CLL Research: Patients with CLL Resistant to Venetoclax; BTK Inhibitors Effective Next?

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CLL Research: Patients with CLL Resistant to Venetoclax - Are BTK Inhibitors Effective Next Option?

Professor John Seymour, MBBS, Ph.D., and his team at Peter MacCallum Cancer Centre, in Melbourne, Australia, recently published the results of a study in blood®, a publication of the American Society of Hematology. The article entitled BTK Inhibitor Therapy is Effective in Patients with CLL Resistant to Venetoclax. Dr. Seymour is a CLL specialist and serves as Director of Cancer Medicine and Director of Haematology at “Peter Mac.” Professor Seymour is a frequent presenter on the latest in CLL at multiple symposia and conferences.

Highly effective Bruton’s Tyrosine Kinase inhibitors (BTKis) such as ibrutinib (Imbruvica®), acalabrutinib (Calquence®), and the investigational BTKi zanabrutinib (Brukinsa®), and the B-cell lymphoma-2 inhibitor, venetoclax have transformed the treatment landscape for chronic lymphocytic leukemia (CLL). Results from multiple clinical trials show venetoclax to be an effective salvage therapy for patients whose disease progresses while being treated with a BTKi. Data on follow-on BTKi treatment in patients with CLL resistant to venetoclax is limited.

Background - Are BTK Inhibitors Effective for Patients with CLL Resistant to Venetoclax?

Venetoclax effectively treats relapsed or refractory (R/R) chronic lymphocytic leukemia, including patients with traditional adverse prognostic indicators. Traditional unfavorable prognostic indicators include deletion 17p, deletion 11q, unmutated IGHV, and mutated TP53. These unfavorable indicators are referred to as “traditional” because they had a more significant impact on outcomes before the introduction of targeted therapies when only chemoimmunotherapy was an option.

Venetoclax-based therapies frequently result in deep remissions, including undetectable measurable residual disease (uMRD). Unfortunately, progression on long-term treatment with venetoclax is common. Venetoclax resistance mechanisms include mutations of BCL2 such as the “Gly101Val”; and upregulation of other pro-survival proteins (through signaling within the microenvironment of the CLL cell). These pro-survival proteins may be interrupted by B-cell receptor inhibitors such as the BTKis and the phosphoinositide 3-kinase (PI3K) inhibitors such as idelalisib (Zydelig®), duvelisib (Copiktra®), and umbralisib (UKONIQ™). The graphic below depicts how the Gly101Val mutation blocks venetoclax.

Methods – Study Shows After Disease Progression on Venetoclax; BTKi Therapy is Effective

In this study, investigators retrospectively reviewed data from 23 consecutive patients with R/R CLL treated at the Royal Melbourne Hospital and Peter MacCallum Cancer Centre between September 2011 and September 2019. These patients received BTKi therapy for CLL after developing disease progression on venetoclax. These patients had participated in one of four clinical trials. These patients received doses of venetoclax ranging from 100mg a day to 600mg a day, with the majority receiving the standard dosage of 400mg a day. Seven patients received concurrent rituximab as part of their clinical trial. Disease progression occurred during continuous venetoclax therapy in 22 patients and during venetoclax re-treatment in one patient. The re-treated patient had stopped venetoclax after attaining a complete remission and resumed venetoclax on subsequent disease progression. Twenty-one patients received ibrutinib 420mg daily, and two patients received zanabrutinib 160mg twice a day.
The table below shows the pre-BTKi patient characteristics for the 23 patients with CLL resistance to venetoclax:

Results - Study Shows After Disease Progression on Venetoclax; BTKi Therapy is Effective

The median age when patients started a BTKi was 72 years (range, 50-89). The median time from diagnosis to initiating venetoclax (19 patients had data) was eight years (range, 3-19). The median time from diagnosis to starting a BTKi was 11 years (range, 5-22). This cohort was heavily pre-treated with a median number of prior treatments of four (range, 2-9). No patient had previously received a BTKi or PI3Ki drug. Twenty-one (91%) had received the chemoimmunotherapy combination of fludarabine, cyclophosphamide, and rituximab previously.

The median duration of remission before patients experienced disease progression on venetoclax was 29 months (range, 1-59). The overall response rate to venetoclax was 91% (21 patients), with 15 experiencing partial response (PR) and 6 reaching complete response (CR), including four (17%) getting to uMRD.

All patients had ceased venetoclax due to disease progression on venetoclax. Eighteen patients experienced a relapse of their CLL, and five developed Richter’s Transformation (RT). Of the five RT patients, three developed the more common diffuse large b-cell lymphoma (DLBCL), and two cases were the Hodgkin variant of RT. Each patient who developed RT received salvage chemotherapy first. Two patients received autologous stem cell transplants (SCT). All RT patients achieved durable control of their transformed disease, and it was CLL progression that triggered the BTKi treatment. Clinicians found the Gly101Val mutation at the time of progression in 8 (42%) of 19 patients tested.

The median interval between stopping venetoclax and starting a BTKi was one month (range, <1-11) for patients who had disease progression on venetoclax. The median time between stopping venetoclax in patients treated for Richter’s was 25 months (range, 18-39).

Twenty patients (91%) achieved objective responses to BTKi treatment with 16 PRs and 4 CRs. The median progression-free survival (PFS) after starting BTKi treatment was 33 months (range, 2-53). At a median follow-up of 33 months, 11 patients (48%) remained on BTKis, including one patient who interrupted BTKi treatment to undergo allogeneic SCT. The median overall survival from BTKi initiation was 42 months. There were eight deaths in this heavily pre-treated group.

Patients who had achieved remissions on venetoclax greater than 24-months showed a slightly longer PFS on BTKi treatment of 34 months compared to only 24 months in those with venetoclax induced remissions of less than 24-months. All eight patients who achieved CR/uMRD on venetoclax were in the subgroup that experienced longer PFS from BTKi therapy.

Conclusions

These data indicate that BTKi therapy is an effective option for patients with heavily pre-treated, high-risk CLL after disease progression on venetoclax. This benefit includes patients with prior Richter’s in remission and those with CLL harboring the BCL2 Gly101Val mutation.

This retrospective study is promising, but prospective clinical trials are needed to validate therapeutic sequencing in the age of novel targeted drug therapies.

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