Genetics and immunophenotyping help guide CLL treatment selection, but more knowledge is needed

An education session at the 2022 European Hematology Association Congress presented updates on the use of genetic and immune characteristics to select the optimal treatment pathway in chronic lymphocytic leukemia (CLL).

An education session at the 2022 European Hematology Association (EHA) Congress featured speakers providing an update on the state of using genetic and immune characteristics to select the optimal treatment pathway in chronic lymphocytic leukemia (LLC). However, they noted the need for longer-term data and more research on treatment tolerance 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.

LLC genes and microenvironment

Dimitar Efremov, MD, PhD, of the International Center for Genetic Engineering and Biotechnology in Trieste, Italy, kicked off the session with his presentation of a “rather broad” topic: the role of microenvironment and genetic damage in influencing of CLL and response to treatment. He presented a table of the most common genetic lesions and the pathways by which they are linked to CLL (eg. miR-15a/16-1 the deletion, found in approximately 85% of the 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 example, macrophages induce resistance to venetoclax by upregulating the MCL-1 protein, and interleukin-4 increases surface expression of immunoglobulin M and reduces the ability of ibrutinib to inhibit signaling B cell receptors.

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

He also referenced the results of recent studies that support the possibility that genetic damage could lead to resistance to ibrutinib. 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, from Oslo University Hospital in Norway, explained how she and her colleagues are using functional testing to guide precision medicine in CLL. Their technique of co-cultivating LLC cells ex vivo allows them to mimic drug resistance signals in vivo and identify treatment possibilities, and integrating this data with laboratory and genomic data can produce machine learning algorithms to predict treatment outcomes.

A case study presented by Skånland describes a woman with relapsed CLL who exhausted all available treatment options. The investigators’ tests were able to trace the patient’s sensitivity to various treatments and changes in sensitivity at different times in her history of treatment response and disease progression. He identified that her CLL may have been sensitive to a combination of idelalisib and venetoclax, and that the regimen seemed effective once 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, presenting a challenge for aiming to use precision medicine to improve outcomes.

Skånland and his colleagues plan to incorporate their biomarker validation model into an ongoing precision medicine trial in Norway. “We are now performing these tests on patients who have been treated in clinical trials,” she explained, as the trials will provide more data on how well patients tolerated the treatment and how whose tolerance can be correlated with other characteristics.

CLL sequential therapies

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

While the decision tree for frontline disease offers clear stratification based on mutations and patient fitness, the recommended path for relapsed disease “looks a bit different,” Al-Sawaf said. Stratification may not always apply in the real-world clinical setting, and instead he suggested considering patient age, physical fitness, tolerability of prior regimen, genetic characteristics, treatment strategy preferred, as well as the quality and duration of previous remission.

He presented data on the effectiveness of 3 treatment sequencing strategies in relapsed/refractory CLL: retreatment with the same drug class, change in agent type, or combination of retreatment and switch.

Additionally, he noted that allogeneic stem cell transplantation is an effective option to consider in healthy patients with recurrent disease who have a TP53 mutation, but clinicians should discuss the pros and cons of various therapies with their patients when making each treatment decision. Previous lines of treatment can make patients worse enough that they are no longer good candidates for stem cell transplantation if their condition relapses.

Al-Sawaf concluded his speech by arguing for greater cooperation in collecting larger amounts of prospective data on treatment sequencing in CLL. Given the amount of treatment combinations and pathways available, as well as the heterogeneous states of drug access and reimbursement around the world, “we need to find ways to make 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.

Martin E. Berry