Update: the Onkopedia recommendations on chronic lymphocytic leukemia (CLL)
Under the scientific leadership of Prof. Dr. Clemens Wendtner, the Onkopedia recommendations on CLL have been updated. Relevant changes are summarized here with a focus on the associated diagnostics:
1) Adaptation to the current WHO classification: This continues to describe CLL as indolent (lymphocytic) B-cell lymphoma characterized by a leukemic course with at least 5,000 clonal B-lymphocytes per μl in the peripheral blood. In contrast to previous versions, B prolymphocytic leukemia (B-PLL) is no longer included as a distinct entity in the current version of the WHO classification, but is absorbed into other entities, including prolymphocytic progression of CLL (defined as having >15% prolymphocytes). Thus, the diagnosis of CLL can be made unchanged by blood count and multiparametric immunophenotyping in the majority of cases; the genetic risk profile is an additional factor.
2) In first-line therapy, age is no longer used as a stratification parameter. Therapy is predominantly based on specific therapy-limiting comorbidity and genetic risk profile rather than on calendar age. Chemotherapy-free treatment with BTK inhibitors, anti-CD20 antibodies, and the BCL2 inhibitor venetoclax is the first priority. Analysis of major genetic risk factors is recommended for treatment selection:
- del(17p13) or TP53 mutation in FISH and molecular genetics.
- complex karyotype (≥3 aberrations) in cytogenetics
- unmutated IGHV status in molecular genetics
3) Second-line therapy also focuses on chemotherapy-free treatments. Second-generation BTK inhibitors have been included at major changes. In addition, the option for allogeneic hematopoietic stem cell transplantation arises in case of unfavorable prognosis and loss of efficacy of BTK inhibitors and venetoclax. The choice of relapse therapy depends on clinical parameters such as the type of primary therapy and the remission duration achieved with it, in addition to the patient's age and comorbidity. In addition, altered biology of CLL based on clonal evolution should be considered. From a diagnostic point of view, this includes in particular:
- Acquisition of a del(17p13) or TP53 mutation or a complex karyotype. In case of clinical suspicion of a relapse of CLL, it is therefore explicitly recommended to initiate molecular (cyto)genetic testing again in order to be able to exclude newly occurred and therapy-relevant high-risk aberrations (in particular del(17p13), TP53 mutation and complex karyotype) with certainty.
- After therapy with BTK or BCL2 inhibitors, specific resistance mutations (including in the BTK, PLCG2, and BCL2 genes, respectively) may also occur, the detection of which makes it inappropriate to repeat the corresponding therapy. These resistance mutations are detected by sequencing the corresponding genes in molecular genetics.
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PD Dr. med. Gregor Hörmann, PhD