Chronic lymphocytic leukemia: from molecular pathogenesis to novel therapeutic strategies

Abstract

Chronic lymphocytic leukemia is a well-defined lymphoid neoplasm with very heterogeneous biological and clinical behavior. The last decade has been remarkably fruitful in novel findings elucidating multiple aspects of the pathogenesis of the disease including mechanisms of genetic susceptibility, insights into the relevance of immunogenetic factors driving the disease, profiling of genomic alterations, epigenetic subtypes, global epigenomic tumor cell reprogramming, modulation of tumor cell and microenvironment interactions, and dynamics of clonal evolution from early steps in monoclonal B cell lymphocytosis to progression and transformation into diffuse large B-cell lymphoma. All this knowledge has offered new perspectives that are being exploited therapeutically with novel target agents and management strategies. In this review we provide an overview of these novel advances and highlight questions and perspectives that need further progress to translate into the clinics the biological knowledge and improve the outcome of the patients.

Figure 1.

Genetic susceptibility mechanisms. Most susceptibility loci map to non-coding regions of the genome, are mainly located in active promoters or enhancers, and modify the binding sites of a number of transcription factors. As a consequence, the binding sites for SPI1 and NF-κB are disrupted, whereas there is an increased affinity for members of the FOX, NFAT and TCF/LEF families. This, in turn, alters the expression of genes involved in the immune response (SP140, IRF8), cell survival (BCL2, BMF, CASP8, BCL2L11) or Wnt signaling (UBR5, LEF1).

Figure 2.

The chronic lymphocytic leukemia microenvironment. Communication between chronic lymphocytic leukemia (CLL) cells and stromal cells, T cells and nurse-like cells (NLC) is established and maintained by direct contacts, chemokine/cytokine receptors, adhesion molecules and ligand-receptor interactions. CLL cells migrate to tissues attracted by the chemokines CXCL12 secreted by NLC and stromal cells, CXCL13 by follicular dendritic cells (FDC), and CCL19/CCL21 by highendothelial venules, which interact with the CLL receptors CXCR4, CXCR5 and CCR7, respectively. Adhesion molecules (e.g., α4β1 integrin, LFA-1) and their ligands (VCAM1, ICAM, among others) facilitate tumor cell migration and homing. Environmental or auto-/self-antigens and homotypic IG interactions trigger B-cell receptor (BCR) activation capable of driving CLL proliferation.^, Interactions between CD40 and CD40 ligand (CD40L) on activated CD4⁺ T cells are critical in the context of antigen presentation and induction of normal B-cell responses. Activated CLL cells secrete chemokines (CCL2, CCL3, and CCL4) and angiogenic factors that attract T cells and different stromal cells.^, Suppressive factors (IL-10) and immune inhibitory molecules (PD-L1 among others) facilitate tumor cells to evade immuneresponse and maintain tolerance. Anti-tumor CD8⁺ T cells become exhausted by constant exposure to tumor-derived antigens leading to cell exhaustion. Regulatory T cells (Treg) exert an inhibitory effect on CD4⁺ and CD8⁺ cells through secretion of suppressive cytokines. Tumor-released extracellular vesicles carrying noncoding RNA and proteins induce an inflammatory phenotype in T cells, monocytes, and stromal cells.

Figure 3.

Recurrently mutated genes and pathways in chronic lymphocytic leukemia. The main molecular pathways affected by mutations in chronic lymphocytic leukemia are depicted. Genes mutated at higher frequencies (>5%) in newly diagnosed patients are highlighted in bold.

Figure 4.

Evolutionary steps and growth dynamics of chronic lymphocytic leukemia. (Left) The progression of monoclonal B-cell lymphocytosis (MBL) to chronic lymphocytic leukemia (CLL) is a linear process discriminated by the total number of lymphocytes. The presence of driver alterations is associated with rapid progression. Although a few alterations are enriched in CLL compared to MBL, both phases share a similar driver composition. (Middle) The main growth dynamics during the pre-treatment phase of the CLL are shown, including spontaneous regression, logistic growth and exponential growth. The main characteristics associated with each pattern are specified. WBC; peripheral white blood cell count. (Right) Richter transformation to diffuse large B-cell lymphoma (DLBCL) is associated with subset #8, NOTCH1 or TP53 mutations and complex kar yotype. It follows a linear evolution from the CLL clone through the recurrent acquisition of CDKN2A and MYC alterations.

Figure 5.

Recommended therapy for patients with symptomatic chronic lymphocytic leukemia. M-CLL, mutated IGHV; U-CLL, unmutated IGHV; FCR: fludarabine + cyclophosphamide + rituximab; BR: bendamustine + rituximab; V: venetoclax; VR: venetoclax + rituximab; VO: venetoclax + obinutuzumab; I: ibrutinib; IO: ibrutinib + obinutuzumab; A: acalabrutinib; ClbO: chlorambucil + obinutuzumab; R: rituximab; D: duvelisib; AlloHCT: allogeneic hematopoietic cell transplantation; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone; IGHV, immunoglobulin heavy-chain variable region. *Acalabrutinib (A) is approved for both treatment- naïve and relapsed disease by the FDA but not the EMA. #Venetoclax (V) monotherapy is approved for patients with TP53 aberrations who are refractor y or intolerant to ibrutinib or patients without TP53 aberrations who are refractory or intolerant to both chemoimmunotherapy and ibrutinib. Venetoclax plus rituximab (VR) is approved for any patient with relapsed disease. ^†Duvelisib (D) monotherapy is approved for relapsed disease (minimum of two prior therapies) by the FDA but not the EMA. ^‡AlloHCT is recommended for appropriate patients with high-risk disease, defined by TP53 aberrations and/or complex karyotype in whom ibrutinib and/or venetoclax has failed. Allogeneic HCT is also recommended for appropriate patients with transformed disease who have responded to salvage chemotherapy (e.g., R-CHOP).