Venetoclax Plus Obinutuzumab With or Without Ibrutinib Improves Undetectable MRD Rates in Fit Patients With CLL

Barbara Eichhorst, MD

The combination of venetoclax (Venclexta) and obinutuzumab (Gazyva) with or without ibrutinib (Imbruvica) generated higher rates of undetectable minimal residual disease (MRD) and progression-free survival (PFS) vs chemoimmunotherapy in fit patients with chronic lymphocytic leukemia (CLL), according to data from the phase 3 GAIA–CLL13 trial (NCT02950051).¹

Notably, the addition of ibrutinib to the venetoclax/obinutuzumab combination was associated with more grade 3/4 infections.

The findings, which were published in the New England Journal of Medicine, showed that 92.2% (97.5% CI, 44.4%-59.5%) of patients who received venetoclax/obinutuzumab/ibrutinib (n = 231) has undetectable MRD. Compared with patients in the chemoimmunotherapy group (n = 229) who had undetectable MRD at a rate of 52.0% (97.5% CI, 44.4%-59.5%), the rate was deemed significant (P < .001). Similarly, the undetectable MRD rate of 86.5% (97.5% CI, 44.4%-59.5%) with venetoclax/obinutuzumab (n = 229) was significantly higher than with the chemoimmunotherapy group (P < .001).

For patients who received venetoclax/rituximab (Rituxan; n = 237), the rate of undetectable MRD (57.0%; 97.5% CI, 49.5%-64.2%) was not significantly different from that of the chemoimmunotherapy group (P = .32).

Investigators only requested bone marrow biopsy and MRD measurements for those who achieved a clinical complete response, which included 69.0%, 81.0%, 86.9%, and 84.8%, of patients receiving chemoimmunotherapy, venetoclax/rituximab, venetoclax/obinutuzumab, and venetoclax/obinutuzumab/ibrutinib, respectively.

The highest percentage of patients with undetectable MRD in bone marrow were receiving venetoclax/obinutuzumab/ibrutinib (77.9%; n = 180 of 231) or venetoclax/obinutuzumab alone (72.5%; n = 166 of 229). In the venetoclax/rituximab arm, the rate of undetectable MRD in the bone marrow was 43.0% (n = 102 of 237) and in the chemoimmunotherapy arm the rate was 37.1% (n = 85 of 229).

At month 15, the rate of complete response—in accordance with the International Workshop on CLL Guidelines—was 31.05% in the chemoimmunotherapy group (n = 71), 49.4% in the venetoclax/rituximab group (n = 117), 56.8% in the venetoclax/obinutuzumab group (n = 130), and 61.8% in the triplet combination group (n = 143). Of note, patients in the chemoimmunotherapy group demonstrated a high rate of clinical best response, as defined by the International Workshop on CLL Guidelines.

Moreover, at a median follow-up of 38.8 months (IQR, 32.7-46.1), an interim PFS analysis showed that the triplet combination yielded a superior median PFS than chemoimmunotherapy, with an HR of 0.32 (97.5% CI, 0.19-0.54; P < .001). Venetoclax/obinutuzumab also surpassed chemoimmunotherapy in terms of PFS rate (HR, 0.42; 97.5% CI, 0.26-0.68; P < .001). Venetoclax/rituximab did not demonstrate a significant benefit over chemoimmunotherapy (HR, 0.79; 97.5% CI, 0.53-1.18; P = .18).

Lastly, at 3 years of follow-up, in the venetoclax/obinutuzumab/ibrutinib, venetoclax/obinutuzumab, venetoclax/rituximab, and chemoimmunotherapy groups, were 98.4%, 94.2%, 93.0%, and 87.4% of patients were not receiving any additional treatments. The rate of overall survival (OS) at 3 years were similar across all 4 groups, at rates of 95.3%, 96.3%, 96.5%, and 95.0%, respectively.

“In this trial involving patients with CLL and a low burden of coexisting conditions, time-limited combinations of targeted agents such as venetoclax/obinutuzumab and venetoclax/obinutuzumab/ibrutinib led to longer and deeper responses than the current first-line chemoim­munotherapy standard (fludarabine/cyclophos­phamide/rituximab or bendamustine [Bendeka]/ritux­imab),” Barbara Eichhorst, MD, of the German CLL Study Group and the University of Cologne, and co-investigators, wrote in the study.

According to the study authors, venetoclax, either with obinutuzumab or rituximab, has led to a high incidence of undetectable MRD and long PFS in patients who are not fit and those with relapsed disease; however, evidence assessing the treatment’s efficacy in a fit population have been lacking. Additionally, other combinations with BTK inhibitors and BLC2 inhibitors have demonstrated improvements in undetectable MRD and promising durations of disease control in this setting.

To that end, the open-label GAIA-CLL13 trial sought to assess venetoclax plus anti-CD20 antibodies as a first line treatment for patients with advanced CLL, no TP53 aberrations, and a low burden of coexisting conditions. Between December 12, 2016, and October 13, 2019, investigators screened and enrolled 926 patients to receive treatment on the trial. These patients were randomly assigned 1:1:1:1 to receive either 6 cycles of chemoimmunotherapy, or 12 cycles of venetoclax/rituximab, venetoclax/obinutuzumab, or venetoclax/obinutuzumab/ibrutinib. If patients in the triplet regimen arm showed 2 consecutive measurements of undetectable MRD, they had the option to discontinue ibrutinib.

Treatment group demographic characteristics were well-balanced. The median age across the 4 treatment arms was 61, 62, 62, and 60 years, respectively. The percentage of patients above age 65 years, was 34.5%, 35.9%, 35.8% and 35.9%. The percentage of patients with an ECOG performance status of 0 was 71.6%, 72.6%, 72.1%, and 70.6%.

The rate of treatment adherence to the prescribed number of cycles were high. The lowest adherence rate was 81.5% in the chemoimmunotherapy group, and the highest rate was 93.9%, in the venetoclax/obinutuzumab group.

In the venetoclax/obinutuzumab/ibrutinib, 90.5% (n = 209) of patients received at least 12 cycles of therapy; 42 patients discontinued therapy after 42 cycles, 145 discontinued between cycles 13 and 15, and 22 discontinued therapy following cycle 16. Of note, 177 of 198 patients discontinued ibrutinib after confirmed undetectable MRD; 6 completed 36 treatment cycles, and 15 had missing information.

Across all treatment arms, intercurrent illness or adverse events (AEs) were primarily responsible for early treatment discontinuation. Dose reduction of at least 20% with any of the agents were necessary in at least once in 14.8% of the patients in the chemoimmunotherapy group, and 37.4% of patients in the venetoclax/obinutuzumab/ibrutinib group. Treatment discontinuation because of AEs were necessary in 15.3% of patients in the chemoimmunotherapy group, 5.9% of patients in the venetoclax/rituximab group, 5.7% of patients in the venetoclax/obinutuzumab group and 12.6% of patients receiving the triplet combination.

With all the treatment regimens, cytopenia and infections represented the most common grade 3 and 4 AEs. Serious AEs were reported in 47.7% of patients receiving chemoimmunotherapy, 40.1% of patients receiving venetoclax/rituximab, 44.7% of patients receiving venetoclax/obinutuzumab, and 50.2% of patients receiving venetoclax/obinutuzumab/ibrutinib.

During the trial, 36 patients (3.9%) experienced fatal AEs, this included 10 patients in the chemoimmunotherapy (4.6%), 8 patients in the venetoclax-rituximab group (3.4%), 9 in the venetoclax/obinutuzumab group (3.9%), and 9 patients in the venetoclax/obinutuzumab/ibrutinib group (3.9%). Twelve deaths occurred in the timeframe leading up to week 12, and 24 deaths occurred during follow-up.

In addition, 6, 4, 6, and 2 patients, respectively, receiving chemoimmunotherapy, venetoclax/rituximab, venetoclax/obinutuzumab, and venetoclax/obinutuzumab/ibrutinib, experienced Richter’s transformation and their disease progressed to either diffuse large B-cell lymphoma or Hodgkin lymphoma. Secondary neoplasia occurred in 16.7%, 8.9%, 10.1% and 10.4% of these patients, respectively.

“With improved survival even among patients with advanced-stage CLL, secondary neoplasia has an increasing effect on overall life expec­tancy,” the investigators wrote. “Therefore, reducing the risk of secondary neoplasia might influence the choice of treat­ment, particularly in patients with CLL that ex­presses mutated IGHV.”

They concluded by noting that the toxic effect profiles across the 3 experimental groups were similar. They pointed out that the incidence of tumor lysis syndrome (TLS) was higher than in the CLL14 trial (NCT02242942). Of note, no deaths in the trial were attributed to TLS. The triplet regimen was also associated with a higher rate of TLS (8.2%) than what had previously been reported with venetoclax/ibrutinib; they hypothesize that this is related to the simultaneous adminis­tration of obinutuzumab with ibrutinib, which led to rapid CLL cell depletion. Investigators also acknowledged that the rate of atrial fibrillation was higher in the triplet regimen arm (7.8%) than had been previously reported in the E1912 trial (NCT02048813; 4.5% with ibrutinib alone). They were not able to explain this finding, although they speculate that the higher median patient age in this trial (61 years vs 58 years) may be a contributing factor.

According to the investigators, the findings from this trial confirm the efficacy of the triplet combination regimen, but the data cannot answer whether this treatment provides greater benefit than continuous BTK inhibitor therapy or doublet combinations with BLC2 inhibitors. Moreover, they acknowledge that some of the benefits of venetoclax/obinutuzumab/ibrutinib are lessoned by the need for dose reduction and early treatment discontinuation, because of AEs.

To that end, they note that the ongoing phase 3 CLL17 trial (NCT04608318) seeks to compare the benefit of venetoclax regimens (venetoclax/obinutuzumab and venetoclax/ibrutinib) to treatment with a continuous BTK inhibitor (ibrutinib).²

Editor’s Note: This research was supported by AbbVie, Janssen, and Roche.

References

1. Eichhorst B, Niemann CU, Kater AP; GAIA-CLL13 Investigators. First-line venetoclax combinations in chronic lymphocytic leukemia. N Engl J Med. 2023;388(19):1739-1754. doi:10.1056/NEJMoa2213093
2. Ibrutinib monotherapy versus fixed-duration venetoclax plus obinutuzumab versus fixed-duration ibrutinib plus venetoclax in patients with previously untreated chronic lymphocytic leukaemia (CLL) (CLL17). ClinicalTrials.gov. Updated March 21, 2023. Accessed May 22, 2023. https://clinicaltrials.gov/ct2/show/NCT02048813