Median PFS for FCR treated CLL patients with IGHV-M was 14.6 years vs 4.2 years for patients with IGHV-UM. V+O and I+R look to be superior

[AussieNeil]

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."

Note:

IGHV-M = mutated IGHV

IGHV-UM = unmutated IGHV

PFS = progression free survival

frontline = first treatment

In the associated commentary by Matthew Davids MD, Functional cure reported in CLL, ashpublications.org/blood/a...

"..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

[spi3]

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.

[Sushibruno in reply to spi3]

I hope so, for the cure 🙏🏼🙏🏼

[Skyshark]

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

ashpublications.org/blood/a...

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.

ashpublications.org/blood/a...

CLL13 V+O was for wider age range with CIT being a mixture of FCR and BR, 35% were over 65.

thelancet.com/journals/lano...

[Sushibruno]

the outcome of fcr is amazing. Too bad there’s a chance of developing these other diseases. I would’ve gladly have done this if it wasn’t for that.

[Poodle2 in reply to Sushibruno]

I agree with you. The MDS/AML risk was too scary...

[DanBro1]

Neil, what would we do without your wonderful information that you share and explain with us!! Gracias!!

[GMa27]

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.

[seoul1949]

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!

[Altindal22]

Thank you Neil it is so encouraging to read about all the new information you provide for the community let’s pray for long remission for all🙏

[Skyshark]

The difference a year makes. KM charts are dynamic and move as the trial progresses.

This report from the end of 2023 is now quite old, it used 3-year results for GAIA/CLL13 trial. GAIA/CLL13 published 4-year results in June 2024.

thelancet.com/journals/lano...

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

[Lil0ppie]

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.

[Skyshark in reply to Lil0ppie]

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.

E1912 results at 5-years

[Lil0ppie in reply to Skyshark]

Perfect. Thanks for the clarification.

[AussieNeil Partner Administrator in reply to Lil0ppie]

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.

Neil

[8531]

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.

Sorry for the long first post.

[AussieNeil Partner Administrator in reply to 8531]

Thanks for sharing your husband's experience with FCR. I suspect you haven't had any replies, because I used the default posting setting which allows this post to be found through internet searches, so others with CLL who are looking for support can find us. healthunlocked.com/cllsuppo...

With respect to your question, your observation that "your first treatment is supposed to be your longest remission" was established when we only had the older style chemoimmunotherapy drugs, such as FCR and BR and by extension bendamustine and obinutuzumab. Your husband probably would have had a longer remission from FCR if he had been able to continue with the rituximab infusions.

The problem is that all treatment drugs select for any sub-clones that arise from random DNA errors during cloning. The bigger problem with the older chemo based drugs, the FC in FCR and bendamustine, is that they work by corrupting the DNA during cloning. That typically results in an increase in the tougher to treat CLL subclones with 17p del or mutated TP53. Rituximab and obinutuzumab can destroy CLL cells with 17p del or mutated TP53, but it's harder to drive down the CLL to undetectable Measurable Residual Disease levels with the chemo part of the treatment unable to work all that well, so long remissions are less likely.

Unfortunately there is also a higher likelihood with FCR of some level of permanent bone marrow damage compared to other, particularly targeted therapy treatments, so you tend to see incomplete recovery of platelet, red blood cell/haemoglobin, neutrophil and other white blood cell counts after FCR treatment. The anti-CD20 monoclonal antibody treatments (rituximab and obinutuzumab), also suppress healthy B cell recovery for upwards of a year after the last infusion. The end result can be neutropenia and hypogammaglobulinemia (low IgA, IgG, IgM, etc., immunoglobulin/antibody counts), with the consequence of frequent infections, your husband is unfortunately experiencing.

Obinutuzumab works slightly differently and is more effective than rituximab, so your husband's remission from B+O might surprise you, but for his next treatment, you would be wise to search out opportunities to switch to a targeted therapy. Look into opportunities for clinical trials, compassionate access programs from the providers of new treatment drugs, or charity support. Like your husband, my only treatment option outside of a clinical trial was FCR. I was able to enrol in an international clinical trial that also included the Netherlands. (There was still a 1 in 3 chance of getting FCR or BR. My path with FCR was expected to be like your husband's but I was fortunate to be assigned to the acalabrutinib + obinutuzumab + venetoclax arm.) Unfortunately, the Netherlands and South Africa have been slow in moving to the more effective, but more expensive targeted therapy treatments.

Of note, those switching to maintenance therapy with a BTKi 'brutinib' after chemo treatment are averaging around 6 to 7 years before their 'brutinib' stops working, with some in the early ibrutinib clinical trials now into their second decade of treatment on it.

With respect to reducing infection frequency, this post includes tips on living well with a compromised immune system healthunlocked.com/cllsuppo...

If your husband's IgG count is low enough, (typically under 4.0) he may qualify for IgG replacement therapy. Prophylactic antibiotics is the other used approach to help reduce infection frequency, but doesn't help with viral and fungal infections.

Neil

[8531 in reply to AussieNeil]

Thank you for your very informative reply, I will keep reading and learning from this wonderful group 🙂

[scarletnoir]

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.

[skipro]

Neil

I appreciate all of your knowledge and expertise.

Well, there are times that I do very well researching things, sometimes all of my health problems including CLL make it hard to focus.

I am in one of those periods now.

Just wondering if you have comparative numbers for secondary primary malignancies for the following categories

1. CLL on general

2. Patients treated with FCR?

3. v with BTKi

4. v with Ven

based on my state of mind, prefer to see just the numbers as opposed to citations.

Thank you so much for all you do for this group and for me

Skipro

[AussieNeil Partner Administrator in reply to skipro]

Skyshark is our expert responder to these types of questions

[Skyshark in reply to AussieNeil]

Don't think I am. I'm far more into KM charts and PFS.

[skipro]

👍

[AussieNeil Partner Administrator]

Skipro, here are some past posts covering some of what you asked about

healthunlocked.com/cllsuppo...

healthunlocked.com/cllsuppo...

Neil

[Skyshark in reply to AussieNeil]

Just found this (by our forum sponsors).

youtube.com/watch?v=uFryPyK...(Not working as expected?)

Which had SPM counts from FLAIR trial (at 20:46). That was for combined Ven + Ibr until twice the time it took to reach MRD. The minimum time on Ven+I was 2 years but many were exposed to both Ven and BTKi for much longer, equivalent to 2 or 3 rounds of short duration treatments. The median time on treatment for u-IgHV was 2 years and mean 3 years. The median and mean time on treatment for m-IgHV was 4 years.

The direct comparison with FCR about halves the risk. Due to the extended exposure it's likely much lower than that for short duration therapy. BCC/SCC risk is still high, while MDS/AML risk is much reduced.

Missing info on SPM for Monoclonal antibodies and combos.

As I said before I haven't been paying much attention to SPM or AE's. I have a vague idea I've seen a comparison for Acala v's Ibr and the SPM risk for Acala was about half of that of Ibr.

SPM count for FLAIR trial.