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Ibrutinib and Rituximab (IR) is Superior to Chemo-immunotherapy (CIT) in CLL: Big News, or is it really? And did they get it right?

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When CNN has a headline that Chemo-free drug combo shows ‘dramatic’ improvement against common leukemia in adults and reports on a medical journal article on a rare disease such as CLL that’s big news, isn’t it?

When New England Journal of Medicine (NEJM), arguably the most prestigious medical journal in the world, publishes Ibrutinib–Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia, that must mean it’s very important.

Well it is big news and it is very important, but it needs to be understood in context of all the ongoing CLL research.

The original data was presented at ASH (American Society of Hematology) Annual Meeting in 2018 as a late breaking abstract to excited press coverage, at least in the hematology world. Even if the lay press didn’t pick it up then, this data was the big buzz at ASH and it was one of the most anticipated oral presentations at the conference.

Here is my interview with the lead researcher, Dr. Tait Shanafelt, and to the actual abstract that proved once and for all in a large collaborative head to head prospective randomized clinical trial (RCT) that patients had improved progression free survival (PFS) with ibrutinib and rituximab (IR) compared to the best CIT we have for young fit patients, FCR (fludarabine, cyclophosphamide and rituximab).

The next step with such important research is to have it published in a peer reviewed journal, and acceptance in the competitive NEJM assures it will be widely read by all specialties and considered strong and significant. The publication also lets the authors add more context, flesh out the details and present more data.

So, the hype is true. Ibrutinib and rituximab is better than the best CIT we have for CLL, FCR (fludarabine, cyclophosphamide and rituximab).

But the missing piece is at that same ASH 2018 meeting, Dr. Jennifer Woyach presented the results of Alliance A041202, another large collaborative RCT, that studied a different “gold standard” chemo-immunotherapy, namely bendamustine and rituximab (BR) versus ibrutinib (I) versus ibrutinib plus rituximab (IR) in older patients who likely wouldn’t tolerate FCR. Here is the link to my interview with Dr. Woyach and her abstract.

Again, the ibrutinib therapy was superior to the best CIT we have for the older population in terms of PFS.

For those of us who have been following the ibrutinib story for the last 7 or 8 years, we were not surprised.

We knew it was better from our own experiences and that of fellow patients, but now we had the data to back us up.

And if one had been paying attention to all the research, the following also would not have been a surprise either.

There was no difference in the outcomes of ibrutinib on its own versus using it combined with rituximab.

In the PFS data from the graph below taken directly from the abstract, we can see the solid black line for BR shows more folks progressed, while both the solid (I) and broken (IR) grey were superior and nearly identical to each other. The closer the lines hug the top of the chart, the fewer CLL patients that were progressing.

So, if I and IR are pretty much identical in their results in the BR trial, can we be certain that they will also be equivalent if they both had been compared to FCR?

The absolute correct technical answer is no because different populations were studied in the 2 trials.

Without another large head to head trial (and that is never going to happen), we will never be 100% certain.

That said, all the CLL experts agree and all the data in the Alliance trial above and in many others have repeatedly shown no benefit to adding rituximab to ibrutinib. It may never be 100% certain, but it’s pretty close.

So, don’t get carried away with the opening of the CNN article:

When used together, two drugs that treat the most common leukemia in adults significantly increase survival and lower the risk that the disease will worsen, according to a new study.”

The heavy lifting is being done by one drug, ibrutinib and that may be all you ever need.

Research has now shifted to asking what is the best combination of non-chemo drugs to use to treat chronic lymphocytic leukemia, and while that combo will very likely include ibrutinib, it is not likely to include rituximab.

Stay strong,

Brian

Brian Koffman MDCM DCFP, DABFM, MS Ed

Co-Founder, Executive VP and Chief Medical Officer
CLL Society, Inc.