Genetics, Immunophenotyping Help Drive CLL Treatment Selection, but More Knowledge Needed

An education session at the 2022 European Hematology Association (EHA) Congress featured speakers delivering updates on the status of using genetic and immune characteristics to select the optimal treatment pathway in chronic lymphocytic leukemia (CLL). However, they noted the need for longer-term data and more research on treatment tolerability in order to translate this clinical knowledge into real-world survival.

Session chair Sarka Pospisilova, PhD, of Masaryk University in Brno, Czech Republic, introduced the “3 excellent speakers” to a large crowd gathered in Vienna for the EHA2022 Congress, as well as those watching virtually.

CLL Genes and Microenvironment

Dimitar Efremov, MD, PhD, of the International Centre for Genetic Engineering and Biotechnology in Trieste, Italy, kicked off the session with his presentation of a “rather broad” topic: the role of the microenvironment and genetic lesions in influencing CLL and response to treatment. He presented a table of the most frequent genetic lesions and the pathways by which they relate to CLL (eg, miR-15a/16-1 deletion, found in about 85% of samples, is linked to the cell cycle and apoptosis pathways).

Not only do genetic and microenvironmental factors play a role in the development of CLL, but they can also affect resistance to certain drugs, Efremov said. For instance, macrophages induce venetoclax resistance by upregulating the MCL-1 protein, and interleukin-4 increases surface expression of immunoglobulin M and reduces the capacity of ibrutinib to inhibit B-cell receptor signaling.

Furthermore, knowledge is evolving about the impact of genetic lesions on interactions between CLL cells and the microenvironment. Efremov cited research on positive and negative cell cycle regulators in human and murine CLL B cells, as well as how genetic mechanisms can trigger Richter transformation in the disease.

He also referenced findings of recent studies that support the possibility that genetic lesions can drive ibrutinib resistance. For example, progression-free survival and overall survival are lower after ibrutinib treatment in patients who have TP53 mutation and deletion.

Immunophenotyping and Drug Sensitivity in Lymphoid Malignancies

Next, Sigrid Skånland, PhD, of Oslo University Hospital in Norway, explained how she and her colleagues are using functional assays to guide precision medicine in CLL. Their technique of co-culturing CLL cells ex vivo allows them to mimic in vivo drug resistance signals and identify treatment possibilities, and integrating these data with laboratory and genomic data can yield machine learning algorithms to predict treatment outcomes.

One case study presented by Skånland described a woman with relapsed CLL who had exhausted all available treatment options. The investigators’ testing was able to plot the patient’s sensitivity to various therapies and the changes in sensitivity at different time points in her history of treatment response and disease progression. It identified that her CLL may be susceptible to a combination of idelalisib and venetoclax, and that regimen did appear to be effective once it was tried—but unfortunately the patient had to stop the regimen due to adverse effects. The prediction model can predict sensitivity to a particular therapy but not tolerability, Skånland said, which presents a challenge to aim of using precision medicine to improve outcomes.

Skånland and colleagues are planning to integrate their biomarker validation model into an ongoing precision medicine trial in Norway. “We are now doing these assays on patients who have been treated in clinical trials,” she explained, as the trials will yield more data on how the patients tolerated therapy and how their tolerance may correlate with other characteristics.

CLL Sequential Therapies

Finally, Othman Al-Sawaf, MD, of the University Hospital of Cologne in Germany, delivered a talk on behalf of his colleague Kirsten Fischer, MD, who was unable to attend. First, he compared the European Society for Medical Oncology guidelines on treatment for first-line and relapsed/refractory CLL.

Whereas the decision tree for first-line disease offers clear stratification based on mutations and patient fitness, the recommended pathway for relapsed disease “looks a bit different,” Al-Sawaf said. The stratification may not always apply in the real-world clinical setting, and he instead suggested considering patient age, fitness, tolerability of prior regimen, genetic features, preferred treatment strategy, and quality and duration of prior remission.

He presented data on the efficacy of the 3 strategies of therapy sequencing in relapsed/refractory CLL: re-treating with the same drug class, switching agent types, or a combination of both re-treating and switching.

Additionally, he noted that allogeneic stem cell transplant is an effective option to consider in fit patients with relapsed disease who have a TP53 mutation, but clinicians need to talk through the advantages and drawbacks of various therapies with their patients at the time of each treatment decision. Prior lines of treatment may worsen patients’ condition enough so they are no longer good candidates for the stem cell transplant if their condition relapses.

Al-Sawaf concluded his talk with a plea for greater cooperation in harvesting larger amounts of prospective data on treatment sequencing in CLL. Considering the amount of combinations and treatment pathways that are available, as well as the heterogenous states of drug access and reimbursement worldwide, “we need to find ways to do these concerted efforts within cooperative groups and industry, even if they have competing interests, to set up randomized studies to compare different sequencing strategies,” he said.