The classification of chronic lymphocytic leukemia (CLL) into ist disease stages in routine practice and clinical trials is still based on the Rai and Binet system, which assesses physical signs and blood parameters. In the era of new targeted therapies (BTK, PI3K, BCL2 inhibitors, anti-CD20 antibodies), the iwCLL response criteria have been adapted and, for example, a new response category "partial remission (PR) with lymphocytosis" has been added for BTK and PI3K inhibitors. In addition, measurable residual disease (MRD) is playing an increasingly important role. MRD is determined by next-generation sequencing (NGS) or flow cytometry, usually at the end of therapy or during the course of therapy with potent targeted therapies. [1][2]

The measurement of MRD plays an important role as a surrogate endpoint in clinical trials and is generally a critical measurement to assess treatment success during or after therapy, or to intensify or change therapy if necessary. [3] The data are based on the combined analysis of two studies of the German CLL Study Group [4] (CLL8 and CLL10) and further studies [2][5][6][7] (ELEVATE-TN, GLOW, FLAIR, CAPTIVATE) with different combinations of targeted therapies, which are currently investigating the role of MRD. In particular, the use of BCL-2 inhibitors with high CR rates has further increased the relevance of MRD analysis. [8][9][10] In addition, the first study to base the duration of treatment (BTK and BCL2 inhibition) on the presence of MRD negativity (FLAIR) has recently been published. [11]

According to iwCLL and NCCN guidelines, a sensitivity of 10-4 (MRD4) should be achieved using the standardized ERIC method [12] MRD negativity is defined as < 1 CLL cell per 10,000 WBC. [1][3] A sensitivity of 0.001% is currently achieved at the MLL Munich Leukemia Laboratory.

In addition to the previously used antibodies against CD45, CD19, CD5, CD20 and CD79b, the new CLL MRD panel now also includes the markers CD43, CD81 and ROR1. ROR1 in particular is an important marker that is expressed on CLL cells but not on physiologically mature B cells. Especially in CLL with weak expression of CD5 or strong expression of CD20 or CD79b, ROR1 ensures reliable detection of CLL cells in the MRD area. The additional use of CD43 and CD81 also allows differentiation from immature B cells, which also express ROR1. This new CLL-MRD panel has been validated at MLL and replaces the previous MRD assay.

Referenzen:

[1] Wierda WG et. al. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 4.2020, NCCN Clinical Practive Guidelines in Oncology. J Natl Compr Canc Netw 2020;18(2):185-217.

[2] Wierda WG et. al. Measurable residual disease in chronic lymphocytic leukemia: expert review and consensus recommendations. Leukemia 2021;35:3059-3072. Wierda WG et. al. Ibrutinib Plus Venetoclax for First-Line Treatment of Chronic Lymphocytic Leukemia: Primary Analysis Results From the Minimal Residual Disease Cohort of the Randomized Phase II CAPTIVATE Study. J Clin Oncol 2021;39(34):3853-3865.

[3] Hallek M et. al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood 2018;131(25):2745-2760.

[4] Kovacs G et. al. Minimal Residual Disease Assessment Improves Prediction of Outcome in Patients With Chronic Lymphocytic Leukemia (CLL) Who Achieve Partial Response: Comprehensive Analysis of Two Phase III Studies of the German CLL Study Group. J Clin Oncol 2016;34(31):3758-3765.

[5] Sharman JP et. al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet 2020;18;395(10232):1278-1291.

[6] Kater AP et. al. Fixed-Duration Ibrutinib-Venetoclax in Patients with Chronic Lymphocytic Leukemia and Comorbididties. N Engl J Med 2022;1(7).

[7] Hillmen P et. al. Ibrutinib and rituximab versus fludarabine, cyclophosphamide, and rituximab for patients with previously untreated chronic lymphocytic leukaemia (FLAIR): interim analysis of a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2023;24(5):535-552.

[8] Seymour JF et. al. Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab. Blood 2022; 140 (8): 839–850.

[9] Munir T et. al. Impact of Minimal Residual Disease on Progression-Free Survival Outcomes After Fixed-Duration Ibrutinib-Venetoclax Versus Chlorambucil-Obinutuzumab in the GLOW Study. J Clin Oncol 2023;41(21):3689-3699.

[10] Eichhorst B et. al. First-line Venetoclax Combinations in Chronic Lymphocytic Leukemia. N Engl J Med 2023;388(19):1739-1754.

[11] Munir T et. al. Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease. N Engl J Med 2024;390:326-337.

[12] Rawstron AC et. al. A complementary role of multiparameter flow cytometry and high-throughput sequencing for minimal residual disease detection in chronic lymphocytic leukemia: an European Research Initiative on CLL study. Leukemia 2016;30:929-936.