Precision Medicine Management of Chronic Lymphocytic Leukemia

Abstract

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in western countries, with an incidence of approximately 5.1/100,000 new cases per year. Some patients may never require treatment, whereas others relapse early after front line therapeutic approaches. Recent whole genome and whole exome sequencing studies have allowed a better understanding of CLL pathogenesis and the identification of genetic lesions with potential clinical relevance. Consistently, precision medicine plays a pivotal role in the treatment algorithm of CLL, since the integration of molecular biomarkers with the clinical features of the disease may guide treatment choices. Most CLL patients present at the time of diagnosis with an early stage disease and are managed with a watch and wait strategy. For CLL patients requiring therapy, the CLL treatment armamentarium includes both chemoimmunotherapy strategies and biological drugs. The efficacy of these treatment strategies relies upon specific molecular features of the disease. TP53 disruption (including both TP53 mutation and 17p deletion) is the strongest predictor of chemo-refractoriness, and the assessment of TP53 status is the first and most important decisional node in the first line treatment algorithm. The presence of TP53 disruption mandates treatment with biological drugs that inhibit the B cell receptor or, alternatively, the B-cell lymphoma 2 (BCL2) pathway and can, at least in part, circumvent the chemorefractoriness of TP53-disrupted patients. Beside TP53 disruption, the mutational status of immunoglobulin heavy variable (IGHV) genes also helps clinicians to improve treatment tailoring. In fact, patients carrying mutated IGHV genes in the absence of TP53 disruption experience a long-lasting and durable response to chemoimmunotherapy after fludarabine, cyclophosphamide, and rituximab (FCR) treatment with a survival superimposable to that of a matched general population. In contrast, patients with unmutated IGHV genes respond poorly to chemoimmunotherapy and deserve treatment with B cell receptor inhibitors. Minimal residual disease is also emerging as a relevant biomarker with potential clinical implications. Overall, precision medicine is now a mainstay in the management and treatment stratification of CLL. The identification of novel predictive biomarkers will allow further improvements in the treatment tailoring of this leukemia.

Targeting p53 in chronic lymphocytic leukemia

“…In CLL, as in many cancers, the key approach to improve clinical outcome is treatment tailoring in every individual CLL patient based on the clinical and biological features of the disease [3,97]. Whole genome and whole exome sequencing studies have allowed a better understanding of CLL pathogenesis and have led to the identification of genetic lesions with potential clinical relevance [3,97]. TP53 is mutated and/or deleted in approximately 10% of CLL patients at the time of first treatment requirement, and the frequency of this genetic lesion rises progressively upon subsequent relapses and reaches 60% in CLL that have transformed to Richter syndrome [34].…”

“…BCRi and BCL2i, however, do not directly target the p53 protein and do not restore the function of the disrupted p53 pathway. The persistent lack of a fully functional p53 conceivably explains the observation that TP53 mutated patients have a poorer outcome compared to TP53 wild type patients even when treated with BCRi and BCL2i treatment, posing the need to explore novel avenues for optimizing therapy in this subset of CLL patients [97,98]. Importantly, TP53 disruption remains a poor biomarker also in patients treated with a fixed duration combination of a BCL2i and an anti-CD20 antibody, as it is the case with venetoclax-obinutuzumab in the CLL14 trial [58].…”

Immune-Mediated Dermatoses in Patients with Haematological Malignancies: A Comprehensive Review

“…Each group includes tumours with aggressive or indolent biological behaviour, that in turn results in an acute or chronic clinical course and a different prognosis [ 1 , 2 ]. B-cell chronic lymphatic leukaemia is by far the most common form, with a reported incidence of approximately 5.1/100,000 new cases per year in Western populations [ 3 ].…”

A step ahead toward precision medicine for chronic lymphocytic leukemia

“…The concept of precision medicine applied to human tumors implies the personalized tailoring of clinical management and treatment choices according to the status of an array of molecular biomarkers, in conjunction with other patient features. 1 In chronic lymphocytic leukemia (CLL), the extensive body of genetic data that have been accumulated in recent years has led to the identification of many new molecular biomarkers with prognostic value. However, only a few of these serve the role of true predictors for choosing the most appropriate treatment for any given patient.…”

“…However, only a few of these serve the role of true predictors for choosing the most appropriate treatment for any given patient. 1 , 2 The active search for molecular predictors in CLL is becoming increasingly more important in the current therapeutic landscape of the disease, that ranges from chemo-immunotherapy with both old and newer monoclonal antibodies (mAb) to chemo-free options based on B-cell receptor (BCR) inhibitors, targeting either Bruton tyrosine kinase or phosphatidyilinositol-3-kinase, and BCL2 inhibitors. 3 , 4 …”