Recent phase III trials and FDA approvals in first-line chronic lymphocytic leukemia (CLL) have altered the landscape for patients requiring treatment.
At last year’s American Society of Hematology (ASH) meeting, ibrutinib (Imbruvica) with or without rituximab (Rituxan) proved superior to bendamustine (Bendeka) plus rituximab in older CLL patients. And ibrutinib-rituximab topped the most active chemoimmunotherapy regimen — fludarabine, cyclophosphamide, rituximab (FCR) — for many young CLL patients.
Ibrutinib has been FDA approved as monotherapy for first-line CLL since 2016, and earlier this year it was approved in combination with obinutuzumab (Gazyva). And just last week, the combination of venetoclax (Venclexta) plus obinutuzumab received approval for untreated patients with CLL.
Nitin Jain, MD, of MD Anderson Cancer Center in Houston, told MedPage Today that “the big question in the field” will be which option clinicians choose in the frontline setting for a new patient needing treatment — chemoimmunotherapy, an ibrutinib-based regimen, or venetoclax/obinutuzumab.
FCR in IgVH Mutated CLL
At a median follow-up of 33.4 months, the phase III ECOG-ACRIN trial demonstrated that ibrutinib-rituximab improved progression-free survival (PFS) and overall survival (OS) over FCR in patients ages 70 and under.
- PFS (HR 0.35, 95% CI 0.22-0.50, P<0.00001)
- OS (HR 0.17, 95% CI 0.05-0.54, P<0.0003)
“With the caveat that it looks like the benefit was mostly seen in patients with unmutated IgVH,” said Jain.
In patients with IgVH-mutated disease, there was no significant PFS difference between ibrutinib-rituximab and FCR (HR 0.44, 95% CI 0.14-1.35, P=0.07).
“For young fit patients with IgVH mutation without deletion 17P or TP53 mutation, that’s the group of patients I think chemoimmunotherapy should still remain the standard of care,” said Jain.
“That’s certainly also my thinking,” Jennifer R. Brown, MD, PhD, of Dana-Farber Cancer Institute in Boston, told MedPage Today. “In the mutated subgroup we have three different studies that suggest that FCR is potentially curative — 55% of patients with the mutated IgVH are still in remission 12 years later — and it’s 6 months of therapy.”
Brown said it could be argued that the ECOG trial established ibrutinib as a reasonable option for the mutated group of patients.
“But personally, I feel like in these FCR-eligible patients who are young and fit, ibrutinib continuously has a lot of downsides,” she said. “Continuous therapy forever — you never feel like you’re off treatment, you don’t feel like you’re in remission, you don’t ever go away from being a patient ever.”
Plus, there are the added costs and ibrutinib can carry significant toxicity. For higher-risk patients with 17p and 11q deletion or TP53 mutation, Jain and Brown agreed that novel agents are the preferred course of therapy.
Ibrutinib- vs Venetoclax-Based Regimens
“I think both of these strategies have their pluses and minuses,” Jain said. “With ibrutinib, certainly there’s a long track record — many more patients have been treated with that, now we have long-term follow-up data — but it’s a drug which needs to be given continuously, indefinitely.”
While the ECOG-ACRIN trial reported benefit of ibrutinib-rituximab over FCR in younger patients, a separate trial in older patients reported at ASH, the ALLIANCE study, found that while both ibrutinib alone and ibrutinib-rituximab were superior to bendamustine-rituximab, there was no additional benefit with the addition of rituximab to ibrutinib.
“There’s not really much data supporting the use of rituximab with ibrutinib,” said Brown, pointing out that two randomized trials showed no added PFS benefit with the addition of rituximab, “as well as in vitro scientific rationale for why you would not use it.”
“Personally, I wouldn’t use it, even despite that ECOG study,” said Brown.
Ibrutinib plus obinutuzumab received FDA approval in first-line CLL based on results of the phase III ILLUMINATE study. At a median 31 months follow-up, the combination demonstrated an improvement in PFS over chlorambucil-obinutuzumab (HR 0.23, 95% CI 0.15-0.37, P<0.0001). Patients with high-risk disease — those with unmutated IgVH, 17p deletion or TP53 mutations, or 11q deletion — also experienced improved PFS (HR 0.15, 95% CI 0.09-0.27).
“Obinutuzumab is a little bit more complicated, because it’s a more potent antibody,” Brown explained. “In vitro it still works, but we still don’t really have definite data that it adds much to ibrutinib except in terms of more rapid debulking.”
She said that perhaps for patients with very high-risk disease, adding this CD20-directed antibody could be considered to help reduce tumor burden and relieve symptoms more quickly.
Venetoclax-obinutuzumab offers the newest option in frontline CLL after the FDA approved the combination last week, based on results of the CLL14 study of 432 patients with previously untreated disease.
According to FDA labeling, obinutuzumab is started alone for the first 3 weeks, and to minimize the risk of tumor lysis syndrome, patients are monitored while daily venetoclax is started on day 22 in a ramp-up phase of progressively higher doses: 20 mg for week 1, 50 mg for week 2, 100 mg for week 3, 200 mg for week 4, and then finally 400 mg for week 5 and beyond. In all, obinutuzumab is given for six 28-day cycles while venetoclax is given for 12 cycles.
Jain said that patients considered at high risk of tumor lysis syndrome shouldn’t automatically receive ibrutinib first. “I would argue that it’s still OK to use venetoclax/obinutuzumab as long as you follow the risk-management strategy.”
Brown noted that venetoclax is better tolerated than ibrutinib. “The ramp up is usually well tolerated too, it’s just a matter of the monitoring process,” she said. “And then people get to stop it after a year, which obviously reduces side effects, cost, and possibly also the outgrowth of resistance.”
She cautioned that there’s a “huge discrepancy” between the real-world data on ibrutinib and what was seen in the clinical trials. “In the real-world data, we had a report that 40% of patients discontinued ibrutinib at a median of 6 months for adverse events, and [the] median PFS in that study was 3 years.”
She said that perhaps this has improved as physicians gained more experience with the drug, but in her experience venetoclax has lower discontinuation rates and fewer adverse events, which may make venetoclax/obinutuzumab in first-line more appealing.
In CLL14, the combination demonstrated significant improvements in progression-free survival compared with chlorambucil plus obinutuzumab (HR 0.33, 95% CI 0.22-0.51, P<0.0001) and overall response rate (85% vs 71%, respectively, P=0.0007) at 28 months median follow-up.
Three months after completion of therapy, the venetoclax combination also led to higher rates of minimal residual disease (MRD)-negativity compared with the chlorambucil combination as measured in the bone marrow (57% vs 17%, respectively, P<0.0001) and peripheral blood (76% vs 35%, P<0.0001).
“Personally, I’m quite enthusiastic about the venetoclax-obinutuzumab regimen,” said Brown. “It’s time-limited and you get very deep remissions — high levels of undetectable MRD — so that hopefully [by] stopping therapy you can still have very sustained remissions.”
For patients, the argument really comes down to a question of 1-year therapy with venetoclax/obinutuzumab versus lifelong therapy with ibrutinib, Jain said. “At the end of the day, I think both are very effective options and the clinician should provide both options to the patients.”
Jain noted that in many ways the discussion now mirrors the one physicians have been having the past year about best second-line CLL therapy after upfront chemoimmunotherapy. “A lot of my patients are choosing time-limited therapy with venetoclax over ibrutinib,” he said, noting that many worry about “taking a pill forever and ever.”
The experts agreed that while there is already evidence that venetoclax can be an effective therapy following ibrutinib, there’s no data to suggest that sequencing in the opposite manner would be problematic, considering these are two different classes of drugs — a Bruton tyrosine kinase inhibitor in the case of ibrutinib and a selective inhibitor of BCL2 in the case of venetoclax.
Brown highlighted, however, that the data on venetoclax after ibrutinib progression is not as good as venetoclax in frontline or ibrutinib-naive patients.
“What we need to learn over the coming years is whether there’s a significant differentiation, one versus the other in terms of order, but right now there are no data at all to really address that well,” she said.
Ibrutinib has been shown to elicit responses in patients following a wide variety of treatments, including multiple rounds of chemoimmunotherapy, said Brown, “so there doesn’t seem to be too much reason to worry about using ibrutinib after venetoclax.”
Jain recommended that patients who start on venetoclax be salvaged with an ibrutinib-based regimen if they relapse.
“I don’t expect that we should see a significant resistance,” he said.
Comorbidities, Other Considerations
As ibrutinib carries an increased risk of bleeding, especially when combined with anticoagulants for atrial fibrillation or blood clots, Jain said there’s an argument for opting for venetoclax first for such patients.
“That’s what I would do in my practice,” he said.
On the other hand, the main contraindication for venetoclax is renal failure, so if a patient had a creatinine of 2.5 mg/dL, Jain would likely opt for ibrutinib.
“Those patients were not studied in the clinical trial setting,” he said, but added that poor kidney function is also a risk factor for worsening tumor lysis syndrome. “That’s the patient where I would be concerned about using venetoclax/obinutuzumab.”
Brown noted that ibrutinib works particularly well on lymph nodes, but doesn’t clear blood or bone marrow very effectively. In contrast, venetoclax clears blood and marrow very effectively and is not quite as good on lymph nodes. “It’s possible if you have one disease pattern versus the other, you might favor one versus the other,” she said.
Jain disclosed research funding or other financial relationships with AbbVie, Adaptive Biotechnologies, ADC Therapeutics, AstraZeneca, Bristol-Myers Squibb, Celgene, Cellectis, Genentech, Incyte, Infinity, Janssen, Novartis, Novimmune, Pfizer, Pharmacyclics, Seattle Genetics, Servier, and Verastem.
Brown reported research funding or other financial relationships with AbbVie, Acerta/AstraZeneca, BeiGene, Boehringer, Celgene, Gilead, Invectys, Janssen, Loxo, MorphoSys, Pharmacyclics, Roche/Genentech, Sunesis, Sun Pharmaceutical Industries, TG Therapeutics, and Verastem.