Chemoimmunotherapy in the First-Line Treatment of Chronic Lymphocytic Leukaemia: Dead Yet, or Alive and Kicking?

Abstract

The paradigm of first-line treatment of chronic lymphocytic leukaemia (CLL) is currently undergoing a radical change. On the basis of several randomised phase III trials showing prolongation of progression-free survival, chemoimmunotherapy is being replaced by treatment based on novel, orally available targeted inhibitors such as Bruton tyrosine kinase inhibitors ibrutinib and acalabrutinib or bcl-2 inhibitor venetoclax. However, the use of these agents may be associated with other disadvantages. First, with the exception of one trial in younger/fit patients, no studies have so far demonstrated benefit regarding the ultimate endpoint of overall survival. Second, oral inhibitors are extremely expensive and thus currently unavailable due to the absence of reimbursement in some countries. Third, treatment with ibrutinib and acalabrutinib necessitates long-term administration until progression; this may be associated with accumulation of late side effects, problems with patient compliance, and selection of resistant clones. Therefore, the identification of a subset of patients who could benefit from chemoimmunotherapy would be ideal. Current data suggest that patients with the mutated variable region of the immunoglobulin heavy chain (IGHV) achieve fairly durable remissions, especially when treated with fludarabine, cyclophosphamide, and rituximab (FCR) regimen. This review discusses current options for treatment-naïve patients with CLL.

Assessment of two main therapeutic regimens of chronic lymphocytic leukemia in a major referral center in Syria

“…Despite this, CIT is still widely used instead of target therapies in first-line treatment for untreated fit CLL patients in low-income countries such as Syria. The reasons for this fact include the huge increases in treatment costs, and the lack of transparency and freemarket competition, especially in countries with significant healthcare budget constraints [13,27,28].…”

“…The toxicity and cost differences between CIT and ibrutinib are significant. Moreover, due to financial demands, the availability of novel inhibitors is limited [13], especially in a resource-limited country like Syria.…”

Herbal NF-κB Inhibitors Sensitize Rituximab-Resistant B Lymphoma Cells to Complement-Mediated Cytolysis

“…This chemo-immunotherapy is being strengthened by treatment based on novel targeted inhibitors such as bcl-2 inhibitor venetoclax or Bruton tyrosine kinase inhibitors, ibrutinib. However, the use of these agents may be associated with other disadvantages such as late side effects, problems with patient compliance, and selection of resistant clones ( 39 ). Herein, we identified another approach to conquering the resistance to rituximab-mediated CDC effect by reducing CD59 expression with herbal NF-κB Inhibitors.…”

A comprehensive assessment of lymphocyte subsets, their prognostic significance, and changes after first‐line therapy administration in patients with chronic lymphocytic leukemia

“…Although it is being phased out in favor of newer targeted therapies (venetoclax, Bruton tyrosine kinase inhibitors), it still remains a viable option for untreated patients with mutated IGHV without TP53 dysfunction, especially in countries with significant limitations in their healthcare budgets. 18 CIT can aggravate disease‐related immunosuppression with a decrease in lymphocyte counts, resulting in a higher frequency of infections including opportunistic ones. FCR (fludarabine, cyclophosphamide, rituximab) treatment causes a depletion of CD4 + cells and also to a lesser extent, CD8 + and NK cells.…”

“…Chemoimmunotherapy (CIT) has long been the standard of care in the treatment of CLL. Although it is being phased out in favor of newer targeted therapies (venetoclax, Bruton tyrosine kinase inhibitors), it still remains a viable option for untreated patients with mutated IGHV without TP53 dysfunction, especially in countries with significant limitations in their healthcare budgets 18 . CIT can aggravate disease‐related immunosuppression with a decrease in lymphocyte counts, resulting in a higher frequency of infections including opportunistic ones.…”