Dr Fürstenau on Safety Data From the GAIA/CLL13 Trial in Untreated CLL

Moritz Fürstenau, MD, Division of Haematology, Immunology, Infectiology, Intensive Care, and Oncology, University of Cologne, discusses the safety profile of venetoclax (Venclexta) plus obinutuzumab (Gazyva) with or without ibrutinib (Imbruvica) vs chemotherapy in fit patients with previously untreated chronic lymphocytic leukemia (CLL), according to data from 

the phase 3 GAIA/CLL13 trial (NCT02950051)

The toxicities observed with both the doublet and triplet regimens in this trial were consistent with previous data, Fürstenau begins. Among patients treated with the venetoclax plus obinutuzumab doublet, hematological toxicities including neutropenia and low platelet counts were observed, he reports. Infections, including upper respiratory tract infections and pneumonia, were also reported. These AEs were within the anticipated range for this combination and did not exceed what is typically expected, Fürstenau notes. However, the addition of ibrutinib to this regimen introduced more ibrutinib-associated toxicities. The triplet therapy group experienced a higher incidence of cardiac AEs, infectious complications including atypical and invasive fungal infections, and increased bruising, which aligns with the known class effects of BTK inhibitors, Fürstenau explains.

It is important to note that the GAIA trial included younger, fit patients with fewer comorbidities, which may not reflect the real-world CLL population, he emphasizes. In older or more frail patients, the safety profile might differ, necessitating greater attention to potential drug interactions and prior health conditions, Fürstenau adds.

When considering the application of these findings to a broader patient population, it is crucial to pay close attention to potential interactions between the treatment regimen and other medications the patient may be taking, he continues. Although results from the GAIA trial are reassuring for a fit patient population, they underscore the need for careful monitoring and management of toxicities in more vulnerable patients, he says. Clinicians must remain vigilant in managing these therapies, particularly in a real-world setting where patient profiles can be significantly more varied and complex than those seen in clinical trials, Fürstenau concludes.

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Moritz Fürstenau, MD, discusses the safety of venetoclax plus obinutuzumab with/without ibrutinib in fit patients with chronic lymphocytic leukemia.

Dr Fürstenau on the Rationale for the GAIA/CLL13 Trial in Previously Untreated CLL

Moritz Fürstenau, MD, Division of Haematology, Immunology, Infectiology, Intensive Care, and Oncology, University of Cologne, discusses the rationale for launching the phase 3 GAIA/CLL13 trial (NCT02950051) investigating venetoclax (Venclexta) plus obinutuzumab (Gazyva) with or without ibrutinib (Imbruvica) vs chemoimmunotherapy in previously untreated, fit patients with chronic lymphocytic leukemia (CLL).

The rationale behind investigating venetoclax-based combinations in the GAIA trial was multifaceted, driven by existing evidence and the need for further comparative analyses in various patient populations, Fürstenau begins. The GAIA trial specifically examined 3 different time-limited venetoclax combinations.

One of these combinations, venetoclax plus obinutuzumab, has already received FDA approval for the first-line treatment of patients with CLL, he explains. Previous phase 2 and phase 3 trials demonstrated significant efficacy with this combination in certain patient subgroups, particularly older patients, Fürstenau says. Given these data, the GAIA trial evaluated whether this combination would also outperform the established standard regimen of fludarabine, cyclophosphamide, and rituximab (FCR) in the first-line setting in fit patients, he elucidates. This comparison is crucial because determining a superior alternative to FCR could significantly impact patient outcomes, Fürstenau reports.

The second combination investigated was venetoclax plus rituximab (Rituxan). The overall rationale for GAIA was to conduct a direct comparison between the 2 CD20-directed antibodies used in CLL management: obinutuzumab and rituximab, he continues. By evaluating the efficacy of venetoclax plus rituximab, the researchers determined whether rituximab could provide the same efficacy as obinutuzumab, Fürstenau notes, adding that this comparison is important for optimizing treatment protocols.

The third combination explored was a triplet regimen comprising venetoclax, obinutuzumab, and ibrutinib, he expands. This combination represented a logical progression in the effort to enhance treatment efficacy, according to Fürstenau. By adding ibrutinib to the already-potent venetoclax and obinutuzumab combination, the researchers assessed whether this triplet could offer superior efficacy, he emphasizes. Additionally, the trial evaluated the toxicity profile of this more intensive regimen, balancing its potential benefits against the risks to determine its suitability for broader clinical use, Fürstenau concludes.

Moritz Fürstenau, MD, discusses the rationale for launching the phase 3 GAIA/CLL13 in previously untreated, fit patients with chronic lymphocytic leukemia.

Dr Fürstenau on the Efficacy of Frontline Venetoclax-Based Combinations in CLL

Moritz Fürstenau MD, Division of Haematology, Immunology, Infectiology, Intensive Care, and Oncology, University of Cologne, discusses 4-year follow-up findings from the phase 3 GAIA/CLL13 trial (NCT02950051) investigating venetoclax (Venclexta) plus obinutuzumab (Gazyva) with or without ibrutinib (Imbruvica) vs chemoimmunotherapy in previously untreated, fit patients with chronic lymphocytic leukemia (CLL).

The GAIA trial’s primary end point analysis, which was published in 2023, evaluated differences in undetectable minimal residual disease rates and progression-free survival (PFS) between the venetoclax-based doublet and triplet and chemoimmunotherapy. The trial protocol initially allowed comparisons between the venetoclax arms and chemoimmunotherapy arm. Both venetoclax-based combinations generated superior PFS outcomes compared with chemoimmunotherapy. However, direct comparisons between the venetoclax-containing arms were not permitted in the primary analysis.

The 4-year follow-up analysis compared these venetoclax-containing arms. At a median follow-up of 50.7 months (interquartile range, 44.6-57.9) the doublet yielded a significantly longer median PFS than chemoimmunotherapy (HR, 0.47; 97.5% CI, 0.32-0.69; 

 < .0001), as did the triplet (HR, 0.30; 97.5% CI, 0.19-0.47; 

 < .0001). This analysis also showed that the doublet had superior PFS outcomes compared with venetoclax plus rituximab (Rituxan; HR, 0.57 [97.5% CI, 0.38-0.84; 

 = .0011]), as did the triplet (HR, 0.38; 97.5% CI, 0.24-0.59; 

 < .0001). The estimated 4-year PFS rates in the triplet and doublet arms were 85.5% (97.5% CI, 79.9%-91.1%) and 81.8% (97.5% CI, 75.8%-87.8%), respectively. These rates were 70.1% (97.5% CI, 63.0%-77.3%) and 62.0% (97.5% CI, 54.4%-69.7%) in the venetoclax/rituximab and chemoimmunotherapy arms, respectively.

Although there was no significant PFS difference between the venetoclax/obinutuzumab and venetoclax/obinutuzumab/ibrutinib arms, the survival curves for these arms were distinctly separated, Fürstenau says. Furthermore, in the largest subgroup of patients with unmutated IGHV, the addition of ibrutinib to venetoclax and obinutuzumab provided a significant PFS benefit. This is a higher-risk group with more dynamic disease, Fürstenau noted.

Moritz Fürstenau MD, discusses 4-year follow-up findings from the phase 3 GAIA/CLL13 trial in patients with CLL.

Moritz Fürstenau MD

Articles

Dr Fürstenau on Safety Data From the GAIA/CLL13 Trial in Untreated CLL

Dr Fürstenau on the Rationale for the GAIA/CLL13 Trial in Previously Untreated CLL

Dr Fürstenau on the Efficacy of Frontline Venetoclax-Based Combinations in CLL