Real-World Study Shows Limited Implementation of Reccomended Biomarker Testing in CLL

[Jm954]

Targeted Oncology May 4th 2021

In an interview with Targeted Oncology, Dr Mato , a hematologc oncologist and the director of the CLL Program at Memorial Sloan Kettering Cancer Center, discusssed biomarker testing in CLL, and the future of BTK inhibitors in the CLL paradigm.

Data presented at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition offer key insights into the developing chronic lymphocytic leukemia (CLL) space, both in terms of clinical practice and evolving Bruton’s tyrosine kinase (BTK) inhibitors.

Biomarker-driven care has become a major focus point. For many patients with mutations in the tumor, an inhibitor or immunotherapy may be a better option for patients than standard chemotherapy. However, testing for these mutations is underperformed, according to data from the informCLL registry study (NCT02582879), eventhough they should be the standard of care for all patients, according to Anthony R. Mato, MD.

The study found that fluorescence in situ hybridization (FISH) testing was performed in only 28% of patients.Immunoglobulin heavy chain (IGHV) was performed in just 12% of patients. Of the patients who received prognostic biomarker testing, 24% had 17p deletion, 27% had TP53 mutation, and 71% had unmutated IGHV.1

In terms of BTK inhibitors, 2 studies were presented. One study centered round the next-generation, non-covalent BTK inhibitor pirtobrutinib (LOXO-305) and the other covered the triplet combination of a BTK inhibitor, mTOR inhibitor, and immunomodulatory drugs (IMids). Both studies yielded promising results. For the pirtobrutinib, of the 186 patients treated at 7 dose levels, a response was seen at the first dose level of 25 mg once daily. The overall response rate was 57% and the median duration of response was 6.7 months.2 The triple combination study has met its primary endpoint of an acceptable safety profile.

Much more here: targetedonc.com/view/real-w...

Jackie

[AussieNeil Partner Administrator]

This appalling situation is why it is so very important to find a specialist who keeps up with recent developments in CLL treatment. In the USA, there is absolutely no excuse to omit FISH testing (which is not an expensive test) to work out what treatment best suits you. Likewise IGHV and TP53 testing if your specialist is considering a chemo treatment (typically BR or FCR), because you are unlikely to have a durable response to these treatments if you are 17p del, TP53 mutated or IGHV unmutated. This testing is also becoming increasingly important in other countries, as access to non-chemo treatments are gradually being approved - provided there is a demonstrated need! You need the 17p del (from FISH) and TP53 test results to prove this!

The CLL Society has been trying to get this message out to CLL treating specialists since 2017, partnering with Dr Mato to spread the message over and over again. So it is very disappointing to see the situation only slowly improving, despite the expansion of the CLL Society's Test before Treat Program: cllsociety.org/cll-101/test...

Here's the CLL Society's Test before Treat one pager:

cllsociety.org/docs/CLL%20T...

Dr bkoffman may wish to comment further.

Neil

[Jm954 Administrator in reply to AussieNeil]

When Neil says ‘unlikely to respond’ I think he is referring to the likely length of response.

Almost everyone will initially respond to chemo but if you have 17p del, mutated TP53 or are IGHV unmutated then you are unlikely to have a durable response and it will almost certainly be no more than a couple of years.

Your first treatment is the most important in terms of length of remission and overall survival, so it’s important to get this treatment exactly right for you based on the pretreatment profile of your own CLL.

Jackie

[AussieNeil Partner Administrator in reply to Jm954]

Jackie,

Thanks for that clarification; I've edited my reply accordingly. To expand a bit more:

1) If you are 17p del or TP53 mutated, depending on the damage to this part of the CLL DNA, you might manage several years of remission, maybe even more, but you'll likely get a much longer remission with a newer, non-chemo treatment. Sadly, we've had some members only manage a few months of remission before needing their second treatment. That's a very disappointing result after putting up with the challenges of treatment, particularly if it was avoidable.

2) If you are IGHV unmutated and if non-chemo treatments are available to you, then your specialist should never offer you an older chemo treatment. Unfortunately, very few countries outside of the USA provide the newer non-chemo treatments for those with unmutated IGHV, but the situation is changing. Importantly, it's increasingly becoming the case that the more effective non-chemo treatments for unmutated IGHV folk are becoming available for subsequent treatments. Even more importantly, chemo treatments increase the likelihood of developing 17p del or TP53 mutated CLL, so it is even more important to have FISH testing for subsequent treatments.

Per the referenced interview with Dr Mato in Jackie's post, FISH testing was performed in only 28% of patients. "Of the patients who received prognostic biomarker testing, 24% had 17p deletion, 27% had TP53 mutation."

Back in 2018, per this report: cllsociety.org/2019/08/ash-... it was found that :-

* Not only was the testing not being done, when it was done, the results were often not being used to best inform therapy.

* More than 1/3 of the 70 pts with del(17p) received chemotherapy or chemo-immunotherapy (CT/CIT) which is most unlikely to work.

* Of the 14 previously untreated pts with mutated TP53, (36%) received CT/CIT that is generally not indicated in with mutated

Neil

[Smakwater in reply to AussieNeil]

Amen

[bennevisplace]

Thanks Jackie. I find those numbers startlingly low. How are we doing in the UK, do you know?

[Jm954 Administrator in reply to bennevisplace]

I think it’s better than this but there will still be some out of date doctors who think that if it was done at diagnosis then it probably doesn’t need doing again. However, we know that genetic changes such as 17p can be acquired and access to a targeted treatment is based on patients being tested for these types of CLL.

It could be argued that if you’re having a targeted treatment anyway, then does it need to be done? We would say yes, because it’s best practice.

In the UK treatment decisions are made by the whole team of haematologists in a unit, not just one as in other countries, which does offer safeguards.

The most extensive pretreatment testing in the UK is probably done as part of a clinical trial.

Jackie

[bennevisplace in reply to Jm954]

Yes I seem to remember the team discussion thing, but I thought that was part of the trial protocol.

Expert opinion aside, just based on revelations from our members I'd say being sent into treatment without FISH and IGHV is close to medical negligence.

[Jm954 Administrator in reply to bennevisplace]

Sadly in some countries, the healthcare systems do not cater for these tests and they aren't readily available. In addition, samples don't travel well in heat or cold for many hours or even days. It's easy to forget how lucky we are really.

[bennevisplace in reply to Jm954]

Indeed we are.

[Beattiem-UK]

Thank you Jackie and Neil for keeping us up to date on this discussion.

[Kokobean]

This is such important information to continue sharing with new members. My husband and I comment often on how different things could have been if we had gone along with the hematologist who didn’t think the IGHV test was necessary. I had been on this site for awhile, so we moved on to a specialist. He was unmutated as I suspected and has been on ibrutinib for 2 years. This is in the US and only 3 years ago. I hope things are changing, but we really need to be aware and take charge of our health and the health of our loved ones.

[Jm954 Administrator in reply to Kokobean]

Thank you for telling your story.

It's easy to think that everything in the USA is perfect but non specialist oncologists are often not up to date with the recent developments in CLL and its treatment.

Well done on advocating for yourselves and getting the right treatment

Jackie

[Big_Dee in reply to Jm954]

Hello Jm954

I don't think the testing protocols are that black and white. I had FISH and IGHV test in USA at diagnoses of CLL and was 0% un-mutated. My CLL Specialist gave me choice of B+R or ibrutinib. I chose B+R. I am close to 3 years in remission. I was also given additional 3 FISH tests before and after treatment, also another IGHV test after treatment. I suspect there is more going on here than is known.

[Jm954 Administrator in reply to Big_Dee]

I’m sure you’re right, we do not know as much as we would like about this complex and heterogeneous disease.

Remember we are quoting statistics and there are always outliers who will buck the trend. Statistics tell us nothing about how any individual person will behave.

I really hope you’re an outlier and have many more years in remission.

Jackie

[Mystic75 in reply to Kokobean]

My husband switched to a CLL specialist after his Hem-Onc didn't seem to make sense to us. It didn't make sense because he was basing his option on false assumptions.

Sometimes these doctors still think within the old treatment types where one size fits all. So they counsel the patient the same way, regardless how different each patient's actual profile may be, even if they have the FISH test.

I also do not understand why a FISH test only includes abnormalities above a certain cutoff, especially for 17p.

D.

[SofiaDeo]

And I also recall, when I first presented, my hem-onc ran a full gamut FISH, not just the CLL panel. He told me he thought it was CLL, but wanted to verify it wasn't something similar to CLL. He wasn't a CLL specialist, just a savvy hem onc I think! Of course my insurance wouldn't pay for this, I had to, if I recall correctly it was under $500 (maybe closer to $300). When I had repeat FISH after a decade, the new onc ran the standard FISH panel looking for only the main CLL ones.

I don't know how they get the CLL diagnosis without running a FISH, boggles my mind.

[Jm954 Administrator in reply to SofiaDeo]

The CLL diagnosis is made from flow cytometry, testing with various CD antibodies to pic up markers on the surface. The combination of positive and negative results tells them what the cells are.

FISH detects genetic, chromosomal, changes inside the cells.

Jackie

[SofiaDeo in reply to Jm954]

Right, but my first hem-onc explained to me that the combo testing could identify potential rare abnormalities, instead of simply relying on one test alone. And I agreed with him, and still do. From what I am reading, a number of studies are looking at combined FISH-flow in several disease states as giving superior information, or at least the same info with less cost/greater ease. I found this article intriguing:

ncbi.nlm.nih.gov/pmc/articl...

If I ever develop resistance to all standard CLL meds, I probably will pay for full flow cytometry & FISH panels, seeking a marker that a medicine normally used in other disease states may be able to be useful in my CLL. Hopefully that will be moot for me & Venclexta will continue to work without resistance developing!

[Jm954 Administrator in reply to SofiaDeo]

The article says the technique is still experimental and they don't have the probes they need for it to be useful. It could be some time before it ever becomes established as a routine diagnostic tool.The current use of flow and genetic testing is well established (plus cheap!) and able to guide treatment and prognosticate for individual patients.

I hope the Venetoclax keeps working its magic for you.

Jackie