Pirtobrutinib triple trial Cycle 7 update

[SeymourB]

Hi, ya'll!

I'm now finishing up Cycle 8 of:

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 in Houston, TX.

clinicaltrials.gov/study/NC...

Originally, this trial was going to end for me at the End of Cycle 7 if I achieved uMRD5 (1 CLL cell in 100,000 White Blood Cells) on clonoSEQ - which I did indeed achieve. But they had already extended the trial to 9 cycles for all patients no matter what MRD status before I hit Cycle 7.

Now, the rumor is that they are extending the trial to 13 Cycles for all patients no matter what MRD status. I am annoyed, but on the other hand the additional cycles may provide even deeper and longer remission. They'll just never know how long a remission after only 7 Cycles - which is very short in targeted therapy time.

I had even achieved uMRD6 at the End of Cycle 4, although Adaptive Biotechnologies clonoSEQ could still sequence one of my 2 clones at that time. At End of Cycle 7, they could not even find one clone to sequence out of about 2 million WBCs.

I won't pound all the other stats from ClonoSEQ, but I find it all fascinating. Maybe if there is interest, I could do a separate post on what I've learned about it.

Blood stats and range:

WBC 6.3 K/uL 4.1 10.5

RBC 5.25 M/uL 4.3 6.04

Hgb 15 gm/dL 13.3 17.4

Hct 45.2 % 39.5 51.8

MCV 86 fL 82 99

MCH 28.6 pg 26.6 33.2

MCHC 33.2 gm/dL 31.1 35.2

RDW-SD 46.6 fL 37.5 49.7

RDW-CV 14.7 % 11.6 15.5

Platelet count 254 K/uL 160 397

MPV 9.2 fL 9.1 12.6

Neutrophil Abs 3.79 K/uL 1.95 7.25

Lymphocyte Abs 1.3 K/uL 1.01 3.24

Monocyte Abs 1.2 K/uL 0.24 0.85

Eosinophil Abs 0 K/uL 0.02 0.5

Basophil Abs 0.01 K/uL 0.02 0.09

IgA 57 mg/dL 85 499

IgM 17 mg/dL 35 242

IgG 338 mg/dL 610 1,616

So, only monocytes a little high. Could be some gut trouble (occasional diarrhea), some osteoarthritis. They don't pursue such a low number

Flow Cytometry Lymphocyte Subset Panel - Details

WBC Count, LymphSub Add 6.3 K/uL

Gated Lymph Region, LymphSub Add 14.5 %

CD3+ 87.2 % 54.9 90.4

CD3+ Absolute 852 cells/mcL 410 2259

CD3+CD4+ 57.4 % 31.1 60.6

CD3+CD4+ Absolute 561 cells/mcL 263 1426

CD3+CD8+ 30.6 % 10.8 39.7

CD3+CD8+ Absolute 299 cells/mcL 30 891

CD4+/CD8+ Ratio 1.88 ratio (calc) 1.8 3.5

CD16+CD56+ 12.8 % 1.2 25.4

CD16+CD56+ Absolute 125cells/mcL 0 520

CD19+ 0 % 4.9 21

CD19+ Absolute 0 cells/mcL 27 447

I don't know how often other people get this type of Flow Cytometry. It's one of my favorites, because it gives B-cell, T-cell, and NK-cell counts. We have a B-cell cancer. The ALC (Absolute Lymphocyte Count) is not just our B-cells, but also T-cells and NK cells. What this test shows is that the therapy I'm on has zapped all of my B-cells (both the good and the CLL cells) that flow cytometry can measure. All that remains in my ALC is mostly T-cells and NK cells. Someday, I hope they get rid of the usual CBC plus Differential, and just do it all by Flow Cytometry or sequencing.

What the above Flow Cytometry also shows is that my CD4+/CD8+ Ratio is improving. CLL ruins the balance of CD4 (Helper T-cells) and CD8 (Cytotoxic or Killer T-cells). A low ratio indicates T-cell Exhaustion - the T-cells not able to fight infections as well. T-cells don't get enough love in the papers and magazines. Sadly, antibodies get all the love.

What I wish they would also count is Plasma B-cells to get an idea of how many cells actually make antibodies. Truth be told, many of these cells - B, T, NK, Plasma B, and even neuts and monos are tissue resident, and unmeasurable. But we should at least measure the ones in the blood, I think.

That brings me to the BMB - Bone Marrow Biopsy. In trials, they generally do one at the start, before treatment, and one at the end after treatment stops. They don't like to do more, because people find them painful or at least uncomfortable. I again did not suffer much at all, and we drove 350 miles the next day back to New Orleans. I credit the talented nurses who do this at MDA.

Microscopic Description, BONE MARROW BIOPSY and BONE MARROW CLOT

Quality: Adequate

Cellularity: 30%

Megakaryocytes: Adequate in number, morphologically unremarkable

Infiltrate: Not identified.

Microscopic Description, BONE MARROW SMEARS/TOUCH PREPS,

Quality: Adequate

Megakaryocytes: Present, no significant dysplasia

Granulocyte lineage: Orderly maturation, no significant dysgranulopoiesis

Erythrocytes: Mild megaloblastoid maturation, no significant dyserythropoiesis

Lymphocytes: Not increased.

Plasma cells: Not increased.

HEMATOPATHOLOGY BONE MARROW DIFFERENTIAL - Details (and ranges)

Adequacy Satisfactory for evaluation

Total cells counted 500

BM Blast 1% 0 5

BM Progranulocyte 0% 2 8

BM Myelocyte 5% 5 20

BM Metamyelocyte 6% 13 32

BM Granulocyte 18% 7 30

BM Eosinophil 0% 0 4

BM Lymphocyte 7% 3 17

BM Monocyte 4% 0 5

BM Pronormoblast 1% 1 8

BM Normoblast 56% 7 32

BM M:E Ratio 0.6 ratio 3 4

I'm happy with the BMB results. Cellularity was originally 80-90% back in February. I think 30% is in the normal range for men my age.

Normoblasts are nucleated red blood cell precursors of normal red blood cells. They were 8% back in February when my Lymphocytes were 85%. Not sure why it's a bit high. I have good RBCs, Hemoglobin, and Hematocrit on the CBC. Could be that it all settles down once I stop therapy. If anyone could weigh in, I'd appreciate it.

Now, the baby pictures. Trials don't actual do things by blood counts. Remission is usually based on sizes of nodes and spleen. I need to re-read the iwCLL 2018 guidelines, but I don't think they accept MRD status alone for Complete Remission yet.

CT Neck with Contrast Lymphoma - Details

Impression

1. No cervical adenopathy.

2. Continued decrease in size of the left intraparotid node.

3. No acute sinusitis."

FINDINGS:

Lymph nodes:

There has been a continued decrease in size of nodes in the neck.

A 1.1 x 0.9 cm left intraparotid node (series 3 image 65) previously measured 2.4 x 2.2 cm

So, my problem node or infiltration of the parotid has come down dramatically from original 4.4x5.0cm, and is below the 1.5cm iwCLL progression cutoff.

CT CHEST ABDOMEN PELVIS W CONTRAST LYMPHOMA

Impression:

Further interval improvement/decrease in the sizes of the multicompartmental lymph nodes in the chest, abdomen and pelvis. Interval improvement in the prior splenomegaly.

New diffuse hepatic steatosis.

CT CHEST ABDOMEN PELVIS W CONTRAST LYMPHOMA CHEST FINDINGS:

Lines and Tubes: None.

Lungs and Pleura: Again seen multiple tiny sub-5 mm bilateral lung nodules, may be prior postinflammatory sequela and followed (7/47, 40, 95, 101, 113, 120). No new suspicious pulmonary nodule. No consolidation. No pleural effusion.

Cardiomediastinum: The heart is normal in size. No pericardial effusion.

Tiny anterior mediastinal soft tissue, likely thymic remnant. Again seen mild prominence of the right and left pulmonary arteries.

Again seen moderate size gastroesophageal hiatal hernia.

Lymph nodes: Further interval decrease in the sizes of the prior improving multicompartment lymphadenopathy. For example, residual 1.5 x 1 cm right retrocrural node (6/70) compared to 1.9 x 1.1 cm on 3/21/2023.

Hepatobiliary: New diffuse hepatic steatosis limits detail evaluation of the liver parenchyma for the small and/or subtle focal liver lesions. Few indeterminate hepatic hypodense lesions measuring up to 1.2 cm are again seen, may be benign/cysts and followed. Again seen status post prior cholecystectomy with mild biliary ductal prominence.

Spleen: Interval improvement in the previously seen splenomegaly. Currently spleen is enlarged measuring 11.4 x 10.4 cm (craniocaudal by AP) compared to 13.6 x 1.7 cm on 3/21/2023.

Pancreas: No focal suspicious lesion. No evidence of main pancreatic ductal dilatation.

Adrenal Glands: No suspicious nodule.

Kidneys: Subcentimeter indeterminate renal hypodensities may be benign and followed. No hydronephrosis.

Urinary Bladder: Mild prominence of the urinary bladder wall may be from chronic postobstructive hypertrophic changes related to prostatomegaly.

Gastrointestinal Tract: Diffuse mural thickening of the sigmoid colon may be from muscular hypertrophy related to colonic diverticulosis and underdistention or inflammatory, and this may be correlated clinically and followed. No intestinal obstruction.

Reproductive Organs: Again seen prostatomegaly protruding into the base of the urinary bladder. Unremarkable seminal vesicles.

Peritoneum/Retroperitoneum: No free fluid or free gas.

Lymph Nodes: Further interval decrease in the sizes of the prior improving multicompartment abdominopelvic lymphadenopathy. For example, the 1 cm in short axis lower retroperitoneal node (6/45) compared to 1.3 cm on 3/21/2023 and 1.7 cm on 2/14/2023.

Lines and Tubes: None

CT CHEST ABDOMEN PELVIS W CONTRAST LYMPHOMA MUSCULOSKELETAL FINDINGS:

Degenerative changes in the spine. No suspicious destructive bony lesion. Again seen tiny subcentimeter skin tag in the right anterolateral chest wall (6/143), may be correlated clinically.

OTHER: Again seen 1.3 cm aneurysm of the distal celiac artery (6/197).

The numbers in parentheses are the CT slice numbers,

So the residual 1.5 x 1 cm right retrocrural node stands out - right at the iwCLL cutoff of 1.5cm. Dr. Swaminathan said it could be due to the gut issues I've had, or scarring from the CLL, and didn't seem concerned. I'm not sure if the Trial Protocol will have another CT Scan down the road, or if this is something that can be measured via a preferable sonogram.

Also, 11cm sounds like a normal size spleen to me. I've seen quite a range of sizes quoted, and wikipedia has a table based on hight and sex. I'm about 177cm or 5 feet 10 inches.

I have another 6 cycles to go after this, but I'm ecstatic about the progress. I've been told that all 6 of the early patients that started the trial back in January and February are making similar progress, and are at uMRD6 on clonoSEQ. Some later patients have more trouble. In addition to the occasional diarrhea (once or twice a month, never more than 1 day in a row), I had notable additonal fatigue at the start of Cycle 3, when Venetoclax ramped up to the full 400mg.

The original trial plan was for 60 patients total, with 40 in Cohort 1 (treatment naive CLL/SLL), and 20 in Cohort 2 (Richter's), but I heard they want to grow Cohort 1 to 60 participants, and Cohort 2 to 30 or more.

I don't know when they'll publish preliminary results - maybe an abstract next year now that it's been extended to 13 cycles. For me, the final trial day will come on February 19, 2024.

Oh, and I'm Trisomy 12, IGHV unmutated, mutations in NOTCH1 and BCL2, originally diagnosed in early 2011.

=seymour=

[DriedSeaweed]

Thanks for the update. Did they explain why they are doing additional cycles? Just to be sure it can be maintained longer?

[SeymourB in reply to DriedSeaweed]

DriedSeaweed -

Only so that all participants get the same length of treatment - but not why that matters. I presume there are statistical factors.

Verbally, I've heard things like "so that you have the best chance at the longest remission."

The extension was still not approved by higher ups as of an email I received yesterday, but I notice that they had already scheduled my visits through November, which is one cycle beyond the current last cycle, Cycle 9.

=seymour=

[Skyshark in reply to SeymourB]

Unmutated get better results faster than mutated on both V+O and V+I but proliferation rate is higher so relapse sooner.

Mutated take longer to get to uMRD if at all but mutated with wildtype TP53 have longest remission. MAJIC trial is extending 1st line V+O and A+V for those that don't get to uMRD to find out if they ever will achieve it.

[SeymourB in reply to Skyshark]

Skyshack -

Interesting details. Thanks much!

=seymour=

[SofiaDeo in reply to Skyshark]

It's interesting you state "mutated take longer to get to uMRD if at all", I haven't heard that, do you have a reference? The earliest data states mutated generally have longer progression free survival and overall survival. But this was in the days when only straight chemo was available.

Responses to BTKi's in unmutated have been noted to occur faster. But I haven't seen where mutated "have problems" reaching uMRD. And the most recent data I am seeing is discussing how the BTKi's have changed statistics such that both mutated and unmutated now enjoy similar PFS's, instead of the disparity of earlier generations who only had standard chemo regimens.

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

nature.com/articles/s41375-...

So I am unclear why you say "if at all" regarding mutated folk reaching uMRD since they used to be the group with overall better responses.

[Skyshark in reply to SofiaDeo]

BTKi monotherapy rarely reaches uMRD. It keeps the lid on CLL. Page 12 of the ELEVATE supplement shows just 10% get to uMRD on Acalabrutinib.

static-content.springer.com...

"In IgHV-unmutated CLL (U-CLL), the proliferation rate is higher compared with IGHV-mutated CLL (M-CLL). Yet, why CLL cells differ in their mutational rates is unknown."

That is relative u-CLL to m-CLL and not in relation to normal B-Cells. All CLL cells are slower dividing than normal and even slower to die. The slower proliferation of m-CLL is what makes it more likely they never need treatment. 40% of CLL patients are u-CLL at diagnosis but over 50% at first treatment.

clinical-lymphoma-myeloma-l...

This is about short/fixed duration therapies. Typically on a Venetoclax + a n other regime ~75% reach uMRD.

ashpublications.org/blood/a...

"uMRD rates were higher in patients with unmutated vs mutated IGHV in PB (84% vs 67%) and BM (64% vs 53%)."

The above report is quite confused as they added 43 subjects from the MRD arm that had achieved uMRD and were then given a placebo (a total of 86 were uMRD but the other 43 continued Ibrutinib). Although they had effectively had a Fixed Duration of V+I they skew the PFS results making them nonsense. There were 30 u-CLL, 8 m-CLL and 5 with unknown IgHV. The addition subjects from the MRD arm had a m-CLL/u-CLL ratio of 0.26 (8/30) while the natural ratio of the FD cohort was 0.63 (63/99). this shows that m=CLL is less likely to reach uMRD but still have better PFS.

"Best uMRD rates were 77% (95% CI, 70-83) in PB and 60% (95% CI, 52-67) in BM in the all-treated population (Figure 3A). In patients without del(17p), uMRD rates were 76% (95% CI, 69-84) in PB and 62% (95% CI, 54-70) in BM. uMRD rates for patients with del(17p) and/or mutated TP53 were 81% (95% CI, 67-96) in PB and 41% (95% CI, 22-59) in BM."

The above would indicate that subjects with TP53 damaged status are more likely to reach uMRD in PB but not BM. There were only 2 of the 43 from MRD arm with TP53 damaged, both were u-CLL.

ascopubs.org/doi/full/10.12...

U-CLL and damaged TP53 have shorter PFS. (This is a poster for 4 years without the MRD addition.)

pharmacyclicsmedinfo.com/do...

For V+O there is a smaller gap between m-CLL and u-CLL but it is still there. While damaged TP53 again showed a reduction in likelihood of achieving uMRD.

ashpublications.org/view-la...

Again a shorter PFS, slide 15.

medically.gene.com/global/e...

Both the 6 year CLL14 and 4 year CAPTIVATE FD have presented PFS for uMRD/dMRD. Both show similar trends of dMRD having much shorter remission (and OS for CLL14) but as yet they do not show if there is also an IgHV or TP53 correlation.

With these uncertainties there is a good case for extensions of fixed duration therapies for both m-CLL and u-CLL. M-CLL to reach uMRD and u-CLL to achieve deeper MRD with expectation of longer PFS.

[SofiaDeo in reply to Skyshark]

But your sentences when you made that statement were talking about V&O and V&I protocols. You made a statement about *that specific patient therapy set* & when I asked for the reference, started by talking about BTK monotherapy! It's very confusing when switching patient groups/treatments suddenly. And the statements don't necessarily cross across patient groups. You can't make a statement like "patients rarely reach uMRD" without confusing people when your statement is about solo BTK treatment, yet are talking about V&O, V&I, do you see that?

[SeymourB in reply to Skyshark]

Skyshack -

Another thing to keep an eye on in studies is the detection limut. In the past, MRD was assumed to mean 1 in 10K WBCs. But now that there are multiple technologies to measure residual dusease, it's goid to add the detection limit.

Dr. Wierda in 2021 recommended changes to nomenclature, but old habits die hard.

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

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

So when you see MRD by itself, assume MRD4 (10 to the 4th power - 10k), which is easier to achieve, and may not last as long as MRD6.

Also, hidden in all this is an assumption that IGHV unmutated always grows. But it can plateau at any level in anyone. The averages hide this.

I'm expecting that the statistical outcomes of various combos of BTKi plus O&V will be similar, but Pirtobrutinib will have fewer people discontinuing the BTKi due to adverse effects will be noticeably lower,and that, too, will affect overall outcomes.

The trial I'm on is small. It's a Phase 2. Larger trials, especially those that include more FiSH types and comorbidities will differ from earlier trials in statistical outcome. It's hard to find ourselves in trial stats.

=seymour=

[Skyshark in reply to SeymourB]

The problem with renaming uMRD to uMRD4 is that there are hundreds of reports that would now need revision or have unclear meanings.

[SofiaDeo in reply to Skyshark]

Perhaps moving forward, people will start using uMRD4 and uMRD6 to specify, and we will just have to "know"/learn that earlier studies weren't as sensitive. I agree it will be a problem, similar to how journals now may use "CIT" for the old standard chemotherapeutic agents, when previous information says "chemotherapy", and people are now using the term "chemotherapy" to mean "any drug used to directly treat cancer."

[SeymourB in reply to Skyshark]

I think Wierda addresses that by advising using the numeral in future papers, so that MRD alone means MRD4.

[bennevisplace in reply to Skyshark]

Yes, there's evidence for IGHV status correlating with proliferation rate karger.com/aha/article/140/...

but...

Do you have separate results forTrisomy 12 in those studies? Both Seymour and another member who posted recently, unmutated and ZAP70 +, had a long TTFT not indicative of a high proliferation rate.

Also, the authors of the above paper make the point"...the percent deviation of the immunoglobulin heavy chain gene variable region sequence from the germline sequence (IgHV%) is a continuous variable. CLL patients’ survival correlated with a continuous increase of IgHV% deviation. The higher the percent deviation, the better was the treatment outcome, suggesting that IgHV% is a continuous and not a dichotomized prognostic variable". A point made by Seymour himself, in reply to neurodervish.

AFAIK, Trisomy 12 is regarded as "intermediate risk", and that's surely never been more than a rough guide. Furthermore, according to haematologica.org/article/v... "Intriguingly, a subset of patients with complex karyotypes carrying trisomy 12, trisomy 19, and additional trisomies seem to correspond to a particular genetic subgroup with favorable outcome". Mutated or unmutated (Table 1).

[Skyshark in reply to bennevisplace]

Not a lot on Tris 12+, about half the reports are for FC-R and B-R.

Intermediate but considered poor with NOTCH1.

CLL14 trial 40 out 211 on V+O had Tris 12+. 30 were u-CLL. 17 with Notch1 of which 16 were u-CLL. 7 del(13q), fairly evenly split but whereas the m-CLL only had Tris 12+ and del(13q) the 4 u-CLL subjects had a range of other markers half of them being del(11q).

At 3 years from start of treatment when PFS for u-CLL and m-CLL with TP53wildtype was >80% they said

"Interestingly, in patients with trisomy 12 (18% of patients), there was no progression or death event with VenG during the observation period, which is a remarkable result with yet-unknown biologic background."

ashpublications.org/blood/a...

The lack of KM charts for Tris 12+ show they were more interested in NOTCH1 and ATM, well a flat line at 100% is kinda boring.

This response for Tris 12+ is unlikely be the case now as u-CLL PFS has headed south to a median of 66 months. PFS at 72 months was 47% and at 84 months is about 30%, 28% of u-CLL were Tris 12+.

medically.gene.com/global/e...

[bennevisplace in reply to Skyshark]

Thanks for these observations. That last ref is revealing, as compared with the 3 year K-M curves I recall. Is there evidence ( I asssume they are testing along the way) for emergent mutations in the course of the study?

Various articles on Trisomy 12 have given me the impression that 12+ is a subtle prognostic marker, the combination with other genetic abnormalities+/- IGHV status being more significant. Here ncbi.nlm.nih.gov/pmc/articl... the researchers highlight a favourable dual marker, Trisomies 12 +19, while acknowledging that cohort to be IGHV-M enriched. A curiosity of this study is that an apparently random selection of 12+ cases included such a small percentage of confirmed NOTCH1 (Table1).

[SeymourB in reply to bennevisplace]

bennevisplace -

It really annoys me when a paper has no raw demographic data, or they do not break each FiSH type out into IGHV mutated and unmutated in tables. Sometimes details are in a sentence, when they should be in tables.

Trisomy 12 is so wierd. It's not a copy error or a crossover error. They don't even quite know why it causes symptoms, except that genes on other chromosomes get over or under expressed.

I look forward to the day when single cell sequencing can be applied to a million cells cheaply. We'll certainly see a lot more variation then. ClonoSEQ is the best we have at the moment. For other cancers, like AML, they don't just sequence the BCR (B-cell Receptor), but include a handful of other genes as well, I believe.

=seymour=

[bennevisplace in reply to SeymourB]

I was looking for a breakdown of the study groupings too. From that paper: "Details of the study cohort and the methodologies used are provided in the Online Supplementary Appendix", except that appendix seems to be unavailable online.

[Skyshark in reply to bennevisplace]

This CLL14 report has a nice graphic of genetic markers.

ashpublications.org/blood/a...

A python script can extract them. But there is no way to correlate them to progression events in CLL14 KM plots.

I've also seen a report that had a pretty "fantail" of markers but I've lost the link and don't know what trial it was for.

There is also page 8 of this report but I've no idea what these genetics are.

nature.com/articles/s41467-...

[bennevisplace in reply to Skyshark]

Transcriptopmic profiles, gene enrichment analyses... over my head I'm afraid.

I'll save it for a rainy day.

[Name-1]

Thank You SeymourB

[Greenbunnies]

what fantastic results - and how brilliant to get all that information!

[SeymourB in reply to Greenbunnies]

Greenbunnies -

There was more that I did not include, like the MRD4 test via Flow Cytometry (1 in 10L WBCs), which was negative as expected. Also there was a CG Chromosome Analysis that failed to find my Trisomy 12. Oh, and my Uric Acid was a bit high at 8.5 mg/dL - back on the allopurinol. In discussing that, they said that it's not likely due to cells dying, since that battle is long over for several cycles now. Burgers? Timing of the test vs hydration? I did 82oz for that day and 96 oz the day before. But I may have only had 12oz since midnight at the time of the draw.

=seymour=

[Greenbunnies in reply to SeymourB]

As my radiologist friend says, the trouble with tests and scans is they give us a lot of information that just creates more questions and is probably not significant anyway! But it's fantastic to see such great results in all the right areas. And improving T cell function! I wish I could get mine checked routinely. Hoping my new consultant will take an interest.

[Indolent]

Great results! It certainly looks like you are winning the battle.

[Pacificview]

A very encouraging report! I would be dancing a jig or some other happy dance.Thank you for sharing your info.

May the rest of the cycle produce an even longer remission if not cure.....

[SeymourB in reply to Pacificview]

Pacificview -

I danced a silly dance with my wife, and laughed, and giggled. She wondered why I didn't celebrate every day. I'm still on therapy for months. As good as this waypoint is. I'm a little wary that some other illness that I've ignored because of being in therapy may rise in importance. That 1.5cm intracrural node, that tiny aneurism the abdominal CT found, the high Uric Acid, floaters in both eyes, etc. Each needs a plan. So I'm more sober than I might have been.

It's like the day after the Christmas that I got my first bicycle. Surprise is over. New, different surprises are on the ride.

=seymour=

[Justasheet1]

Definitely something to be thankful for. Im extremely happy for you.

Jeff

[Stamphappy]

SeymourB, this is so encouraging! I'm so happy for you! Thanks a million for not only participating in this trial, but for your informative post. I'll be anxious to read your next one 😊 . Keep the faith. You're all in my prayers.

[tesoro5858]

Excellent news! I am so happy with your progress and that of the other trial participants. Thanks for including your detailed test results. I especially found the lymphocytes phenotyping numbers helpful as I had a report from the NIH of my results, which were not discussed with me since the numbers were not available during my visit.

[spi3]

My hubby's trial had/has him on O&A&V and 6 months ago he was declared MRD negative in his blood and had a minut cll in his bone marrow - his Dr wanted him to stay on A&V another 6 months so that my hubby can get into a longer remission- -also I just read there is a third test to determine MRD -it is to take a lymph node biopsy- I'm going to ask his Dr whats that all about in October--the thing to determine if your tolerance and body can handle the treatments - if so think of this as a blessing- because I really do think these O&A&V are Angel warriors sent from God

[Wiemer65]

Seymour

I can’t say enough how happy I am for you. Keep it up.

[neurodervish]

Congrats Seymour! I wonder if you hold the record for the longest time to treatment for an unmutated CLLer? 12 years is impressive. Plus you managed to hold out until all the coolest drugs were discovered, and you got them in a combo!

[SeymourB in reply to neurodervish]

neurodervish -

You may recall from older posts that I originally tested as IGHV mutated back in 2013.

In 1999, the great Terry Hamblin had written the seminal article on using IGHV (then called IGVH) as a prognostic marker.

"We have sequenced the Ig VH genes of the tumor cells of 84 patients with CLL and correlated our findings with clinical features. A total of 38 cases (45.2%) showed ≥ 98% sequence homology with the nearest germline VH gene; 46 cases (54.8%) showed >2% somatic mutation. Unmutated VH genes were significantly associated with V1-69 and D3-3 usage, with atypical morphology; isolated trisomy 12, advanced stage and progressive disease. Survival was significantly worse for patients with unmutated VH genes irrespective of stage. Median survival for stage A patients with unmutated VH genes was 95 months compared with 293 months for patients whose tumors had mutated VHgenes (P = .0008). The simplest explanation is that CLL comprises 2 different diseases with different clinical courses. One, arising from a memory B cell, has a benign course, the other, arising from a naı̈ve B cell, is more malignant." [1]

Back then, I was reading Chaya Venkat's great blog, CLL Topics. Oh, how she could write!

"Sounds reasonable we should all go out and get our IgVH gene mutation status ascertained. Not so fast. This is something that only the best of the research labs are able to do, it is an expensive and time consuming process, and not too many oncologists even know what it takes to get it done. So what is one to do?" [2]

In 2011, when I was diagnosed, my CD38 was 12.5%, which Damle, et al. found in 1999 to correspond to mutated IGHV.

"Those patients with unmutated V genes displayed higher percentages of CD38+ B-CLL cells (>=30%) than those with mutated V genes that had lower percentages of CD38+ cells (<30%)." [3]

But my ZAP70/CD19 was 20% - which corresponds to unmutated IGHV (>=20%) according to Crespo, et al:

"In all patients in whom at least 20 percent of the leukemic cells were positive for ZAP-70, IgVH was unmutated, whereas IgVH mutations were found in 21 of 24 patients in whom less than 20 percent of the leukemic cells were positive for ZAP-70 (P<0.001)" [4]

So, I eventually asked my hemo/onco if they had a direct IGVH test, because that's what Hamblin used. He had never ordered one. He found one, and my IgVH Mutation Status came back as "Mutated, VH3-7 family", and the IgVH Mutation Rate was 15.44%

What a relief! The years passed, ALC slowly climbed, spleen and a few lymph nodes grew, I was more and more fatigued, and less able to even telecommute to my job as an IT firewall and network management engineer. So, I got a referral to M.D. Anderson in August, 2022 (11 .5 years after dx), and chose Dr. Philip A. Thompson to have a look. Being the intelligent guy that he is, he repeated all tests.

My IGHV Somatic Mutation Status now came back as Unmutated! The IGHV Gene was no longer IGVH3 family, but specifically IGHV1-69 -IGHJ6 - just like Hamblin's article above!

He explained that either the original IGVH test was wrong, or I was bi-clonal, and the unmutated clone outgrew the mutated one.

ClonoSEQ also found that I was unmutated, and did find 2 different dominant clones, one of which was "unproductive". I still haven't gotten a good explanation about what all that means, but the gist is that the unproductive one does not result in an Ig molecule on the surface of the B-cell. Dogma says that the B-cell silences the 2nd set of IG genes, so that only one gets presented on the surface. But nobody who has done ClonoSEQ that I have talked to so far (a tiny handful) had an unproductive clone show up. So, could the unproductive clone be in a separate cell? I've discussed this some with MDA, and truth be told, this is down in the weeds. Most doctors don't think bi-clonal CLL happens, or if it does, it's a matter of both Kappa and Lambda genes, and not 2 different IGHV genes.

In any case, ClonoSEQ is not finding either of the previous dominant clones. It did find 1,839 Total Unique IGH Sequences, and 2,347 Total Sequences out of 2,169,196 Total Nucleated Cells. It listed no new Dominant Sequences, which is defined as a sequence that comprises at least 3% f all like sequences, and 0.2% of Total Nucleated Cells, and be carried byt at least 40 estimated genome equivalents in the sample.

So, the whole IGHV mutated vs unmutated thing has nuances. Newer IGHV tests are likely more reliable. Accept the long ride no matter the prognostics, and always remember that some of us are on the edge of the Bell curve. Prognostics are not Predictions.

=seymour=

References:

[1] ashpublications.org/blood/a...

Unmutated Ig VH Genes Are Associated With a More Aggressive Form of Chronic Lymphocytic Leukemia

Hamblin, et al., Blood (1999) 94 (6): 1848–1854.

[2[ clltopics.org/PI/IgVH_CD38.htm

IgVH Gene Mutation Status and CD38 Expression

by Chaya Venkat. Date: May 17, 2002

[3] sciencedirect.com/science/a...

Ig V Gene Mutation Status and CD38 Expression As Novel Prognostic Indicators in Chronic Lymphocytic Leukemia

Damle, et al., Blood 1999 Sep 15;94(6):1840-7.

[4] nejm.org/doi/10.1056/NEJMoa...?

ZAP-70 Expression as a Surrogate for Immunoglobulin-Variable-Region Mutations in Chronic Lymphocytic Leukemia

Marta Crespo, B.S, et al, May 1, 2003 N Engl J Med 2003; 348:1764-1775

[bennevisplace in reply to SeymourB]

Fascinating stuff.

Thanks for posting your results in detail Seymour, and congratulations - again - on the tremendous success of your ongoing treatment. So pleased for you.

[Pacificview in reply to SeymourB]

Thats a loy of minutia!

[SeymourB in reply to Pacificview]

Pacificview -

It's the slight curve in one or two tea leaves that foretells the future. Trick is to find which leaf. 😉

=seymour=

[neurodervish in reply to SeymourB]

Great info Seymour, thanks!

Altho I was diagnosed in 2013, I didn't find HU until 2015—midway thru chemoimmuno treatment and feeling green about the gills. I spent my first 2 CLL years in the wilderness, doing deep breathing with a slow mantra sung to the tune of Carly Simon's “I Haven't Got Time for the Pain.” (There really is a soundtrack for every moment.)

This forum saved me. Reading Terry Hamblin & Chaya Venkat felt like a revelation. Downloading Venkat's blood lab tracking spreadsheet (thanks to AussieNeil ) was life-changing too. My hope is to give back even a fraction of the usefulness this community has given me.

And now I'll spend this evening with “Suddenly Seymour” playing in my head. It's a pretty good tune, so thanks for that too.

[SeymourB in reply to neurodervish]

neurodervish -

One more time through the Seymour Krebs Cycle is good for the spirit.

=seymour=

[Skyshark in reply to SeymourB]

"Most doctors don't think bi-clonal CLL happens, or if it does, it's a matter of both Kappa and Lambda genes, and not 2 different IGHV genes."

Does this mean when both Lambda and Kappa free light chain are elevated it indicates bi-clonal?

[SeymourB in reply to Skyshark]

Skyshack -

I've never seen an IGHV report result that says "bi-clonal." I'm not sure that testing platforms are ready for it. There's been a dogmatic assumption that there's always a single clone, although there can be multiple sub-clones as disease progresses. In that case, the IGHV genes are still the same or closely related on all the subclones.

Usually, Kappa greatly outnumbers Lambda because of light chain exclusion in the cell.

en.wikipedia.org/wiki/Allel...

On Flow, Kappa is usually positive dim, and Lambda is usually Negative. They might also report a Kappa:Lambda ratio on Flow that shows something like 1K or more to 1 ratio.

In bi-clonal CLL due to light chains, there's apparently actually 2 different cells, and this has been confirmed by sequencing.

But there can be other bi-clonal signs. A paper below shows that there can be multiple different heavy chain sequences. Triclonality and beyond is a possibility, though even more rare. It would indicate to me that whatever triggered the original FiSH mutation (Trisomy, 13Q, 11Q, 17P, etc) either affected more than 1 cell, or happened again later.

How common is it, I wonder? The Sanchez paper assesses incidence, but includes other B-cell chronic lymphoproliferative disorders (B-CLPDs), like hairy cell leukemias, and sees it in 5% of B-CLPDs. The Sheikholeslami paper says 0.7% of CLL cases his lab has seen.

I imagine that the growing use of ClonoSEQ at diagnosis will identify more cases. My clonoSEQ didn't happen till after 12 years of watch and wait. I only have so much time with the doctor, and theoretical stuff is further down my list.

=seymour=

References:

sciencedirect.com/science/a...

Incidence and clinicobiologic characteristics of leukemic B-cell chronic lymphoproliferative disorders with more than one B-cell clone

Sanchez, et al, Blood, Volume 102, Issue 8, 15 October 2003, Pages 2994-3002

"Molecular biclonalilty/triclonalilty was defined when 3 or 4 unrelated VDJH, DJH gene rearrangements and/or translocations involving the 14q32 IGH gene locus were found. Secondary rearrangements to a pre-existent VDJH or DJH gene rearrangement were not taken into account for definition of biclonalilty/triclonalilty."

----

ijpmonline.org/article.asp?...

Biclonal chronic lymphocytic leukemia: A study of two cases and review of literature

Ghodke, et al., Indian J Pathol Microbiol. 2017 Jan-Mar;60(1):84-86.doi: 10.4103/0377-4929.200019.

----

onlinelibrary.wiley.com/doi...

Bi-clonal disease in patients with chronic lymphocytic leukaemia as detected by analysing IGHV mutation status

Sheikholeslami et al., Br J Haematol. 2007 Nov;139(3):507-9. doi: 10.1111/j.1365-2141.2007.06805.x. Epub 2007 Sep 14.

[CycleWonder]

Great results! Thank you for sharing!

I am in Cycle 12 of my trial of just Pirtobrutinib and not a MRD yet. My ALC continued to drop. Last test it was at 12.66, dropping from 241.61.

[SeymourB in reply to CycleWonder]

CycleWonder -

Please refresh my memory - what are your markers?

How many cycles will you be doing?

=seymour=

[CycleWonder in reply to SeymourB]

I am not sure of my markers. Neil said I had run-of-the-mill CLL.

[country76]

Congratulations!! I am Trisomy 12 mutated. What is your % of Trisomy 12. This is my Fish and Flow after Ibrutinib 14 mos then Alacabrutinib since 2019.

Fish

11% Trisomy 12

Flow Cytometry

CD5 (dim)

CD19

CD20 (bright)

CD38 (Dim)

CD200 (Dim)

FMC7

kappa

Lymphocytes consist of 51% B cells, 19% CD4+T cells, 24% C8=T cells, and 5% NK cells.

T cells demonstrate a reversed CD4/CD8 ratio (0.8) no antigen aberrancy.

IgG 782 (600-1,500)

IgA 71 (40-375)

Igm 10 (30-190)

[SeymourB in reply to country76]

country76 -

At dx in 2011, GenPath FiSH saw 44.7% Trisomy 12.

In May, 2016, LabCorp FiSH saw 49% Trisomy 12.

In November 2016, LabCorp FiSH saw 64% Trisomy 12. Did LabCorp buy new equipment?

In April, 2018 Quest FiSH saw 68% Trisomy 12.

In August, 2022, M.D. Anderson FiSH saw 60.5% Trisomy 12, 38% normal, and a couple others below cutoffs.

In February, 2023 (a week before treatment), M.D. Anderson FiSH saw 70.5% Trisomy 12, 29.5% normal, and a couple others below cutoffs.

They have not repeated FiSH during the trial. But they did do a thing called CG Chromosome Analysis of 20 cells from bone marrow. A week before treatment, it found 8 out of 20 cells were Trisomy 12:

47,XY,+12[8]/46,XY[12]

At end of Cycle 7 (September 5, 2023), it found Normal male karyotype, 46,XY[20].

That's my fish story!

=seymour=

[CoachVera55]

Congrats & thanks for all the detailed information. My W&W was 13yrs 8mos & on BTKI Therapy 5 months now. How well did you tolerate things, any major hiccups???

[SeymourB in reply to CoachVera55]

CoachVera55 -

I had a major infusion reaction to my Day 1 dose of Obinutuzumab, plus a laboratory (not clinical) Tumor Lysis Syndrome at the same time that was probably due to the addition of Pirtobrutinib to the Obinutuzumab on Day 1, my lymph nodes, spleen, and ALC at about 80K. I spent 3 days in hospital. All subsequent infusions were totally normal - not even a headache.

I've had no headaches, rashes, heart or bleeding problems. Occasional diarrhea and sinus infections with low grade fever (99.6F/37.5C max) that's probably due to low immunity. Profound fatigue when I hit 400mg Venetoclax, especially after exertion. Some high creatinine and Uric Acid - I've gone off and back on Allopurinol several times. Slightly high monocytes. I developed an odd neuropathy (numbness) in 2 fingers and thumb of my right hand, and the right side of the front of my face. MRI normal. MDA says that neuropathy due to therapy would likely manifest on both sides of the body. It's declined a lot since it first happened.

I think hydration is really important all through treatment. I'm aiming for 100oz per day now to keep that creatinine low. 64oz just doesn't seem enough - I'm 5 foot 10 inches (177cm) and weigh 250 lbs (113kg, 17.8 stone), and I've seen things that says hydration need depends on body weight somewhat.

All in all, it's been really easy on me. I do long for some energy, but not enough to cut dose of anything.

=seymour=

[CoachVera55 in reply to SeymourB]

You have to end strong & enjoy a long long remission. Stay Strong, you got this🙏🏾Yes & shoot for that 1gal of water per day at the minimum. I can stay right here at this effective tolerable low dose of Zanubrutinib 🤷🏽‍♀️ We are all different & Thank GOD for the options🎉

[LeoPa]

Wow, congratulations, you are doing really well!

[laurieq]

My husband is in the same trial at MDA in Cohort 2 - Richter's. He's doing well - will have all the above testing as well as a PET at the end of Cycle 4 in late October. He has intermittent diarrhea/bloating with the Veneteclax, but otherwise is tolerating it well.

Best of luck to you!

[SeymourB in reply to laurieq]

laurieq -

I had a couple of Richter's scares. I have a NOTCH1 mutation associated with Richter's, but PET/CT came back as not too bright, and a core biopsy of the parotid lump on my face was typical CLL cells.

I wish you and your husband all the best. Keep us posted, if it's not too much trouble.

=seymour=

[Zia2]

Congrats Seymour 🎈So happy for you !

[GumboKing]

Really happy for you SeymourB and all others doing well on the trial.

Paul

[81ue]

Thank you for the good news update on this trial treatment and congratulations on doing well!

RE cellularity, that seems to be significantly changed from the treatment (if I understand it right, it got rid of the bad cells in the marrow which would explain why 80% with bad cells went down to 30% showing good cells and normal for your age).

[SeymourB in reply to 81ue]

81ue -

I think you're right.

I found this small treasure on the CLL Society site under Home » CLL Information & Management » Newly Diagnosed » Basic Biology

cllsociety.org/2017/01/basi...

Basic Guide to the Bone Marrow Report of a Patient with CLL and SLL

By William G. Wierda, MD, PhD. January 4, 2017

"The cells in the spongy space are normally surrounded by fat, and when the bone marrow report indicates the “cellularity” this refers to the amount of the space that has cells in it; the remainder is fat. In normal individuals, as we age, we lose cells from the marrow and the space is replaced with fat. The “rule of thumb” to give the expected normal cellularity (“normocellular”) for an individual is 100-age. For example, a normal individual who is 70 years old should have a cellularity of roughly 30% (70% fat). When CLL is present in the marrow, the cellularity is typically increased, so the example of a 70-year old with CLL may have a marrow cellularity up to 80 or 90% (“hypercellular”), with the majority of the cells being CLL cells. A hypocellular marrow (too few cells) can be seen in patients with CLL who have been over-treated with chemotherapy. In order for patients to be considered in remission after treatment, not only must they have <30% lymphocytes, their marrow must also be normocellular for their age."

I'm 68, so normal cellularity would be about 32. I won't sweat the difference between 30 and 32, because the formula is an approximation.

My lymphocyte percentage on September 5 was 7%.

Dr. Wierda also explained that they look at how clumped the cells are:

"An “interstitial” pattern indicates that the CLL cells are mixed in with the normal cells and fat and not clustered. There are too many of them but they are evenly integrated. This pattern is associated with an intermediate growth rate.

A “diffuse” pattern is where most of the cells seen under the microscope are CLL cells, that replace the normal cells and fat. The cellularity in these cases is typically 95-100%, and this pattern is associated with aggressively growing CLL."

Mine said:

"Interstitial and diffuse lymphocytic infiltrate is present, consider small mature lymphocytes. The lymphocytic infiltrate comprises approximately 80% of total bone marrow cellular elements."

So, not as aggressive as some people, but still pretty serious.

All this is also important why bone marrow biopsy early in treatment is not very helpful unless they suspect multiple types of blood disorders. It shouldn't be done "just in case."

=seymour=

[laurieq]

My husband's cellularity was 5% on the BM biopsy and 20% on the bone marrow clot in August - he completed R-CHOP in March.

[SeymourB]

Thanks!