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Review
. 2023 Feb 14:13:1112616.
doi: 10.3389/fonc.2023.1112616. eCollection 2023.

Measurable residual disease in chronic lymphocytic leukemia

Giulia Benintende  1 , Federico Pozzo  2 , Idanna Innocenti  3 , Francesco Autore  3 , Alberto Fresa  3 , Giovanni D'Arena  4 , Valter Gattei  2 , Luca Lurenti  1
Affiliations
Review

Measurable residual disease in chronic lymphocytic leukemia

Giulia Benintende et al. Front Oncol. .

Abstract

Measurable residual disease (MRD) is defined as the presence of residual cancer cells after treatment in patients with clinically undetectable disease, who would otherwise be considered in complete remission. It is a highly sensitive parameter which indicates the disease burden and predicts survival in this setting of patients. In recent years, MRD has gained a role in many hematological malignancies as a surrogate endpoint for clinical trials: undetectable MRD has been correlated to longer progression free survival (PFS) and overall survival (OS). New drugs and combinations have been developed with the aim to achieve MRD negativity, which would indicate favorable prognosis. Different methods to measure MRD have also been devised, which include flow cytometry, polymerase chain reaction (PCR) and next generation sequencing (NGS), with different sensitivity and accuracy in evaluating deep remission after treatment. In this review, we will analyze the current recommendations for the detection of MRD, with particular focus on its role in Chronic Lymphocytic Leukemia (CLL), as well as the different detection methods. Moreover, we will discuss the results of clinical trials and the role of MRD in new therapeutic schemes with inhibitors and monoclonal antibodies. MRD is not currently used in the clinical practice to evaluate response to treatment, due to technical and economical limitations, but it's gaining more and more interest in trials settings, especially since the introduction of venetoclax. The use of MRD in trials will likely be followed by a broader practical application in the future. The aim of this work is to provide a reader-friendly summary of the state of art in the field, as MRD will soon become an accessible tool to evaluate our patients, predict their survival and guide physician's therapeutic choices and preferences.

Keywords: ASO-PCR; chronic lymphocytic leukemia; flow cytometry; measurable residual disease; next generation sequencing; surrogate endpoint.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Evolution and requirements for flow cytometry panels for MRD testing in CLL in 2007 (A), 2013 (B) and 2016 (C).
Figure 2
Figure 2
Example of the gating strategy employed for MRD detection in the flow cytometry panel. The green dots represent normal B cells, while the violet dots represent CLL cells. The gates are set up hierarchically. (A) Singlets are selected on FSC-H/FSC-A; the same population is refined on SSC-H/SSC-A; leukocytes are selected through the CD45 staining on CD45/SSC; mononuclear cells are selected on FSC/SSC (P1) and B cells are selected on CD19/CD20 (P2). (B) CLL cells are further characterized according to CD5/CD79b (P3), CD81/CD20 (P4), CD5/CD20 (P5), CD43/CD81 (P6) and CD5/CD200 (P7) expression. Courtesy of Prof. Giovanni D´Arena and Dr. Antonella Aiello.
Figure 3
Figure 3
Graphical representation of ASO-PCR procedure (A) and output (B).
Figure 4
Figure 4
Role of MRD in the clinical practice and potential use in routine management of CLL patients.
Figure 5
Figure 5
Rate of MRD negativity obtained by ibrutinib monotherapy, ibrutinib combined with anti CD20 monoclonal antibodies or with BR.
Figure 6
Figure 6
Rate of MRD negativity obtained by venetoclax monotherapy and venetoclax combined with anti CD20 monoclonal antibodies.
Figure 7
Figure 7
CAPTIVATE study design and results in terms of MRD negativity.
See this image and copyright information in PMC

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