A trial and some tribulations

[SeymourB]

After final screening on February 14 (Valentine's Day!), a week later, I started the NCT05536349 trial , "Time-limited Triplet Combination of Pirtobrutinib, Venetoclax, and Obinutuzumab for Patients With Treatment-naïve Chronic Lymphocytic Leukemia (CLL) or Richter Transformation (RT)" at M.D. Anderson

clinicaltrials.gov/ct2/show...

History:

I had been Watch & Wait for 12 years, Trisomy 12, with mutated IGHV VH3-7 family. In August, 2022, I went for a consult at M.D. Anderson with Dr. Philip Thompson. I had been feeling more fatigued, and had a firm lump on the left side of my face that was perceptably growing. He did a workup that included a PET/CT (because of the lump), genetic tests, and an new CLL FiSH panel.

The PET/CT and a core biopsy found that my left side parotid gland had CLL infiltration, and was "4.5 x 3.2 cm with increased activity maximum SUV 5.6". Spleen was "6.9 cm in craniocaudal dimension, maximum SUV of 3.9 which is slightly higher than the liver with a maximum SUV of 3.4."

The genetic tests showed NOTCH1 and BCL2 gene mutations. The new FiSH panel showed I was now unmutated, IGHV1-69 -IGHJ6. Dr. Thompson said that I was probably bi-clonal. The new clone probably wouldn't have allowed a 12 year W&W.

In November, 2022, I developed mildly high uric acid (7.8mg/dL) and "Abnormal lymphocytosis with many cells showing irregular nuclei." WBC had increased from 83.5K to 104K. I

By January, Dr. Thompson had moved back to Australia. My case was handed off to Dr. Mahesh Swaminathan, who Dr. Thompson had described as a former top resident. Dr. Mahesh Swaminathan noted the abnormal lymphocytes were not included in the November count. He asked my local hemo/onco to do another flow cytometry to rule out a transformation. That flow showed it was still CLL. WBC had increased to 126.7K, with an ALC of 124K.

Trial Qualification:

MDA still had not received the pirtobrutinib for the trial in January, 2023. It finally arrived the first or second week of February. We drove from New Orleans to Houston in time for Valentine's Day to do the preliminary screening - many blood tests (16 tubes, if I recall correctly), urine test, a CT, and a bone marrow biopsy. I had already done an echo cardiogram and EKG in New Orleans at the hospital where I had once worked in IT. The MDA bone marrow biopsy went really well - only zinged a nerve once, and no soreness afterward.

The BMB showed 80-90% CLL involvement and cellularity. WBC was now down to 107.5, ALC 92.45K. Uric acid was now 8.7mg/dL, and creatinine had gone slightly above normal at 1.25mg/dL. Dr. Swaminath said that it looked like the difference since January, along with the high uric acid, was due to spontaneous tumor lysis. RBC had continued its slow fall. Platelets were nicely normal at 248 with normal morphology. Altogether, it meant I was good to start the trial a week later.

You, sir, are in danger. We watch people like you.

Because of the uric acid and creatinine, Dr. S decided it would be safer to admit me for the Day 1 standard 1/10th dose obinutuzumab infusion so that they could monitor for TLS (Tumor Lysis Syndrome - bad kidney numbers that could lead to kidney failure and beyond). Dr. Burger was the attending hemo/onco in the hospital. The MDA hospital is 22 stories tall, with over 900 patient rooms - mostly private rooms, I think. It's almost always totally booked. So the floor I was on, floor 16, was entirely dedicated to leukemia, and had 48 private rooms. The staff at the clinic called the hospital "The Taj Mahal."

The Trial Began with Obin Tribulation:

I had a fairly bad reaction to the obinutuzumab - sudden diarrhea, low blood pressure (84/57), sweating, and dizziness. I presume it was a cytokine reaction, not an IgE allergic reaction, because I didn't get itchiness or mouth swelling. They stopped the infusion to do a 500mL bolus of saline, which calmed the blood pressure back toward normal. But I had also spiked a 39.1C/102.4F fever, so they ordered blood and urine cultures plus Zyvox/Cefepime antibiotic. Days later, I saw in the portal that those cultures were normal. WBC down to 101.2, LDH 1532! I'm still sorting through all the tests results and notes by nurses that I can see in the patient portal. They kept waking me up for vital stats and blood draws.

Sometime that same evening, they started the pirtobrutinib - four 50mg pills - because the 100mg pills were not available. That, combined with the obin could lead to TLS, although I think obin could do it by itself. The trial protocol calls for allopurinol throughout the trial.

Fun Note: Obinutuzumab would be a great Scrabble word.

I had started the allopurinol back in January, which kept the uric acid normal throughout my stay. So the TLS symptoms they were looking for were creatinine, which had peaked at 1.41mg/dL the next morning, and venous potassium at 4.6mEq/L. Their range for venous potassium is different from a regular potassium level - 3.4-4.5 vs. 3.5-5.1. My urine darker than I had ever seen it.

They debated whether to do the other 9/10ths of obin on Day 2. The trial nurse made a call, and it wasn't absolutely necessary, so they skipped it. But I was still in the hospital for 2 more nights due to high creatinine and potassium, getting saline.

When they finally went to take the IV out (they had placed 2, in case one got blocked or something), they noticed that my arm had swollen. Then, I lost the top layer of skin along with the tape! There were blisters where some of the easier to remove tape had been. Tape that had been on the other arm after blood draws did not have the same effect at all. So I guess it was another cytokine thing (we can blame anything on cytokines, right?) - a contact dermatitis instead of a true allergy.

I finally got discharged in time for a Friday night Houston Rodeo week traffic jam. It took over an hour to go 30 miles to our friend's place.

Day 8 and 15 got better

For the Day 8 infusion, they decided it would be wiser to split it in halves, and admit me. I had no problem at all. They still did blood draws.

For Day 15, they split the obin in halves again, but we did it outpatient. Outpatient IV at MDA's Ambulatory Treatment Center still has a private room, though much smaller. I was looking forward to chatting with fellow patients. So we chat more in the waiting room.

I still need to unpack all the creatinine and potassium numbers. I could see it go up during and after the infusions. But they didn't even draw blood during the infusion on Day 15 - and that was fine with me. My arms look like I lost a fight with a wild animal.

Effectiveness:

I feel a bit tired, but elation from finishing infusions without adverse effects helped some.

It's really hard to gauge this, because who want daily bone marrow biopsies? So we go with the proxy - serum. I've really got to check my numbers.

It took 3 days for:

WBC to go from 101.2 to 12 Ku/L. It went as low as 4.0 on Day 9 before rebounding to 13.3.

ALC to go from 79.38 to 5.04 Ku/L. It went as low as 2.24 on Day 8 before rebounding to 7.08.

Platelets went down to 265 down to 77 and back up to 528. Last seen at 454.

RBC started at 4.5, went down to 3.77, and back up to 4.63.

Hgb started at 11.9, went down to 10.1, and back up to 12.5.

It's only been 3 weeks since I started on February 21st. Last bloods were on March 8th. I have a blood draw back here at home in New Orleans on Thursday, via Quest Diagnostics. I'm sure they'll be different in odd ways, but MDA mostly cares about my kidney stats, I think. I noticed differences in report formatting at MDA some pathologists include much more info on RBC oddities on differentials, for example. Some leave out anything other than Neuts and Lymphs from differentials. All my differentials at MDA are manual, and cells counted varies from 100 to 125.

Obin infusions will be monthly for the next 5 months, and I'll start Venetoclax ramp up next week, with multiple blood draws (6 hour and 24 hour) to check for TLS. I'll probably be admitted again the first week or two.

No bone marrow biopsy till September. They'll do ClonoSEQ.

Insurance Tribulations:

Neither MDA nor Blue Cross Blue Shield of Louisiana play nice on the playground. I'm sure they need physical therapy for all the shoulder shrugging and repetitive pointing to each other. Dr. Swaminathan is doing (has done?) a letter to ask that Blue Cross Blue Shield cover this trial as In Network treatment. I'll be talking to the Veterans Administration in Houston next Monday to see what all they might cover, as well.

=seymour=

[CycleWonder]

That is quite the journey! I am glad you are doing so well after the first not-so-great infusion day and that you have wonderful medical care. Hopefully all the insurance stuff will get worked out.

[spi3]

I'm sorry your treatments started off rough. My husband's creatinine was also high and he had to do IVs to get them down. He is on Acalabrutinib and Venetoclax (finished obinutuzumab) - it's been a year, and his blood test reflects a UMRD! We are waiting for 20 April when his Dr will do a bone density biopsy. We are praying that too will be UMRD and he will be and have a deep remission- he has a port (do you have one - this helped a lot) Question since you were in the USCG do you have federal blue cross? Because we do and they pay and we pay the co-pays. Also, my husband has to drink 3 liters of water each day to keep his kidneys in good shape. I'm wishing you tons of success in your immunotherapy treatments .

[SeymourB in reply to spi3]

spi3-

I think if your husband is on a triple combination, the odds are good for uMRD4 (0.01%) or even uMRD6 (ClonosSEQ).

My brother lives in Natick, and urged us to come up to Dana Farber. But my wife has no experience driving in snow, and would be out of work for an extended period. As it is, she's using up all her FMLA (Family Leave Medical Act) days, and her paychecks are short. She's been such an angel-wife/momma-bear throughout all this. Much of it is just as traumatic for her - and for you, I imagine.

I do not have a port. We debated the pros (less trauma to the arm) and cons (possible infection). I've got good veins, so I don't suffer the trauma that my wife does of multiple attempts for even a single IV. I've got 5 more infusions - 1 per month - starting next week.

Did your husband have any problems with Venetoclax plus Acalabrutinib plus Obinutuzuman? Neutropenia? Low platelets? Low Red Blood Cells? I'm expecting some of that based on odds from other trials. I expect the triplet combos to be more harsh. If I had my own choice, I would have done just pirtobrutinib plus venetoclax for a year or two, and skipped the obinutuzumab entirely.

I was in the USCG in ancient times, back in the 1970s. No discos with my haircut!

I have Blue Cross Blue Shield of Louisiana HMO. M.D. Anderson is in Texas, and is out of network for them. Verbally, MDA told us, "No problem, we take BCBSLa" without saying at what percentage and whether they do balance billing or not. I kept pushing for an estimate, and finally received it the morning we were signing the papers for the trial. The estimate did not list insurance coverage, and was a half a million dollars. 20% of a half a million is a huge amount to pay for treatment. It was not complete - it did not include venetoclax, which I estimate to be another $75K. Balance billing could mean we have to pay it all. So we've appealed to MDA's Patient Advocacy. In addition, Nurse Practitioner (PhD) Jackie Broadway-Duren wrote a letter to fulfill the following paragraph in the BCBSLa list of benefits:

bcbsla.com/myaccount/benefits

"1. This Benefit Plan shall provide coverage to any Qualified Individual for routine patient costs of items or services furnished in connection with his/her participation in an Approved Clinical Trial for cancer or other Life-Threatening Illness. Coverage will be subject to any applicable terms, conditions and limitations that apply under this Benefit Plan, including Copayment, Deductible, or Coinsurance amounts shown on the Schedule of Benefits.

2. A "Qualified Individual" under this section means a Member that:

a. Is eligible to participate in an Approved Clinical Trial according to the trial protocol with respect to treatment of cancer or other Life-Threatening Illness;

b. And either,

1) The referring healthcare professional is a Participating Provider and has concluded that the individual's participation in such trial would be appropriate based upon the individual meeting the requirements in paragraph a, above; or

2) The Member provides medical and scientific information establishing that the Member's participation in such trial would be appropriate based upon the Member meeting the conditions described in paragraph a, above.

3. An "Approved Clinical Trial" for the purposes of this paragraph means a Phase I, II, III, or IV clinical trial conducted in relation to the prevention, detection, or treatment of cancer or other Life-Threatening Illness that:

a. The study or investigation is approved or funded (which may include funding through in-kind contributions) by one or more of the following:

1) The National Institutes of Health.

2) The Centers for Disease Control and Prevention.

3) The Agency for Health Care Research and Quality.

4) The Centers for Medicare & Medicaid Services.

5) Cooperative group or center of any of the entities described in paragraphs (i) through (iv) or the Department of Defense or the Department of Veterans Affairs.

6) A qualified non-governmental research entity identified in the guidelines issued by the National Institutes of Health for center support grants.

b. The study or investigation is conducted under an investigational new drug application reviewed by the Food and Drug Administration.

c. The study or investigation is a drug trial that is exempt from having an investigational new drug application."

We haven't seen an acknowledgement of the letter by BCBSLa yet. Once they receive it, it goes to a committee. I sure hope it's retroactive. I really think this trial is to their financial advantage, if only for the fixed duration aspect. I'm sure they pay out many millions for lifetime ibrutinib and acalabrutinib treatment for people not on Medicare part D.

I think other insurance companies have similar lingo deep in their benefits. It's like dealing with Willy Wonka. MDA could do a much, much better job of assuring that all such issues are covered during on-boarding to the center and on-boarding to the trial. We started on this journey in August, 2022, with verbal assurances. We spoke to people in the business office - usually lower level staff - who also gave verbal assurances. Doctors and nurses often waive off financial questions, or simply say vaguely, "We'll work with your insurance on that." Nurse Jackie Broadway-Duren was Dr. Philip A. Thompson's nurse, and I'm happy to say that she knows the inner working of MDA. The M.D.A Case Worker was helpful for some other things, like housing.

The MDA instructions are only for 64 oz (~2 liters) water, but I think 3 is a better target. It's a little harder to do with benign prostate hyperplasia. My output seems limited to about 200mL at a time. I can stretch it, but had at one embarrassing accident at MDA getting from the garage to the clinic - heavy traffic on the freeway delayed access. I used my hat to cover. MDA has signs in the lavatories advising that if one has an accident, they will provide a change of clothes. We debated whether it would be more traumatic wearing scrubs than a well placed hat. Nobody wears scrubs in the clinic. Plus I was late for the blood test, and just wanted to be done with it.

Throughout this whole classic anxiety nightmare, I've been trying to do deep breathing and look at distant trees and listen to the birds like our family psychologist taught us. I've cried with my wife several times. My wife does all the driving, and that was surreal in Houston. We have some bad traffic here in New Orleans on bridges over the Mississippi, but nothing like 10 lanes of traffic in each direction with multiple exits on each side of the freeway, and highways running parallel at multiple levels - GPS cannot depict that 3D nightmare properly. Plus, the annual Houston Livestock Show and Rodeo started, and closed some streets and booked all hotels near MDA, which is close to NRG Stadium, solid for over a week.

=seymour=

[spi3 in reply to SeymourB]

1st I'm so glad you and your wife are supporting each other. I called my insurance customer service number in back of my medical card to give them a heads up when my husband got sick. They were very supportive The Dr's must justify why a particular test, treatment etc and they, insurance will pay. Out of pocket last year (starting in March 2022) was minimal (including PET scans, BMB,) All the medications on the trial are free. My husband had no side-effects at all except at the beginning of Venetoclax he had a slight headache that went away with coffee. This March, 1 year later, his blood test in February reflected UMRD! We are hoping that in April after his BMB that too will show UMRD! God bless you and your wife during this journey and you will be in my prayers. Please feel free to reach out anytime.

[Zia2]

So interesting to read!! Thank you for the post and information. I’m so happy for you! Sounds like it’s going really well so far. Congratulations on being accepted and keep posting when you can. Best!

[Skimom]

Seymour, Thank you for sharing your experience! I am still in w&w and really liked hearing your detailed experience. Keep fighting the insurance! And keep your spirits up.

Diana

[Justasheet1]

SB,

You are awesome. Thank you for sharing your story with us. Please keep us updated.

Jeff

[SofiaDeo]

Wow. Just....wow. What a trip. I hope your continued journey is boring and uneventful. Thanks so much for the documentation!

[bennevisplace]

It's a heck of a story Seymour, told in your inimitable style. Looking forward to reading part two. Wishing you all the best. Get a deal with Netflix man.

[CLLCalifornia-USA]

Seymour, you are one amazing man to power through everything and still be able to share your details for the rest of us. May your strength continue and the trial be exactly what works for you. Please continue to share. Thanks. Sally

[Phil4-13]

SeymourB, thank you for your precise reporting. There is so much to understand, so as not to be overwhelmed and nervous. I send my best wishes for your "trial ride" to become smoother and smoother. 🙂Sandra

[SeymourB in reply to Phil4-13]

Phil4-13 -

I would say that understanding often comes well after the overwhelming nervousness. All the numbers change meaning when there's a tube in one's arm and the pump alarm sounds. "Where did that careful, calm nurse go? Oh, must have been a change of shift."

=seymour=

[Jm954 Administrator]

That sounds like a seriously good combination of drugs and, given your markers, it's great choice.

Wishing you all the very best and a smooth treatment journey.

Jackie

[SeymourB in reply to Jm954]

Jackie -

I think I've read in these pages that venetoclax has it's own personalized experience, which I've yet to experience. My neuts have barely scratched the bottom end of normal, and since recovered. There's a valley just over the horizon, I expect.

I thank you and many others for posting questions and answers over the last decade or so that I've been reading, and showing the way home.

=seymour=

[Jm954 Administrator in reply to SeymourB]

Thank you for your kind words and the thoughtful contributions that you make here too.

My counts never dipped at any point, I hope yours hold up too and you can sail through this treatment to U-MRD 🎉

Jackie x

[Smakwater]

SeymourB,

The first thing that came to mind when I read your post was a Dr. Brian Koffman quote "Smart Patients get Smart Care".

Well written, very clear and concise.

Thanks for participating in a trial and taking time to share the effort.

Your strength is a burst of encouragement!

JM

[SeymourB in reply to Smakwater]

Thanks, JM!

[Ghounds]

Thanks for this detailed account and wishing you well for the next stage.

[9876]

thanks for posting about your experience, it’s really helpful, good luck going forward on this trail.

[Pacificview]

Wow, trials and tribulations indeed. Very well written I might add. Very glad to hear it has been working for you!

[Analeese]

I echo all the wows that you have received. I thought my initial treatment to O was wicked, but I think you definitely have beat me all to pieces. After having an anaphylactic reaction I did end up in scrubs because I also wet my pants. After they revived me, I did not understand and thought for sure I had spilled water. Hopefully the rest of your journey will work out well. The V can have some gnarly side effects, but well worth it in the end. you make me very glad that I am on Medicare. It was very easy to maneuver and I hospital pharmacy helped me without any stress on my part. Best of luck with the rest of your journey. Hopefully your numbers will improve.

[SeymourB in reply to Analeese]

Analeese -

I'm very afraid of an anaphylactic reaction - especially if people keep saying, "Now where did we put the epi-pen. It's not where we stored it?" and "They're such a nice shade of blue. Matches the gown, don't you think?" Of course, in a hospital or well run clinic, those shouldn't be problems.

I was awake through it all - who can sleep through incessant needle sticks and oral temperature? I even emailed myself notes for later. Well I did until they put ice packs in my arm pits a few times for awhile.

When the nurse's assistant took my BP once on my swollen arm (the arm with the infusion tubes still connected), I asked her to compare it to the other arm - and sure enough, swollen arm very low BP, "good" arm normal. I guess that just doesn't happen that often in school.

=seymour=

[Analeese]

it was a terrible experience. I will have to admit. I was admitted to the hospital for a few days after that, and they immediately knew what to do and how to slow down the infusion and add more meds. I never had a problem after that. it too five minutes to revive me. When I came to there was probably a dozen people standing in front of me with all kinds of medical equipment. They definitely were prepared for any situation.

I am so sorry that they tortured your poor arm because that is totally unacceptable. On the other hand after my one year of treatment, I am uMRD. Very happy about that. And as a bonus, my immune system has completely recovered.

[tesoro5858]

Thank you for posting these details. I trust that you are at THE BEST CANCER CENTER for this trial. I am happy that I was able to talk with you and your wife on March 8!Susan

[Ernest2]

Big thanks for sharing all that, and the very best of luck as you go forwards.

Best wishes,

Ernest