Taking the Next Step in Double Refractory Disease: Current and Future Treatment Strategies for Chronic Lymphocytic Leukemia

Abstract

Chronic lymphocytic leukemia (CLL) is a monoclonal B-cell lymphoproliferative disease with a high annual incidence in Western countries. As B-cell receptor (BCR) signaling and intrinsic apoptotic resistance play critical roles in the development and survival of CLL cells, therapeutic approaches targeting these pathways have been extensively investigated to tackle this incurable disease. Over the last decade, several Phase 3 trials have confirmed the superior efficacy of covalent Bruton tyrosine kinase inhibitors (cBTKis) and venetoclax, a selective B-cell lymphoma 2 (BCL2) inhibitor, over chemoimmunotherapy. This has been demonstrated in both the treatment-naïve and relapsed/refractory (RR) settings and includes patients with high-risk molecular features. However, these drugs are not curative, with patients continuing to relapse after treatment with both cBTKis and BCL2is, and the optimal treatment strategy for these patients has not been defined. Several novel agents with distinct mechanisms have recently been developed for CLL which have demonstrated efficacy in patients who have previously received cBTKis and BCL2i. In particular, novel BCR-signaling targeting agents have shown promising efficacy in early-phase clinical trials for RR-CLL. Furthermore, cancer immunotherapies such as bispecific antibodies and chimeric antigen receptor T-cells have also shown anti-tumor activity in patients with heavily pretreated RR-CLL. Personalised approaches with these novel agents and combination strategies based on the understanding of resistance mechanisms have the potential to overcome the clinical challenge of what to do next for a patient who has already had a cBTKi and venetoclax.

Keywords:

• CLL
• BTK inhibitor
• BCL2 inhibitor
• bispecific antibody
• CAR-T cell therapy

Abbreviations

AcalaObi, acalabrutinib + obinutuzumab; AE, adverse event; AKT, protein kinase B; ALL, acute lymphoblastic leukemia; BAD, BCL2 associated agonist of cell death; BAK, BCL2 antagonist/killer; BAX, BCL2 associated X-protein; BCL2, B-cell lymphoma 2; BCL2i, BCL2 inhibitor; BCL-XL, B-cell lymphoma-extra large; BCR, B-cell receptor; BH3, BCL2 homology domain 3; BIM, BCL2 interacting mediator of cell death; BiTE, bispecific T cell engager; BLNK, B-cell linker; BOVen, zanubrutinib + obinutuzumab + venetoclax; BR, bendamustine + rituximab; bsAb, bispecific antibody; BTK, Bruton tyrosine kinase; cBTKi, covalent BTK inhibitor; CAR, chimeric antigen receptor; ChlObi, chlorambucil + obinutuzumab; CI, confidence interval; CIT, chemoimmunotherapy; CLL, chronic lymphocytic leukemia; CR, complete response or remission; CRS, cytokine release syndrome; ERK, extracellular signal-regulated kinase; FCR, fludarabine + cyclophosphamide + rituximab; FCμR, Fc receptor for immunoglobulin M; FDA, US Food and Drug Administration; G, grade; HR, hazard ratio; IbObi, ibrutinib + obinutuzumab; IbR, ibrutinib + rituximab; IbVen, ibrutinib + venetoclax; ICI, immune checkpoint inhibitor; ICANS, immune effector cell-associated neurotoxicity syndrome; IdR, idelalisib + rituximab; IGHV, immunoglobulin heavy chain variable region; IKZF, IKAROS family zinc finger; mAb, monoclonal antibody; MAIC, matching-adjusted indirect comparison; MAPK, mitogen-activated protein kinase; MCL1, myeloid cell leukemia-1; mDoR, median duration of response; mOS, median overall survival; mPFS, median progression free survival; mTOR, mammalian target of rapamycin; ncBTKi, non-covalent BTK inhibitor; NF-κB, nuclear factor kappa light chain enhancer of activated B cells; NGS, next-generation sequencing; NHL, non-Hodgkin’s lymphoma; NR, not reached; ORR, overall response rate; OS, overall survival; PBMC, peripheral blood mononuclear cell; PD1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PI3K, phosphatidylinositol-3-kinase; PIP3, phosphatidylinositol-3,4,5-triphosphate; PKCβ, protein kinase C beta; PLCG2, phospholipase C gamma 2; PR-L, partial response with lymphocytosis; ROR1, receptor tyrosine kinase-like orphan receptor 1; RR, relapsed or refractory; RR, relative risk; RS, Richter’s syndrome; scFV, single chain variable fragment; SLL, small lymphocytic lymphoma; SYK, spleen tyrosine kinase; TN, treatment naïve; uMRD, undetectable minimal residual disease; VenObi, venetoclax + obinutuzumab; VenR, venetoclax + rituximab.

Acknowledgments

The authors thank Jeff K. Davies for his comments on the manuscript. The figures were created in Biorender.

Disclosure

MH is a former employee of AstraZeneca. JCR reports speakers’ fees from Janssen and expenses from NURIX. The authors report no other conflicts of interest in this work.