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SAN DIEGO -- A fixed-duration oral combination significantly reduced the risk of disease progression or death compared with chemoimmunotherapy in fit patients with previously untreated chronic lymphocytic leukemia (CLL), the phase III AMPLIFY trial showed.

The progression-free survival (PFS) rate at 3 years reached 76.5% with acalabrutinib (Calquence) plus venetoclax (Venclexta), as compared with 66.5% with investigator's choice of standard chemoimmunotherapy options (HR 0.65, 95% CI 0.49-0.87, P=0.0038), reported Jennifer Brown, MD, PhD, of the Dana-Farber Cancer Institute in Boston.

A third arm evaluating acalabrutinib-venetoclax plus intravenous obinutuzumab (Gazyva) also topped chemoimmunotherapy when it came to PFS, with a 3-year rate of 83.1% (HR 0.42, 95% CI 0.30-0.59, P<0.0001), according to findings presented at the American Society of Hematology annual meeting here.

Overall survival (OS) was significantly prolonged with acalabrutinib-venetoclax versus chemoimmunotherapy -- either fludarabine, cyclophosphamide, and rituximab (FCR); or bendamustine plus rituximab (BR). With the obinutuzumab regimen, however, OS was significantly improved only after censoring for COVID-19 deaths, said Brown.

Both investigational regimens had tolerable safety profiles, with a low incidence of the cardiac adverse events (AEs) typically associated with Bruton's tyrosine kinase (BTK) inhibitors such as ibrutinib (Imbruvica), including atrial fibrillation and hypertension.

"Patients with treatment-naive CLL have several treatment options, including continuous BTK inhibitor therapy, fixed-duration venetoclax-based regimens, and chemoimmunotherapy, for low-risk patients," Brown explained during a press briefing. "While fixed-duration venetoclax plus ibrutinib -- a first-generation BTK inhibitor -- can result in deep durable responses, cardiac toxicity remains a concern, particularly in older patients."

Acalabrutinib is a highly selective, second-generation BTK inhibitor with improved safety and tolerability compared with ibrutinib; the drug is currently .

AMPLIFY is "a very important study introducing a novel option," Alexey Danilov, MD, PhD, of City of Hope in Duarte, California, told 番茄社区app, adding that it's anticipated that acalabrutinib-venetoclax will be approved as the first oral doublet for treating frontline CLL in the U.S. "I think many patients do -- in my clinic at least -- prefer finite-duration therapy to continuous BTK inhibitors."

The field is indeed moving toward time-limited chemotherapy-free regimens, agreed Brown. Currently, is the only approved option of that sort, based on data from the .

Danilov, who was not involved in the research, pointed to the fact that there were no cases of substantial clinical tumor lysis syndrome (TLS) in AMPLIFY; the risk of TLS, associated with venetoclax during initiation due to rapid reductions in tumor volume, requires that clinicians monitor patients' blood chemistry during the ramp-up phase of the BCL2 inhibitor.

"Introduction of [acalabrutinib-venetoclax] will alleviate some of the concerns that we have with the current CLL14 regimen, such as infusion-related reactions [and] the necessity to conduct frequent blood checks, even though they're not going away completely," said Danilov.

Data from the , which is now fully accrued and testing acalabrutinib-venetoclax versus venetoclax-obinutuzumab, will help make clear which time-limited option is best for upfront CLL. But for now, Brown said she may continue to use venetoclax-obinutuzumab in very low-risk patients and consider the BTK inhibitor-venetoclax combination for patients with somewhat higher risk.

All-Oral Regimen or Add IV Obinutuzumab?

A good deal of discussion following Brown's presentation centered on whether adding IV obinutuzumab to the otherwise all-oral regimen is necessary, and if so, for whom.

Acalabrutinib-venetoclax "is a very well-tolerated oral regimen, which is really going to be suitable for anyone, and I think easy to use in the community," she said.

"At this point, I don't see a full justification to use [acalabrutinib-venetoclax plus obinutuzumab] across the board in all patients," said Danilov. Even though PFS is better with obinutuzumab, "unfortunately this benefit is offset by increased frequency of adverse events. So I think we will still have to define who these patients are."

Brown said physicians will need to take account of the patient in front of them, noting that for younger and fitter patients, the AEs are pretty manageable. While adding obinutuzumab adds more work for the patient and more toxicity, "I see it for young, fit, maybe higher-risk patients, unmutated [IGHV] patients who really want to maximize that PFS," she said.

In the obinutuzumab-containing arm, patients with unmutated IGHV did just as well as those with mutated IGHV, Brown observed, "suggesting that the addition of obinutuzumab may overcome the adverse impact of unmutated IGHV."

COVID deaths in the trial occurred in 10 patients on acalabrutinib-venetoclax, 25 patients on the obinutuzumab arm, and 21 of those assigned to chemoimmunotherapy.

"We have to recognize the study was truly done at the height of the pandemic, and the COVID deaths were mostly in unvaccinated patients," said Brown. "But it is nonetheless the case that you do get more neutropenia, you do get more infections with obinutuzumab, and so in terms of your patient when you're considering this, you have to think about their risk of infection, their risk of low blood counts versus how much additional benefit you think that they may derive from pushing their disease burden down that much further."

Study Details

Brown presented an interim analysis of the phase III trial, an international study that enrolled 867 treatment-naive CLL patients who met criteria for requiring treatment. They were randomized 1:1:1 to either 14 cycles of oral acalabrutinib-venetoclax, 14 cycles of acalabrutinib-venetoclax plus IV obinutuzumab, or six cycles of either FCR or BR, according to investigator's choice and patient fitness.

Participants had a median age of 61 years, 65% were men, and 59% had unmutated IGHV status. Patients were excluded if they had 17p deletions or TP53 aberrations, and they had to have low-risk comorbidity scores.

The primary endpoint was PFS, assessed by independent review committee, for acalabrutinib-venetoclax versus chemoimmunotherapy.

PFS improved with both acalabrutinib-venetoclax regimens regardless of IGHV status, though the best results in unmutated IGHV were observed with the addition of obinutuzumab. Across the three study arms, the 3-year PFS rates for mutated versus unmutated IGHV, respectively, were as follows:

• Acalabrutinib-venetoclax: 86% vs 68.9%
• Acalabrutinib-venetoclax plus obinutuzumab: 83.6% vs 82.8%
• Chemoimmunotherapy: 79.9% vs 56.8%

Secondary endpoints included PFS for the obinutuzumab regimen, undetectable measurable residual disease (MRD), and OS.

Undetectable MRD, measured in peripheral blood, was highest in the obinutuzumab arm (95%), followed by the chemoimmunotherapy arm (73%) and the acalabrutinib-venetoclax arm (45%).

OS significantly improved with acalabrutinib-venetoclax compared with chemoimmunotherapy (94.1% vs 85.9% at 3 years; HR 0.33, 95% CI 0.18-0.56), while no significant OS benefit was observed with the addition of obinutuzumab (87.7%; HR 0.76, 95% CI 0.49-1.18).

In a preplanned analysis censoring for COVID deaths, OS was prolonged in the obinutuzumab-containing arm (HR 0.47, 95% CI 0.22-0.95).

Across the board, the most common AE was neutropenia: 31% with acalabrutinib-venetoclax (27% grade ≥3), 40% in the obinutuzumab-containing arm (35% grade ≥3), and 38% with chemoimmunotherapy (32% grade ≥3). Serious AEs occurred in 25%, 38%, and 27% of patients, respectively.

In terms of cardiac events, 9.3% of patients receiving acalabrutinib-venetoclax and 12% of patients receiving those drugs plus obinutuzumab had an event, as compared with 3.5% of those on chemoimmunotherapy.

Side effects associated with first-generation BTK inhibitors were low, Brown noted: atrial fibrillation occurred in 0.7% of the acalabrutinib-venetoclax arm, 2.1% of the obinutuzumab-containing arm, and 0.8% of the chemoimmunotherapy arm. Hypertension occurred in 4% of the acalabrutinib arms and in 2.7% of the chemoimmunotherapy arm.

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