We are in a “golden age” for 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,” he said at the NCCN 2019 Annual Congress: Hematologic Malignancies. “What is the role of chemoimmunotherapy in the management of CLL?”
To address this question, Dr Zelenetz moderated a debate between 2 investigators, both of whom played key roles in the development of chemoimmunotherapy and small-molecule inhibitors.
William G. Wierda, MD, PhD, Section Chief–Chronic Lymphocytic Leukemia, MD Anderson Cancer Center, Houston, TX, argued in favor of small-molecule inhibitors, while Jennifer R. Brown, MD, PhD, MS, Director, Chronic Lymphocytic Leukemia (CLL) Center, Dana-Farber Cancer Institute, Boston, MA, supported an ongoing role for chemoimmunotherapy in CLL.
No, There Is Not a Role for Chemoimmunotherapy
“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.”
In terms of developing an approach to management for patients with CLL, according to Dr Wierda, the goals of therapy are “shifting and evolving.”
“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,” he said. “And then came the small-molecule inhibitors, particularly BTK inhibitors, which were very effective at managing and controlling the disease.” Patients on 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 noted.
Now, we have ushered in a new era with the introduction of BCL-2 small-molecule inhibitors, which have led to very deep remissions, and according to Dr Wierda, “better, deeper remissions than we were able to achieve for most patients with chemoimmunotherapy.”
One approach with small-molecule inhibitors is to treat to a sustained and durable period of disease control (particularly with BTK inhibitors).
“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,” he said.
Three important patient features must be established before selecting a course of treatment, including the patient’s fluorescence in situ hybridization activity (ie, deletion in 17p), TP53 mutation status (which can change), and IGHV mutation status (which does not change).
Dr Wierda highlighted several phase 3 randomized clinical trials that compared chemoimmunotherapy to BTK inhibitor–based therapy—RESONATE-2 (ibrutinib vs chlorambucil), iLLUMINATE (ibrutinib plus obinutuzumab vs chlorambucil plus obinutuzumab), the 3-armed Alliance study (ibrutinib monotherapy vs ibrutinib plus rituximab vs bendamustine-rituximab), and finally, the ECOG E1912 trial (ibrutinib plus rituximab vs fludarabine, cyclophosphamide, and rituximab [FCR] as a front-line therapy).
“All of these trials were based on PFS, and all were positive in terms of showing longer PFS for the ibrutinib-based arm compared to chemoimmunotherapy,” he reported.
Although the RESONATE-2, iLLUMINATE, and Alliance trials demonstrated no overall survival (OS) improvements, Dr Wierda argues that this is due to their shorter follow-up.
“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. “I think these data clearly show that there is improved PFS with BTK inhibitor–based therapy.” He also noted the caveat that this type of treatment requires patients to commit to and stay on therapy.
Another trial reported this year—CLL14—compared venetoclax plus obinutuzumab with chlorambucil plus obinutuzumab. This trial was also positive, favoring PFS outcomes for the patients who received treatment with venetoclax. Dr Wierda pointed out that fixed-duration treatment is important for some patients (particularly those with comorbidities), and this trial demonstrated similar PFS with venetoclax-based therapy—a fixed-duration treatment—compared with ibrutinib-based therapy.
“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 FCR over bendamustine-rituximab. Data show a plateau on the survival curve for patients treated with FCR who have a mutated V gene, which is not appreciated with bendamustine-based treatment, he said.
Dr Wierda and colleagues have recently been testing the efficacy of combination treatment with ibrutinib and venetoclax in a phase 2 trial and have seen “very, very high [minimal residual disease] MRD-negative rates, about 70% in patients who have had combined therapy for 18 months,” he said. Another large phase 2 trial—CAPTIVATE—is confirming these observations.
Yes, There Is a Role for Chemoimmunotherapy
Dr Brown argues that, despite all these new agents, there still remains an ongoing role for chemoimmunotherapy in the treatment of CLL.
She said that although treatment with ibrutinib or venetoclax plus obinutuzumab did improve PFS in the trials discussed by Dr Wierda, these treatments did not impact OS, meaning patients are not living longer on these drugs.
“Admittedly, RESONATE-2, which compared ibrutinib to chlorambucil, did report an overall survival benefit, but this was due to the very poor comparator of chlorambucil, and very limited crossover,” she said. But as seen in the iLLUMINATE and Alliance trials, the OS curves completely overlap.
Although ECOG E1912 did report an OS benefit with ibrutinib plus rituximab, she said this was “based on extremely few events, many of which were not clearly related to the disease or its treatment,” adding 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 half 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 FCR.
The low-risk mutated IGHV subgroup did equally well with chemoimmunotherapy as with targeted agents in the ECOG E1912 and 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-obinutuzumab as with venetoclax-obinutuzumab.
“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, with significant cardiac, infectious, musculoskeletal, and skin toxicities seen over time.
Financial toxicity is another significant issue with these drugs. An estimate of the cost impact of moving oral targeted therapy from the relapsed setting to the front line revealed 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 frontline ibrutinib,” she said. “We know that most patients cannot afford this.”
Another cost-effectiveness analysis, comparing 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.
In summary, Dr Brown maintains that young, fit patients with CLL and IGHV mutation should clearly receive FCR. “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.”
She noted Dr Wierda’s argument that the crossover in these trials prevents us from seeing a clear OS benefit and countered by arguing 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,” she said.
The treatment goal in these patients, she says, is time-limited novel combinations that reduce toxicity and maintain survival. “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 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 cost considerations, 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.”
