Despite dramatic improvements in treatment outcomes over the last couple of years, chronic lymphocytic leukemia (CLL) has remained an incurable disease that requires intermittent therapy during episodes of disease progression.¹ In patients with relapsed/refractory (rr) CLL, treatment options often include pathway inhibitors (PIs) such as Bruton’s tyrosine kinase inhibitors (BTKis), phosphatidylinositol 3-kinase inhibitors (Pl3Kis) and B-Cell lymphoma-2 inhibitors (BCL-2is) due to their high efficacies, long remission durations and manageable safety profiles.¹ When selecting the best therapy for rrCLL patients, factors to be considered include patient age, comorbidities, del(17p)/TP53 mutation status, immunoglobulin heavy chain (IGHV) mutation status and prior treatment or the number of prior therapy lines.¹

BTKis are protein kinases that can disrupt B-cell receptor signaling and trigger lymphocytosis.¹ Previously, treatment with the BTKi ibrutinib resulted in significantly prolonged median overall survival (OS) (67.7 vs. 65.1 months) and progression free survival (PFS) (44.1 vs. 8.1 months) compared with the monoclonal antibody ofatumumab at 6 years’ post-randomization follow-up.² While single-agent ibrutinib has demonstrated significant survival benefit among rrCLL patients across most clinical and genomic risk groups, those with TP53 mutations and complex karyotype had reduced PFS and OS.¹ On the other hand, second-generation BTKis such as acalabrutinib appear to be as effective as ibrutinib and are considered as therapeutic alternatives in patients intolerant to ibrutinib.¹ While no head-to-head clinical comparison between acalabrutinib and ibrutinib is available, acalabrutinib had achieved an estimated 18-month PFS of 82% in the ASCEND study with no differences across risk groups, similar to ibrutinib.³ However, some patients would eventually acquire BTKi resistance and must cease treatment due to disease progression.¹ Currently, therapeutics aimed at overcoming BTK mutation resistance, including reversible noncovalent BTKis, such as LOXO-305 and ARQ-531, are in early clinical development.⁴ These noncovalent BTKis can only circumvent the commonly acquired BTKi resistance due to the cysteine to serine mutation (C481S) by not requiring an interaction with C481 at the conventional BTKi binding site.⁴

The selective inhibitor of PI3Ki δ, idelalisib, is another treatment option for CLL patients who have experienced relapse after chemoimmunotherapy.¹ In combination with rituximab, idelalisib has significantly improved overall response rate (ORR), PFS and OS when compared with rituximab alone among rrCLL patients with comorbidities.¹ In particular, idelalisib has an improved ORR of 81% versus 13%, PFS of 93% versus 46% at 24 weeks and an OS of 92% versus 80% at 12 months when compared to rituximab alone, respectively.⁵ Additionally, a post-hoc analysis showed that this survival benefit was extended to patients with complex karyotype and TP53 mutations.¹ However, idelalisib along with other Pl3Kis, such as duvelisib and umbralisib, are usually reserved for later lines of therapy due to their associations with immune-mediated adverse events and increased risks of infection.¹

Venetoclax, an inhibitor of the antiapoptotic BCL-2 protein, is a fixed duration regimen that can result in deep remissions.¹ After 4 years of follow-up in the MURANO study, the PFS was 57.3% with venetoclax and rituximab versus 4.6% with bendamustine and rituximab in previously treated CLL patients.⁶ The progression rate after treatment discontinuation was 32% at 2 years.⁶ Impressively, the venetoclaxrituximab combination eradicated the disease and undetectable minimal residual disease (uMRD) was attained in 62% of the patients.¹ Although the most frequent cause of venetoclax treatment cessation is disease progression, the other reason could also be venetoclax resistance arising from BCL-2 mutations, BCL-2 associated X protein (BAX) mutations, and the upregulation of antiapoptotic proteins, e.g. induced myeloid leukemia cell differentiation protein (MCL-1) and BCL-xL.¹

Continuous therapy with BTKis and fixed duration of venetoclax with anti-CD20 monoclonal antibodies have led to significantly improved treatment outcomes. Currently, second-generation BTKis are being incorporated into CLL therapy, and newer combinations of PIs with other agents are being trialled.¹ However, Dr. Carol Moreno, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, pointed out that triple drug combinations did not result in appreciably higher uMRD rates when compared to double combinations.

As the goal of CLL therapy is to prolong survival and improve quality of life, and MRD negativity is significantly associated with better treatment outcomes, many clinical trials are now using uMRD as a prognostic marker for PFS and OS after chemoimmunotherapy and allogeneic transplantation, and also as an indicator endpoint for therapy discontinuation.^1,7 However, the importance of obtaining uMRD still largely depends on the target population and the corresponding treatment objectives. For example, achieving uMRD is not critical in very old patients (>80 years) or among patients with comorbidities.⁷ Instead, achieving durable disease control is more reasonable to avoid exposure to more toxic drugs like chemoimmunotherapy.⁷ In contrast, achieving uMRD in younger patients may significantly minimize the risk of subsequent relapse and provide long-term disease remission.⁷

Dr. Moreno summed up, “Several combinations of different small molecules are being investigated to avoid treatment discontinuation associated with singulations. In addition, treatment modalities should be chosen based on risk communication with the patient from the initial to the second and subsequent lines of therapy.”