During a presentation at the 2019 Society of Haematological Oncology Annual Meeting, Dr Jain said recent clinical trial findings have helped clarify therapy choices based on the patient’s age, comorbid conditions, and mutation status but that questions about optimal regimens and the duration of therapy remain unanswered.
In analyzing which patients derived the most benefit from the former standard of care, Jain said data from prior studies showed frontline FCR therapy resulted in favorable long-term progression-free survival (PFS) in patients with IGHV mutations who had achieved undetectable minimal residual disease (MRD).
They designed a phase II study testing the combination of ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) for the frontline treatment of patients with CLL with mutated IGHV and without TP53 aberrations. Investigators included obinutuzumab because previous results showed that the drug induced higher rates of MRD negativity than rituximab. Patients received 3 cycles of iFCG followed by ibrutinib for 9 cycles and obinutuzumab for either 3 or 9 cycles, depending upon response and MRD levels. After 12 cycles, ibrutinib therapy stopped for those with undetectable bone marrow and continued for those with detectable MRD. The study enrolled 45 patients with a median age of 60 years (range, 25-71) with CLL categorized on the Rai stage as 0 (n = 1), I or II (n = 22), and III to IV (n = 22).
In findings presented at the 2018 ASH Annual Meeting and updated in August 2019, investigators found that response improved over time. At 3 months, 39% of patients had complete response (CR) or CR with incomplete hematologic recovery (CRi) and 89% were MRD-negative. At 12 months, CR/CRi was 73% and MRD negativity was 100%.
I find your addition ("but FCR still has its place") to the post title a bit misleading based on the referenced article. I think the point of the article is to show that adding novel agents with a reduction in chemoimmunotherapy (3 cycles instead of 6) seems to drastically improve results. Of course I'm jumping to conclusions, but 45 patients with 100% achieving MRD- at 12 months is unparalleled.
"Jain said those findings were superior to results from other trials evaluating 6 cycles of FCR, ibrutinib plus FCR, or FC plus obinutuzumab, for patients with IGHV-mutated disease."
Thanks for sharing Jackie. More evidence that combination treatment is probably the future way forward. 100% MRD undetectable is a pretty good result!
I’m personally more and more convinced that trying to achieve disease annihilation (that sub group of MRDU who will never again relapse ) is surely a good strategy especially early in disease.
I would love to see a study or say adding both venetoclax and obinituzimab to those patients currently showing good response to Ibrutinib to see if they too could get to MRDU. Interesting to see here how the use of I with drugs thaf work very differently to it has worked so well.
I also wonder what the disease would look like in someone who eventually did relapse from one of these super combinations. It would seem logical that the disease might be less likely to have become resistant as any clone that was resistant to one of the treatment should in theory have been killed by the other.
None of us know really what the best long term option is for us. On the one hand we could try a series of drugs one after the other moving from one to the next if and when the CLL becomes resistant to each drug. The alternative would be to hit it with a combo up front for a relatively short period with the goal of eradication and the hope that the CLL wouldn’t have had a chance to get resistant to the combo and it would work again. Even if there isn’t a cumulative effect of several drugs stopping resistance to each other lets take ibrutinib alone if you were destined to get resistant to it after say five years of continuous use perhaps we can split that five years into five separate single years (or even less) in combo with something else to get to MRDU.
With antibiotics we generally don’t like giving them to people continuously
Unless we can avoid it because of this issue of genetic mutation in his case of the bacteria.
Anyway nobody really knows of course which is why trials which compare different strategies in the very long term is going to be crucial for us.
I'm unmutated, lymph nodes getting bigger and still loosing weight so I think I'm three months from treatment. So my question is, where are we in approval process of obinutuzumab plus veneticlax. I read impressive stats on this combo and would like to get back to full productivity ASAP. (which I still am right now). Anyway will I have to find a trial or is this pretty close to approval for treatment naive.
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I think the point of the article is to show that adding novel agents with a reduction in chemoimmunotherapy (3 cycles instead of 6) seems to drastically improve results. Of course I'm jumping to conclusions, but 45 patients with 100% achieving MRD- at 12 months is unparalleled. 
Five-year results for the iFCG regimen: first-line treatment of CLL patients with mutated IGHV and without del(17p)/TP53 mutation
