Minimal residual disease in chronic lymphocytic leukemia: A consensus paper that presents the clinical impact of the presently available laboratory approaches

Abstract

Chronic lymphocytic leukemia (CLL) is a malignancy defined by the accumulation of mature lymphocytes in the lymphoid tissues, bone marrow, and blood. Therapy for CLL is guided according to the Rai and Binet staging systems. Nevertheless, state-of-the-art protocols in disease monitoring, diagnostics, and prognostics for CLL are based on the assessment of minimal residual disease (MRD). MRD is internationally considered to be the level of disease that can be detected by sensitive techniques and represents incomplete treatment and a probability of disease relapse. MRD detection has been continuously improved by the quick development of both flow cytometry and molecular biology technology, as well as by next-generation sequencing. Considering that MRD detection is moving more and more from research to clinical practice, where it can be an independent prognostic marker, in this paper, we present the methodologies by which MRD is evaluated, from translational research to clinical practice.

“Immuno‐flowFISH” for the Assessment of Cytogenetic Abnormalities in Chronic Lymphocytic Leukemia

“…As outlined previously, a 2‐ to 3‐color panel consisting of CD19/CD5 is unsuitable for the detection of MRD by flow cytometry. Most international protocols require a minimum of 4‐colors to be reproducible and have sufficient minimum sensitivity (10 −4 dependent on cell number analyzed) for MRD detection of CLL by flow cytometry . The addition of FISH to standard immunophenotyping has resulted in the potential to increase the MRD sensitivity with a smaller 2‐ or 3‐antibody panel.…”

“…A positive result requires detection of one abnormal cell in 20 assessed giving low diagnostic sensitivity (5–7% sensitivity) . This ultimately limits the use of this technique for detection of low‐level disease or subclones, including use in minimal residual disease (MRD) monitoring whereby a 0.001% detection limit is required . Significant developments have been made to improve the clinical utility of FISH with regards to accurately detecting and monitoring the subclonal architecture of CLL.…”

Approach to the Adult Acute Lymphoblastic Leukemia Patient

“…It is detected by molecular methods that use leukemia-specific or patient-specific molecular markers (fusion gene transcripts, or immunoglobulin/T-cell receptor (IG/TR) gene rearrangements), as well as by multi-parametric flow cytometry. Once MRD-based follow-up becomes more efficient [172,173,174,175], so does the effect of novel therapies, as is the case of blinatumomab or CAR-T cells, as presented in the article.…”

Clinical Approach to the Patient in Critical State Following Immunotherapy and/or Stem Cell Transplantation: Guideline for the On-Call Physician

“…The absorber has a surface of about 45,000 m 2 compared to a conventional hemofilter with a surface of 1 to 1.5 m 2 , with a molecular cutoff of about 60 kDa, removing cytokines as well as other toxins and drugs. Multiple studies provide evidence of IL-6 cytokine removal [94,95]. There are no randomized controlled studies in this population.…”