transformation.
Conclusions and perspectives
Recent molecular studies have provided many insights into the processes that govern the development and pro- gression of CLL, including many novel mutated genes clustered in different functional pathways. The CLL epigenome is reprogrammed through the modulation of regulatory regions that appear de novo in the disease, whereas other regions maintain functions already present in different stages of B-cell differentiation. Analysis of the CLL microenvironment has provided clues to understand the survival of tumor cells and resistance to therapy. All this knowledge has offered new perspectives that are being exploited therapeutically with novel agents and strategies. However, these studies are also raising new questions. The relationship between the remarkable molecular heterogeneity of the disease and the clinical diversity is not well understood. The disease is always preceded by a premalignant state (MBL) which shares most molecular drivers with overt CLL. In many cases, these molecular drivers remain constant over time. However, clonal evolution is also possible and is usually associated with exponential tumor growth, progressive disease and, in some cases, disease transformation. Most studies have been performed in pretreated patients and it is not fully understood how the genome and epigenomic alterations and microenvironmental interactions influence the evolution of the disease. Translating new knowledge into clinical practice will require an effort to obtain an integrated view of all these factors in order to understand the disease better and design effective treatments and management strategies.
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