ASH 2017: Dr. Adrian Wiestner on Combination Therapy in CLL (chronic lymphocytic leukemia)

At ASH 2017, in Atlanta, Dr. Adrian Wiestner who leads the CLL research team at the National Institute of Health spoke about the combination therapies for chronic lymphocytic leukemia.

We have discussed combinations often on these pages but Dr. Wiestner brings a thoughtful and nuanced perspective to this critical discussion about the future of CLL treatment.

Key Take Aways:

• Combinations of venetoclax and monoclonal antibodies (mAb) or venetoclax and ibrutinib are, in some circumstances, leading to remission rates that are better than that achieved with chemo-immunotherapy.
• The Murano trial that combine venetoclax and rituximab had an amazing 83.5% MRD (minimal residual disease) negative rate in the peripheral blood.
• There is a price for this. While these are not controlled trials with the venetoclax/mAb trials, there are higher rates of neutropenia (low neutrophil counts) and a suggestion there may be more serious infections, especially those normally seen in those with impaired immunity. Neutrophils are important for fighting infection and can be boosted with “growth factors” such as Neupogen or Neurlasta that stimulate the bone marrow to make more neutrophils to provide a margin of safety.
• While adding a mAb to venetoclax markedly improves responses rates, it doesn’t seem to improve ibrutinib’s efficacy and some ibrutinib combination trials are not being amended to not add a mAb but venetoclax instead.
• The combination of ibrutinib and venetoclax is particularly effective. More on this soon from EHA ((European Hematology Association) Conference last month in Stockholm.
• Adding ibrutinib to the “gold standard”, chemo-immunotherapy FCR (FRCi) results in high levels of complete remissions with similar short-term toxicity as compared to FCR alone.
• This suggests that the small but very serious long-term risk of a secondary blood (myeloid) cancer would be the same for FRCi as it is for FCR alone.
• If this FCR-ibrutinib combination proves to be a potentially curative approach, each patient and doctor must decide what is his or her acceptable risk of developing a secondary more dangerous cancer for this shot at a cure.
• While there is a push for “fixed duration” treatments, where the patient can stop treatment after a fixed time, Dr. Wiestner makes a strong scientific argument to be made to indefinitely continue B- cell receptor (BCR) inhibitor therapy such as ibrutinib.

As we have said before, combinations are clearly the future for CLL treatment. We are learning more about the best combinations and better understanding the risks and benefits involved.

You can watch my ASH 2017 interview with Dr. Wiestner below or read the transcript here:

Here is Dr. Ian Flinn presenting his data on the combination of venetoclax and obinutuzumab (Gazyva) at ASH 2017 where in a small study 100% of patients achieved MRD neg. in their peripheral blood.

Here is Dr. Matt Davids’ research on the combination of FRC plus ibrutinib (FCRi) with “83% achieving BM MRD-neg, significantly higher than the 20% rate seen historically with FCR alone.”

Here is Dr. Nitin Jain’s abstract in the combination of ibrutinib and venetoclax.

I will be presented exciting updated data soon from the recent EHA conference.

We have frequently referenced the MURANO including here.

Here is the link to the MURANO abstract.

Thanks for reading and revisiting this recurrent theme.

Stay strong

We are all in this together.

Brian