This is an abstract from the Lancet article. There's a fair bit of detail missing regarding the profile of the CLL patients in terms of IgHV mutation status etc and the follow up is still very short but they are claiming that this is the best response ever published in patients with CLL unrestricted by prognostic markers (except they don't tell us in this abstract what they were for this cohort).
"Fludarabine, cyclophosphamide, and rituximab (FCR) can improve disease-free survival for younger (age ≤65 years) fit patients with chronic lymphocytic leukaemia with mutated IGHV. However, patients with unmutated IGHV rarely have durable responses. Ibrutinib is active for patients with chronic lymphocytic leukaemia irrespective of IGHV mutation status but requires continuous treatment. The trial was based on the premise that time-limited ibrutinib plus FCR would induce durable responses in younger fit patients with chronic lymphocytic leukaemia.
Ibrutinib was given orally for 7 days, then up to six 28-day cycles were administered intravenously of fludarabine, cyclophosphamide and rituximab with continuous oral ibrutinib (420 mg/day). Responders continued on ibrutinib maintenance for up to 2 years, and patients with undetectable minimal residual disease in bone marrow after 2 years were able to discontinue treatment. The primary endpoint was the proportion of patients who achieved a complete response with undetectable minima lresidual disease in bone marrow 2 months after the last cycle of ibrutinib plus FCR.
85 patients with CLL were enrolled. del(17p) was detected in four (5%) of 83 patients and TP53 mutations were noted in three (4%) of 81 patients; two patients had both del(17p) and TP53 mutations. Median patients' age was 55 years. At data cutoff, median follow-up was 16·5 months. A complete response and undetectable MRD in bone marrow 2 months after the last cycle was achieved by 28 (33%, 95% CI 0·23–0·44) of 85 patients (p=0·0035 compared with a 20% historical value with FCR alone). A best response of undetectable minimal residual disease in bone marrow was achieved by 71 (84%) of 85 patients during the study. One patient had disease progression and one patient died (sudden cardiac death after 17 months of ibrutinib maintenance.
Ibrutinib plus FCR is promising as a time-limited combination regimen for frontline CLL."
The UMRD-6 numbers look much better in the iFCG study (though it was only for mutated patients), and iFCG is only three cycles, so half the chemo of the iFCR trial. (Which hopefully means half the expected long term AML/MDS, one of the aims of the study.)
So glad to see FCR still has it's place! I sometimes feel badly when comments put down chemo treatments and make it sound like a bad choice. So many still need chemo and for many it's successful. 💕
Its always great to read about a successful study, but I do not know how helpful this study is in deciding treatment options other than to say that adding ibrutinib to FCR shows some short term benefit. Maybe at the time the study was designed there was some question if that would be the case. Given that ibrutinib has an entirely different mechanism of action than FCR, you would expect some improvement over FCR alone.
Its a small group and as Jackie points out, without knowing IGHV status its really hard to know the relevance of these results. Since FCR doesn't treat 17p effectively and ibrutinib does, that would skew the numbers right there.
I think the iFCG study, as avzuclav points out, is the better designed trial. One reason people would pick ibrutinib over FCR would be the toxicity of FCR and possible increased risk of other cancers. iFCG combines ibriutinib with a shorter chemo cycle and substitutes Gazyva for Rituxan, Gazyva is a stronger version of Rituxan.
An evolving view of cll is that treating it is a long game, not a short one. I think this would have been a better trial with an ibrutinib arm only to compare with the FCR - I arm. The FCR -I arm would no doubt win at five years out. I would want to see what it looks like ten years out.
Some of those people with mutated IGHV will still be in remission and if they have not gotten a secondary cancer, choosing FCR will look like a great choice. But there might be some in the group who have not progressed purely due to the ibrutinib, most people who start on ibrutinib as a first drug have not progressed thus far. Has the added toxicity of FCR helped or hurt them?
Until we know more about ibrutinib and venetoclax long term, FCR will have its place for cll treatment, primarily among younger people with mutated ighv cll looking for a knockout punch to their cll.
Does adding ibrutinib help? Short term it appears to help. I dont think this study helps with the long term answer. But yes, if you take FCR and add ibrutinib, in the short term the odds for a good result are better.
It has to be personalized. I do not think FCR added benefit to those in this study with 17p cll, it might have made it worse long term.
FCR is not indicated for those with 17p cll. I think even in the UK, where FCR is standard frontline therapy, they will do a FISH test before treating and if a person has 17p deleted or TP53 mutated Cll they are eligible for ibrutinib. Why FCR does not work with 17p has something to do with the TP53 cancer fighting gene being missing in 17p cll.
In some countries, like the UK, FCR is still used with unmutated cll cases so long as they are not 17p deleted. Generally speaking, the remissions with FCR with unmutated Cll are shorter than the remissions with mutated Cll. Some people with non 17p unmutated Cll still do very well with FCR.
In the US, FCR is generally not the favored treatment for any type of unmutated Cll. Ibrutinib or venetoclax is preferred. But FCR does work for non 17p cll, its just on average a shorter remission than for those with mutated Cll.
People with mutated cll starting out on FCR have a decent chance of being cured.
And also a higher risk of incurring mutations in their DNA that may lead to other cancers, p17 del and destruction of their bone marrow and imune system
My specialist has indicated that FCR as second-line (after V+O) might still be a potential cure in my case down the line. Nice to have that in my pocket.
If FCR is likely to cure you then almost certainly you will have a fantastic response to V+O and who knows what will be available by then in years to come. Good genetics is good genetics, whatever treatment you have
I've never heard of people having FCR after V+O but certainly some people have had a BTKi after V+O with good results.
That's what I'm hoping! I chose V+O over FCR primarily because I had to have treatment during a pandemic and knew that FCR would cause more immediate damage to my immune system, whereas V+O would slowly improve it. But no bones about it, 3/4 specialists who looked at my case said FCR was probably my best shot. Still, my specialist feels very strongly about the potential of V+O
Also, I think the reason FCR-after-V+O is unheard of is that V+O is still new enough that for those whom it works well (good markers) it's still working whereas for those whom it works poorly, FCR is a bad option anyway.
From the publication, a very bold and impressive statement -
"The proportion of patients who achieved undetectable minimal residual disease in bone marrow with ibrutinib plus FCR is, to our knowledge, the highest ever published in patients with chronic lymphocytic leukaemia unrestricted by prognostic marker status." Published:June 14, 2019
Thanks, still not much detail regarding the patient's CLL characteristics. I can't understand why they aren't publishing it but it may be in the full article behind the Lancet paywall.
Please find my experiences over the combination therapy of chemo Rituximub and Bandamustine that I very much like to share with you
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In mid 2013, I was Diagnosed having CLL (accidental finding on routine blood test)
Since then I was under W&W for a long period till 2017. Same year in November I had a TIA at work place and was admitted and treated. Fortunately its mild and left me with no damage.
However since the episode of my TIA, I started experiencing increased fatigue and malaise and at the end of 2018, its noticed during my blood work, there was sudden spike of Leucocytes and low Neutrophils. Then my Oncologist suggested that its was the right time to start Chemo with Bendamustine + Rituximub (6 cycles of BR spread over 6 months)
Accordingly in Jan 2019, I had first Cycle of B+R (administered very slow for 5 days) It’s a nice feeling as I didn’t felt any side effects. Subsequently in February 2019, I was administered 2nd cycle of BR for 2 days which was also quite uneventful. I was very happy with chemo as there was no side effect. But after 2 weeks of 2nd cycle, suddenly I started experiencing side effects of chemo mainly skin itch over my face neck and shoulders. Initially the itch was so terrible over my forehead eye brows cheeks neck & shoulders. I was referred to Dermatologist who diagnosed it as Eosonophilic Folliculitis. The skin itch (EF) was attributed to the Chemo drugs Bendamustine and Rituximub. There were different of opinions that some felt that the reaction was solely due to Rituximub, and some experts felt its due to Bendamustine.
I underwent series of Consultations with Dermatologists in Geneva, as well as in India (Indian) I had good recovery from the itch but not fully as I am coping with some degree of skin itch still. I continue taking anti histamines steroid creams etc, Having said that, I must also confess that the BR treatment gave me remission from CLL as my blood counts came back to normal.
My Oncologist was very happy to notice the efficacy of BR as I was blessed with remission with only 2 cycles of BR. However the remaining BR cycles were discontinued as it may endanger my life with severe reaction if continued.
Overall RITUXIMUB is a wonderful drug with maximum benefit of curative effect. However, one has to anticipate and accept the side effect that it may brings to you. But it depends upon individuals, as some may tolerate and some may not, for the R. I am happy for my remission as it has improved quality of my life too. I believe that my above described experiences will answer some of your concerns at least. Nevertheless please bare in mind the efficacy of the drug Rituximub and well prepare to face certain minor side effects (tolerable) and expect quick remission from CLL. wish you all the best. If you need further clarification please do not hesitate to write on this platform .
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Dr. John Allan - Chronic Lymphocytic Leukemia (CLL) Patients @Undetectable Measurable Residual Disease (MRD) after Ibrutinib Plus Venetoclax
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