Rituximab combination approved to treat adult CLL

The drug is used in combination with fludarabine and cyclophosphamide.

Yesterday, the FDA announced its approval of the monoclonal antibody rituximab in combination with fludarabine and cyclophosphamide for patients with previously untreated chronic lymphocytic leukemia and patients with chronic lymphocytic leukemia who have failed on prior therapies.

This is the third drug approved for CLL since 2008, according to Richard Pazdur, MD, director, office of oncology drug products at the FDA. Ofatumumab (Arzerra; GlaxoSmithKline, Genmab) was approved in October for the treatment of CLL that is refractory to fludarabine and alemtuzumab. Bendamustine (Treanda, Cephalon) was approved in March 2008 for treatment-naive CLL.

The FDA based its approval of the drug on PFS survival results from two phase-3 studies, CLL8 and REACH, which both compared rituximab plus fludarabine and cyclophosphamide with fludarabine and cyclophosphamide alone.

REACH was a global, multicenter, randomized, open-label trial. It enrolled 552 patients with previously treated CD20-positive CLL. No patient had prior therapy with rituximab (Rituxan, Genentech).

Results indicated that those patients assigned treatment with rituximab had a 32% improvement in PFS compared with those on fludarabine and cyclophosphamide alone (P=.02). Patients in the rituximab arm had an average 26.7 months PFS vs. 21.7 months in the fludarabine and cyclophosphamide arm. Results of this study were originally presented at the 50th ASH Annual Meeting.

CLL8 was also a global, multicenter, randomized, open-label trial. It included 817 patients with previously untreated CD20-positive CLL. In this study, patients assigned the addition of rituximab had a 79% improvement in PFS compared with those on fludarabine and cyclophosphamide alone (P,.01). The median PFS for patients assigned rituximab was 39.8 months vs. 31.5 months for those assigned fludarabine and cyclophosphamide alone.

The FDA also analyzed data from these trials on patients aged 70 years and older. It concluded that there was no evidence that adding rituximab to chemotherapy benefited this patient population compared with chemotherapy alone.

Rituximab carries a boxed warning for infusion reactions, which can occur during infusion or within 24 hours afterward. About 59% of patients treated with the drug had an infusion reaction that resembled an allergic reaction. - by Leah Lawrence

I am glad that the FDA recognized that this combination - that we refer to as FCR - is significantly superior to FC, or fludarabine plus cyclophosphamide. Actually, even without the FDA approval, hematologists and oncologists in the country have been using FCR - and some people use fludarabine plus rituximab (FR) - in front-line and previously treated treatment of CLL.

As we all know, the M.D. Anderson Cancer Center colleagues, led by Michael Keating, MD, first developed this combination of rituximab with FC almost 10 years ago when he started to treat both treatment-naive CLL patients, as well as previously treated CLL patients. It was about six years ago that he presented the first data on this combination, which showed a dramatically improved outcome for CLL patients over any other treatment that CLL patients had been offered in the past.

Gradually, this treatment became adopted throughout the country, even though rituximab had never received FDA approval for the indication of CLL - it was only approved for non-Hodgkin's lymphoma. My observation has been that even in the European countries, the rituximab combination with chemotherapy had started to take hold because of clear superiority over the same drugs without rituximab. The CLL8 and REACH trials were disciplined and properly conducted trials of FC vs. FCR. They showed, in a randomized prospectively conducted trial, the superiority of FCR over FC. Keating's work did not include a comparative arm, it was a single-institution-based, single-arm study; however, now these new and prospectively conducted randomized trials clearly have confirmed those earlier results, which, in turn, have led to this approval by the FDA for inclusion of rituximab in combination with chemotherapy in CLL.

In my opinion, this recognition by the FDA is good for our CLL patients, and it is an important step toward a better outlook for patients with CLL. Even though in this particular approval it was said that PFS was significantly better when rituximab was added, the fact remains that some of the data from Keating also demonstrated that even OS of those FCR-treated patients in his group - a large number of patients - was improved compared with historical controls treated without rituximab.

Everything is moving in the right direction, but unfortunately, we still are far away from a cure for this condition, and that is where the current research is concentrating.

- Kanti R. Rai, MD
Chief, Hematology Oncology, Long Island Jewish Medical Center, Hyde Park, N.Y.

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