Frontline Ibrutinib/Venetoclax Elicits Responses in Waldenström Macroglobulinemia, But Has Safety Concerns

The combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) produced rapid and deep responses in previously untreated patients with Waldenström macroglobulinemia but there was a higher-than-anticipated rate of ventricular arrhythmia that prompted stopping treatment, according to data from a prospective phase 2 trial (NCT04273139) presented during the 2022 ASH Annual Meeting.

In the overall patient population (n = 45), the regimen elicited an overall response rate (ORR) of 100%; this included a very good partial response (VGPR) rate of 40% (n = 18), a partial response (PR) rate of 53%, and a minor response rate of 7%. Notably, there would need to be 19 VGPRs for the study to meet its primary end point. The median time to response (TTR) was 1.9 months.

In those who harbored CXCR4 mutations, the time to response was faster and the VGPR rate was higher than what has been observed with single-agent ibrutinib in the first-line setting, according to lead study author Jorge J. Castillo, MD, clinical director of Bing Center for Waldenström Macroglobulinemia at Dana-Farber Cancer Institute, Boston, MA. In those with CXCR4 mutations and those with CXCR4 wild-type disease, the median TTR was 1.9 months (log-rank, P = .28).

Additionally, in the subset of patients with CXCR4 wild-type disease, the doublet elicited an ORR of 100%, which included a VGPR of 50% (n = 14), a PR of 46%, and a minor response of 4%; in those with CXCR4 mutations, the ORR was also 100%, and included a 24% VGPR (n = 4), a 65% PR, and a 12% minor response rate (P = .15).

“BTK inhibitors are probably one of the most effective agents we have to treat patients with Waldenström,” Castillo said in a presentation of the data. “These therapies give us an indefinite duration of therapy. BCL-2 antagonists have been used in the relapse setting; they have provided a high degree of efficacy; however, the duration of therapy is a little unclear at this time.”

Castillo noted that past study findings have shown that combining the BTK inhibitor ibrutinib with the BCL-2 antagonist, venetoclax, has been shown to be safe and effective in patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). As a result, the investigators wanted to determine whether similar outcomes could be achieved in those with Waldenström macroglobulinemia.

To this end, the study authors conducted a single-arm, multicenter phase 2 prospective trial with the goal of identifying a treatment regimen that is free from chemotherapy and induces deeper responses. 

The phase 2 study enrolled 45 patients with a median age of 67 years (range, 39-81); 67% of patients were male. Participants were placed on a 24-cycle treatment regimen. Cycle 1 consisted of oral ibrutinib given at a daily (QD) dose of 420 mg. Ibrutinib was continued into cycle 2, with a ramp-up regimen of oral venetoclax, given at 100 mg, 200 mg, and 400 mg QD. In cycles 3 to 24, patients received 420 mg of ibrutinib and 400 mg of venetoclax QD.

At a median follow-up of 11 months, the estimated 12-month progression-free survival (PFS) was approximately 92%. The estimated overall survival rate was approximately 95%.

There were 7 adverse effects (AEs) of grade 4 or 5, with most AEs being grade 2 and 3. The most common grade 2 AEs were muscle/joint pain (n = 14) and reflux (n = 10). The most common grade 3 AE was neutropenia (n = 10).

Castillo noted that there was only 1 patient who experienced disease progression, and that person had achieved a VGPR after 7 cycles. Two deaths occurred due to ventricular arrythmia. As Castillo explained, patients enrolled on the trial experienced high-than-expected rates of ventricular arrythmia.

This finding prompted the investigators to conclude treatment earlier than they had intended.

Castillo noted that the investigators are continuing follow-up of the patients who have now been off therapy since March 2022, when another patient experienced a grade 2 cardiac-related event during a stress test.

However, Castillo said there is still value in continuing to study the combination.

“It could be that these patients really had a higher risk profile. Most of these patients were older individuals over 65 [years]; they were men, they had other cardiac risks, including hypertension, prior history of arrythmias, prior history of coronary artery disease. So maybe it has something to do with that,” Castillo explained. “There is always the idea in which ibrutinib and venetoclax can actually interact with each other and increase the serum levels, and that might induce these arrhythmias … But again, as of today, all that is just pure hypothesis. Now, I think what we see from these experiments, is that the combination is actually very powerful. So I think there is value on continuing [and] evaluating concurrent BTK and BCL2 inhibition.”

Castillo was asked to clarify the use of “very powerful,” as 1 of the moderators noted that there were no complete responses associated with treatment and a VGPR rate of approximately 40%, and why those findings seen in CLL trials perhaps did not translate to Waldenström macroglobulinemia. 

“That was something that we were hoping to see,” Castillo said. “But again, we [are] still unclear if complete responses should be the outcome that we should aim for in these patients. Now I want to remind everybody here that pretty much nobody completed their 24 months of therapy. We had about 40% of patients complete at least a year, [and] about 60% of patients did not complete a year of therapy. So these are the responses that I'm providing at this time, [which] is a median time of [venetoclax and ibrutinib] exposure for about 11 months. So there is always a possibility that we can get into deeper responses with longer treatments.”

Reference

Castillo JJ, Sarosiek S, Branagan R, et al. Ibrutinib and venetoclax in previously untreated Waldenström macroglobulinemia. Blood. 2022;140(suppl 1):564-565. doi:10.1182/blood-2022-155610