Biology and Treatment of High-Risk CLL

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Background

In the era of chemoimmunotherapy, treatment options were limited for patients with primary high-risk chronic lymphocytic leukemia (CLL), as defined by the presence of TP53 loss and/or mutation. The development of targeted therapy approaches has changed paradigms in CLL treatment fundamentally and enriched opportunities for primary high risk and purine-analogue refractory CLL as well as for CLL patients with an early relapse after chemoimmunotherapy. At present, BTK-inhibitors such as ibrutinib or acalabrutinib and the BCL2-inhibitor venetoclax in combination with obinutuzumab or rituximab have almost completely replaced chemoimmunotherapy with fludarabine/cyclophosphamide/rituximab (FCR) or bendamustine/rituximab (BR) in 1st- and 2nd-line CLL treatment. Pi3K inhibitors such as idelalisib lost their role in front line treatment due to an unfavorable safety profile but remain an alternative for 3rd line. Due to this wider range of approved drugs and novel compounds available in clinical trials, identifying patients and timepoints for allogeneic stem cell transplantation has become a difficult task in CLL treatment, which is further challenged by the availability of alternative cellular treatment strategies based on CAR-T- and CAR-NK-cell products.

Although the switch to chemo-free treatment regimens significantly improved the prognosis of TP53 deficient patients, response rates and survival remain behind those observed in standard-risk CLL. Other biologic markers conferring refractoriness or early treatment failure have yet not clearly been defined, but markers under investigation are the presence of a complex karyotype, gain of the MYC gene locus, mutation of NOTCH1, and the presence of defined subsets of stereotyped B-cell receptors. The presence of TP53 deficiency, MYC gain, NOTCH1 mutation, and loss of the CDKN2A/B gene loci were also identified as hallmark genomic alterations in Richter transformation, which is the transformation of CLL into aggressive lymphoma, often having a dismal prognosis due to a lack of established treatment options.

Only a profound understanding of biomarkers predicting non benefit from standardized treatment protocols will enable a personalized approach to tailor best effective and cost saving drug combinations for each CLL patient. While the identification of biomarkers in the past mainly focused on genomic analyses, the characterization of tumors has nowadays become more comprehensive by the application of “omic” technologies allowing an integrative analysis of genomic, epigenomic, transcriptomic, proteomic and metabolomic data. Furthermore, an improved understanding of the CLL microenvironment can promote better incorporation of immune modulatory approaches into treatment concepts. Given this complexity, comprehensive analyses taking all aspects into account will necessitate the development of large-scale databases.

The scope of the proposed article series on “Treatment and Characteristics of High risk CLL” is to discuss the definition of high risk CLL in a changing treatment landscape and to provide a state-of-the-art overview by invited review articles on targeted and immunotherapeutic treatment options and on biologic markers associated with high risk disease character. Building up on the contemporary view provided, original research articles will add novel clinical, translational and biological data to the field and perspectives will discuss how to further refine the definition of high risk CLL and optimize treatment designs for high-risk CLL and Richter transformation.

Keywords: CLL, TP53, biomarkers, targeted therapy, immunotherapy

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