Revolution of Chronic Lymphocytic Leukemia Therapy: the Chemo-Free Treatment Paradigm

Abstract

Purpose of Review Over the last years, targeted anticancer therapy with small molecule inhibitors and antibodies has much replaced chemoimmunotherapy, which has been the gold standard of care for patients with chronic lymphocytic leukemia (CLL). Here we give an overview of novel targeted agents used in therapy of chronic lymphocytic leukemia, as well as efforts to overcome resistance development, focusing on approved drugs since they gained high relevance in clinical practice. Recent Findings Novel agents moved to the forefront as a treatment strategy of CLL due to their outstanding efficacy, almost irrespectively of the underlying genetic features. Inhibition of Bruton's tyrosine kinase (BTK), a key molecule in the B cell receptor pathway, achieved dramatic efficacy even in poor-risk and chemo-refractory patients. Further success was accomplished with venetoclax, which specifically inhibits anti-apoptotic BCL2 and induces apoptosis of CLL cells. Summary Inhibition of BTK or BCL2 is very effective and induces prolongation of progression-free and overall survival. Approved combination treatments such as venetoclax or ibrutinib with obinutuzumab show high responses rates and long remission durations. However, evolution and selection of subclones with continuous treatment leads to resistance towards these novel drugs and disease relapse. Hence, comparison of sequential treatment with combinations and discontinuation of therapy are important aspects which need to be investigated. Keywords Chronic lymphocytic leukemia. BCR signaling. BTK inhibitor. Venetoclax. BCL2 inhibitors This article is part of the Topical Collection on Leukemia

Recurrent XPO1 mutations alter pathogenesis of chronic lymphocytic leukemia

“…Sequential treatment with these agents is also effective. However, a subset of patients develop resistance to inhibitors of BCR pathways and BCL2 and have a relatively poor prognosis, spotlighting the need for further investigation of novel therapies [19]. Preventing this from occurring in high risk patients is also important for which new therapies are needed.…”

Neutralization of B-Cell Activating Factor (BAFF) by Belimumab Reinforces Small Molecule Inhibitor Treatment in Chronic Lymphocytic Leukemia

“…Our former study not only provided a functional explanation for the reportedly impaired efficacy of rituximab to induce NK cell reactivity in CLL, but also introduced BAFF neutralization as means to increase the efficacy of CD20 antibody treatment in this disease [ 24 , 57 ]. As combined application of idelalisib, ibrutinib or venetoclax with anti-CD20 antibodies has meanwhile been approved and rapidly changed treatment paradigms in CLL [ 58 , 59 ], we reason that belimumab may reinforce CLL treatment by a dual mechanism that comprises sensitization to both, (i) antibody-dependent cellular cytotoxicity induced by CD20 antibody treatment and (ii) induction of cell death by small molecule inhibitors.…”

“…Among the three small molecule inhibitors, venetoclax appears particularly suitable for first clinical evaluation in a combinatorial approach with BAFF neutralization, because the combination of this Bcl-2 inhibitor and rituximab is the recommended second line treatment (category 1 according to NCCN Guidelines v.4.2020) employing targeted therapy together with CD20 antibody application. Addition of belimumab appears warranted as available data revealed a clonal evolution of CLL cells upon venetoclax treatment, despite its high efficacy [ 11 , 43 , 58 , 60 ]. This highlights the need for effective combinatorial approaches allowing for early elimination of minimal residual disease, prevention of development of secondary resistance and/or relapse and reduction of treatment time/toxicity.…”

Molecular Remission Using Low-Dose Immunotherapy with Minimal Toxicities for Poor Prognosis IGHV—Unmutated Chronic Lymphocytic Leukemia

“…However, molecular remission in CLL is often very rare. With evolving novel targeted CLL therapies, ibrutinib (Bruton’s tyrosine kinase (BTK) inhibitor) demonstrated improved clinical outcomes as well as superior overall and progression-free survival relative to fludarabine, cyclophosphamide, and rituximab (FCR) among younger patients [ 13 , 14 ]. Ibrutinib also targets interleukin-2-inducible kinase within T cells, suggesting possible off-target effects that could contribute to the disruption of immune homeostasis in the longer term [ 15 ].…”