TKIs or Chemoimmunotherapy for Frontline CLL Management?

Clinicians and patients now have several options for frontline management of chronic lymphocytic leukemia (CLL); exactly which option is preferred remains up for debate. In just such a debate at the 11th Annual National Comprehensive Cancer Network (NCCN) Hematologic Malignancies Congress, held September 30–October 1 in New York, two experts discussed the pros and cons of chemoimmunotherapy vs continuous tyrosine kinase inhibitor (TKI) therapy.

Steven Coutre, MD, of the Stanford Cancer Institute in California, argued that TKI therapy should be preferred in most cases. Ibrutinib, he said, is approved for initial treatment of CLL based on both an overall survival (OS) advantage compared with chlorambucil and on long-term safety data.

The RESONATE-2 trial compared ibrutinib with chlorambucil specifically in treatment-naive patients aged 65 years and older. Coutre emphasized that these were generally “average” CLL patients, as it is a malignancy that tends to affect older patients. The study included 269 patients, and at 8 months there was a stark difference with regard to objective response rate (ORR): 82% with ibrutinib vs only 30% with chlorambucil.

The ORR with the TKI was higher than chlorambucil at all time points studied. Though most of the responses were partial responses, 11% of ibrutinib patients did have a complete response, compared with 5% of chlorambucil patients. Further, the 18-month progression-free survival (PFS) rate was 90% with ibrutinib, compared with 52% with chlorambucil, for a hazard ratio (HR) of 0.16 (95% CI, 0.09–0.28; P < .0001).

The 24-month OS rate was 98% with ibrutinib, compared with 85% with chlorambucil, for an HR of 0.16 (95% CI, 0.05–0.56; P = .0010). There were only three deaths in that time frame with the TKI, compared with 17 deaths in the chlorambucil group. The study also showed sustained improvement in platelet count in those with thrombocytopenia, and in hemoglobin in those with anemia, with ibrutinib.

These improvements in outcome came without substantial toxicity, Coutre said. “Most of the common adverse events in the ibrutinib arm were lower grade, and did not result in treatment discontinuation.” He said the real value of the study will be to show how patients fare with ibrutinib as upfront therapy; of 11 patients that discontinued the drug due to adverse events, 11 are still alive, and 5 patients were progression-free without any subsequent therapy.

The other experience with upfront ibrutinib is a smaller study intended for long-term follow-up. Among 27 treatment-naive patients, 85% responded, with 52% achieving a partial response. Only one patient has progressed to date, Coutre said, yielding a 30-month PFS rate of 95.8%.

“[Ibrutinib] is holding very nicely in an admittedly small group of patients,” he said. “Why use a less convenient therapy? It’s easy to take a pill. Why not use a better tolerated therapy?” He added that though many think of the agent as being primarily for “unfit patients,” it should be considered in treatment-naive, fit patients as well.

But William G. Wierda, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, argued that there isn’t true data on the OS advantage of TKI therapy over chemoimmunotherapy. The RESONATE-2 trial, he said, offers only weak evidence. “Chlorambucil is an unfair, unreasonable comparator,” Wierda said. It has been shown inferior to other drugs before, and is being used less frequently than in the past.

Though ibrutinib is very effective in controlling relapsed/refractory disease, Wierda said, there are challenges with its use as first-line therapy. It must be taken continuously, and is a costly agent. “While some people may think it’s more convenient, I would not necessarily agree with that,” he said, noting that compliance with an everyday pill can be difficult. There are also toxicities that increase in elderly patients, while the longer-term side effects aren’t known.

“I think there is a value in getting a good complete remission,” Wierda said, so that patients can have a treatment-free period.

Chemoimmunotherapy could offer that outcome, in various combinations. In one study, investigators compared chemoimmunotherapy regimens combining chlorambucil with either obinutuzumab or rituximab with each other and with chlorambucil alone.

Though no difference in OS has yet been seen in the head-to-head comparison, the obinutuzumab regimen showed a significantly longer PFS (P < .0001). That regimen did have a better OS rate than chlorambucil alone, with an HR of 0.41 (95% CI, 0.23–0.74; P = .0022).

Another study, the COMPLEMENT-1 trial, compared ofatumumab and chlorambucil with the latter agent alone. This again was a positive trial, showing a PFS advantage with the chemoimmunotherapy approach, though no OS advantage. Other studies have found similar results with other chemoimmunotherapy regimens, though Wierda did note that these regimens carry challenges including myelosuppression and the risk of infection, as well as a risk for Richter’s transformation and for secondary myelodysplastic syndromes and acute myeloid leukemia.

“I would be the first person to tell you that I would love to get rid of chemotherapy,” Wierda said. “I think we’re headed in that direction.” He said that though ibrutinib has “transformed” the management of CLL, “it is not the last drug, and I think we have a lot of work still to go.”