Venetoclax Shows Impressive Activity in Relapsed/Refractory Waldenström Macroglobulinemia

Jorge Castillo, MD

Venetoclax (Venclexta) proved to be safe and highly active when used in patients with relapsed or refractory Waldenström macroglobulinemia (WM), including those who previously received BTK inhibitors and those harboring CXCR4 mutations, according to data from a phase 2 trial (NCT02677324) published in Journal of Clinical Oncology.¹

Data showed an overall response rate (ORR) in 84% (95% CI, 66%-95%) among 32 evaluable patients in the study. Additionally, the major response rate was 81% (95% CI, 63%-93%) with venetoclax, the very good partial response (VGPR) rate was 19%, the partial response (PR) rate was 61%, and the minor response (MR) rate was 3%. No patients achieved a complete response (CR) to treatment.

“Currently, the main treatment options for patients with this disease are chemotherapy or drugs known as proteasome inhibitors [PIs], in combination with monoclonal antibodies, or newer agents called BTK inhibitors,” lead study author Jorge Castillo, MD, clinical director of the Bing Center for Waldenström macroglobulinemia at Dana-Farber Cancer Institute, stated in a press release.²

“While these therapies are highly effective, they’re each associated with undesirable [adverse] effects: chemotherapy, with nausea, hair loss, fatigue, secondary leukemia, and others; BTK inhibitors, with hypertension, heart arrhythmia, and bleeding,” Castillo added. “BTK inhibitors also need to be taken indefinitely. This study sought to determine if venetoclax can be as effective as these treatments while avoiding some of their downsides.”

BCL-2, an essential regulator of the intrinsic pathway of apoptosis, is overexpressed in lymphoplasmacytic cells in patients with WM—particularly those with MYD88 mutations. Venetoclax is approved for use in patients with chronic lymphocytic leukemia (CLL) and acute myeloid leukemia. Results from a prospective phase 1 study examining venetoclax in 4 patients with WM showed that all achieved a major response to the agent.³

The prospective, multicenter phase 2 trial enrolled adult patients with a diagnosis of WM who were previously treated, had an ECOG performance score of 0 to 2, acceptable bone marrow function, creatinine clearance of at least 50 mL/min, and adequate hepatic function.

Patients with central nervous system involvement, active human immunodeficiency virus, hepatitis B infection, or hepatitis C infection were excluded. Other exclusion criteria include concurrent therapy for other cancer, or those who are pregnant or breastfeeding.

The first 6 patients enrolled to the trial were administered oral venetoclax at a once-daily dose of 200 mg for 1 week, followed by 400 mg daily for 1 week, and then 800 mg daily for 2 years. The remaining patients received venetoclax at a daily dose of 400 mg for 1 week, followed by 800 mg daily for 2 years. Three days prior to starting venetoclax, all patients received allopurinol at a once-daily dose of 300 mg, plus 2-liter hydration per day for tumor lysis prophylaxis. Allopurinol was continued for 4 weeks, and if oral hydration was not optimal, patients went on to receive 2 L of intravenous saline prior to the first dose of venetoclax.

The primary objective of the research was to determine the ORR with venetoclax, including the MR, PR, VGFR, and CR. Secondary objectives comprised major response rate, time to response, duration of response, progression-free survival (PFS), time to next treatment (TTNT), and safety.

The median age among the 32 study participants at the time of venetoclax initiation was 66 years (range, 39-80), with a median age of 58 years (range, 38-72) at the time of their WM diagnosis. All 32 patients had MYD88 L265P mutation and 53% had a CXCR4 mutation. Thirty-eight percent of patients had a high-risk International Prognostic Scoring System for Waldenström Macroglobulinemia score, 38% had a low-risk score, and 25% had an intermediate-risk score.

The median number of prior therapies received was 2 (range, 1-10), with 38% of patients having received at least 3 prior therapies. The most common prior therapies received included anti-CD20 monoclonal antibodies (88%), PIs (66%), BTK inhibitors (50%), and chemotherapy (47%). Notably, 34% of patients were refractory to their most recent therapy. Of the 11 patients who were refractory, 4 were refractory to PI-based regimens, 3 to BTK inhibitors, 2 to single-agent CD20 monoclonal antibodies, 1 to bendamustine (Bendeka) and rituximab (Rituxan), and 1 to a PI3K inhibitor.

Sixty-six percent of patients completed all therapy cycles, and received a median number of 25.5 cycles of treatment (range, 1-26). Thirty-four percent of patients did not complete therapy due to several factors, including disease progression and initiation of new treatment (n = 6), inability to swallow pills (n = 1), protocol noncompliance (n = 1), nonresponse (n = 1), issue related to medical insurance coverage (n = 1), and persistent pancytopenia (n = 1).

Additional data indicated that the ORR achieved with venetoclax was lower in those with refractory vs relapsed disease, at 60% vs 95%, respectively (P = .03). The ORR with the agent was also lower in those who received 3 or more prior lines of therapy vs fewer than 3 lines, at 63% vs 95%, respectively (P = .04). Neither prior BTK inhibitor exposure nor positive CXCR4 mutational status was noted to be linked with a lower ORR with venetoclax. However, major response rate was found to be significantly lower in those with refractory vs relapsed disease, at 50% vs 95%, respectively (P = .007).

The median time to major response was 5.1 months (95% CI, 4.7-8.2), and the median time to MR was 1.9 months (95% CI, 1.1-2.1). Moreover, prior exposure to BTK inhibitors was associated with a longer time median time to MR vs those who were not previously exposed, at 4.5 months and 1.4 months, respectively (P < .001).

The median time to major response was also longer in those with prior BTK inhibitor exposure vs those who did not receive those agents, at 8.5 months vs 4.4 months, respectively (P < .001); this was also the case for those who received 3 or more prior lines of therapy vs fewer lines, at 10.8 months vs 4.8 months, respectively (P = .03), and those with refractory vs relapsed disease, at 8.2 months vs 4.7 months, respectively (P = .007).

With a median follow-up time of 33 months (range, 24-38), the median PFS was 30 months (95% CI, 27-38). The 12- and 24-month PFS rates were 83% (95% CI, 64%-93%) and 80% (95% CI, 60%-90%), respectively. The only factors associated with a worse PFS were refractory disease and having received at least 3 prior lines of therapy.

The median DOR for the 19 patients who achieved a PR with treatment was 34 months (95% CI, 29-37); it was 37 months (95% CI, 10–not evaluable) in those who experienced a VGPR. Additionally, 1 patient who had a MR with venetoclax, the median DOR was 9 months.

A total of 12 patients began a new therapy following venetoclax, and the median TTNT had not yet been reached. The 30-month rate without subsequent therapy was 76% (95% CI, 57%-88%); this rate was lower for those with refractory disease vs relapsed disease, at 60% (95% CI, 25%-83%) vs 85% (95% CI, 60%-95%), respectively (P = .006). The overall survival rate at 30 months was 100% (95% CI, 89%-100%).

Twenty-two percent of patients required a dose reduction for reasons including neutropenia (n = 2), fatigue (n = 1), diarrhea (n = 1), multiple grade 2 events (n = 1), and dosing noncompliance (n = 1).

Grade 2 or higher adverse effects (AEs) occurred in 94% of patients who received venetoclax. However, only 22% of patients experienced grade 4 AEs, which included neutropenia (n = 6), and febrile neutropenia (n = 1). One patient with generalized lymphadenopathy (3.7 cm), splenomegaly (27 cm), and leukocytosis (59 K/uL), reported a laboratory tumor lysis syndrome (TLS) that was managed in the inpatient setting; the patient responded to intravenous fluids and 1 dose of rasburicase (Elitek).

The study authors found the results of the trial encouraging for venetoclax’s efficacy for previously treated WM. They wrote future studies are warranted on combination of venetoclax with anti-CD20 monoclonal antibodies or BTK inhibitors.

“The precise sequencing of BTK and BCL-2 inhibitors in WM remains to be clarified, and further study will be required to address this point,” the study authors concluded. “In CLL, resistance to venetoclax post–BTK [inhibitor] exposure has been observed, whereas BTK [inhibitors] appeared effective after venetoclax. Our results suggested similar levels of efficacy for venetoclax for either BTKi-naïve or previously exposed patients, thereby offering a meaningful, active treatment option for those previously exposed to a BTK [inhibitor].”

References

1. Castillo JJ, Allan JN, Siddiqi T, et al. Venetoclax in previously treated Waldenström macroglobulinemia. J Clin Oncol. 2022;40(1):63-71. doi:10.1200/JCO.21.01194
2. Venetoclax shown to benefit patients with Waldenström macroglobulinemia, including some who relapsed after previous therapy. News release. Dana-Farber Cancer Institute; November 18, 2021. Accessed January 18, 2022. https://bit.ly/3rt1Zj1
3. Davids MS, Roberts AW, Seymour JF, et al. Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma. J Clin Oncol. 2017;35(8):826-833. doi:10.1200/JCO.2016.70.4320