iwCLL 2021 | Genomic profiling and treatment decisions in the non-chemotherapy era
Romain Guièze, MD, of Université Clermont Auvergne, Clermont-Ferrand, France, gives an overview on his presentation at iwCLL 2021, on the topic of genomic profiling and treatment decisions in the non-chemotherapy era. Prof. Guièze explains that multiple studies have shown improved progression-free survival (PFS) with new targeted therapies in comparison to chemoimmunotherapy. Nevertheless, Prof. Guièze reports that it is essential to determine TP53 and IgHV mutation status, as patients with IgHV mutations have been shown to have greater benefit with obinutuzumab plus venetoclax therapy than ibrutinib therapy. On the contrary, obinutuzumab plus venetoclax therapy in patients with mutant TP53 has been associated with a shorter PFS. Finally, Prof. Guièze emphasizes the importance of genomic profiling in relapsed patients, in order to detect potential mutations in the BTK and/or BCL2 genes. This interview took place at the 19th International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Biennial Meeting, held virtually in 2021.
Transcript (edited for clarity)
My presentation was on genomic profiling and its potential impact on treatment decision. The first we know in CLL that TP53 alteration, including 17p deletion and TP53 mutation together with IgHV unmutated status, have an adverse impact on patient outcome in the era of chemotherapy. But this factor are still important in the era of new drugs. So, we have in CLL targeted therapy, including BTK inhibitor and BCL-2 inhibitor, venetoclax...
My presentation was on genomic profiling and its potential impact on treatment decision. The first we know in CLL that TP53 alteration, including 17p deletion and TP53 mutation together with IgHV unmutated status, have an adverse impact on patient outcome in the era of chemotherapy. But this factor are still important in the era of new drugs. So, we have in CLL targeted therapy, including BTK inhibitor and BCL-2 inhibitor, venetoclax. And over the last three years, we have multiple study that have demonstrated that new drugs, including acalabrutinib or ibrutinib or venetoclax, are associated with a better PFS compared to chemoimmunotherapy. But this PFS benefit is really clear for patient with adverse genomic factor, but less clear for patient with favorable genetic markers, such as mutated IgHV or normal FISH analysis. So, genomic profiling can help if you want to give chemoimmunotherapy, you have to check that the patient has no adverse genetic factor.
And another important role of genetic factor is whether or not it can predict or can be associated with a differential response to BTK inhibition versus BCL-2 inhibition. And we know for example, that IgHV status has no impact in frontline in patient treated with ibrutinib. While IgHV mutated has positive impact on PFS when patients are treated by frontline obinutuzumab plus venetoclax. So, IgHV can be relevant for choosing between ibrutinib or venetoclax-based therapy. And notably the combination of obinutuzumab and venetoclax, that is a time-limited regimen is a very effective combination in a patient with mutated IgHV.
So finally, we also have a differential impact of the TP53 mutation or 17p deletion. And for example, we know that the continuous treatment by BTK inhibitors, such as ibrutinib in the frontline setting is efficient whether the patient have TP53 mutation or not. While in the patient treated with the frontline of obinutuzumab plus venetoclax, the patient with TP53 alteration have a clearly shorter PFS. So, this suggests that a continuous treat treatment with ibrutinib is maybe a better option than a frontline treatment with a time-limited approach such as obinutuzumab-venetoclax.
So finally, we also talked about the strategy for the patient at relapse, and again, genomic features are very important and they can help to assess the mechanisms of resistance. For example, the resistance to BTK inhibitor involve BTK mutation, PLC gamma 2 mutation and resistance to the BCL-2 inhibitor involved BCL-2 mutation, and also 1q, that is the MCL1 locus, amplification. And checking with another patient that has been previously exposed to one of these drugs, has the resistant mutation or alteration is very important and may help for choosing or for switching the drug class in patients who presented with resistant mutation.
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Disclosures
Romain Guièze, MD, discloses links to Janssen, Roche, Amgen, Astrazeneca and Abbvie.
