Zanubrutinib Plus Obinutuzumab/Venetoclax Associated With Durable uMRD4 Outcomes in Treatment-Naive CLL

Treatment with the combination of zanubrutinib (Brukinsa), obinutuzumab (Gazyva), and venetoclax (Venclexta; BOVen) increased the likelihood of achieving undetectable minimal residual disease (uMRD) levels in the peripheral blood and bone marrow among patients with treatment-naive chronic lymphocytic leukemia (CLL), according to long-term follow-up findings from a phase 2 trial (NCT03824483). 1

These results, which were presented at the 2024 ASH Annual Meeting, also showed that retreatment with zanubrutinib plus venetoclax induced responses among patients with relapsed CLL and was associated with peripheral blood uMRD achievement in patients who had optimal decreases in peripheral blood MRD levels after receiving the full dose of venetoclax for 1 month.

At a median follow-up of 57 months (range, 4-63+), 96% of evaluable treatment-naive patients (n = 50) had MRD levels lower than 10–4 per flow cytometry (uMRD4) in the peripheral blood at end of treatment (EOT) or as their best MRD level. Moreover, 92% of patients had uMRD4 in both the peripheral blood and the bone marrow, meeting the trial’s primary end point. All patients in the latter group met the prespecified treatment discontinuation criterion and discontinued therapy after a median of 10 months (interquartile range, [IQR], 8-12). uMRD levels were first observed in the peripheral blood at 2, 4, 6, and 8 months in 2%, 26%, 53.1%, and 77.6% of patients, respectively.

Phase 2 Trial Design and Prior Findings

The multicenter, investigator-initiated phase 2 trial enrolled patients with previously untreated CLL/SLL requiring treatment per International Workshop on CLL (iwCLL) guidelines. Eligible patients needed to have an ECOG performance status of 0 to 2, an absolute neutrophil count of at least 1,000 cells/µL, and a platelet count of at least 75,000 µL, provided that platelet counts were attributed to CLL.

Patients received zanubrutinib at 160 mg twice daily; obinutuzumab at 1000 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycles 2 through 8; and venetoclax ramp-up dosing to a target dose of 400 mg daily starting on cycle 3. The BOVen regimen was administered for a minimum of 8 cycles and a maximum of 24 cycles. Patients with uMRD in the blood and marrow discontinued treatment.

Patients with relapsed CLL following initial treatment with the BOVen regimen received venetoclax ramp-up dosing to a target dose of 400 mg daily in combination with zanubrutinib at 160 mg twice daily for 12 to 24 cycles. Retreatment was discontinued after 12 cycles if patients achieved uMRD4 in the peripheral blood and bone marrow. The protocol-defined retreatment criteria were as follows: MRD levels of at least 1% with characteristic phenotype of CLL in the peripheral blood confirmed at least 28 days later; or increased lymph node levels, spleen size, or extramedullary CLL levels confirmed histologically.

The primary cohort (n = 39) was enrolled between March 2019 and October 2019. The expansion cohort (n = 13) was enrolled between July 2020 and April 2021.

Previously reported findings from the phase 2 trial showed that at a median follow-up of 25.8 months (IQR, 24.0-27.3), 89% (95% CI, 75%-97%) of evaluable patients (n = 37) achieved uMRD in both the blood and bone marrow, meeting the prespecified criteria to discontinue treatment after a median of 10 cycles (IQR, 8-12).2 After a median of 15.8 months (IQR, 13.0-18.6) of post-treatment surveillance, 94% of those 33 patients had uMRD.

Additional Long-Term Efficacy Data

At median follow-up, patients had a median age of 62 years (range, 23-77), the male: female ratio was 3:1, 71% of patients (n = 52) had unmutated/germline IGHV, and 17% of patients had TP53 mutations and/or 17p deletions. 1

Consistent with previously reported findings, investigators showed that a 400-fold reduction in peripheral blood MRD levels (ΔMRD400) per immunosequencing at cycle 5 day 1 (after 1 month of receiving venetoclax at 400 mg) was the optimal cutoff to predict bone marrow uMRD4 levels within 8 months. Among patients who achieved ΔMRD400 (n = 21), 100% had bone marrow uMRD within 8 months, with a median time to bone marrow uMRD of 6 months (IQR, 6-6), and a median time on therapy of 8 months (IQR, 8-10). Conversely, among patients who did not achieve ΔMRD400 (n = 14), 21% had bone marrow uMRD within 8 months, with a median time to bone marrow uMRD of 11 months (IQR, 10-15.5), and a median time on therapy of 13 months (IQR, 12-17.5).

Investigators also showed that ΔMRD400 achievement did not appear to correlate with traditional CLL risk factors. Among patients with TP53 mutations or 17p deletions (n = 5), 80% achieved ΔMRD400, and 20% did not. Furthermore, among patients with unmutated IGHV (n = 25), 60% achieved ΔMRD400, and 40% did not.

Achievement of ΔMRD400 was associated with longer MRD4-free survival, despite achievers receiving less therapy than those who did not achieve ΔMRD400 (P < .001). Among patients who achieved (60%) and did not achieve (40%) ΔMRD400, the median MRD4-free survival was 51 months and 23 months, respectively (HR, 4.5; 95% CI, 1.5-14.1; log-rank P < .001).

Treatment with the BOVen regimen also resulted in durable uMRD4 outcomes. Among patients who achieved bone marrow uMRD4, the median MRD4-free survival was 34 months (95% CI, 23-not reached). MRD4-free survival was calculated from EOT until the date of a positive MRD4 test or the last confirmed uMRD4 level. In contrast, in the phase 3 CLL14 trial (NCT02242942), venetoclax plus obinutuzumab elicited a median MRD4-free survival of 21.7 months in patients with treatment-naive CLL with bone marrow uMRD4.3

Long-Term Safety Outcomes in the Frontline Cohort

All-cause grade 1/2 adverse effects (AEs) that occurred in at least 15% of patients included fatigue (58%), decreased platelet counts (52%), diarrhea (48%), bruising (48%), cough (39%), nausea (37%), anemia (37%), constipation (35%), infusion-related reaction (33%), and decreased neutrophil counts (31%), nasal congestion (29%), insomnia (23%), myalgia (23%), gastroesophageal reflux disease (23%), arthralgia (21%), rash (21%), dyspnea (19%), increased aspartate aminotransferase levels (19%), dizziness (17%), abdominal pain (17%), postnasal drip (15%), sore throat (15%), hypocalcemia (15%), sinusitis (15%), increased alkaline phosphate levels (14%), and headache (14%).1

The most common grade 3 AEs included decreased neutrophil counts (8%); decreased platelet counts (8%); lung infection (6%); diarrhea (4%); rash (4%); skin infection (4%). Additionally, grade 3 fatigue, increased alkaline phosphate levels, headache, oral mucositis, hypophosphatemia, rash, increased blood bilirubin levels, heart failure, purpura, and infusion-related reactions occurred in 1 patient each.

Grade 4 decreased neutrophil counts, infusion-related reaction, and atrial fibrillation occurred in 19%, 2%, and 2% of patients, respectively. Furthermore, 1 patient had grade 3 febrile neutropenia, and 1 patient had an Achilles tendon partial tear. One grade 5 AE occurred in 1 patient with intracranial hemorrhage on day 1 of cycle 1. Investigators did not observe laboratory or clinical tumor lysis syndrome per Howard criteria.

Retreatment Cohort Outcomes

In total, 16 patients were retreated with zanubrutinib plus venetoclax after meeting protocol-defined retreatment criteria. The median retreatment follow-up was 14 months (range, 1-38+), and the median treatment-free interval prior to retreatment was 29 months (range, 7-54). Overall, 25% of patients had MRD levels of at least 1% without increased lymph node levels or spleen size, and 75% of patients had MRD levels of at least 1% with increased lymph node levels or spleen size.

Ninety-five percent of retreated patients had unmutated/germline IGHV. Four patients in the retreated population had TP53 mutations and/or 17p deletions, which were present prior to initial therapy in 3 patients and acquired prior to retreatment in 1 patient.

In total, 31% of patients achieved ΔMRD400 with initial BOVen therapy, 50% of patients did not achieve ΔMRD400, and ΔMRD400 data were not available for 19% of patients.

Among the 12 iwCLL response assessment–evaluable patients, the iwCLL overall response rate was 92%. Among the 13 patients evaluable for MRD response assessment, the peripheral blood uMRD4 response rate was 46%. Seventy-five percent of patients who achieved ΔMRD400 with initial BOVen therapy (n = 4) achieved peripheral blood uMRD with retreatment vs 29% of those who did not achieve ΔMRD400 with initial therapy (n = 7), indicating that initial ΔMRD400 achievement correlates with peripheral blood uMRD achievement during retreatment.

The most common any-grade AEs occurring in at least 10% of patients who were retreated included upper respiratory infection (44%), COVID-19 (38%), cough (25%), diarrhea (25%), fatigue (25%), hyperkalemia (19%), influenza (19%), bruising (13%), headache (13%), nasal congestion (13%), nausea (13%), night sweats (13%), and decreased platelet counts (13%), all of which were grade 1/2. Additionally, 1 patient had grade 3 neutropenia with retreatment.

References

1. Soumerai JD, Dogan A, Seshan V, et al. Multicenter phase II trial of zanubrutinib, obinutuzumab, and venetoclax (BOVen) in treatment-naïve chronic lymphocytic leukemia: 5-year follow up, retreatment outcomes, and impact of MRD kinetics (ΔMRD400). Blood. 2024;144(suppl 1):1867. doi:10/1182/blood-2024-205697
2. Soumerai JD, Mato AR, Dogan A, et al. Zanubrutinib, obinutuzumab, and venetoclax with minimal residual disease-driven discontinuation in previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: a multicentre, single-arm, phase 2 trial. Lancet Haematol. 2021;8(12):e879-e890. doi:10.1016/S2352-3026(21)00307-0
3. Al-Sawaf O, Zhang C, Lu T, et al. Minimal residual disease dynamics after venetoclax-obinutuzumab treatment: extended off-treatment follow-up from the randomized CLL14 study. J Clin Oncol. 2021;39(36):4049-4060. doi:10.1200/JCO.21.01181