Progress update - Pirtobrutinib triple trial for treatment naive

[SeymourB]

I finished Cycle 4 of the fixed duration Pirtobrutinib combo trial at M.D. Anderson for Pirtobrutinib, Obinutuzumab, and Venetoclax on June 13, 2023.

clinicaltrials.gov/study/NC...

In addition to the usual blood tests - CBC, differential, metabolic, electrolyte, and immunoglobulin tests, they did a Flow Cytometry MRD4 test that I can compare to my pre-treatment Flow Cytometery MRD4:

Feb 14: Aberrant cells as percentage of total analyzed events 91%

June 13: Negative for minimal residual chronic lymphocytic leukemia/small lymphocytic leukemia, at a sensitivity of 0.01%

So, after only 4 cycles, we've achieved MRD4 status (<1 CLL cell in 10,000 WBCs) in the blood. No bone marrow biopsy was done - I have that scheduled for the end of Cycle 7. I was elated, to say the least!

A separate Flow Cytometry indicated that all of my lymphocytes in my blood are T-cells and NK cells - there were no CD19+ cells.

Selected other results:

WBC 5.9K/uL

RBC 5.53 M/uL

Hgb 14.4 gm/dL

Platelets 191 K/uL

Neutrophil Abs 3.64 K/uL

Lymphocyte Abs 1.3 K/uL

Monocyte Abs 0.95 K/uL - a little high

CD4+/CD8+ Ratio 1.76 - a little low still

They informed me that the trial protocol has been changed. For non-Richter's patients, they've extended the trial from a mininum of 7 cycles to a minimum of 9 cycles, and added more ClonoSEQ MRD testing. They have not updated the clinicaltrials.gov page above to reflect it. I asked for, and was given a revised protocol that was more detailed than the original protocol they gave me. It clarified the conditions for ending at Cycle 9, and the level of MRD needed.

"Patients will have MRD assessed in PB at the end of C4 by NGS. Patients will have MRD assessed by NGS in PB and BM at the end of C7.

(1) Patients who achieve U-MRD in BOTH PB and BM (by next generation sequencing [clonoSEQ) under a threshold of 10-5 at the end of C7 AND confirm U-MRD by NGS under 10-5 in PB at the end of C9 can stop both pirtobrutinib and venetoclax at that time (treatment will stop once the results of NGS MRD are available which can take up to 2-3 weeks from the time of sample collection). These patients will be monitored by PB MRD by NGS approximately every 3 months for the first 12 months off therapy, and then approximately every 6 months.

(2) All other patients, including those patients with inconclusive NGS MRD testing or missed sample will continue pirtobrutinib and venetoclax until the end of C13 and stop therapy end of C13 (irrespective of MRD status at end of C13). These patients will have NGS MRD assessed in PB at end of C9 and then in both PB and BM at the end of C13. These patients will be monitored by PB MRD by NGS approximately every 3 months for the first 12 months off therapy, and then approximately every 6 months."

Note that NGS here means ClonoSEQ. ClonoSEQ can indicate MRD down to 1 CLL cell in 1 million WBCs, which is called MRD6 (1 in 10 to the 6th power). Their target, however, is MRD5 (1 in 100,000 cells).

I think the researchers really value the extra MRD data, and the opportunity to track it while still treating. I think the added 2 cycles are to respond to possible questions that 7 cycles is just too short, and might not be as durable as MRD after a longer regimen.

I was surprised and very happy to hear that they did a ClonoSEQ on my PB (peripheral blood) as part of my End of Cycle 4 testing. It takes a couple of weeks for those results to come back, and the results are not posted in the M.D. Anderson patient portal. So I emailed the doctor, and received a reply:

"Residual Sequence Detected ESTIMATED MRD VALUE: Detected below LOD: Range >0 -1 residual cells/million."

I take this to mean that we may have achieved MRD6, so I emailed asking for the full report for clarification, and am still waiting. I also note that it does still say Residual Sequence Detected, which I take to mean that there are indeed CLL cells in the blood enough to sequence. When Adaptive Biotechnologies submitted their test for FDA approval, they had to pick a standard cutoff, and the cutoff has to be above the detectablility level for the genetic sequencing, since that can vary somewhat at low levels.

If anyone else has done ClonoSEQ and can comment, please do!

Meanwhile, I had a brain and neck MRI for a presumably unrelated neuropathy problem in my face and right hand, and it showed that the parotid gland lump on my face is still 2cm. That's greater than the 1.5cm size required for Complete Remission by iwCLL standards. So it seems entirely possible to achieved MRD4 or MRD6 and be in a Partial Remission. I expect it's also possible for remaining CLL cells to lurk in lymph nodes or spleen at a higher level than in blood and bone marrow. Even so, as long as the lymph and nodes are small, I care not about their size. I think MRD is a better indication of remission.

But even so, I am thrilled with the results! I will continue to fight the fatique that started at the beginning of Cycle 3 when Venetoclax hit 400mg.

=seymour=

A somewhat old (2 years) MRD Reference, but useful especially for terminology:

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

Measurable residual disease in chronic lymphocytic leukemia: expert review and consensus recommendations

Leukemia. 2021; 35(11): 3059–3072.

[Phil4-13]

SeymourB, great news. I'm very happy for you! 🙂 Sandra (Phil 4:13)

[AussieNeil Partner Administrator]

You have every reason to be thrilled with your results. Fantastic news. I hope that many others prove to achieve similar results on this new protocol.

Thank you for comprehensively sharing your results.

Neil

[Stamphappy]

That's so good to hear, SeymourB! So glad things are going well for you. 😃 Thank you for sharing your experience and for paving the way for those of us in W&W. Wishing you all the best and continued success in kicking CLL to the curb!!

[Tangolover]

So glad to hear this wonderful news!

[CycleWonder]

These are amazing results. I have to admit I am a bit jealous. My last absolute lymphocyte count after being on just Pirtobrutinib was 20k, down from 269k but not as low as yours. And I’m on cycle 9!

Congratulations are in order

[SeymourB in reply to CycleWonder]

CycleWonder -

I can't lay all of my apparent success to the Pirto. I think the Obin really hammered the ALC down, too. Plus, I didn't start from as high a point as you. My peak ALC was 124K about a month before the trial. My ALC had zoomed to that in a little over a month from 78K:

Aug 8, 2022 Lymphocyte Abs 70.96

Nov 11, 2022 Lymphocyte Abs 26.05

Nov 11, 2022 Abnormal Lymphocyte Abs 67.63 (so, normal + abnormal ALC 96.68)

Dec 5, 2022 Lymphocyte Abs 78.63

Jan 20, 2023 Lymphocyte Abs 124.17

Feb 14, 2023 Lymphocyte Abs 92.45

Feb 21, 2023 08:15 AM Lymphocyte Abs 79.38

Feb 22, 2023 03:21 AM Lymphocyte Abs 78.57

Feb 22, 2023 11:57 AM Started Obinutuzumab 1/10th days (C1D1)

Feb 22, 2023 19:38 Started Pirtobrutinib 200mg

Feb 23, 2023 01:19 AM Lymphocyte Abs 88.04 K

Skipped C2D2 9/10ths dose of Obin due to infusion reaction

Feb 24, 2023 02:47 AM Lymphocyte Abs 5.04K

Dr. Thompson left MDA between November, 2022, and January 2023. He was concerned about a possible Richters transformation because of the abnormal lymphocytes and sudden increase in lymphocytes between August and November. He had already recommended me for the trial. A Flow Cytometry here in New Orleans (actually, sent out to ARUP lab) in January still showed CLL.

Most of the loss in blood ALC happend in the first 3 days after the initial dose of Obinutuzumab and a couple doses of Pirtobrutinib.

I am Trisomy 12, unmutated IGHV (formerly mutated IGHV in a test from 2013), with NOTCH1 and BCL2 mutations.

=seymour=

[CycleWonder in reply to SeymourB]

Thank you for the very detailed response. I believe my CLL was “plain vanilla” as Neil described it.

It appears the treatment combo you are in is working well. My hope is that you have a long remission.

It is inspiring to all of us to see new approaches that are allowing CLL patients to be treated for a short time and then have a treatment holiday. It’s not a cure but much better than taking meds forever.

[Ernest2]

Great news, many thanks for sharing

Best wishes,

Ernest

[ava1967ir]

so glad to hear this amazing result🌺

[tesoro5858]

Seymour, I am so glad to hear how well you are doing since I saw you at MDA in March. You are definitely getting excellent care! Susan

[gardening-girl]

Fantastic news! Thanks for the detailed report!

[42828]

Hello, I'm in a bit of a predicament. I've had venetoclax and ibrutinib, both eventually stopped being effective. I'm now on idelalisib but if that becomes inaffective I've been told no pirtobrutinib is available. The manufacturer hasn't made any more. That could change but for the time being there's none available. I'm worried 😟

[SeymourB in reply to 42828]

42828 -

The trial I am on was delayed due to availability of Pirtobrutinib. I haven't seen or looked for supply chain issues with it. Can you provide a link to the manufacturing problem?

My understanding is that Pirtobrutinib is FDA approved for relapsed/refractory mantle cell lymphoma, but not for CLL yet. A doctor could prescribe it off-label for CLL, but a clinical trial is your best bet.

There are 12 Pirtobrutinib trials for CLL listed on clinicaltrials.gov:

clinicaltrials.gov/search?t...

=seymour=

[Peggy4]

Excellent news 🎉

Peggy

[Zia2]

Congratulations SeymourB! Pretty amazing!!

[PoisonDwarf]

That’s excellent news. Everything to celebrate there. Thank you for sharing.

[johnliston]

Seymour, Did they say why they used Pirtibrutinib instead of one of the other BTKs?

john

[SeymourB in reply to johnliston]

johnliston -

This is a clinical trial. What attracted me to it was that it is fairly short (originally 7 cycles, now 9 cycles), has ClonoSEQ testing, and is a combo, which all indications from previous combo trials leads to longer remissions. Pirto also has significantly fewer adverse effects. The main problem I've had, apart from a significant initial infusion reaction to Obinutuzumab, has been significant fatigue when Venetoclax hit 400mg/day.

My original doctor at M.D. Anderson was Dr. Philip Thompson. I saw him for an assessment of possible need to treat. He said I was ready to begin treatment, and we discussed existing therapies and clinical trials. He recommended this trial to me because I am high risk due to unmutated IGHV, NOTCH1, and abnormal lymphocytes . Alas, he moved back to Australia a few months later. My loss, Australia's gain. Even so, I'm happy with Dr. Swaminathan and MDA in general (except for their billing department, I must say).

=seymour=

[johnliston in reply to SeymourB]

Seymour, I was down there for the I/V trial in 2018. I had Dr. Jain for my Dr. and he ran the trial. I didn't get to UMRD 10-4 until nearly 2yrs into the trial, it lasted for 18 mos and then flipped positive but stiil low. I'm almost 3 yrs after trial still low MRD, but I'm getting Rituxan for AIHA and that might be helping keep it low. I also originally tested Mutated IGHV in 2005, and then tested Unmutated in 2018 at MDA. They assumed the first test must have been bad.

The reason I asked about Pirtobrutinib is because I thought that was reserved for when the other BTKs stopped working so you would have another line of available treatment.

Good luck and I hope you get a long remission.

john

[CycleWonder in reply to johnliston]

I was also treatment naive and on a trial for Pirtobrutinib.

[SeymourB in reply to CycleWonder]

CycleWonder -

I suspect that the trial you are on will help significantly in better documenting adverse affects in Pirto by itself. We should be grateful for your involvement and sacrifice.

Have they discussed the possible treatment paths after the trial if you have a remission? I presume you could still do V&O.

=seymour=

[CycleWonder in reply to SeymourB]

Thank you Seymour. I feel incredibly lucky actually. My big sacrifice has been to have a bone marrow biopsy. That turned out to be much less uncomfortable than expected.

I am also grateful for the frequent follow up and the moral support from this group and my doctor and his staff.

Not having to pay for the meds is also nice.

Afterwards, we haven’t discussed too much. The landscape keeps changing quickly so I expect by the time that decision rolls around, the options will be much different.

I’ve had very few adverse affects - some skin issues early on, and that’s about it. No nausea, no diarrhea, no heart issues.

Another benefit was my son reading the study protocol, along with all the potential side effects, and finally allowing himself to realize I was pretty sick at the time. He had been supportive but wondering if I needed to worry so much about Covid, etc. Reading the study protocol provided enough sobering detail for him to blast through his wishful thinking about my health.

We have a weird disease, one where I can go on a bike ride, which he sees, and then experience severe fatigue for three days after (which my son would not witness).

The crux is my son didn’t want me to sick. Of course, none of us want to have a diagnosis either.

[SeymourB in reply to johnliston]

johnliston -

> I also originally tested Mutated IGHV in 2005, and then tested Unmutated in 2018 at MDA. They assumed the first test must have been bad.

How interesting! What FiSH type(s) do you have?

> The reason I asked about Pirtobrutinib is because I thought that was reserved for when the other BTKs stopped working so you would have another line of available treatment.

No reservation. It's a theoretical treatment path thing for relapsed/refractory CLL based on the BRUIN trials - that Pirto looks better after another BTKi fails because it isn't affected by the biggest resistance mutation from previous BTKi's - the one at C481 in the BTK protein. Pirto has it's own resistance mutations, and the path after Pirtobrutinib is not clear. Much depends on genetic testing if and when I relapse. Both Obinutuzumab and Venetoclax can also have resistance mutations.

But since the response to Pirto was so good in R/R, it was natural to try it in treatment naive. But I doubt that we'll see a Pirto monotherapy. Combos seem to lead to less resistance and longer remission. I'm hoping for several years remission - and will continue reading studies on bispecific antibodies and BTK degraders.

=seymour=

[johnliston in reply to SeymourB]

Seymour, My first FISH test said I was 13q deleted. My second test showed no deletions. While it not unusual to pick up a deletion I've never heard of anyone losing one so that first test was probably bogus too.

I talked to my HEM/ONC last week and she said that since I've gotten a good remission out of my I/V treatment that repeatng it would be an option when I need treatment again, but I think I might get more bang out of V/O.

john

[SeymourB in reply to johnliston]

johnliston -

The whole "the test was wrong" thing bothers me a lot.

We seldom find out the details of how tests are done - what instrument, what version of software (that does indeed matter), what reagents, sometimes even what lab, the initials of the technician. There's no systematic quality control for the lab to contact us to say, "we found a bad batch on reagents, and your test might need to be repeated." I think this info should be on the report from the lab.

The thing about V/O is that the O has a greater impact on immune function for a longer time. But it also gives a deeper response in trade.

I've done really well with infections during the trial, but I don't eat indoors at a restaurant, and I don't like standing in a line in a queue. I mask. I have a hand sanitizer bottle in my pocket. My wife does the same - and she's a teacher. But recently, we've had a relative stay with us who does not mask like my wife. So we're taking a bit more risk. I don't think it's a deadly risk for me, though. Much depends on the quality of medical care given on weekends.

=seymour=

[GumboKing]

All great news SeymourB. Re your 2cm node. I had a 1.6 cm node even reaching MRD at 10-4 and had to stay on my I+V trial for another 12 cycles. The 1.6 cm node was still there. Probably stretched for ever. But I guess the extra year on I+V made my remission deeper.

Congrats. Paul

BTW, I can't help but wonder what follows the "B". I'm a B also and must be kin to half of Louisiana.

[SeymourB in reply to GumboKing]

GumboKing -

I'm very French on my mom's side, even before the Acadians arrived, but the B is Irish on my Dad's side. Even so, I have no doubt that we could be cousins based on evidence from my 23andMe results. PM me if you want to pursue - I love genealogy!

=seymour=

[GumboKing in reply to SeymourB]

I'll do it but 1st I'm preparing for the family feed later today.

[bennevisplace]

Wow, congratulations on those lab results Seymour. You're doing fantastically well, with at least another 5 cycles to smoke out those residual CLL cells.

[country76]

Congratulations !!! Encouraging and good news.

[country76]

Are you mutated?

[SeymourB in reply to country76]

IGHV unmutated.

[Nurseq]

Seymour- it’s great reading your post. My husband is 65- CLL transformation to Richter’s. Just started this same clinical trial at MDA last week. Would be interesting to stay in touch to see how you both do. He transformed after 2, years of watch and wait, 6 months of Acalibrutinib and 6 R_chops.

[JuciyJ]

I had been on Ibrutinib for 5 years and it seems to have run its course. I found out today I start this trial next week. 13q muted muted tp53

[avzuclav]

SeymourB that sounds like an excellent result after such a short time on treatment.

I haven't had a clonoSEQ test done but I hope to someday. From what I've seen, they have very detailed test reporting. I wonder if you could get MDA to send you the actual pdfs? Here's a helpful document ("for healthcare providers") that walks through the clonality and tracking reports:

clonoseq.com/wp-content/upl...

Page 11 of 19 briefly mentions results which fall beneath the limit of detection (LOD).

If you really want to get into the weeds, here's 50 pages of clonoSEQ technical information:

clonoseq.com/wp-content/upl...

In any case, congrats on the result!

[SeymourB in reply to avzuclav]

Dr. Swaminathan gave me a printed copy of the Cycle 4 report today in clinic.

He also mentioned that Adaptive Biotechnologies offers training, and hinted that maybe curious patients could look into to see if we can get in. So I need to call Adaptive to inquire. I've had some college level classes in genetics and immunology, so I think I have a chance of understanding much of it.

I've combed through the Clonoseq web site and PubMed for papers on NGS (Next Generation Sequencing) for MRD in general.

=seymour=

[noeagaman]

That is great news SeymourB! I hope that you continue to benefit greatly from this trial and thank you for volunteering as that will help us all out down the road.

Chris