BENDAMUSTINE REMAINS AN OPTION FOR CLL

NEW YORK (Reuters Health) - The bifunctional alkylating agent bendamustine may be suitable first-line therapy for some patients with chronic lymphocytic leukemia (CLL), according to the Guideline Committee of the Italian Society of Hematology (SIE, SIES, GITMO).

Other researchers warn, however, that the committee's guidance may already be outdated.

Dr. Antonio Cuneo from University of Ferrara and other members of the Italian expert panel used GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methodology to develop a prescriptive position for the use of bendamustine in the first-line treatment of CLL.

The panel found no head-to-head studies of bendamustine versus the standard fludarabine-cyclophosphamide-rituximab (FCR) treatment, but based on first-line studies of bendamustine, they concluded that bendamustine alone was not a favorable alternative to FCR.

Based on other indirect comparisons of efficacy and safety, they support bendamustine alone as a reasonable treatment for patients who are candidates for FCR but who have contraindications to rituximab.

The combination of bendamustine and rituximab might be considered as an alternative to FCR in young and fit patients and should be a recommended option in the elderly fit patient, according to the July 7th Leukemia Research online report.

The panel also favors bendamustine alone over chlorambucil and deems bendamustine plus rituximab to be an alternative for patients not eligible for FCR but who can receive rituximab.

"The therapeutic scenario in CLL is being rapidly modified by the introduction of effective BCR-targeted treatment which showed durable efficacy in the relapsed/refractory setting," the authors caution. "Their introduction in the first-line setting appeared to produce durable responses and their possible combination with several monoclonal antibodies and chemotherapeutic agents, including bendamustine, may change treatment paradigm in the next years."

"That does not mean that bendamustine is the best alternative treatment," Dr. Matt Kalaycio from the Taussig Cancer Institute at the Cleveland Clinic in Ohio told Reuters Health by email. "There is no clear evidence that bendamustine-based regimens are superior to chlorambucil based regimens. Furthermore, the SIE, SIES, GITMO Group did not consider studies exploring dose-adjusted ('FCR-lite') or sequential fludarabine regimens."

"Neither did they examine entirely different regimens, such as those based on pentostatin, cladribine, alemtuzumab, lenalidomide, or high-dose methylprednisolone," Dr. Kalaycio said. "When bendamustine is compared to this broader range of regimens, a different question than raised by the Italian group, it can claim neither the greatest demonstrable efficacy nor the least demonstrable toxicity for any given subgroup."

"Bendamustine will retain an important role in the treatment of CLL long after FCR is discarded," Dr. Kalaycio added. "FCR will be considered too toxic in an age where agents, like ibrutinib, promise efficacy without undue toxicity. Bendamustine lends itself to combination therapy with novel agents much better than FCR."

Dr. Richard van der Jagt from University of Ottawa, Canada and a consensus panel reviewed the use of bendamustine for the treatment of CLL two years ago in a Current Oncology report. He told Reuters Health, "The question of bendamustine as single agent is really not a question of relevance given the data suggesting superiority of BR (bendamustine and rituximab) over bendamustine as single agent only, and also in the era of agents like obinutuzamab and ibritinib and PI3 Kinase inhibitors."

"Their statement that bendamustine alone has not been tested against FCR may be true but irrelevant for those reasons," Dr. van der Jagt said. "I agree with the panel that bendamustine may be advised in patients intolerant of rituximab, although this is a rare situation."

Much of the data in this report were also contained in his paper. On that basis, Dr. van der Jagt said, "My preference therefore, is to use FCR in young healthy patients with good renal function and to use BR in older patients especially in the roughly 40% deemed unfit for FCR."

"I do not think BR is about to disappear given its track record of efficacy together with tolerability, even when compared in a randomized fashion to FCR," Dr. van der Jagt concluded. "I think the reader should take away that this report is somewhat skewed and at times contradictory in its analysis of older data with very selective endpoints and without due consideration of all relevant facts that should be kept in mind."

Dr. Cuneo did not respond to a request for comments.