Smart Patients Get Smart Care™

The World’s Leading Authority for Chronic Lymphocytic Leukemia Patients

ASH 2018: Dr. Woyach on ibrutinib with or without rituximab versus bendamustine plus rituximab

In science and medicine, information is constantly changing and may become out-of-date as new data emerge. All articles and interviews are informational only, should never be considered medical advice, and should never be acted on without review with your health care team.

Dr. Brian Koffman - CLL Society

By Brian Koffman, MD

This is really big news.  Practice changing news.

Dr. Jennifer Woyach of Ohio State presented the results of the large phase III Alliance A041202 collaborative multi-centered trial that was designed to see if we should change how we treat chronic lymphocytic leukemia in older patients who have never been treated before.

The findings were so important that it was rewarded one of the six prestigious spots for the plenary presentations at ASH 2018.

This trial was powered to discover which is the best frontline treatment for CLL patients 65 and older, a cohort that represents the majority of chronic lymphocytic leukemia patients.

There were 3 arms:

  1. Bendamustine plus rituximab (BR) given over six one-month cycles if tolerated then stopped- generally the recommended and most commonly used chemo-immunotherapy for this age group.
  2. Ibrutinib (I) – the oral BTK inhibitor that is taken indefinitely and has revolutionized care in CLL.
  3. Ibrutinib and rituximab (R)- adding to the ibrutinib backbone, rituximab, the most commonly used monoclonal antibody in treating CLL that has been shown to add significant benefit when added to chemotherapy or novel agents such as venetoclax.

Take Aways:


  • Between 12/9/2013 and 5/16/2016, 547 patients were registered of which 2/3 were men. The average age was 71.
  • 28% had either deletion 11q or 17p making them high risk.
  • Cross-over was allowed so if patients progressed, they could switch to their potentially best treatment. In my opinion, this is the only ethical way to run a trial.


  • Progression free survival (PFS) was 43 months in the BR arm, meaning that ½ the patients had progressed by approximately 3½ years.
  • PFS has not been reached in either ibrutinib arm meaning that less than ½ had not progressed when the data was last reviewed.
  • At 2 years out, 74% of the BR group were alive and progression free compared to 87% who were receiving I and 88% who were on IR.
  • There was a clear statistical and real clinical benefit for those in both the 2nd and 3rd arms that included ibrutinib.
  • There was no evidence of any benefit found by adding rituximab to ibrutinib as those two trials arms were nearly identical in terms of PFS.

Adverse Events:

  • These are difficult to assess as BR is only six months and done, compared to the two ibrutinib containing arms which is taking until progression of intolerance.
  • Blood related problems, mostly low counts such as anemia, low platelets and low neutrophils were more common in the BR arm.
  • Non-blood related adverse events were more common in the ibrutinib arms:
    • Atrial fibrillation was more common at a rate of between 10%-20% at any time during treatment.
    • Hypertension was more common and can be seen anytime but developed most often early in treatment.
    • There was a numerically but not a statistically significant increase in the number of unwitnessed deaths. “Unexplained or unwitnessed death over the entire observation period was seen in 2 (1.1%), 7 (3.9%), and 4 (2.2%) pts (p=0.24) in Arms 1, 2, and 3 respectively”.
    • Ibrutinib may cause more serious ventricular heart irregularities that might explain this. It must be and is being studied.
    • Unlike in other studies, there was no statistically significant increased bleeding risk in the ibrutinib arms.
    • Only 14% discontinue either ibrutinib arm.

Future Trials

  • New research will be looking at fixed duration combinations of non-chemo novel therapies that include ibrutinib plus obinutuzumab with or without venetoclax.
  • Here is a link to that trial that is now open and at multiple sites across the USA.


The role of bendamustine plus rituximab in CLL patients is increasingly limited.

Our mission is to make sure the news from ASH 2018 is heard by all chronic lymphocytic leukemia patients, and maybe more importantly by all the doctors who treat them. The implication of these research findings should be game changing. We want to make sure that it is, and all patients enjoy the benefits of where the science is leading us.

Our next mission is to reduce the adverse events associated with ibrutinib by perhaps using a fixed duration therapy. So, our work is far from over and more trials are needed.

Please enjoy this important interview with Dr. Woyach from ASH 2018:

Here is a link to the actual abstract: Ibrutinib Alone or in Combination with Rituximab Produces Superior Progression Free Survival (PFS) Compared with Bendamustine Plus Rituximab in Untreated Older Patients with Chronic Lymphocytic Leukemia (CLL): Results of Alliance North American Intergroup.

Stay strong.

We are all in this together.


Brian Koffman MDCM DCFP, DABFM, MS Ed

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

Dr. Brian Koffman, a well-known doctor, educator, and clinical professor turned patient has dedicated himself to teaching and helping the CLL community since his diagnosis in 2005. He serves as the Executive Vice President and Chief Medical Officer of the CLL Society Inc.

Originally published in The CLL Tribune Q1 2019.