We are in a “golden age” in chronic lymphocytic leukemia (CLL), according to Andrew D. Zelenetz, MD, PhD, Medical Oncologist, Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York City.
“We’ve made enormous progress in the treatment and management of the disease with multiple new agents, and we’ve seen a lot of data over the last few years about exciting new small-molecule inhibitors. But this has raised an important question—What is the role of chemoimmunotherapy in the management of CLL?” he asked at the NCCN 2019 Hematologic Malignancies meeting.
To address this question, Dr Zelenetz moderated a debate between 2 investigators who have played key roles in the study of chemoimmunotherapy and small-molecule inhibitors.
William G. Wierda, MD, PhD, Section Chief, Chronic Lymphocytic Leukemia, M.D. Anderson Cancer Center, Houston, TX, argued in favor of small-molecule inhibitors, whereas Jennifer R. Brown, MD, PhD, MS, Director, Chronic Lymphocytic Leukemia Center, Dana-Farber Cancer Institute, Boston, MA, supported the role of chemoimmunotherapy in CLL.
Con: There Is No Role for Chemoimmunotherapy in CLL
“We’re in a new era,” said Dr Wierda. “We have more effective treatments than we have ever had. And I would argue that these days, there really isn’t a role for chemoimmunotherapy in the front line or in relapsed therapy.”
According to Dr Wierda, the goals of therapy are “shifting and evolving,” in the management of patients with CLL.
“With chemoimmunotherapy, our intent was to treat patients to a deep remission, and that was because we could appreciate a long progression-free survival [PFS] with that strategy. And then came the small-molecule inhibitors, particularly BTK [Bruton’s tyrosine kinase] inhibitors, which were very effective at managing and controlling the disease,” said Dr Wierda.
Patients using these small-molecule inhibitors did not achieve deep remissions and were not able to discontinue treatment, but they had very long and durable periods of disease control, he argued.
The introduction of BCL-2 small-molecule inhibitors ushered in a new era in CLL; these agents have led to very deep remissions, and “better, deeper remissions than we were able to achieve for most patients with chemoimmunotherapy,” Dr Wierda said.
One approach with small-molecule inhibitors is to treat to a sustained and durable period of disease control, particularly with BTK inhibitors, he added.
“The other strategy that has emerged is deep remissions with fixed-duration treatment with BCL-2 small-molecule inhibitor–based therapy, which I would argue is better than being exposed to genotoxic chemoimmunotherapy,” Dr Wierda said.
According to Dr Wierda, 3 important patient features must be established before selecting the course of treatment, including the patient’s FISH activity (ie, 17p deletion), TP53 mutation status (which can change), and IGHV mutation status (which does not change).
Dr Wierda highlighted several recent phase 3 randomized clinical trials that compared chemoimmunotherapy and the BTK inhibitor ibrutinib (Imbruvica).
All these studies showed longer PFS with ibrutinib versus chemoimmunotherapy.
Although the RESONATE-2, iLLUMINATE, and Alliance trials demonstrated no overall survival improvement, Dr Wierda argues that this was because of their short follow-up period.
“The trials were all designed to look at PFS, not overall survival, but with longer follow-up we may see differences in overall survival emerging,” he said. He noted the caveat that this type of treatment requires patients to continue therapy long-term.
“The other key point to remember is that if these patients fail chemoimmunotherapy, they can go onto a small-molecule inhibitor–based therapy, which is associated with a very long survival,” he added. “We may not ever see an overall survival difference in these trials, because patients will cross over to the alternative treatment.”
If chemoimmunotherapy is being considered, Dr Wierda supports the use of the FCR (fludarabine, cyclophosphamide, and rituximab [Rituxan]) regimen over bendamustine (Bendeka) plus rituximab. Data show a plateau on the survival curve for patients treated with FCR who have a mutated IGHV, which is not appreciated with bendamustine-based treatment, he said.
Dr Wierda and his colleagues have recently been testing the efficacy of combination treatment with ibrutinib and venetoclax (Venclexta) in a phase 2 trial, and have seen “very, very high MRD [minimal residual disease]-negative rates, about 70% in patients who have had combined therapy for 18 months,” he said.
Pro: There Is a Role for Chemoimmunotherapy in CLL
Dr Brown argues that despite all these new agents and recent studies, there remains a role for chemoimmunotherapy in the treatment of CLL.
She said that although treatment with ibrutinib or with venetoclax plus obinutuzumab (Gazyva) did improve PFS in the studies discussed by Dr Wierda, these treatments did not affect overall survival, meaning patients are not living longer on these drugs.
“Admittedly, RESONATE-2, which compared ibrutinib and chlorambucil, did report an overall survival benefit, but this was due to the very poor comparator of chlorambucil, and very limited crossover,” Dr Brown said. But as seen in the iLLUMINATE and Alliance trials, the overall survival curves completely overlap.
Although ECOG E1912 did report an overall survival benefit with ibrutinib plus rituximab, she said that this was “based on extremely few events, many of which were not clearly related to the disease or its treatment.” She added that these data are “not believable,” and will need to be further evaluated with longer follow-up.
In fact, she added, PFS is not even improved for the 50% of patients with low-risk disease, and those patients can have prolonged treatment-free remission with chemoimmunotherapy—or even cure—if they are candidates for the FCR regimen.
The low-risk subgroup of patients with IGHV mutation did equally well with chemoimmunotherapy as with targeted agents in the ECOG and in the Alliance trials, at least with current follow-up, she pointed out. Even in the CLL14 trial, the subgroup with IGHV mutation did as well with chlorambucil plus obinutuzumab (chemoimmunotherapy) as with venetoclax plus obinutuzumab (combined immunotherapy).
“In no other disease do we give up potentially curative therapy for the requirement of continuous therapy with ongoing residual disease, cumulative side effects, and clearly no cure, which is what we’re talking about with ibrutinib,” she said. “Even if, eventually, ibrutinib did have similar PFS, it would still have the requirement of continuous therapy, toxicity, and cost.”
In terms of side effects with ibrutinib and venetoclax, they are “mixed and distinct from chemoimmunotherapy, but not necessarily better,” she said; they are associated with significant cardiac, infectious, musculoskeletal, and skin adverse events seen over time.
Financial toxicity is another significant issue with these drugs, Dr Brown noted. An estimate of the cost impact of moving oral targeted therapy, such as ibrutinib, from the relapsed setting to the front line is associated with a 6-fold increase in cost.
“And this is not all to the healthcare system. It’s also out of pocket to the patient, with estimates of about $60,000 out-of-pocket costs for Medicare patients receiving front-line ibrutinib,” she said. “We know that most patients cannot afford this.”
Another cost-effectiveness analysis, which compared ibrutinib at its current price with chlorambucil, did not show that ibrutinib was cost-effective with any set of assumptions when given in the front-line setting.
Dr Brown maintains that young, fit patients with CLL and IGHV mutation should clearly receive the FCR regimen. “It’s 6 months of therapy for a possible cure,” she said. But young, fit patients with CLL without IGHV mutation, or older patients, can also receive chemoimmunotherapy (FCR or bendamustine plus rituximab).
“I agree with Bill that if patients are candidates for FCR, it’s clearly more effective and clearly has the potential for cure,” she noted. “But bendamustine plus rituximab can be effective in the older patients as well, and they can have prolonged remissions, even though you don’t see the same plateau.”
Discussing Dr Wierda’s argument that the crossover in these studies prevents us from seeing a clear overall survival benefit, she argued that novel agents work very well in the second line, but it is still unclear if chemoimmunotherapy will work after ibrutinib.
“So we may be losing a line of therapy if we don’t use it in appropriate patients early on as we manage the disease over their lifetime,” Dr Brown advised.
The treatment goal is time-limited novel combinations that reduce toxicity and maintain survival, according to Dr Brown. “Venetoclax plus obinutuzumab is definitely getting us closer than continuous BTK therapy in that it does result in undetectable MRD and high 2-year PFS, even after stopping therapy at 1 year,” she said.
But she added that “there are a number of limitations.” First, follow-up remains very short compared with the 10 years needed to rival the FCR cure for patients with CLL and IGHV mutation; the cost is still high; and the long-term complications of venetoclax are still unknown.
BTK inhibitors are now being combined with venetoclax, and although these are highly effective in inducing undetectable MRD, they are unlikely to be available to patients routinely in the near future, given their costs, she added.
“Chemoimmunotherapy is our only known potential cure—with FCR for the fit, mutated patients—and it can also result in prolonged treatment-free intervals for patients who are older,” said Dr Brown. “As we manage CLL as a chronic disease over a lifetime, we need to continue to have this in our armamentarium.”