Current Treatment Options for Refractory/Relapsed CLL

Chronic Lymphocytic Leukemia – A Treatable Condition

Chronic lymphocytic leukemia (CLL) is a heterogeneous lymphoproliferative disorder that typically occurs in older individuals − the median age at diagnosis is 72 years. Approximately one-third of patients are progressing already at the time of diagnosis. Currently, it is very well treatable, and many patients can achieve long-term disease control. However, despite recent advances in therapy, most of them will relapse sooner or later.

According to international recommendations, relapsed disease should be treated only if symptomatic. The response to second and subsequent lines of therapy depends on several factors, such as clinical stage, the presence of adverse prognostic markers, and the number of previous lines of therapy (especially purine analog therapy).

Targeting B Lymphocyte Receptors

The mechanism of targeted therapy, which improves the prognosis of both newly diagnosed patients and those with refractory/relapsed (R/R) disease, involves blocking signaling pathways essential for the survival of leukemic cells. The B lymphocyte receptor (BCR) signaling pathway regulates various cellular processes, including proliferation, differentiation, apoptosis, and cell migration. The BCR pathway is crucial for the normal development and survival of B lymphocytes.

BCR inhibitors include Bruton kinase (BTK) inhibitors and phosphatidylinositol-3-kinase (PI3K) inhibitors. The inhibition of these pathways shows high clinical efficacy even in high-risk patients with poor prognosis or in patients refractory to chemotherapy.

Bruton Kinase Inhibitors

BTK inhibition is revolutionary in the treatment of CLL. BTK is an active molecule at the beginning of the BCR signaling cascade. The first available inhibitor is ibrutinib, used in monotherapy and in combination with the anti-CD20 antibody rituximab. Second-generation, more specific BTK inhibitors, such as acalabrutinib and zanubrutinib, show greater selectivity than ibrutinib with minimal off-target activity and an expectedly more favorable safety profile.

PI3K Inhibitors

Constitutive activation of PI3K results from the aberrant regulation of the BCR signaling pathway. PI3K activation is crucial for the proliferation and survival of CLL cells. The first drug from this group is idelalisib, which selectively inhibits the PI3Kδ isoform, thus promoting apoptosis. It is used in combination with rituximab. Second-generation drugs in this group (duvelisib, umbralisib) have shown sufficient activity with an acceptable safety profile in clinical studies for patients with CLL.

Targeting Apoptosis Regulation − BCL-2 Inhibitors

Low-molecular BCL-2 inhibitors, an anti-apoptotic protein highly expressed by CLL cells, have great therapeutic potential. Venetoclax selectively targets BCL-2 and in a phase II study induced an objective response to therapy in 77% of patients with R/R CLL/SLL and 17p deletion. The combination of venetoclax with rituximab is currently the only approved combination with a fixed duration of administration (24 months) for this indication.

Treatment Resistance

A common problem for patients with R/R CLL is the development of resistance to BTK or BCL-2 inhibitors. Over 80% of patients develop resistance to ibrutinib due to the substitution of cysteine for serine at the binding site (C481S mutation), and the emergence of this resistance is consequently associated with a poor prognosis.

In some patients, resistance to venetoclax (G101V mutation in the BCL-2 gene) was observed. This mutation, which reduced the binding affinity of the BCL-2 protein to venetoclax, preceded disease progression and could potentially serve as a biomarker for clinical relapse.

The use of combinations of new targeted therapies can increase treatment efficacy and reduce resistance development and therapy toxicity. Combination therapy also induces deeper responses and in some cases can be used for a limited duration.

Recommendations for Practice

The choice of appropriate therapy depends on the type of previous treatment, the patient's response to previous therapy, and its side effects. Comorbidities and the safety profile of the proposed treatment also need to be considered. According to the recommendations of the Czech Hematological Society of the JEP CLS, patients with late relapse (≥ 3 years) after chemoimmunotherapy might benefit from its repeated application.

For early relapses, refractory disease, or if 17p deletion or TP53 mutation is present, targeted therapy should be initiated. Combinations of venetoclax + rituximab or BCR inhibitors (ibrutinib, acalabrutinib, idelalisib + rituximab combination) are recommended. In patients in good condition, allogeneic hematopoietic stem cell transplantation may be considered. After failure of BCR inhibitor therapy or its intolerance, venetoclax monotherapy appears suitable.

Conclusion

Available treatment regimens for patients with R/R CLL are only partially effective. Patients for whom none of the available options are suitable should, if possible, be included in clinical trials with new drugs or combinations.

Several clinical evaluations of new regimens are currently in progress. Dual and triple combinations of targeted therapies, bispecific antibody therapy, and chimeric antigen receptor (CAR-T) T-cell therapy bring hope to patients.

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Sources:
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