Current Treatment of Refractory/Relapsed Chronic Lymphocytic Leukemia: A Focus on Novel Drugs

Abstract

Recently, the use of novel targeted drugs has changed the treatment paradigms in chronic lymphocytic leukemia (CLL). Among the several drugs used for the management of relapsed/refractory (R/R) CLL, Bruton tyrosine kinase inhibitors (ibrutinib and acalabrutinib), phosphatidylinositol 3-kinase inhibitors (idelalisib and duvelisib), B-cell lymphoma 2 inhibitor (venetoclax), and novel CD20 monoclonal antibodies have demonstrated the greatest improvements in survival among R/R CLL patients. However, patients with relapsed but asymptomatic CLL do not need immediate alternative treatment and should be observed until evident sign of progression. Among available approved treatments, venetoclax + rituximab for 24 months or ibrutinib as continuous therapy is recommended. Another, less recommended, option is idelalisib in combination with rituximab. The correct treatment selection depends on the type of prior therapy, response to previous treatment and side effects, presence of comorbidities, and the risk of drug toxicity. Allogeneic hematopoietic stem cell transplantation and investigational therapies such as chimeric antigen receptor-T-cell therapy are promising treatment options for high-risk patients, including those progressing after 1 or more targeted therapies. The present review discusses current treatment strategies for patients with R/R CLL.

BTLA/HVEM Axis Induces NK Cell Immunosuppression and Poor Outcome in Chronic Lymphocytic Leukemia

“…The landscape of available therapies for CLL management has been enriched by the inclusion of small-molecules inhibitors, such as ibrutinib, idelalisib or venetoclax [ 5 , 6 , 7 ]. However, resistance mechanisms related to these novel treatments, together with the profound immunosuppression associated to CLL progression suggest that ICB-based therapy could benefit a subset of these patients.…”

“…To date, the landscape of CLL treatment includes chemotherapy and anti-CD20 monoclonal antibodies (mAb) [ 4 ]. Within the last years, new therapeutic options have become available, including Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, phosphatyidilinositol-3 kinase inhibitor idelalisib and B-cell lymphoma 2 (BCL-2) antagonist venetoclax [ 5 , 6 , 7 ]. Despite the fact that these therapies have been effective in patients who relapsed after chemotherapy, resistance mechanisms have already been reported [ 8 , 9 ].…”

The Effect of Dietary Intervention With High-Oleocanthal and Oleacein Olive Oil in Patients With Early-Stage Chronic Lymphocytic Leukemia: A Pilot Randomized Trial

“…However, serious complications are observed in this type of therapy as they can produce toxicity especially in elderly patients such as those participating in our study. The clinical challenge is to be able to block the progress of the disease in its early stages so that there is no need for the patient to start any chemotherapeutic schedule (8,9,32).…”

“…Oleocanthal has already been shown to induce cytotoxicity and apoptosis in vitro in human acute promyelocytic leukemia HL-60 cells, myeloma ARH-77 cells and murine myeloma MOPC-31C, to cause G1 arrest in ARH-77 cells and to promote their apoptosis by the activation of caspase-9/-3. It has been demonstrated that oleocanthal could induce apoptosis through the suppression of Akt/RANKL (receptor activator of nuclear factor B ligand) which could lead to p38 MAPK signaling a caspase-9 activation or through the induction of cleaved caspase-3 and cleaved PARP (9). A recent research showed that the described cytotoxic effects of EVOOs are related to their content in oleocanthal (22).…”

“…Nevertheless, currently accessible therapies are partly effective in some patients (9). The big challenge is to be able to limit the progression of the disease through a dietary intervention, so that the patient will not need chemotherapy.…”