With So Many Options for CLL, the Best Treatment May Be a Clinical Trial

Theodore Bosworth

Disclosures

January 18, 2018

The treatment strategies for chronic lymphocytic leukemia (CLL) are evolving so quickly that the best option for many patients—perhaps most patients—is not the latest therapy to show an advantage over a previous standard, but enrollment in a clinical trial. This is not just the case in the relapsing/remitting setting. Therapeutic options are in rapid transition from first-line to deep salvage.

"Active participation in a clinical trial has never been more critical than it is today," said Matthew S. Davids, MD, associate director of the Center for Chronic Lymphocytic Leukemia at Dana-Farber Cancer Institute in Boston. Dr Davids was among several experts making this case at the 2017 annual meeting of the American Society of Hematology (ASH).

Active participation in a clinical trial has never been more critical than it is today.

Some combination regimens in CLL are already impressive, particularly relative to historical controls, but new combinations currently being evaluated have strong potential to be even better. This is the justification for urging enrollment in clinical trials. In late-stage disease, optimal sequencing is still unclear because new therapies have proliferated so quickly that comparative data are limited. In the first-line setting, newer therapies in fit patients have the potential for cure.

Cure is now a "tantalizing prospect," according to a group of investigators from the University of Texas MD Anderson Cancer Center. They reached this conclusion on the basis of recently published results from the FCR300 study, which has the longest follow-up ever for a CLL trial.[1] After 10 years, a small but substantial proportion of the group with the most favorable characteristics, including mutated immunoglobulin heavy chain variable gene (IGHV) and early achievement of minimal residual disease (MRD) negativity, remain in remission.

This trial did not involve the targeted therapies that have been associated with large improvements in progression-free survival (PFS), particularly in relapsed or refractory (R/R) disease. Rather, it was achieved with the classic chemoimmunotherapy regimen FCR (fludarabine, cyclophosphamide, and rituximab). In the 114 patients with mutated IGHV, PFS at 12.8 years was 79.8%. Among these, 42 patients have not relapsed, suggesting the emergence of a plateau in patients with mutated IGHV at approximately 10 years.

Conversely, the PFS rate after the median 12.8 years of follow-up among the 51% of the study population with unmutated IGHV in this study was substantially lower (8.9% vs 53.9%). MRD negativity was associated with a boost in long-term PFS, but few of these patients were among those with no evidence of disease past 10 years.

Yet, a clinical trial might be the answer for longer PFS in fit patients with unmutated IGHV or other unfavorable characteristics. Dr Davids presented such a study at the 2017 ASH meeting. In this study, the BTK inhibitor ibrutinib was added to FCR for six cycles, followed by ibrutinib maintenance.[2] Of 35 evaluable patients, bone marrow MRD negativity was achieved in 39%, which is nearly double the proportion seen with FCR alone in previous studies. Of those entered, 57% had unmutated IGHV.

Ibrutinib provided as a maintenance monotherapy is already indicated first-line in CLL patients who are not candidates for FCR. Relative to a time-limited therapy with chlorambucil, ibrutinib maintenance therapy provided an overall survival benefit in the RESONATE-2 trial.[3] These data changed practice, but candidates for this therapy might still be reasonably considered for a clinical trial. In an overview presentation on CLL that she made at the ASH meeting, Kirsten Fischer, MD, of the Center for Integrated Oncology at the University of Cologne in Germany, pointed out the limitations of ibrutinib monotherapy.

"First, there is consensus that patients generally favor finite use of an oral medication," Dr Fischer said, pointing to one concern expressed by patients placed on an open-ended regimen of ibrutinib. Second, unacceptable side effects or eventual resistance often limit the duration of benefit in patients on ibrutinib monotherapy. She suggested that clinical trials testing time-limited combinations to achieve deeper response are an appealing path to more durable disease control.

The goal is not just a delay in progression, but MRD negativity and durable responses.

"The available data suggest that MRD negativity or other surrogates of good disease control may prolong the survival of patients with CLL," Dr Fischer said. Now, with an expanding number of targeted therapies with different mechanisms of action, there is the potential for rational combinations with synergy leading to deeper responses and inhibition of clonal evolution leading to resistance.

The experimental data supporting complementary effects from ibrutinib and the BCL-2 inhibitor venetoclax have already led to phase 2 clinical trials with these drugs in combination in the front-line setting, according to Dr Davids. He cited a third trial in which venetoclax and ibrutinib are being combined with the anti-CD20 monoclonal antibody obinutuzumab. He said that the rationale for an ibrutinib-venetoclax combination is sound.

"Our group showed that these two drugs have distinct and complementary effects on CLL cell mitochondria. Whereas venetoclax increases the propensity for CLL cells to undergo apoptosis, ibrutinib causes CLL cells to selectively become more dependent on BCL-2 for survival," Dr Davids explained.

In the relatively rapid sequential introduction of the novel targeted agents ibrutinib, the phosphoinositide 3-kinase (PI3K) inhibitor idelalisib, and venetoclax for the treatment of CLL, the approvals were typically based on efficacy in the R/R setting in patients with adverse cytogenetics. These studies provided proof that each of the pathways targeted by these drugs are viable for CLL control, but such experts as Dr Davids and Dr Fischer believe that combinations now in clinical trials are the next step. The goal will not just be the delay in progression typically achieved with single-agent maintenance therapy, but MRD negativity and durable responses.

"The current challenge is to identify the best combination of treatments with a finite duration to achieve long-term control," Dr Fischer said.

The number of phase 3 clinical trials now under way is dizzying.

The potential combinations, many of which are already in clinical trials, are seemingly limitless. This is true in the first-line setting, where relatively well-tolerated targeted agents can expand options in both fit and older, frailer patients and in the R/R setting. The number of phase 3 clinical trials now under way is dizzying, and results are already starting to accrue. Just a day after Dr Fischer spoke, venetoclax plus rituximab in a time-limited regimen was reported to be associated with an 80% reduction in the risk for progression or death relative to bendamustine plus rituximab in the ASH late-breaker MURANO study.[4] The study enrolled patients with CLL after two or more prior lines of therapy.

Second-generation iterations of novel agents, such as the BTK inhibitor acalabrutinib and the PI3K inhibitors umbralisib and duvelisib, are in clinical trials, creating the potential for novel combination strategies closer to the beginning than the end. Dr Davids made an analogy between the current potential of novel therapies to transform outcomes in CLL and the success that followed an expanded array of cytotoxic agents for diffuse large B-cell lymphomas. As in diffuse B-cell lymphomas, improvements in outcome may include cure in some patients. Dr Fischer agreed; she suggested that combinations that include novel agents might permit the focus to shift from PFS to overall survival in a growing number of settings in CLL.

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