ibrutinib resistance testing

[Marymary19]

Can please somebody tell me the name of the test that confirms actual resistance to Ibrutinib? I could not find it. Thanks in advance

[Canuck901]

I think your title is the name of the test

[Marymary19 in reply to Canuck901]

I was looking for the technical term. Thank you anyway

[sllincolorado in reply to Marymary19]

Per my doc " next generation sequencing panel" . Mine is being done in US by medfusion. Should have results next week.

[sllincolorado in reply to sllincolorado]

similar but less sensitive test per AussieNeil is "immunophenotype flow cytometry test"

[Hidden]

neogenomics.com/test-menu/b...

[Marymary19 in reply to Hidden]

thanks

[avzuclav in reply to Marymary19]

There are two testable mutations for ibrutinib resistance. Hidden posted one of the two (the BTK mutation). The other is PLCG2. This link shows the test for both.

BTK Inhibitor Acquired Resistance Panel

neogenomics.com/test-menu/b...

[Jm954 Administrator]

Hi Marymary,

I think the more technical term is BTK mutation testing. It's a mutation in the Kinase enzyme that enables resistance and there are several different posssible types.

There's more about it here: ashclinicalnews.org/educati...

It says here " ..... resistance to ibrutinib primarily occurs through the acquisition of mutations in BTK (the most common is BTK C481S) or its immediate downstream target, PLCG2. These mutations have been detected using high-sensitivity assays in 85 to 90 percent of patients at disease relapse. Clonal evolution is a hallmark of ibrutinib resistance, with researchers noting a recurrent deletion in 8p in patients at the time of relapse." Abnormalities in Chromosome 8 are usually associated with a complex karyotype which is in itself a poor prognostic feature.

Are you worried about it for your Mom? If she's taking a reduced dose that may affect her response but resistance is one thing to check for. Unfortunately it not a routine test and can be difficult to get done but definitely worth asking your Mom's doctor about it.

The important thing is not to stop the ibrutinib as this can cause the CLL to 'flare' where it can rapidly get out of control.

All the best

Jackie

[Marymary19 in reply to Jm954]

Hi Jm954

Yes , I am worried for my mom. Yesterday when I saw her blood test results I got a bad feeling. Today she has taken the full dose and I am trying to think positive.

Thank you so much for replying

All the best to you

Mary

[Marymary19]

thank you all for replying. I was just wondering ... but is the resistance to a drug like Ibrutinib forever? I mean, can someone, who has developed resistance, switch to a new therapy and after some time go back to ibrutinib? sorry if it sounds like a stupid question

[cllady01 Former Volunteer]

Mary, there are no stupid questions, we are all learning. Your questions has led me to find what is being done--my mind is no able to hold the answers to all the questions we have about CLL and the meds., so here is an article about a study of exactly what you ask.

"As the use of ibrutinib in clinical practice increases, the problem of resistance is becoming apparent, and new methods of overcoming this clinical problem arise. In this review, we summarize the mechanisms of BTK inhibitors’ resistance and discuss the post-ibrutinib treatment options."

Scroll down to r:

9. Alternate Kinases Inhibitors and Drugs Potentially Overcoming Ibrutinib Resistance

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

Best wishes, and keep us up on how things go.

(Don't know how I got to the wrong post by you, sorry--too much back and forth to get copy for link, I guess ).

[Marymary19 in reply to cllady01]

Cllady, I will read your article carefully.

Thanks for sharing it

[diandgord]

My husband took ibrutinib with excellent control of his CLL for 6 to 7 years. He was hospitalized April 2019 with sepsis, again end of Nov. 2019 with sepsis. Never really fully recovered. Suddenly in April 2020 his ibrutinib stopped working , to start venetoclax. Rapid downhill course with lymphoma. Died April 28.

[sllincolorado in reply to diandgord]

I am so sorry for your loss. Thank you for being your husband's caregiver. And thank you for caring for all of us by providing this information about your husband's journey.

[Newdawn Administrator in reply to diandgord]

I’m so sorry to hear of the loss of your husband after episodes of sepsis which are really nasty.

Hope you are coping and thanks for letting us know. Such a difficult time anyway without coping with the loss of a loved one during it.

Best wishes and my condolences to you and yours.

Newdawn

[Jm954 Administrator in reply to diandgord]

Thank you for taking the time to let us know about the loss of your lovely husband, so sorry to hear your sad news.

Please accept our heartfelt condolences to you and your family.

very best wishes

Jackie

[Marymary19 in reply to diandgord]

I am sincerely sorry for the loss of your husband

Please accept my condolences to you and your family

[cllady01 Former Volunteer in reply to diandgord]

So sorry to hear of your loss. My condolences to you and your family/friends.

[PaulaS Volunteer in reply to diandgord]

I’m so very sorry to hear of the death of your husband. Thank you for letting us know what happened.

Heartfelt condolences to you and your family. May you find peace and strength to cope with your terrible loss.

Paula

[MsLockYourPosts Passed Volunteer in reply to diandgord]

Thank you for posting about your husband. I am so sorry for your loss. It must be especially difficult that during this time of isolating you aren't able to have the kinds of physical support that one would normally have. You are always welcome to come here for emotional support and virtual hugs. Your husband was fortunate to have had a partner at his side from the day he was diagnosed.

[larrymarion]

I was taking iburtinib for 5.5. years and had resistance testing by ohio state for most of that time. The ohio state lab report called it BTK resistance mutation, blood.

my understanding is that the btk resistance mutation test is a predictive analytic--it predicts whether resistance will form over the next six to 18 months.

not sure if resistance remains a factor even after discontinuing treatment. not a big deal these days because there are so many other options. key alternative is venetoclax.

note that there are several other BTK inhibitors, typically called second or third generation, which feature slightly different formulations. these advanced formulations avoid most of the side effect issues of ibrutinib. they also avoid the BTK C4118S mutation that can lead to resistance.

of course the newer generation drugs could eventually trigger their own resistance mutations, but that may not be seen/known for many years.

BTW, here's the text from my BTK resistant mutation report:

Comments from the Doctor's Office

Good result- the test that looks for resistance to ibrutinib remains negative.

BTK Specimen

Source --Peripheral blood

BTK C418S

Mutation NOT DETECTED

BTK Level 0.0 % <0.1 %

BTK

Interpretation

The BTK C481S mutation is NOT detected by digital

droplet PCR in DNA extracted from immunodensitypurified B-cells.

Methodology/Limitations:

A quantitative polymerase chain reaction (PCR) assay was used to detect BTK C481S mutations using

fluorescently-labeled probes for the wild-type sequence and the mutant BTK C481S sequences. Mutations besides BTK C481S (c.1441T>A and c.1442G>C) will not

be detected by this assay.

The sensitivity of detection is approximately 0.1% mutation-bearing cells in the analyzed sample: samples with signal below that cutoff will be reported as negative. Serial monitoring may be useful for assessing the clinical significance of low levels of BTK mutation level or the presence of mutation in minimally involved CLL samples.

[Marymary19]

Hi larrymarion, I was thinking that the test has to be done when the blood results shows an increase of WBC count just to confirm that Ibrutinib is not working any more. All the best

[Jm954 Administrator in reply to Marymary19]

That can be the case as you've said or it can be done as part of monitoring and it can be predictive of relapse by up to 18 months ahead of clinical evidence.

Jackie

[Marymary19 in reply to Jm954]

Ok, thanks Jm954

[sllincolorado]

This is what I learned today: you can test negative for BTK resistance but still be resistant. Per my doc: " there are patients who become resistant to acalabrutinib that do not have those mutations mentioned above (BTK or PLCg mutations) -- those are the known mechanisms of resistance, but there are clearly others as well"

Since I have a few palpable nodes, which I did not have 6 weeks ago, I will go have another set of labs and and in person appt with my doc.

Not sure what this means for me but I think it is good for all of us to understand that blood tests can be used to test for BTK resistance but a negative result may not be completely conclusive.

[Justasheet1 in reply to sllincolorado]

Sorry to hear about your problems. The testing issue sounds like the covid testing. I guess it’s true that medicine is not an exact science.