Relative risk for secondary bone marrow cancer within 5 years after initial CLL chemoimmunotherapy treatment (typically BR or FCR)

[AussieNeil]

In countries where targeted therapies ('brutinibs, venetoclax, obinutuzumab/rituximab) are now available, the remaining reason that FCR (Fludarabine+Cyclophosphamide+Rituximab) is still sometimes recommended for the treatment of CLL is that it can be curative* about 55% of the time - but only if your CLL is IGHV mutated. Unfortunately, the chemo constituents of FCR bring with them around a 10% risk of the subsequent development of Acute Myeloid Leukaemia (AML) or a Myelodysplastic Syndrome (MDS), where your bone marrow increasingly struggles to make blood cells. Also, in countries with universal health care systems (that's nearly all of the world other than the USA), gaining approval for the more expensive targeted therapy treatments relies on evidence that the newer treatments have long term cost and health advantages over BR (Bendamustine+Rituximab) and FCR. Hence this study, Trends in risk for therapy-related myelodysplastic syndrome/acute myeloid leukemia after initial chemo/immunotherapy for common and rare lymphoid neoplasms, 2000-2018 being of interest, particularly for those contemplating whether FCR is worth the risk over more modern treatments.

Abstract: pubmed.ncbi.nlm.nih.gov/374...

Attached, I've included the plots of the Relative risk for tMDS/AML occurring within 5 years after initial chemo/immunotherapy for a first primary lymphoid neoplasm. (tMDS/AML is the abbreviation for therapy-related MDS/AML). The Abstract Interpretation: Although tMDS/AML risks are significantly elevated after initial chemo/immunotherapy for most LNs, patients treated more recently have lower tMDS/AML risks, except after CLL/SLL. Though rare, the poor prognosis following tMDS/AML emphasizes the importance of continued efforts to reduce treatment-associated toxicity.

If you look at the three 5 year study groups covered in this report, the standardized incidence ratios (SIRs) for CLL/SLL and DLBCL haven't improved, while there has been some degree of improvement in other blood cancers. For CLL, the increased risk of developing tMDS/AML is somewhere between 3 and 20% and still averaging about 10% over the last 5 year period, from 2012 to 2017. Dr Davids noted "a 6.3% cumulative risk of therapy-related myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)" from the 19 year long term follow up report in his commentary.

* Long term follow-up of those treated with FCR, has shown that if you make to 7 years in remission, your remission is likely to last 20+ years. That is, early FCR recruits that achieved 7 years of progression free survival, have recently entered into their third decade of living without their CLL returning. (CLL researchers are reluctant to say 'cured', but I think most of us would consider surviving 20+ years post cancer treatment as a cure!)

I can't see any justification for Bendamustine+Rituximab (BR) treatment when targeted therapies are available. You don't see this curative effect with BR. We are yet to see if this effect occurs with combination targeted therapies, such as venetoclax plus a BTKi or 'mab therapy; CLL researchers were hopeful that this would be seen, perhaps even with unmutated IGHV CLL, given we don't see the big difference in achievable remission times with targeted therapies between mutated and unmutated folk, but we are still a few years off that 7 year point when remissions became indefinite after FCR treatment.

This is an unlocked post

Neil

[Snakeoil]

10%? They are reporting that most recent data shows 1.1% which is nevertheless higher than before. They mention that this seems to match dosage changes.

For patients treated with initial chemo/immunotherapy for CLL/SLL, the only subtype with significantly increasing SIRs over calendar time during the study period, the 5-year cumulative incidence of tMDS/AML increased from 0.49% for patients treated during 2000–2005 to 1.5% and 1.1% for patients treated during 2006–2011 and 2012–2017, respectively.

[johnliston in reply to Snakeoil]

But was the original 10% number for a 5 year period or for a lifetime?

john

[Snakeoil in reply to johnliston]

I could not find that number in this study. Their long term number is 1.9%.

analyses of the 10-year cumulative incidence of tMDS/AML showed the highest risks (>1.0%) among patients treated with initial chemo/immunotherapy for […] CLL/SLL (1.9%) […] after accounting for competing risks of other second malignancies and death

[AussieNeil Partner Administrator in reply to Snakeoil]

Snakeoil and johnliston , as I explained in my post, the accompanying plots from the abstract are those for relative risk, which have been presented as Standardized Incidence Ratios (SIRs). That's a different measure than excess absolute risks (EARs, per 10,000 person-years), and cumulative incidence, which are also reported in the full article: ncbi.nlm.nih.gov/pmc/articl...

Neil

[Snakeoil in reply to AussieNeil]

I see. I had reacted to this paragraph:

Unfortunately, the chemo constituents of FCR bring with them around a 10% risk of the subsequent development of Acute Myeloid Leukaemia (AML) or a Myelodysplastic Syndrome (MDS), where your bone marrow increasingly struggles to make blood cells.

You probably meant to write “10% increased risk” which is much less alarming than “10% risk”.

For those of you who, like me, are new to SIR then most authors I looked at failed to explain it clearly but this page is easy to read and makes sense:

cdc.gov/nceh/cancer-environ...

[AussieNeil Partner Administrator in reply to Snakeoil]

Agreed and now corrected to avoid any future misunderstandings. While the post title and previous discussion were about relative risk, I agree SIR needed more of an explanation, so thanks for the CDC reference explaining it.

[spi3]

Thank you Neil - I think that from this article folks with high risk CLL treatments with Venetoclax- acalabrutinib and obinutuzumab - the long term remission results still remain unknown?

[AussieNeil Partner Administrator in reply to spi3]

Yes, the long term results are still to discovered, because we only have a maximum of about 5 years or so of data for fixed term combination treatments using targeted therapies.

[spi3 in reply to AussieNeil]

Thank you so much and I'm praying for the longest remissions ever!

[BobbyFour]

I think your universal healthcare point is a good one, but at the current price point I don’t see it changing soon. Maybe if targeted therapies come down in price.

[AussieNeil Partner Administrator in reply to BobbyFour]

My specialist just said today that FCR is proving less cost effective than the new therapies. That's because of the extra costs associated with infections and secondary cancers.

Neil

[noeagaman in reply to AussieNeil]

I have experienced plenty of infections since FCR in 2018 which fortunately are coming less frequently now that my doctor increased the dosage of my IVIG's and lessened the time in between infusions. Let's hope that a secondary cancer never comes along. I guess that only time will tell.

Chris

[Skyshark in reply to noeagaman]

If you are getting IVIG's that is part of the increased ongoing costs of FCR. Not just in the IVIG infusion but both yours and consultant's time, clinic time etc.

[AussieNeil Partner Administrator in reply to Skyshark]

That's if the FCR has caused the low IgG immunoglobulin (hypogammaglobulinemia). CLL suppresses plasma cell production, which is why hypogammaglobulinemia becomes increasingly common the longer we live with CLL. Some of us treated with targeted therapies, but not all, have seen some recovery in their ability to make immunoglobulins.

Neil

[BobbyFour]

Too late for me, but I hope you are right!

[GMa27]

5 years after FCR for me. Feeling great. Have had no issues so far. Would love that 20 year plus record & possible "cure".

[Smakwater]

I am still in the petri dish labeled unmutated + venetaclax for two more years to hit the 7 year mark.

So far nothing in the dish.🔬

JM

[biplane]

I had 6 months of Fludarabine in 2000, wbc started up again shortly after and I repeated the Fluara for another 6 months in 2003, about two years on the wbc had risen to about 40k but for some reason it stopped there, for about 15 years my wbc ranged from 40 to 50k. Wish I had an explanation for this but other than the high count life was fine. In 2020 the count went to 60 then up on a regular basis, I will finish cycle 12 of O&V on Aug 11th, all blood work look great, looking forward to it.

Jerry

[kathymac5252]

well, my husband is the poster boy for this. He had BR as the first therapy before Imbrutinib and then developed MDS after CLL went into remission. Specialist said MDS was therapy related. Unfortunately, my husband got diagnosed with CLL just before all the research.

[dwolden in reply to kathymac5252]

My husband has just been diagnosed with MDS. He endured six months of FCR ending in 2014. No sign of CLL now but prognosis for MDS pretty terrifying. He is 73 and feels well but terribly low blood counts across the board. I think I'm in shock but trying to process.

Hope your husband is doing ok. If you have any thoughts to share about treatment or living with MDS and could share, I'd be very grateful.

[kathymac5252 in reply to dwolden]

my husband had high-risk MDS and was treatment driven at that time until he received a stem cell transplant. His doctors all concurred that without it, he would morph into Acute lymphocytic leukemia. He is now a year and a half post transplant and is doing fairly well. He struggled with graph versus host, disease twice, and actually had to have an additional stem cell infusion from his original donor who is an international donor. Not gonna lie, it’s been a tough journey, but the alternative was not good. MDS is scary. All of his numbers were crashing before the transplant. Luckily, for my husband, he had been a very healthy individual with no other health issues. He was 69 when he got his transplant just on the border. Hang in there, research as much as you can, and keep him as healthy as possible.

[dwolden in reply to kathymac5252]

Thank you for your reply. We are experiencing problems with the referral to a transplant facility (Mayo) and not sure his insurance will cover even a consult much less the process. Meanwhile he is receiving chemo at our local cancer center (something called azacitidine) realizing that results might not be great and won't last long. You have had quite a journey too. May your loved one continue to do well.

[AussieNeil Partner Administrator]

Of relevance to this post, is the recent Sustained remissions in CLL after frontline FCR treatment with very-long-term follow-up study report. ashpublications.org/blood/a...

The associated commentary by Dr Matthew Davids is also worth reading;

Functional cure reported in CLL

ashpublications.org/blood/a...

When helping young, fit patients with CLL to decide on initial therapy, a common question I get is: “What would you choose, doc?” A few years ago, my answer to this question for patients with mutated immunoglobulin variable heavy chain (IGHV-M) CLL was fairly straightforward—FCR. We have known for several years that about half of patients with IGHV-M CLL will have durable remission with FCR with only 6 months of therapy.

Over the last few years, new developments have led me to rethink my answer to this question. First, there was the COVID-19 pandemic and concerns that myelosuppression from FCR would impair immune response to vaccination and to infection. Then came a series of trials that chiseled cracks in the foundation that held up FCR as a standard of care. The US ECOG 1912 trial demonstrated not only a progression-free survival (PFS) benefit with continuous therapy with the oral Bruton tyrosine kinase inhibitor (BTKi) ibrutinib plus rituximab over FCR in young, fit patients (even in the subgroup with IGHV-M), but also an overall survival benefit at 5 years of follow-up.2 And the GAIA/CLL13 trial recently reported similar 3-year PFS between FCR and a time-limited 1-year course of a chemotherapy-free regimen of the oral B-cell lymphoma/leukemia 2 inhibitor venetoclax plus obinutuzumab (VO) in patients with IGHV-M CLL.3

Although these results with targeted therapies are promising, the follow-up for these studies is short for a disease like CLL, which has a long natural history. This new report by Thompson et al reminds us that 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. (My emphasis)

Neil

Combination targeted therapies are proving slightly superior to FCR without the AML risk

[dwolden]

A friend reminded me that if the FCR had not been so effective we might not have had this nine years of relative quiet on the cancer front. However. So desperately hard to be part of this 6.3 per cent.

[skipro]

Question

I am IVHG mutated.

I had 3 rounds of FCR (Feb, March, April 2018), stopped for prolonged neutropenia.

Relapsed 2 years later then started V + O March 2023.

Marrow April 2024 was borderline hypo cellular at 30-35%.

Repeat marrow August 2024 now clearly hypo cellular at 10-20%.

My chart note said "could be early MDS due to prior FCR or effect of Ven". Plan to watch cbc and repeat marrow if any cell lines drop.

Any thoughts on hypo cellarity progression over past 4 months

? Ven effect

? Sampling

? FCR late effect at 6+ years

? how do you diagnose MDS

Thx

[AussieNeil Partner Administrator in reply to skipro]

Skipro, other members, such asJm954 would be much more across this type of detail than me.