Venetoclax Consolidation Does Not Prevent Loss of MRD Response Following First-Line Venetoclax/Obinutuzumab for CLL

Chronic lymphocytic leukemia

Venetoclax (Venclexta) consolidation following first-line treatment with venetoclax and obinutuzumab (Gazyva) did not reduce loss of minimal residual disease (MRD) response vs MRD-guided venetoclax consolidation in previously untreated patients with chronic lymphocytic leukemia (CLL), according to results from the phase 2 HOVON 139/GiVe trial (NL5871) published in The Lancet.¹

At a median follow-up of 35.2 months (interquartile range, 31.5-41.3), 50% (95% CI, 32%-68%) of patients who received venetoclax in a 12-cycle consolidation regimen (n = 32) had undetectable MRD in the bone marrow and no progressive disease vs 53% (95% CI, 34%-72%) in the MRD-guided group (n = 30).

At randomization, 84% of patients assigned to consolidation had undetectable MRD. Three months following the 12th consolidation treatment, that number dropped to 59%. In comparison, 87% of patients in the MRD group had undetectable MRD at randomization; 72% were still undetectable at the end of trial evaluation.

Investigators concluded that consolidation treatment does not improve upon deep responses and high rates of undetectable MRD observed with 12 cycles of fixed-duration venetoclax.

“In both study groups, undetectable MRD rate in bone marrow and peripheral blood was higher after end of fixed-duration venetoclax plus obinutuzumab than after consolidation or the observation period, indicating loss of MRD response despite continuous treatment,” wrote lead study author Sabina Kersting, MD, Department of Hematology, HAGA Teaching Hospital, The Hague, Netherlands, and colleagues.

Venetoclax plus obinutuzumab has become a standard first-line treatment for CLL, as BCL-2 inhibitor– or BTK inhibitor–based combination therapies have replaced chemoimmunotherapy regimens in recent years.^2,3 Investigators have established undetectable MRD as a surrogate marker for progression-free survival (PFS), and patients with MRD negativity receive venetoclax consolidation following combination therapy.

HOVON 139/GiVe aimed to determine the efficacy and safety of venetoclax consolidation for this patient population, regardless of MRD status following treatment with venetoclax and obinutuzumab. The trial enrolled adult patients with previously untreated CLL who had ECOG performance status from 0 to 2 and who were considered unfit for first-line fludarabine-based treatment. Patients were also required to have a platelet count of at least 50 x 10⁹ cells/L, an absolute neutrophil count of at least 1.0 x 10⁹ cells/L, and creatinine clearance of at least 45 mL/minute.

All eligible patients received 2 debulking cycles of intravenous (IV) obinutuzumab at 100 mg on day 1 and 900 mg on day 2, plus 1000 mg on days 8 and 15, followed by 1000 mg on day 1 of the second cycle. Investigators then administered 6 cycles of 1000-mg doses of IV obinutuzumab plus 12 cycles of oral venetoclax, progressing from 20 mg, 50 mg, 100 mg, and 200 mg before delivering 400 mg until completion of the final cycle.

Investigators then randomly assigned patients to up to 12 cycles of venetoclax consolidation regardless of MRD status or venetoclax consolidation if MRD was detected in peripheral blood.

The primary end point of the trial was centrally-assessed undetectable MRD in bone marrow and no progressive disease per IwCLL criteria at 3 months following the end of the 12th cycle of consolidation or a corresponding time point established by a local investigator. Secondary end points included overall response rate (ORR), PFS, event-free survival (EFS), overall survival (OS), MRD response rate, and toxicity.

Seventy patients were initially enrolled on the trial. Of the 67 who received venetoclax plus obinutuzumab, 5 patients discontinued treatment due to death (n = 1), withdrawal of consent (n = 1), or excessive toxicity (n = 3). The remaining 62 patients were randomly assigned to venetoclax consolidation or MRD-based consolidation. Of the 32 patients in the venetoclax consolidation group, 28 finished 12 cycles of venetoclax and 4 discontinued treatment due to toxicity or withdrawal of consent.

In the MRD-based consolidation group (n = 30), 1 patient had MRD positivity at randomization and received 3 cycles of venetoclax consolidation before achieving undetectable MRD in the peripheral blood. Notably, 1 patient in this group with undetectable MRD incorrectly received venetoclax consolidation cycles 4 through 12 after showing MRD positivity.

The median ages of patients in the consolidation group and MRD-based consolidation group were 72 years (range, 69-75) and 71 years (range, 68-74), respectively. The majority of patients were male (75% in the fixed-dose group and 67% in the MRD-based consolidation group). Respectively, patients had an ECOG performance status of 0 (53% and 47%), 1 (44% and 47%), or 2 (3% and 7%); Binet stage of A (19% and 10%), B (44% and 37%), or C (38% and 53%); IGHV mutated status (41% and 37%), IGHV unmutated status (53% and 47%), or unknown IGHV mutated status (6% and 17%); and no genomic complexity (78% and 77%), low genomic complexity (16% and 17%), or high genomic complexity (6% and 7%).

Additionally, patients had similar TP53 aberration rates in both groups (16% and 13% in fixed-dose consolidation and MRD-based consolidation groups, respectively); median hemoglobin concentration (12 g/dL [range, 10-13] and 11 g/dL (range, 10-12]); platelet count (143 x 10⁹ cells/L [range, 109-210] and 111 x 10⁹cells/L [range, 79-220]); white blood cell count (110 x 10⁹ cells/L [range, 65-217] and 82 x 10⁹ cells/L [range, 55-175]); lymphocyte count (95 x 10⁹ cells/L [range, 62-160] and 82 x 10⁹ cells/L [range, 55-175]; β-microglobin concentration (4 mg/L [range, 4-5] and 4 mg/L [range, 3-6]); and creatinine clearance (71 mL/minute [range, 57-79] and 73 mL/minute [range, 65-87]).

Furthermore, patients had a CLL-IPI risk score of low-risk (0-1; 0% and 7% in the fixed-dose consolidation group and MRD-based consolidation group, respectively); intermediate risk (2-3; 25% and 7%); high risk (4-6; 56% and 60%); very high risk (7-10; 16% and 13%); or missing (3% and 13%).

In the intent-to-treat population, 63 of 67 patients (94%) on fixed-duration treatment had an ORR, with 31% achieving a complete response (CR). The best response on treatment, including consolidation, was a CR in 55% of patients, partial response in 39% of patients, and stable disease in 3% of patients.

Specifically, at the end of trial assessment, 41% of patients in the consolidation group had a CR with an ORR of 78% compared with a CR rate of 60% and an ORR of 97% in the MRD-guided consolidation group. Progressive disease occurred in 9% and 3% of patients in the consolidation and MRD-guided groups, respectively.

The 3-year PFS rate for all patients was 85% (95% CI, 72%-92%). The 3-year OS rate was 94% (95% CI, 83%-98%) and the 3-year EFS rate was 83% (95% CI, 72%-90%).

Adverse events (AEs) of grades 2 though 4, primarily infections, occurred in 69% of patients in the consolidation group and 37% of patients in the MRD-guided group. The most common grade 3 or worse AEs were infection (6% in the consolidation group vs 3% in the MRD-guided group) and neutropenia (6% vs 7%, respectively). Investigators observed 5 secondary malignancies including four instances of localized skin tumors and 1 instance of prostate cancer.

“[Four] patients discontinued during venetoclax consolidation, indicating the effect of [AEs] during prolonged venetoclax exposure,” the study authors noted. “This finding was emphasized by the small number of AEs in patients who did not receive consolidation venetoclax. Reduced drug exposure has economic benefits and might result in better quality of life, which will be analyzed in further studies.”

References

1. Kersting S, Dubois J, Nasserinejad K, et al. Venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (HOVON 139/GiVe): primary endpoint analysis of a multicentre, open-label, randomised, parallel-group, phase 2 trial. Lancet. 2022;9(3):E190-E199. doi:10.1016/S2352-3026(22)00034-5
2. Awan FT, Al-Sawaf O, Fischer K, Woyach JA. Current perspectives on therapy for chronic lymphocytic leukemia. American Society of Clinical Oncology Educational Book. 2020;40:320-329. doi:10.1200/EDBK_279099
3. Sengar M, Jain H, Rajendra A, Rengaraj K, Thorat J. Frontline therapy of chronic lymphocytic leukemia: changing treatment paradigm. Curr Hematol Malig Rep. 2020;15: 168-176. doi:10.1007/s11899-020-00580-7