Why Some CLL Patients Stop Responding to Venetoclax

Alexander M. Castellino, PhD

December 05, 2018

SAN DIEGO — Acquisition of a specific mutation may explain why some patients with chronic lymphocytic leukemia (CLL) stop responding to venetoclax (Venclexta, AbbVie/Genentech). The drug has made quite a splash in this field since it was approved 2 years ago.

"With every new drug, we always have some concerns about resistant clones emerging," commented Kanti R. Rai, MD, the Feinstein Institute of Medical Research at Hosftra/Northwell and the Joel Finkelstein Cancer Foundation Professor of Medicine and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York.

"Venetoclax is an amazingly effective and powerful drug in CLL, and it has taken a relatively short time to define a resistance mechanism," he added.

This is a "relatively new drug, and not too many venetoclax failures have emerged. This is the first warning, but it is not going to adversely affect using venetoclax," he predicted.

Other experts have suggested that detecting the mutation early could be useful clinically by acting as a signal to add therapies or to change to other therapies.

The new data on the acquired mutation that leads to loss of response were presented here at the American Society of Hematology (ASH) 2018 (abstract LBA-7).

Venetoclax promotes cancer cell death by blocking B-cell leukemia/lymphoma 2 protein (BCL2), which is a key protein associated with cell survival. Patients with CLL have elevated levels of this protein, and by binding to BCL2 at the same site where other pro-BCL2 proteins bind, venetoclax prevents cell survival.

The acquired mutation Gly101Val in BCL2 occurs at the venetoclax binding site, thereby decreasing its effectiveness.

Dr Piers Blombery

"Although venetoclax is a highly effective drug for CLL, most patients eventually relapse," said lead author Piers Blombery, MBBS, of the University of Melbourne, Australia, in an ASH statement. "The mutation we have found helps to explain why venetoclax stops working in some patients. Furthermore, we have shown that in some cases, the mutation can be detected in patients' bone marrow years before clinical signs of relapse appear," he added.

Australian Study Details

Sixty-seven patients with relapsed CLL were treated with venetoclax in three early-phase clinical trials. Blombery and colleagues conducted a focused genomic evaluation in 21 patients with CLL-type progression (as opposed to those who had Richter's transformation).

Of these 21 patients, key information was provided from 15 patients. For these 15 patients, researchers had pre- and postprogression samples for analyses. The Gly101Val mutation was identified from a targeted amplicon next-generation sequencing of a panel of 33 genes recurrently mutated in lymphoid malignancies.

The Gly101Val BCL2 mutation was detected only in the postprogression samples of seven patients, suggesting that the mutation was acquired following venetoclax exposure. In four of the samples, the mutation was seen in 25% to 75% of the CLL cells; in three samples, it occurred in 1% to 5% of the CLL cells, Blombery told Medscape Medical News.

Specific droplet digital polymerase chain reaction assay detected this BCL2 variant after patients had been receiving venetoclax for 19 to 42 months, which was 25 months before overt clinical relapse.

Moreover, the Gly101Val mutation was not detected in a separate set of 400 patient samples across other hematologic malignancies; these patients had not received venetoclax.

"This is evidence that the mutation only develops during venetoclax treatment, so it is something that patients can be screened for. In patients who develop this mutation at a low level, it would be prudent for the hematologist to begin looking for other therapies to use instead," Blombery said.

However, it is unlikely that the Gly101Val BCL2 variant is the sole mechanism for resistance to venetoclax, Blombery observed. Firstly, the mutation was identified in only seven of the 15 samples. Secondly, the observation that up to 75% of the CLL cells carry the mutation implies that in the other 25% of CLL cells, resistance results from a different mechanism, even in the same patient.

For example, his team noted that one patient also had CLL subclones without Gly101Val mutation at progression. In the subclone with exclusive wild-type BCL2, BCL-xL was elevated; the one with Gly101Val mutation had minimal BCL-xL.

"This demonstrates the importance of considering multiple angles of attack with combination therapies — for example, venetoclax and rituximab [Truxima, Celltrion] — rather than relying on a single targeted agent in a disease that has multiple genomic tricks up its sleeve," Blombery said.

Concerns About Resistant Clones Emerging

"Prior to any data being available, it had been suspected that mutations in BCL2 or BCL2 family members or upregulation through other means would confer resistance to venetoclax," Jennifer A. Woyach, MD, of the Ohio State University Comprehensive Cancer Center, Columbus, told Medscape Medical News.

"However, the first report about venetoclax resistance, which was presented and published last year, did not identify these mutations, so these data are completely novel," she added.

"This has the potential to be used in the clinic," Woyach said. "We probably need data from larger groups of patients to confirm the prevalence of this mutation in patients who develop resistance to venetoclax," she added.

These data are completely novel....This has the potential to be used in the clinic. Dr Jennifer Woyach

Commenting on the study, Nadia Khan, MD, Department of Hematology-Oncology, the Fox Chase Cancer Center, Philadelphia, Pennsylvania, noted that the Gly101Val mutation was predictive of venetoclax resistance in roughly half of the resistant CLL samples tested.

"This is not a commercially available assay but may offer some insight into early resistance in the most aggressive CLL subtypes," she told Medscape Medical News.

It will be very interesting to understand whether this resistance mechanism develops in patients who have a Richter transformation, which occurs while patients are receiving treatment with venetoclax, she said.

"The ability to detect the mutation in the peripheral blood prior to the development of overt resistance offers a potential therapeutic advantage. With early detection, therapies can be changed to impact emerging resistance," Khan said.

Blombery indicated how Khan's observation may be put into clinical practice. Talking to Medscape Medical News, he provided his insights into the clinical relevance of GLY101Val BCL2 variant. "It is similar to the C481S variant that confers resistance to the BTK [Bruton tyrosine kinase] inhibitor ibrutinib [Imbruvica, Pharmacyclics], and one can use it in a similar fashion in clinical practice," he said.

Blombery provided two examples. Some patients who achieve a minimal residual disease-negative complete response with venetoclax choose to come off therapy; the presence or absence of this mutation at relapse will guide clinical management, he noted. The absence of this mutation can be a cue to rechallenge the patient with venetoclax; the presence of the mutation can provide guidance to provide an alternate treatment approach.

Additionally, because the mutation can be detected at a low level before overt clinical relapse, the presence of this mutation in patients are still taking venetoclax may signal the need to treat the patient with combination therapy, Blombery noted.

Blombery explained that, on the basis of their data, centers may include the Gly101Val BCL2 mutation into their test panel, as has been done with BTK and PLCG2 mutations, for determining resistance to ibrutinib in CLL.

Dr Blombery has disclosed no relevant financial relationships. Coauthors' disclosures are listed in the abstract.

American Society of Hematology (ASH) 2018. Abstract LBA-7, presented December 4, 2018.

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