ASH Clinical News May 2015 | Page 82

Drawing First Blood We invite two experts to debate controversial topics in hematology and health care Is Fludarabine Dead in CLL? Steven Coutre, MD Mitchell Smith, MD, PhD Disclaimer: The following positions were assigned to the participants and do not necessarily reflect ASH’s opinion, the participants’ opinions, or what they do in daily practice. Agree? Disagree? We want to hear from you! Send your thoughts and opinions on this controversial issue to ashclinicalnews@ hematology.org. 80 ASH Clinical News A few short years ago, fludarabine was considered the gold standard of front-line treatment for chronic lymphocytic leukemia (CLL), providing better response rates than old standby, chlorambucil. Now, in an era of monoclonal antibodies and targeted therapies, fludarabine is losing its place as leader of the pack. ASH Clinical News has invited Steven Coutre, MD, and Mitchell Smith, MD, PhD, to debate the question: “Is fludarabine dead in chronic lymphocytic leukemia?” Dr. Smith will be arguing “no,” while Dr. Coutre will be arguing “yes.” Steven Coutre, MD: We have had fludarabine for decades, and today, the standard front-line treatment for chronic lymphocytic leukemia (CLL) remains chemoimmunotherapy with a fludarabine-based regimen – fludarabine, cyclophosphamide, and rituximab (FCR), or fludarabine, bendamustine, and rituximab (BR). At present, with the newer therapies (such as the Bruton tyrosine kinase inhibitor ibrutinib and the PI3 kinase delta inhibitor idelalisib), we don’t have the randomized trials comparing them with fludarabinebased regimens to give us definitive answers about outcomes such as durable remissions. Having said that, however, there is enough experience with the newer agents to have at least some qualitative impressions. I do think the antibody therapeutics and the kinase inhibitors have an advantage from a side effect profile. The oral drug ibrutinib has been extremely well-tolerated with very favorable quality-of-life results.1 Clearly, for the average older patient with CLL, taking a well-tolerated oral drug is preferred to receiving an intravenous chemotherapy drug. For better or worse, patients do not view these types of newer agents as “real chemotherapy,” which is part of their allure. It is also not hard to imagine that, based solely on the data that we have now, these newer drugs will likely lead to more durable remissions, particularly with the kinase inhibitors. But we can’t draw those conclusions yet until we have the necessary randomized trial data. Mitchell Smith, MD, PhD: Fludarabine is not for everyone. Older CLL patients’ risk for adverse events and toxicities increases as they age, and fludarabine-associated toxicity might also be an issue in patients with renal dysfunction. In younger, fitter patients, however, we do have long-term follow-up data showing impressive results with fludarabine-based regimens.2 We don’t want to completely throw out fludarabinebased regimens, because in the right patient population they can be beneficial. As far as the impact on patient qualityof-life, yes, fludarabine is “real chemotherapy” delivered intravenously; however, this takes place for a defined six-month period. With that limited, six-month regimen, fludarabine leads to years-long survival in some patients with CLL. With these newer oral agents, however, patients will have to take the drug for basi- cally the rest of their lives, and we just do not have long-term data. Late or unexpected toxicities are still a worry. It is a bit premature to ask patients to commit to one of the new oral agents. Dr. Coutre: I would agree that the concept of time-limited therapy with a fludarabinebased regimen can be very attractive compared with the uncertainty of long-term use of cancer drugs, particularly for younger patients. We do have good follow-up for at least three years with ibrutinib and have not seen any new concerns.3 If you are looking at a 20-year horizon of treatment for younger patients, we are never going to be able to answer questions about late side effects in real time. Even with the randomized trials, those issues will take an incredibly long time to address. I believe new agents like ibrutinib and idelalisib will start to dominate the second-line treatment landscape. In the past, patients would relapse after the FCR regimen and would just get FCR again. When bendamustine entered the treatment landscape, patients who relapsed were treated with that because at least it was different. In my mind, there really isn’t a goo