Onkológia 1/2022

Current possibilities of treatment of chronic B-lymphocytic leukemia in Slovakia and world

The treatment of chronic lymhocytic leukemia (CLL) has changed substantially in last few years. After palliative treatment with chlorambucil (CLB), fludarabin (F) in combination with cyclophosphamide (C) have been used. Higher proportion of remissions, even complete ones, has been observed but without increasing the overall survival (OS). Only the combination with the anti-CD20 monoclonal antibody (MAb) rituximab (R) was able to prolong the OS. Unfortunately, the success has not been observed in all patients with CLL. This disease is still divided into two prognostic groups, one aggressive from naïve B-lymphocytes (B-Ly) and the other relatively benign from memory B-Ly. Out of the patients with worse prognosis especially those with mutations of TP53 gene, del 17p13 and del 11q23 have the worst outcome. Another adverse prognostic factor is the non-mutated status of the IGHV gene (variable part of immunoglobuline heavy chain). In these patients, even if complete remissions with FCR or Bendamustine (BEN) + R are achieved, the remissions use to be short. Another obstacle with these patients is their usually higher age, there are only limited possibilities to administer high dose chemotherapy (CHT) in the age group about 70 years. The only cytostatic drug with low toxicity (CLB) is also the least effective – mostly only palliative – treatment. We cannot therefore await any significant effectiveness of CHT in high risk group patients. In this group inhibitors of signaling pathways are used: ibrutinib (IBR), Bruton´s kinase inhibitor, idelalisib (IDE), inhibitor of fosfatidyl-inositol-3 kinase-δ as well their newer derivatives, and inhibitor of bcl2 pathway venetoklax (VEN). They can be used alone, in mutual combination as well as in combination with MAb´s. We present here the results of newest clinical studies of modern drugs in CLL. Fixed time combinations tested in 1st line therapy are IBR + VEN (Captivate study), OBI + VEN (study Hovon 139/Give). Combination of VEN + OBI in comparison with CLB + OBI was the topic of the CLL14 study. IBR + OBI combination was tested in Illuminate study. All of these studies have confirmed good tolerability and high effectiveness of these new non-cytostatic drugs. Other tests were performed in pretreated or resistant patients with CLL. A new inhibitor of Bruton´s kinase Akalabrutinib (AKA) has been compared to IBR in a non-inferiority study. AKA has shown comparable effectiveness, but lower cardiotoxicity. Combination of VEN + R compared to BEN + R was the topic of the Murano study. Combination of both signal inhibitors IBR + VEN was tested in the Clarity study. All combinations tested have proven their effectiveness also in this high risk group of pretreated patients. Another inhibitor of Bruton´s kinase tested is Zanubrutinib. PI3Kδ inhibitor Duvelisib has been already approved by EMA. The development in this field is very fast and other new molecules or combinations can be awaited. We will hope, that in spite of high prices of these new drugs, our health insurance policy will accept, that the fixed duration of treatment with innovative drugs in the group of high risk patients brings them new benefit, which is not achievable with immuno-chemotherapy.

Keywords: chronic lymphocytic leukemia, immunochemotherapy, chemotherapy, monoclonal antibodies, kinase inhibitors, bcl2 signaling pathway, ibrutinib, idelalisib, venetoclax