Dr. Rick Furman of Weill-Cornell answers your questions in our ASK THE DOCTOR feature in our quarterly newsletters, responds to many more questions in the CLLSLL.io group, (an active forum for CLL patients and caregivers worth checking out), and has done pivotal research on new therapies that have redefined how chronic lymphocytic leukemia (CLL) is treated.
He has also been one of the leaders of the growing faction of CLL experts who seek to avoid chemotherapy for most of his patients.
Thanks to Dr. Furman and the patients and team at the [email protected] for first posting this important discussion.
We want to share it again with a difference audience and with my usual commentary.
Take Away Points:
- FCR is a powerful cocktail of chemo-immunotherapy drugs (two chemo drugs: fludarabine, cyclophosphamide, and the monoclonal antibody, rituximab).
- Like all chemo, FCR works by damaging DNA.
- FCR kills the chronic lymphocytic leukemia cells that are sensitive to it. The remaining resistant CLL cells will, by definition, be more refractory to therapy and often harbor a broken piece of DNA. When patients relapse, they may discover that their CLL is now missing the short arm of the 17th chromosome (17p deletion).
- This mutation confers a poorer prognosis with all existing therapies and specifically renders the CLL insensitive to all forms of chemo.
- The DNA damage also increases the risk of MDS (myelodysplastic syndrome), a cancerous form of bone marrow failure that is often difficult to treat.
- CLL and all elderly patients are already at higher risk of MDS and many other types of cancer, even without chemotherapy.
- We don’t know if lower doses of chemo are freer of these long-term problems.
- That said, some 30% of patients treated with FCR for only 6 months are still in remission 10 years later with no further treatment.
- Most of these fortunate patients have the most favorable prognostic markers.
- Ibrutinib is not chemo and does not damage DNA.
- Ibrutinib works well in all types of patients, including those with del 17p.
- It works amazingly well in the upfront treatment of low-risk patients with nearly a 100% progression free survival at 6 years out. These are the same patients that are most likely to have a long remission from FCR, but the numbers are much lower, but admittedly, the data is more mature.
- The data on ibrutinib is now and will always be less mature than the data on older therapies such as FCR.
- Ibrutinib can cause serious side effects, including bleeding, atrial fibrillation and high blood pressure.
- The science suggests that the problems associated with ibrutinib are reversible and usually less dangerous compared to chemotherapy.
- Ibrutinib works best when used upfront in patients without del 17p. Del 17p is rare in that setting, but much more common after treatment with chemotherapy.
Here is Dr. Furman’s commentary:
I believe there are several issues here, but will try to address issues that are of general interest to everyone.
We will never have follow up data on ibrutinib and the novel agents as long as our data on FCR. I do not believe that this should ever serve as reason to not use the novel agents. We do have the ability to apply what we know regarding biology (chemotherapy breaks DNA, ibrutinib does not) to surmise what could be expected with longer term use. My bias is to avoid chemotherapy, especially in younger patients as we don’t know what will happen to bone marrow function when the 50 year old is 70 years old. There is an incidence of myelodysplastic syndrome (MDS) in 70 years old without chemotherapy. Given the risk of MDS in patients after FCR at 10 years, I believe it is fair to be concerned that there will be a potential increase later as well. With the novel agents, there is very little evidence that any toxicities seen are irreversible and therefore being wrong regarding ibrutinib is far less deleterious.
We assume more chemotherapy is always worse, but we do not know what amount of chemotherapy is not dangerous. We can never assume how much of a response one individual will have to a particular treatment. We can only guess how a population of people will do. There are many indicators of response to FCR. The FCR 300 data, which represents 300 patients treated with FCR at MD Anderson Cancer Center suggests a plateau of 30% at 10 years. 75% of this plateau are mutated patients. The other patients really fall everywhere. We also have good data from the German CLL Study Group (CLL4 Trial) that FC is more effective than F, but that this benefit was almost completely due to the marked improvement seen with FC compared with F in patients with deletion 11q. Therefore, in patients not deletion 11q or 17p, FR is likely of equal benefit compared to FCR (with caveats).
Additionally, it is always best to “put our best foot forward first”. This statement was taught to me while in training, and it has always held true. Currently, we know that the most important risk factor leading to progression on ibrutinib is the presence of deletion 17p. At diagnosis, deletion 17p has an incidence of 3-5%. When looking at the pivotal studies for ibrutinib and idelalisib in relapsed patients the incidences of deletion 17p were 35-45%. This would suggest that the way to end up with higher incidences of deletion 17p, and likely having the greatest impact upon long-term response to ibrutinib would be by using chemotherapy, as it does select for deletion 17p.
Do remember that this is just one man’s opinion.
I hope this helps.
Not every one agrees.
Consider these points:
- 6 months and done is appealing for many and might be considered, but I argue only if you are “mutated” and have no poor prognostic markers.
- MDS is still a relatively rare cancer in CLL patients.
- Combinations of adding ibrutinib and chemo have shown positive results and might offer the promise of being able to stop treatment and coast a long time with no treatment. Ibrutinib on its own doesn’t really provide this appealing option.
- There is little data on the efficacy of FCR after progressing on ibrutinib, but there is clear evidence that ibrutinib works well (though not as well as when used frontline) after failing FCR.
- There is always the possibility serious problems could emerge with longer use of ibrutinib.
Each one of us patients has to make our own best-informed decision.
Bottom line for me and the advice I would give if asked:
Avoid chemo, even if one fits the profile of those with the best likelihood of benefiting long term
I am trusting the devil (ibrutinib) we are getting to know for about 7 years now versus the one (chemo) we have known for decades.
But I understand and respect those who decide otherwise.
Brian Koffman, MD 12/5/17