CHEMOTHERAPY FREE COMBO FOR CLL

A novel immune-based combination therapy for the initial treatment of chronic lymphocytic leukemia (CLL) does not appear to improve on results achieved with established regimens that include chemotherapy.

In a phase 2 study, investigators combined rituximab (Rituxan, MabThera and Roche), the monoclonal antibody widely used for CLL, and lenalidomide (Revlimid, Celgene), an immunomodulatory agent that is not approved in these patients.

The idea behind the pairing was to avoid chemotherapy, which is generally not well tolerated by older or infirm CLL patients and is part of all regimens containing rituximab, say the investigators, led by Danelle James, MD, from the Moores Cancer Center at the University of California, San Diego.

All patients enrolled in the study were treatment-naïve, and almost all (88%) responded to the novel therapy, which the investigators describe as "highly active."

The median progression-free survival for 7-cycle courses of the novel combination was around 20 months.

The study results were published in the July 1 issue of the Journal of Clinical Oncology.

But the progression-free survival results are not good enough, according to an expert not involved with the study.

"Current use of first-line rituximab and lenalidomide cannot be recommended," says Paul Barr, MD, from the Wilmot Cancer Center at the University of Rochester in New York, in an accompanying audio commentary."The progression-free survival from the current study appears inferior to that observed with chemotherapy-containing regimens, such as the combination of fludarabine, cyclophosphamide, and rituximab or the combination of bendamustine and rituximab," he says.

"A fairly modest progression-free survival was achieved," Dr. Barr adds.

But there is still hope for chemotherapy-free combinations in CLL.

Ongoing studies are looking at using rituximab and lenalidomide in combination with either ibrutinib (Imbruvica, Pharmacyclics) or idelalisib (Gilead) in refractory or relapsed CLL, Dr. Barr points out.

Ibrutinib, the first-in-class inhibitor of Bruton's tyrosine kinase, has been especially impressive as a single agent in CLL, and has been called "game changing," as reported by Medscape Medical News.

Lenalidomide is approved for multiple myeloma and myelodysplastic syndrome.

Lenalidomide is also active in CLL, Dr. James and colleagues point out.

Overall response rates of 32% to 58% have been reported in patients with relapsed CLL treated with single-agent lenalidomide. However, more than half such patients have developed tumor-flare reaction. Furthermore, a clinical trial examining the use of single-agent lenalidomide in CLL was halted by the US Food and Drug Administration because of safety concerns.

Study Details

In this new study, lenalidomide was initiated at 2.5 mg/day and was escalated, on the basis of treatment tolerability, to a maximum of 10 mg/day for 21 days/cycle for a maximum of 7 cycles. Rituximab was administered at the end of cycle 1 and was continued for 7 cycles.

Patients also received allopurinol and aspirin for prophylaxis of tumor-flare reaction.

The investigators analyzed the 69 study participants on the basis of age — younger than 65 years (median, 56 years) and 65 years old and older (median, 70 years).

At baseline, the older patients were more likely to have elevated serum beta-2 microglobulin levels and high-risk Rai stage than the younger patients, and were less likely to complete the maximum planned therapy.

Despite this, median progression-free survival "did not differ" between the younger and older groups (19 vs 20 months).

The response rate was 95% in the younger group and 78% in the older group. Complete response rates were 20% and 11%, respectively.

Adverse events were similar in the 2 groups.

Nonhematologic toxicity was predominantly grade 1/2, and neutropenia was the most common hematologic adverse event, the investigators report.

The majority of patients reached the maximum lenalidomide dose and experienced a response to a defined 7-cycle course of lenalidomide and rituximab therapy, they summarize.

This study was supported in part by the National Institutes of Health, an American Society of Clinical Oncology Young Investigator Award, a Lymphoma Research Foundation Postdoctoral fellowship, and Conquer Cancer Foundation of the American Society of Clinical Oncology Young Investigator Award. Dr. James and a number of her coauthors report financial ties to Celgene.

J Clin Oncol. 2014;32:2067-2073. Abstract, Audio commentary