An update of the long-term follow-up results from the original 300-patient FCR (fludarabine, cyclophosphamide, and rituximab) study initiated at MD Anderson in 1999, Sustained remissions in CLL after frontline FCR treatment with very-long-term follow-up, reports ~47% of patients with mutated IGHV have achieved remissions approaching 24 years. ashpublications.org/blood/a... Basically, if you have mutated IGHV (IGHV-M) and you achieve a 10 year remission, you have a very good chance of never needing further treatment for your CLL. "Only 4 of 45 patients (9%) with IGHV-M progressed beyond 10 years."
"..for young, fit patients with CLL, we need to consider their outcomes not only at 5 years after starting therapy but also at 20 years and beyond. With a median follow-up of 19 years, they report a median PFS for patients with IGHV-M CLL of 14.6 years. Disease progression beyond 10 years was uncommon, suggesting that some patients had “functional cure” of their CLL; however, a 6.3% cumulative risk of therapy-related myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) was observed."
The big advantages of combination targeted therapies (venetoclax + obinutuzumab and ibrutinib+ rituximab shown in the accompanying PFS plots), are that not only are they proving superior to FCR, you don't need to be a young (aged 65 or younger), fit patient to go through these treatments, there is no longer a significant PFS difference between IGHV-M and IGHV-UM and there isn't the cumulative risk (6.3%) of developing therapy-related myeloid neoplasms (tMNs), i.e. MDS and AML. Of note, these were fatal in 16 of 19 (84%) of the cases.
Dr David comments "Although we are optimistic about the durability of remissions achieved with long-term sequential use of targeted therapies, our answer to that important question today is that we do not know, because follow-up with the targeted therapies is not nearly long enough." This is why the survival statistics you'll find through an online search are so misleading. We don't yet have 10 year survival statistics for the improved combination targeted therapy treatments, because clinical trials for these only commenced within the last 7 years. Hence the question marks in the above PFS plots. Importantly, the median age at diagnosis for CLL is about 70 and the median age for first treatment about 75.
Prior to the advent of targeted therapies, we only had chemoimmunotherapy treatments, typically BR (bendamustine+rituximab) or a very old drug chlorambucil to offer to most patients needing treatment. FCR was the first treatment which was proven to increase life expectancy, but very few patients could benefit from it. According to the US SEER database, seer.cancer.gov/statfacts/h... around 32% of CLL diagnoses occur at or before age 64. The IGHV-M : IGHV-UM ratio is about 50:50 at diagnosis, but because IGHV-M is associated with a longer time to first treatment, more IGHV-UM than IGHV-UM folk need treatment; the ~30% of patients who never need treatment are predominantly IGHV-M.
Dr Davids concludes, "So now when I sit with a young patient with CLL and he or she asks what I would choose for frontline therapy, the answer is less clear than it used to be. Based on the very-long–term data from Thompson et al, FCR remains a reasonable choice for young, fit patients with IGHV-M CLL, particularly in countries where access to frontline targeted therapies is limited. But given the risks of secondary MDS/AML, prolonged myelosuppression, and infectious complications, my usual answer now is that I would choose a targeted therapy regimen and hope that we will continue to develop new approaches to add to the impressive array of novel therapies we already have available for patients with CLL. If past performance is a predictor of future results in CLL, then the progress of the last decade bodes well for the therapeutic advances we are likely to continue to make in the next decade and beyond."
(My emphasis)
Neil
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AussieNeil
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Thank you Neil for sharing- Dr David's is an amazing CLL Expert and is my hubby's Dr. When we 1st met him he informed us excitedly, "there will find a cure in your lifetime " I believe him.
Ibrutinib + Rituximab is not used but is FDA approved.
Alliance trial found no difference between Ibrutinib with or without Rituximab for the 90%(+?) for whom FCR is not suitable. Age was over 65, median age was 71, CIT standard of care was BR.
The benefit of ibrutinib regimens over CIT, with no additional benefit of rituximab when combined with ibrutinib, was consistent for all subgroups of patients defined by TP53 abnormalities, del(11q), complex karyotype, and IGHV
E1912 patients were under 70 years old. CIT was FCR.
It should be noted that although patients on the ibrutinib arm of the E1912 trial also received rituximab, the benefit of adding anti-CD20 therapy with BTKi is unclear and remains an active area of investigation. Two previous randomized trials have demonstrated that while adding rituximab to ibrutinib may improve the depth of remission, it does not improve PFS. Based on this data, most experienced clinicians favor ibrutinib monotherapy when using ibrutinib as first-line therapy in routine practice.
I did FCR 6 years ago & doing great so far. I was hoping for 10 years but seeing it could be 24 or more is a great goal. Not going to think about the other things that could develop. My husband had 3 weeks notice & died from another disease. It was devastating. Changes your whole perspective.
I was treated with FCR in 10/2013-4/2014 as unmutated IGHV, Trisomie 12, and experienced 9 years in complete remission therapiere! Then DLBCL, with R-Chop 14 and since, the MRD is under 1!
The PFS at 4-years for mutated IgHV on the GAIA/CLL13 trial is 91.8%. the PFS for FCR at 4-years is 85.1%.
The 3-years PFS was 92% for GAIA/CLL13 and 87% for FCR. At 4-years the 3-yearPFS for GAIA/CLL13 is now 94%.
As the median time on treatment has moved on a year a large number have overtaken the event at 50 months. This has reduced the reduction in PFS from 10% to 2%. This event will be reduced still more by the time 5 year results are published. There could be more patients found to have progressed, just as one was found at about 39 months.
If the slightly greater than 2%/year drop for CLL13 is maintained it projects to a median of 24 years for mutated IgHV on V+O.
FCR compared to 3 and 4 years results from CLL13 trial of V+O
Thank you. This is so encouraging all around. Looking at the chart. It looks like there are larger drops in % Pfs for VO and IR at about 5 and 7 years, respectively. It’s also possible that I’m reading the chart incorrectly. Is there any explanation for the drop off? Are the cohorts on these treatments older or sicker. Just trying to read the tea leaves.
Yes. The results on the headline chart posted by AussieNeil are for 3-years on the CLL13 trial of V+O (blue line) and 6 years for E1912 trial (orange line).
The trials results are only valid at the date they are reported for. Looking at any fall in the chart after that date is misleading. Which was the point on my post and new KM chart for just FCR and CLL13 at 3 and 4 years (no E1912 I+R).
For E1912 there were 70 IgHV mutated enrolled (bottom LH chart), 14 have progressed. There were 40 that exceeded 5 years on the trial, 3 of which have progressed. The 3 that progressed after the 5 year median do not affect the PFS (yet). Two will affect the 6 year PFS and the third the 7 year PFS. The 5 year PFS is 83% not the apparent 64% that the tail of the line is at.
Similarly the tail of the line for CLL13 recovered 10% as 40 subjects overhauled the patient that progressed at 50 months.
To which I'd add, that with the small numbers enrolled in the clinical trials, when a couple or more of the participants have their CLL progress, you get those big drops in the progression free survival curves. You get much smoother, more accurate curves with more participants, (there's less statistical variation with bigger numbers), but with CLL being a rare cancer, it's difficult to get large clinical trials of typically 1,000 or so participants you see in other phase 3 clinical trials.
Hi everyone, I have been on this group since my husband was diagnosed in July2021 in The Netherlands. He was stage 4 and had major weight loss, he was 52 years old and the standard 1st line treatment is fcr there which they began immediately as he has good markers and is mutated. He had a reaction twice to the rituximab so it was stopped and he only received the f and C for the remainder of his 6 months treatment. He had only partial remission, but the spleen and node's continued to shrink in the following 6 months .
He began losing weight and night sweats and enlarged node's and spleen again in November 2023 so we returned to South Africa and he is on Bendustamine and ozmabzitub from May this year as the newer treatments are so expensive here.
My question is your first treatment is supposed to be your longest remission so we are really worried that this will be a never ending loop of chemotherapy every 2 years. He also has had numerous infections and chest problems from the beginning.
Very interesting. This goes to show the pace at which progress in treatments is being made - for CLL, anyway. In my case, I had BR chemo (not FCR) in 2012, and the CLL has not recurred (TBH, I don't think it will but can't 'know' that for a fact).
When faced with the condition and the different treatments, it is in some ways becoming more complicated for patients. They have to figure 1. how effective the treatment may be 2. its possible side effects 3. whether treatment is continuous or short term and 4. possible effects on lifestyle. Also (I suppose) whether they can have another shot at it if the first option fails, for whatever reason.
The decision making may be harder, but for sure the doctors and patients have more strings to their bow, which can only be a good thing.
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Venetoclax+Rituximab OR Acalabrutinib - What is the best choice?
