Venetoclax Induces Notable ORR But Short PFS in High-Risk Mantle Cell Lymphoma

Yazeed Y Sawalha, MD

Venetoclax (Venclexta), alone or in combination with a BTK inhibitor, improved overall response rate (ORR) in patients with pretreated, high-risk mantle cell lymphoma (MCL), according to findings from a retrospective study. However, investigators concluded that the BCL-2 inhibitor was associated with short durations of progression-free survival (PFS).¹

In high-risk patients with relapsed MCL, most of whom received prior BTK inhibitor treatment, venetoclax alone or in combination resulted in an ORR of 40% and median PFS of 3.7 months (95% CI, 2.3-5.6) at a median follow-up from venetoclax initiation of 16.4 months. The median overall survival (OS) was 12.5 months (95% CI, 6.2-28.2). At 2 years, the PFS rate was 13.8% (95% CI, 6.9%-23.1%) and the OS rate was 37.1% (95% CI, 24.0%-50.2%).

Combination therapy resulted in longer median PFS and OS compared with venetoclax monotherapy, but that did not reach statistical significance (HR 0.32; 95% CI, 0.14-0.70; P = .007).

In a multivariable analysis, having a high-risk Mantle Cell Lymphoma International Prognostic Index (MIPI) score at diagnosis was associated with poorer PFS (HR, 2.56; 95% CI, 1.43-4.65; P = .002). High-risk MIPI score prior to venetoclax (HR, 2.36; 95% CI, 1.17-5.03; P = .022) and disease relapse or progression within 24 months of diagnosis (HR, 3.81; 95% CI, 1.73-8.85; P = .001) were both associated with poorer OS.

“Venetoclax resulted in good ORR but short PFS in high-risk patients with MCL and may have a better role in earlier lines of treatment and/or in combination with other active agents,” investigators concluded.

MCL is a rare, aggressive B-cell non-Hodgkin lymphoma. Frontline treatment typically consists of chemoimmunotherapy with autologous stem cell transplantation in eligible patients and/or maintenance therapy with rituximab (Rituxan). Most patients respond to frontline

chemoimmunotherapy, but relapses are common. BTK inhibitors are the preferred second-line treatment option, but the median PFS with these drugs is typically less than 2 to 3 years, and outcomes following progression are typically poor.

In a phase 1 trial of venetoclax monotherapy in patients with relapsed/refractory B-cell non-Hodgkin lymphoma, the ORR was 75% with a median PFS of 14 months in 28 patients with MCL. Moreover, investigators found the agent to be well tolerated.^2,3

In this retrospective analysis, investigators collected clinical, laboratory, pathologic, and outcome data on 81 patients aged 18 years or older who were treated for relapsed/refractory MCL at 12 US medical centers from January 1, 2010, to November 1, 2019. They then determined the MIPI score for each patient.

The median age at diagnosis was 64 years (range, 38-87), 78% of patients were male, and 95% had stage III/IV disease. Sixteen percent of patients had a low MIPI score, 34% were intermediate, and 49% were high.

At baseline, 61% of patients had a Ki-67 score greater than 30%. Twenty-nine percent of patients had blastoid or pleomorphic histology, 34% had complex karyotype, and 49% had TP53 alterations. Investigators said these data suggest that a significant proportion of patients had high-risk features.

The MIPI score was low, intermediate, and high in 22%, 25%, and 53% of patients, respectively, prior to venetoclax initiation. Seventy-six percent had Ki-67 expression greater than 30%, 45% had blastoid or pleomorphic histology, 36% had complex karyotype, and 33% had TP53 alterations.

About half of patients (51%) received intensive chemotherapy, defined as high-dose cytarabine and/or autologous hematopoietic cell transplantation (HCT) in first remission, 43% received less-intensive chemotherapy, and 6% did not receive chemotherapy. Twenty-six (32%) patients received autologous HCT in first remission and 27 (36%) received rituximab maintenance after first-line treatment. The median duration of first remission was 1.6 years (range, 0.04-6.4).

Patients received a median of 3 (range, 1-8) therapies prior to venetoclax. The ORR to the last treatment prior to venetoclax was 45%. Fifty-five percent of patients had refractory or progressive disease to the last therapy before venetoclax.

The ORR with a BTK inhibitor prior to venetoclax was 66% including a complete response (CR) rate of 20%. Treatment with the BTK inhibitor lasted for a median of 6 months (range, 0.5-69); 82% of patients discontinued for progressive disease and 18% due to toxicity.

Fifty (62%) patients received venetoclax monotherapy, and the median time to venetoclax initiation from diagnosis was 3.9 years (range, 0.2-17.8). Thirty-one (38%) patients received the agent in combination with a BTK inhibitor (20%), an anti-CD20 monoclonal antibody (14%), or others (5%).

Eleven (16%) patients had CR with venetoclax, 16 (24%) had partial response (PR), 7 (10%) had stable disease, and 33 (49%) had progressive disease. Ten patients were known to have TP53 mutations prior to starting venetoclax and 7 of those patients were evaluable for response. The ORR in this population was 28.6% with 1 CR, 1 PR and 5 cases of progressive disease.

Receiving more than 3 lines of treatment prior to venetoclax was the only factor significantly associated with venetoclax response (odds ratio, 0.26, 95% CI, 0.08-0.90; P = .033) in univariable logistic regression analysis.

Ten of 16 patients who received venetoclax plus a BTK inhibitor also received prior treatment with a BTK inhibitor. The ORR for the combination was 33% in this group.

Investigators found that those who had a CR with venetoclax did better than those who had PR. The 2-year PFS rate was 57.7% (95% CI, 22.1%-81.9%) vs 11.9% (95% CI, 0.9%-38.4%), respectively. The 2-year OS was 85.7% (95% CI, 33.4%-97.9%) vs 35.9% (95% CI, 9.5%-64.0%), respectively.

Tumor Lysis Syndrome Is a Concern

Most patients (61%) had low or intermediate (32%) risk for tumor lysis syndrome (TLS). Nonetheless, 10 (12.3%) of patients developed laboratory TLS, including 3 (3.7%) with clinical TLS.

The first TLS event occurred at a venetoclax dose of 20 mg (n = 7) and at 50 mg venetoclax in 2 patients. Seven patients who received venetoclax monotherapy developed TLS as did 3 who received venetoclax in combination.

Investigators noted that patients developed TLS despite mitigation strategies such as stepwise dose ramp-up (89% of patients who developed TLS started with the 20 mg dose), prophylactic intravenous fluids and allopurinol in most patients, and inpatient monitoring for 53% of patients

“TLS remains an important risk with venetoclax in relapsed MCL,” investigators wrote. “Even patients at low risk developed TLS highlighting the limitations of the criteria currently used to define TLS risk categories in MCL and the importance of close monitoring of all patients with MCL who initiate treatment with venetoclax.”

References

1. Sawalha Y, Goyal S, Switchenko JM, et al. A multicenter analysis of the outcomes with venetoclax in patients with relapsed mantle cell lymphoma. Blood Adv. Published online February 21, 2023. doi:10.1182/bloodadvances.2022008916
2. 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
3. Davids MS, Roberts AW, Kenkre VP, et al. Long-term follow-up of patients with relapsed or refractory non-Hodgkin lymphoma treated with venetoclax in a phase 1, first-in-human study. Clin Cancer Res. 2021;27(17):4690-4695. doi:10.1158/1078-0432.CCR-20-4842