Minimal Residual Disease in Chronic Lymphocytic Leukemia: A New Goal?

Abstract

In chronic lymphocytic leukemia (CLL), there is a growing interest for minimal residual disease (MRD) monitoring, due to the availability of drug combinations capable of unprecedented complete clinical responses. The standardized and most commonly applied methods to assess MRD in CLL are based on flow cytometry (FCM) and, to a lesser extent, real-time quantitative PCR (RQ-PCR) with allele-specific oligonucleotide (ASO) primers of immunoglobulin heavy chain genes (IgH). Promising results are being obtained using droplet digital PCR (ddPCR) and next generation sequencing (NGS)-based approaches, with some advantages and a potential higher sensitivity compared to the standardized methodologies. Plasma cell-free DNA can also be explored as a more precise measure of residual disease from all different compartments, including the lymph nodes. From a clinical point of view, CLL MRD quantification has proven an independent prognostic marker of progression-free survival (PFS) and overall survival (OS) after chemoimmunotherapy as well as after allogeneic transplantation. In the era of mechanism-driven drugs, the paradigms of CLL treatment are being revolutionized, challenging the use of chemoimmunotherapy even in first-line. The continuous administration of ibrutinib single agent has led to prolonged PFS and OS in relapsed/refractory and treatment naïve CLL, including those with TP53 deletion/mutation or unmutated IGHV genes, though the clinical responses are rarely complete. More recently, chemo-free combinations of venetoclax+rituximab, venetoclax+obinutuzumab or ibrutinib+venetoclax have been shown capable of inducing undetectable MRD in the bone marrow, opening the way to protocols exploring a MRD-based duration of treatment, aiming at disease eradication. Thus, beside a durable disease control desirable particularly for older patients and/or for those with comorbidities, a MRD-negative complete remission is becoming a realistic prospect for CLL patients in an attempt to obtain a long-lasting eradication and possibly cure of the disease. Here we discuss the standardized and innovative technical approaches for MRD detection in CLL, the clinical impact of MRD monitoring in chemoimmunotherapy and chemo-free trials and the future clinical implications of MRD monitoring in CLL patients outside of clinical trials.

Deciphering the complex circulating immune cell microenvironment in chronic lymphocytic leukaemia using patient similarity networks

“…The diagnosis of CLL was established according to the International Workshop on Chronic Lymphocytic Leukemia guidelines 14 . All incoming CLL samples from all centres were included because they all exceeded the limit for minimal residual disease (1 CLL cell per 10,000 leukocytes) 15 . Of the enrolled patients, 123 were treatment-naïve, 67 patients were treated with novel agents (ibrutinib, idelalisib and venetoclax), and 54 patients were previously receiving immunochemotherapy.…”

Measurable residual disease in the treatment of chronic lymphocytic leukemia

“… 9 This single-tube eight-color assay was able to reliably detect MRD down to 10 −5 . 19 Dowling et al . optimized and validated the eight-color ERIC single-tube assay.…”

“…9 This single-tube eight-color assay was able to reliably detect MRD down to 10 −5 . 19 Dowling et al optimized and validated the eight-color ERIC single-tube assay. 20 The 8-color assay was demonstrated to detect CLL cells below a level of 10 −4 and had good correlation with the six-color method that they utilized for MRD detection (R 2 = 0.991).…”

“…[52][53][54][55][56] Moreover, in MRD detection, ddPCR has the advantage of enabling the accurate and precise detection and quantification of MRD even when a very small number of residual cells remains in samples. 19 As novel drugs, such as venetoclax, and the addition of rituximab to chemotherapy have considerably improved the treatment outcomes of CLL patients, the need for new treatment endpoints has been considered. CLL patients who achieve uMRD throughout the treatment course exhibit a prolonged PFS; therefore, uMRD achievement may be a surrogate endpoint of CLL treatment.…”

“… 52 - 56 Moreover, in MRD detection, ddPCR has the advantage of enabling the accurate and precise detection and quantification of MRD even when a very small number of residual cells remains in samples. 19 …”