COMMENTARY

CLL's 'Very Unusual Year'

Choosing Among the Newly Available Treatment Regimens

Bruce D. Cheson, MD

Disclosures

August 20, 2014

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This is Bruce Cheson, from Georgetown University Hospital and the Lombardi Comprehensive Cancer Center in Washington DC, speaking to you for Medscape Hematology.

For those of us who have been involved in the treatment of chronic lymphocytic leukemia (CLL) for decades, this has been a very unusual year. We went from having fludarabine for decades to bendamustine, and then we had a fight between fludarabine/cyclophosphamide/rituximab (FCR) and bendamustine/rituximab (BR) -- which, depending on how you interpreted the data, was either a win for FCR or a win for BR.

But now, chemotherapy seems to be taking a back seat. There have been 3 treatments for CLL approved recently in the United States.

The first drug approved was chlorambucil and obinutuzumab, the anti-CD20 monoclonal antibody. The good news is that this combination had a major advantage over chlorambucil alone in a randomized trial.[1] The bad news is that it had an advantage over chlorambucil alone.

I don't know about you, but I haven't used chlorambucil for many years. I would certainly like to see how obinutuzumab compares with rituximab when they are combined with bendamustine, and those studies will hopefully give us some answers.

The second drug was ibrutinib, the Bruton tyrosine kinase (BTK) inhibitor, which was approved for patients with relapsed refractory CLL, and very recently for up-front therapy of patients with 17P deletion. Those are the worst-risk patients that we encounter at present.

Also recently approved was idelalisib, the phosphoinositide 3 (PI3) kinase delta inhibitor, plus rituximab, not only for relapsed CLL but also for small lymphocytic lymphoma. How do you choose among these new exciting options?

It's going to be very difficult. The chlorambucil and obinutuzumab combination can be used up front in elderly patients. Ibrutinib for patients with the 17P deletion is a no-brainer at the moment, although there are other interesting drugs for 17P, such as ABT199.

But between ibrutinib and idelalisib, one thing to remember is that the idelalisib study[2] was conducted in patients who had comorbid conditions. They had abnormal renal function and couldn't tolerate chemotherapy. They had what is called a CIRS (Cumulative Index Rating Scale) score > 6.

These were patients who you wouldn't want to give chemotherapy to, whereas the ibrutinib data were generated in standard patients who were eligible for a clinical trial. Hopefully in the future, we will be able to predict which patients are more likely to respond to or be refractory to one or more of these drugs by studying intracellular pathways or other markers of disease responsiveness.

It is a very exciting time. Now we are trying to put drugs together in various combinations and permutations, because what we are seeing now are durable partial remissions. We would like to see some complete remissions so that eventually we can discontinue these drugs, instead of the indefinite administration of costly pharmaceuticals.

This is Bruce Cheson, signing off for Medscape Hematology in a very exciting time for CLL doctors, and particularly for their patients. Thank you for your attention.

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