Dr Wiestner on an Extended Follow-Up Study of Resistance Mutations With Acalabrutinib in CLL

Adrian Wiestner, MD, PhD, senior investigator, Lymphoid Malignancies, lead, Laboratory of Lymphoid Malignancies, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, discusses an extended follow-up investigation into resistance mutations in patients with chronic lymphocytic leukemia (CLL) who were treated with acalabrutinib (Calquence). 

. This trial investigated the use of acalabrutinib in patients with treatment-naive CLL or small lymphocytic lymphoma (SLL) who presented with 17p deletion, 

mutations, as well as those with relapsed/refractory CLL/SLL.

This phase 2 clinical trial was a single-center exploration that studied the efficacy of acalabrutinib—a second-generation BTK inhibitor that offers a potentially favorable adverse effect (AE) profile, Wiestner begins. Notably, with a median follow-up of 6.5 years, the trial demonstrates treatment adherence, he states. The primary objective of this study is to determine the reasons for patient progression, Wiestner elucidates.

BTK inhibitor resistance often correlates with mutations in BTK that affect the cysteine residue that is crucial for drug attachment, or downstream mutations in 

—an immediate signaling molecule, he expands. The study revealed that these mutations are present in approximately 80% of patients with CLL who progress, underscoring the dominant mechanism of resistance to BTK inhibitors, Wiestner explains. This clinical insight sheds light on potential CLL management strategies, he notes.

The findings from the phase 2 trial indicate a need to retarget the same signaling pathway affected by these mutations, Wiestner continues. Noncovalent BTK inhibitors, exemplified by pirtobrutinib (Jaypirca), have emerged as viable treatment options for patients with disease harboring 17p deletions, 

 mutations, he states. Additionally, BTKdegraders utilizing the cellular proteasome system to degrade BTK are under investigation, Wiestner adds.

Understanding mechanisms of BTK inhibitor resistance, especially through comprehensive sequencing approaches, is important for informing the development of targeted and effective treatment strategies for patients with CLL, he concludes.

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Adrian Wiestner, MD, PhD, sheds light on resistance mutations in patients with chronic lymphocytic leukemia who were treated with acalabrutinib.

Adrian Wiestner, MD, PhD, Senior Investigator, Laboratory of Lymphoid Malignancies, National Institutes of Health, National Heart, Lung, and Blood Services, discusses findings from the phase III HELIOS trial, which explored the addition of ibrutinib (Imbruvica) to bendamustine and rituximab (BR) for patients with relapsed/refractory chronic lymphocytic leukemia (CLL).

In the study, 578 patients with relapsed/refractory CLL were treated with BR plus ibrutinib (n = 289) or placebo (n = 289). BR was administered for a maximum of 6 cycles. After this point, patients could continue to receive ibrutinib until disease progression.

At a median follow-up of 17.2 months, the median progression-free survival (PFS) was not reached in the ibrutinib arm compared with 13.3 months with BR alone (HR = 0.203; 95% CI, 0.150-0.276; 

 <.0001). The objective response rate was 82.7% in the ibrutinib arm versus 67.8% in the control group (

These were exciting results, Wiestner notes, since the addition of a targeted therapy improved outcomes seen with chemotherapy. The dramatic improvement in PFS was achieved by maintaining treatment with ibrutinib, Wiestner believes, an approach that could be labeled either maintenance or continuation therapy.

Researchers are now questioning whether another therapy needs to be added to an agent that targets the B-cell signaling pathway, Wiestner suggests. It is unclear whether combination approaches have significantly improved outcomes over single-agent ibrutinib. As a result, the treatment paradigm in CLL could shift toward the use of monotherapy, as opposed to combination strategies.

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Adrian Wiestner, MD, PhD, National Institutes of Health, National Heart, Lung, and Blood Services, discusses findings from the phase III HELIOS trial, which explored the addition of ibrutinib to bendamustine and rituximab for patients with relapsed/refractory chronic lymphocytic leukemia.


Dr. Wiestner Discusses Findings From the Phase III HELIOS Trial

Adrian Wiestner, MD, PhD, Senior Investigator, Laboratory of Lymphoid Malignancies, National Institutes of Health, National Heart, Lung, and Blood Services discusses the findings of the RESONATE II trial, which looked at chlorambucil versus ibrutinib as first-line therapy in patients older than 65 with chronic lymphocytic leukemia (CLL).

Preliminary results from the trial show an improved overall survival and overall response rate with ibrutinib when compared to chlorambucil. Given all the ibrutinib data that has already been presented, those results are not surprising, but a full understanding cannot be determined until all the data is released, says Wiestner.

Even without the complete data, it is clear that studies like RESONATE II demonstrate a shift in the future treatment of CLL, says Wiestner.

Single-agent, targeted therapies like ibrutinib may now be the backbone of therapy for CLL patients.

The question will now become how far can a single agent go, and what the right combinations are to make the best of it, says Wiestner.

Adrian Wiestner, MD, PhD

Articles

Dr Wiestner on an Extended Follow-Up Study of Resistance Mutations With Acalabrutinib in CLL

Dr. Wiestner Discusses Findings From the Phase III HELIOS Trial

Dr. Adrian Wiestner on RESONATE II Trial