This article looks at the interim analysis of E1912, a U.S. randomized phase III trial comparing ibrutinib/rituximab, followed by ibrutinib to disease progression vs 6 months of FCR among patients withCLL younger than age 70.
"Although the study was not stratified by IgHV mutation status, the results are clearly driven by outcomes in IgHV-unmutated patients in whom 3-year progression-free survival was 90.7% (Ibrutinib+R) vs 62.5% for FCR.
Among IgHV-mutated patients, in contrast, 3-year progression-free survival was identical, at 87.7% for ibrutinib/rituximab and 88% for FCR, with just three deaths occurring (two with ibrutinib and one with FCR).
This analysis is particularly important given that among IgHV-mutated patients, three different studies have demonstrated long-term, treatment-free, prolonged progression-free survival (possibly cure!) after 6 months of FCR, with a 54% plateau in the progression-free survival curve with 12-year follow-up.
Patients with normal fluorescence in situ hybridization (FISH) findings or trisomy 12 did not show a significant progression-free survival benefit with ibrutinib/rituximab.
It is essential to understand the toxicity burden of different therapies. Adverse events of grade 3 or higher were similar between the ibrutinib/rituximab and FCR arms, with more nonhematologic toxicity with ibrutinib/rituximab and more hematologic toxicity with FCR. Older patients had higher rates of ibrutinib-associated cardiac toxicities and death in the randomized older patient trial led by Alliance.
Newer combinations that achieve high rates of undetectable MRD including the ibrutinib-plus-FCR regimen, which achieved 84% undetectable MRD in bone marrow at best response, with 16.5-months of follow-up. The MD Anderson group has reported on front-line ibrutinib with venetoclax, with 61% undetectable MRD Venetoclax with obinutuzumab achieved 57% MRD in bone marrow in the CLL14 trial, with a 2-year progression-free survival rate of 88.2%. These regimens have planned discontinuation of therapy in deep remission, which has many advantages: likely prolonged treatment-free remission, decreased toxicity, decreased cost, decreased selection pressure for resistance, and patient satisfaction.
The field of CLL is moving very quickly, and the goal, particularly for younger, fit patients, remains undetectable minimal residual disease and time-limited therapy. Only in this way will we eventually reach a cure."
If I were a young person with mutated cll starting treatment today I would consider the iFCG trial where ibrutinib is added to a short course of FCG (gazyva being substituted for ritiuxumab).
One thing not clear to me in these comparisons is long term toxicity and long term survival. If a 50 yr old person with mutated cll took FCR and was cured, what would their marrow look like ten years out and how would their marrow compare to someone on ibrutinib alone? What is the risk of secondary cancers for both groups ten and fifteen years out?
I think the bigger question will be FCR vs novel drug combinations for the young and mutated. People who are young with mutated cll will likely do well with most therapies.
Will combinations like ibrutinib venetoclax and obinutuzumab (IVO) cure young people at a higher rate and with less toxicity than FCR? I think the answer to that is probably yes. But for a young person starting treatment today with mutated cll looking for a possible cure , as of today FCR is the most proven choice.
The question about FCR vs novel drug combinations is hoping to be answered in the UK FLAIR Study which has several participants in this forum. The difficulty is that these studies need thousands of patients and many many years to see a separation of the different arms.
Ideally, all patients should see an experienced CLL doctor and have their CLL and clinical history examined carefully so that the treatment can be personalised. We are fortunate that for many patients there are several effective treatment that will extend life and, in some circumstances, for some patients, offer a potential cure.
The Flair trial is hugely important and very much a fair fight. We see all too often drug manufacturers putting their drug up against known, inferior and outdated treatments (like chlorambucil) where it was a foregone conclusion their drug would win.
The difficulty is as you write, it will take time to know which treatment is best and many of us have to make treatment decisions now.
If I had to bet today, I would bet IVO outperforms FCR with a higher cure rate with less toxicity. But if I had to choose between the two now, it would give me a lot of pause. We have 20 years of data on FCR, only a few on IVO. Human nature is to think new means better, but that not always true.
It’s nice to have options. For those who are unsure and have access to ibrutinib, I am starting to see ibrutinib as kind of an extension of watch and wait where one can start on ibrutinib and so long as they tolerate it and it works, stay on it indefinitely while this all plays out.
Sushi, when I started ibrutinib it was three 140mg capsules a day, but all taken at the same time. Now I take one 420 mg tablet a day. It’s the same dose, so the change was really not much of a change for me.
One thing about those trials is that it’s easy for us to judge them now but at the time most of them were designed chlorambucil was seen as a standard treatment. And to satisfy a regulator they needdd to use a standard treatment or placebo (where that is appropriate given the condition). The regulators are involved in approving the choice of compactors.
I dont agree at all that at the time clinical trials were being developed for novel drugs that chlorambucil was standard treatment for cll, certainly not in the US . I have read several doctors critical of companies choosing chlorambucil as a comparator drug in trials, most notably Dr Sharman.
This wasn't a criticism I made up. Sharman said putting Chlorambucil against ibrutinib was like putting a Volkswagon against a Ferrari, the outcome of the trial was never in doubt.
Chlorambucil/Leukeran was approved in the USA in 1957!! It was still the treatment of choice in the early to mid 2000s, but then was overtaken for CLL treatment by FCR for young, fit patients and later by BR for older, less fit patients. After Chlorambucil + Obinutuzumab/Gazyva was approved by the FDA for CLL treatment way back in November 2013, some specialists were actually advising their patients to just throw away the Chlorambucil tablets if they weren't able to prescribe Obinutuzumab/Gazyva 'off label' as the sole treatment medication, because they considered that the very little additional benefit provided by Chlorambucil, was offset by the increased risk of side effects.
Chlorambucil is still a very important treatment drug for CLL - particularly in countries which can't afford to subsidise the newer treatments. It's on the WHO list of essential medicines, though even in Australia, where we don't have access to non-chemo drugs unless 17p del/T53 mutated, it is considered superseded!
Chlorambucil/Obinutuzumab was my first treatment. I hated Chlorambucil and every time I complained my previous doctor lowered the dose, but never suggested to drop it altogether.
Jeff if you look at page 14 of this pdf (2015 USA NCCN CLL guidelines), you'll see that obin+chlorambucil was the go-to first-line therapy regimen for frail patients.
Your comment about Ibrutinib is important Jeff as the thinking is developing that Ibrutinib may control CLL for a large number of previously untreated patients indefinitely. Venetoclax is thought to be less likely to hold it for such a long time despite the high rates of U-MRD. (note - no references, I can't remember where I read or saw this)
I do not know about venetoclax Jackie and how long it might work. I did ask my doc about ibrutinib and there is some thought that it might work indefinitely, as you say, particularly for previously untreated patients.
I know with FCR there is a thought out there that if you have not progressed ten years out, you probably never will. With a small first cohort of untreated patients with ibrutinib, something close to 75% have not progressed at 8 years out. If that number holds at ten years out, the debate will intensify as to what the treatment goal should be with cll - go for remissions and time limited therapies or go for long term disease control. And it might be that one plan is better for one person and not the other.
Sue, it's saying that for mutated patients there was no difference between the two treatment groups but for unmutated patients then the Ibruitnib/Rituximab was much better, with a 3 year progression-free survival at 90.7%, but for the unmutated patients treated with FCR it was only 62.5%.
I hope we in the UK go down the path of trying for combinations to achieve long deep remission as opposed to what we and I am on at present (single therepy ) ibrutinib which is going well for me 3 half years but of course resistance could happen at any time likely after 5 years and I believe with combination therepy this could be delayed further possible avoided and also give treatment breaks which would save money and be good for the patient
Just a comment speaking to the general response to this post -
When speaking of a cure, are we saying that cure is defined by a Progression Free Survival beginning with MRD and extending until deceased from defined normal cause?
I am of the perspective that with treatment choices their are comparable measures of irreversible physical change which include compromise to ones immune capability and their impact on quality of life.
I believe that treatment choice is still very complicated and individual. My definition of a cure would be a return to normal biological measure relative to the whole person with a minimal adverse treatment response.
Gene Wilder once said "It's Alive" - Young Frankenstein 1974
In most cancer treatment a five year survival with no recurrence is regarded as cure. Of course that's not true for us and our sneaky CLL and I think it will still be difficult to define a cure even after many years of progression free survival. The UK FLAIR Study will be following all the participants for the rest of their lives and they will be updating the data every year or so one they start reporting. That will be very important to follow. It would be wonderful if cure if also meant restoration of a functional immune system.
You are right, treatment is very complex and very individual, taking everything, including clinical history and other comorbidities into account. It's a nuanced decision but bear in mind that unfortunately not every treatment or combination is available to everyone.
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\"Undetectable Measurable Residual Disease\"
