乌鸦传媒

ATLANTA -- Roughly nine of 10 so-called fit patients with chronic lymphocytic leukemia (CLL) achieved undetectable minimal residual disease (MRD) status after treatment with one of two venetoclax (Venclexta)-based regimens in the randomized GAIA/CLL13 trial.

In the phase III study of nearly 1,000 fit CLL patients, rates of undetectable MRD in peripheral blood were significantly improved at month 15 for those who received either venetoclax plus obinutuzumab (Gazyva) or venetoclax plus obinutuzumab and ibrutinib (Imbruvica) rather than standard chemoimmunotherapy (86.5% vs 92.2% vs 52.0%, respectively; P<0.0001), reported Barbara Eichhorst, MD, of the University of Cologne in Germany.

A third venetoclax arm tested the BCL2 inhibitor in combination with rituximab (Rituxan), which yielded an undetectable MRD rate of 57.0% that was no better than the control arm, she said during a presentation at the American Society of Hematology annual meeting.

"There was a low rate of treatment discontinuation in all arms containing venetoclax," said Eichhorst (over 85% completed 12 cycles of treatment). Toxicities were as expected, she said, with some ibrutinib-specific events observed in the triplet combination arm.

Response rates at month 15 were high among the three venetoclax arms (~95% in each), and included complete responses in 56.8% of those who received venetoclax-obinutuzumab and 61.9% on the triplet versus 31% with chemoimmunotherapy.

With this analysis, the phase III study met the first of its co-primary endpoints (undetectable MRD for venetoclax-obinutuzumab arm versus chemoimmunotherapy); the second co-primary endpoint, a progression-free survival (PFS) analysis for the ibrutinib-containing arm versus chemoimmunotherapy will be performed in 2022.

During a Q&A session, Eichhorst said the triplet regimen might not make sense for every fit patient, as undetectable MRD rates are "already very good" with venetoclax-obinutuzumab. She also pointed to increased rates of serious atrial fibrillation and infections in the ibrutinib arm.

"For all those reasons, I don't think we should already use the triple combination in practice," she said. However, some higher-risk patients -- such as those with unmutated IGHV -- could potentially benefit from the addition of ibrutinib, she added.

Suchitra Sundaram, MD, of the Icahn School of Medicine at Mount Sinai in New York City, said she has offered venetoclax-obinutuzumab to some of her fit CLL patients, "especially in the COVID era, where patients are wanting finite therapy as well as chemo-free therapy."

"It's more a shared decision-making that happens as compared with other regimens," said Sundaram, who was not involved in the study.

While venetoclax plus obinutuzumab received in 2019 for less-fit CLL patients based on results of the CLL14 trial (showing superiority versus chlorambucil-obinutuzumab), the combination had not been compared to standard chemoimmunotherapy regimens for fit patients.

Rates of undetectable MRD in the current study were higher than in that earlier trial, which Eichhorst attributed to the current study excluding patients with del(17p) and TP53 mutations as well as higher treatment adherence, likely due to patient fitness (in CLL14 only 70% of patients finished 12 cycles of venetoclax-obinutuzumab).

As to whether the doublet or triplet will be superior for the fit group of patients, "I don't think we're ready to answer that just yet," said Sundaram. "I think we would all like to see the statistical analysis of the PFS curves."

CLL14 showed that patients with mutated IGHV do pretty well with venetoclax-obinutuzumab alone, Sundaram said, and these patients are also expected to do well in the fit population. Along with the unmutated IGHV group, it would be of interest to see outcomes with the triplet among fit patients with TP53 mutations, she said, as the addition of ibrutinib may potentially be of benefit, "but that remains to be seen."

GAIA/CLL13 randomized 926 fit CLL patients 1:1:1:1 to initial treatment with one of the three venetoclax-based combinations or standard chemoimmunotherapy at centers across Europe and Israel. The co-primary endpoint of undetectable MRD was defined as <10^-4 in peripheral blood. Median follow-up for the present analysis was 27.9 months.

On final restaging, rates of undetectable MRD in bone marrow were:

• Venetoclax-ibrutinib-obinutuzumab: 77.9%
• Venetoclax-obinutuzumab: 72.5%
• Venetoclax-rituximab: 43%
• Chemoimmunotherapy: 37.1%

Chemoimmunotherapy consisted of either fludarabine, cyclophosphamide, and rituximab (FCR) for those 65 and younger, or bendamustine (Bendeka, Treanda) plus rituximab (BR) for those over 65 -- a little less than two-thirds received FCR. For the venetoclax-ibrutinib-obinutuzumab arm, ibrutinib could be stopped after 12 cycles if undetectable MRD was achieved (otherwise given for up to 36 cycles).

For inclusion, patients had to have a cumulative illness rating scale (CIRS) score of 6 or less, and normal creatinine clearance, and they were excluded if they had TP53 mutations or del(17p) on central screening.

Study arms were well balanced. Median patient age was 61 years, median CIRS score was 2, and median creatinine clearance was 85.7 mL/min. On Binet staging, 26.6% were stage A, 37.8% stage B, and 35.6% stage C. For genetic risk factors, del(11q) mutation was detected in 17.5%, trisomy 12 in 16.2%, and del(13q) in 44.6%, while 41.1% had IGHV mutated status and 56% had unmutated IGHV.

The highest treatment completion rates were with venetoclax-obinutuzumab (93.9%), followed by venetoclax-rituximab (92.4%), venetoclax-ibrutinib-obinutuzumab (85.3%), and chemoimmunotherapy (81.5%). The most common reasons for discontinuation were adverse events (AEs) or intercurrent illness.

Dose reductions, meanwhile, were most common with the venetoclax triplet (36.5%), followed by venetoclax-obinutuzumab (21.5%), venetoclax-rituximab (19.3%), and chemoimmunotherapy (14.8%).

Rates of grade 3/4 AEs were highest in the two venetoclax-obinutuzumab arms, 78.3% with the triplet and 82.6% with the doublet, as compared to 76.4% in the chemoimmunotherapy-treated group.

For serious grade ≥3 AEs, neutropenia was the most common across arms (49-56%), and thrombocytopenia appeared more frequently in the obinutuzumab-containing regimens (16-18%). Infections were highest in the ibrutinib (22%) and chemoimmunotherapy (20%) arms, while tumor lysis syndrome was highest with the venetoclax-based doublets (9-10%) and occurred in 7% of those receiving the triplet and 4% of those in the chemoimmunotherapy group. Eichhorst noted that there were some serious ibrutinib-related grade ≥3 AEs, including bleeding and atrial fibrillation in around 2% of patients.

Deaths due to AEs, most commonly from infections, occurred in 3.9% of the venetoclax-based triplet arm, 2.6% of the venetoclax-obinutuzumab arm, 3% of the venetoclax-rituximab arm, and 2.3% of the chemoimmunotherapy arm.

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