CLL investigation

[Wimco]

I am on wait and watch for 2 years. I have changed my haematologist. New haemo has asked for again FISH. In addition he has asked full body CT scan and analysis of spinal fluid. Is that required as I am feeling ok and active and my wbc is stable at 19000 and absolute Lucocytes at 62%. I am having 13 q deletion as per Fish done 3 yeats ago.

[AussieNeil Partner Administrator]

Hi Wimco,

CLL specialists prefer not to do CT scans if possible. They may be done as a baseline check, more so by specialists less experienced with CLL.

Cerebrospinal fluid involvement with CLL can occur, but is quite rare. I would be asking what particular symptom(s) resulted in your new specialist requesting this. Why did you switch specialists?

Neil

[Wimco in reply to AussieNeil]

Thanks Neil. There is no change in my condition. I am not aware why new Hameotologist wants these tests.

[Alex830]

I agree with Neil that these tests are not needed right now if you are stable. I did have a lumbar puncture/spinal tap but that was because there was a chance I had PML disease. Luckily that was not the case. Unless there is a legitimate reason to do the spinal tap, I would avoid it. I found it a fairly unpleasant procedure, more so than the bone marrow biopsy. A repeat of the FISH test is warranted before starting treatment, same goes for the CT scan.

[Wimco in reply to Alex830]

Thanks Alex

[Wimco]

Thanks Jammin

[DriedSeaweed]

Where are you? Someone might be able to suggest a different doctor.

[Astro617 in reply to DriedSeaweed]

I agree.

[lankisterguy Volunteer]

Hi Wimco,

Please be aware that every procedure done on you has some risks, and your doctor must have your approval to do them.

So please expect and ask for a thorough explanation of what benefit/advantage/knowledge you may get from the results. If the doctor cannot explain in terms you understand and convince you that it is worthwhile, you have the option to politely decline.

Just because the doctor is curious, unsure or creating a "baseline" is not sufficient justification.

If the doctor insists, then decline again and leave the exam room, and use the established (NHS?) procedures and protections to defend your rights to protect yourself from intimidation.

Request a different doctor with better experience and knowledge of CLL- it sounds like that doctor is inexperienced and using outdated processes more suitable for NHLs (Non Hodgkin Lymphomas) and not CLL.

-

Len

[Wimco in reply to lankisterguy]

Thanks

[Skyshark]

I'm not finding any reports of CLL with Central Nervous System (CNS) involvement since the introduction of new drugs around 2017. 1% of CLL cases have (had?) CNS involvement at late stages, usually when the patient presented (too) late.

If you don't have symptoms that indicate treatment is needed (see Mayoclinic link below) you don't need any tests other than FBC. Lymphs doubling in 3 months is an indication that treatment is needed.

WBC 17000 >> 19000 in 4 months is not a cause for concern. (increase to 40000 in 4 months would be needed but now the 3 month doubling figure is 38000)

mayoclinic.org/diseases-con...

Bone marrow biopsy, CT scan and NGS are warranted in addition to FISH test during "work up" prior to treatment when the disease indications and symptoms show treatment is needed. Again link to next page of Mayoclinic. If there are large lymph nodes then there may also be a PET scan to identify a lymph node for biopsy and check for transformation.

mayoclinic.org/diseases-con...

Get a 2nd opinion. Your numbers indicate to me that you are in US as they use cells/mm^3. CLLsociety have a list.

cllsociety.org/newly-diagno...

Chances are your insurance would refuse the Lumbar Puncture.

It would be useful to know your IgHV status mutated/unmutated. Mutated without TP53/17p aberrations may never need treatment.

[Wimco in reply to Skyshark]

Thanks my friend

[Teegolf47]

Wilco. The paragraph below is taken from the IWCLL guidelines.

“3.5.2.2. CT scans. CT scans generally are not required for initial evaluation or for follow-up. The staging of CLL does not use CT scans but relies on physical examination and blood counts. Enlarged lymph nodes, if detected only by CT scan, do not change the Binet or Rai stage. It has been shown that patients with Rai stage 0 but abdominal disease detectable by CT scans may have a more aggressive course.84 This requires further investigation before recommending CT scans for routine initial evaluation of patients with CLL. On the other hand, it has been demonstrated that the majority of relapses or progressions in CLL are detected by physical examination and blood counts, not by imaging studies.85 Moreover, the decision for relapse treatment was determined by imaging studies in only 1% of patients85 ; therefore, the routine follow-up evaluation of CLL patients does not require CT scans.”

Also, nowhere in this document is spinal fluid assessment mentioned

ashpublications.org/blood/a...

CT’s are generally not ever needed for staging and it is still way overused in CLL patients. Also keep in mind that radiation from a CT is the equivalent of 100-800 xrays depending on the area of the body scanned and the type of CT machine used.

Always ask your medical team WHY the test is needed and what information they will get that will assist them in treating you.

Terry

[Skyshark in reply to Teegolf47]

CT scan is needed before Venetoclax ramp-up to determine if TLS risk is low nodes10cm.

[Wimco in reply to Teegolf47]

Thanks Terry for detailed guidance

[Wimco in reply to Teegolf47]

Thanks

[Teegolf47]

My response highlighted initial assessment and routine followup which I believe is where Wilco is at in their CLL journey. Tests before treatment use a different set of guidelines.

Terry

[Wimco in reply to Teegolf47]

Thanks

[Rico49]

I'm a little late here and others have covered the subject very well.

I had a spinal tap to evaluate a spinal lesion, not because I had cll , while on w&w.

cll cells were found in my spinal fluid but my hematologists at home and at the Moffitt Cancer center were not concerned as I had no other symptoms and that was a year ago. They felt it could have been from a bad tap.

Once I started O&V both those drugs penetrate the blood brain barrier so should have cleared up. Still no symptoms.

I agree with several others and you may know by now as I'm late responding to your post, but why does he want to do a spinal tap?

Good luck.

[Wimco in reply to Rico49]

Thanks

[AussieNeil Partner Administrator in reply to Rico49]

Thanks for sharing that helpful information Rico, again raising question of why the spinal tap recommendation?

BTKi drugs and venetoclax are small molecules, which helps them cross the blood brain barrier, with ibrutinib successfully used. Immunoglobulins are however quite large. I couldn't find anything specifically about the monoclonal antibody obinutuzumab crossing the blood brain barrier. However this 2002 study reported "the CSF levels of rituximab are approximately 0.1% of serum levels associated with therapeutic activity in patients with systemic non-Hodgkin lymphoma."

ashpublications.org/blood/a...

Likewise a mouse model study from 2013 found a similar amount of IVIg, just (0.009±0.001% of injected dose in the cortex) made it through.

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

The mouse study did note that even this amount might be therapeutically useful.

Wimco, I hope you have found the replies reassuring. CNS involvement with CLL is indeed quite rare. We have nearly 22,000 members and have only had a few posts from members developing it that I recall. I think you'd be having more in the way of symptoms if you had CNS involvement.

Neil

[Rico49 in reply to AussieNeil]

Hi Neil

My memory failed me- should have revisited before posting.. O has possibilities but needs more investigation . Below are two search results on Chat for O first and V second. Thanks for the clarification.

The second paragraph left me a little confused. Is that saying that V by itself may not penetrate the BBB? Thanks

Did find this on chat for Venetoclax:

According to a study published in **Blood**, venetoclax, a selective BCL2 inhibitor approved for the treatment of CLL and AML in adults, has been shown to cross the blood-brain barrier (BBB) and accumulate into the central nervous system (CNS) ¹. The study was conducted on pediatric patients with relapsed and refractory acute leukemia receiving venetoclax in combination with chemotherapy. The study found that the mean concentration of venetoclax in cerebrospinal fluid (CSF) was 3 ng/mL, with a range of <0.1 to 13 ng/mL ¹. The mean plasma-to-CSF ratio was 300 with a range of 67-1003, which is more than 4-fold higher than the blood-to-brain ratio observed preclinically in mice ¹.

The study also noted that venetoclax has a molecular weight of 868.44 which was hypothesized to limit its passage through the tight junctions of the BBB. Moreover, venetoclax is a substrate of the P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) efflux transporters, expressed by endothelial cells at the BBB, which presents an extra hurdle for penetration into the CNS ¹.

Please note that this is a single study and further research is required to confirm these findings..

Source: Conversation with Bing, 11/26/2023

(1) Venetoclax Crosses the Blood Brain Barrier: A Pharmacokinetic Analysis .... ashpublications.org/blood/a....

(2) Venetoclax Cooperates with Ionizing Radiation to Attenuate Diffuse .... aacrjournals.org/clincancer....

(3) Abstract - American Association for Cancer Research. aacrjournals.org/cancerres/....

(4) Venetoclax penetrates in cerebrospinal fluid of an acute myeloid .... link.springer.com/article/1....

(5) undefined. doi.org/10.1182/blood-2020-....

(6) en.wikipedia.org. en.wikipedia.org/wiki/Venet....

Chat showed this for Gazyva.

Gazyva is a brand name for obinutuzumab, which is a type of monoclonal antibody that targets a protein called CD20 on B-cells². The blood-brain barrier (BBB) is a microscopic structure that shields the brain from most circulating drugs⁵. Whether Gazyva can penetrate the BBB is not well established, but some studies suggest that it may have limited or variable ability to do so.

One study found that Gazyva could reach the brain tissue of mice with brain tumors, but only at low concentrations and with high variability. Another study reported that Gazyva could cross the BBB in patients with primary central nervous system lymphoma, a rare type of brain cancer, but the extent of penetration was not quantified. These studies indicate that Gazyva may have some potential to cross the BBB, but more research is needed to confirm its efficacy and safety in treating brain diseases.

Source: Conversation with Bing, 11/26/2023

(1) Gazyva: 7 things you should know - Drugs.com. drugs.com/tips/gazyva-patie....

(2) Explainer: what is the blood-brain barrier and how can we overcome it?. theconversation.com/explain....

(3) Powerful chemotherapy drug reaches brain tumors using novel ultrasound .... news.northwestern.edu/stori....

(4) Frontiers | Effects of Oral Gamma-Aminobutyric Acid (GABA .... frontiersin.org/articles/10....

(5) Gaba Supplements: Glorious, Gimmicky or Just Garbage?. mcgill.ca/oss/article/healt....

[Skyshark in reply to Rico49]

I think it was more surprise at the high concentration of Venetoclax actually found in CSF when indications in the 2nd paragraph show it wasn't expected.

Atomic weight is indication of the size of the molecule, Obinutuzumab has an an atomic weight 146,100, 168 times greater than Venetoclax.

BTKi drugs have atomic weights (440-471) about half that of Venetoclax and about twice that of sugar (220ish). They should cross the blood brain barrier into the CNS with ease.

[AussieNeil Partner Administrator in reply to Rico49]

Interestingly, Bing Chat AI has just found and overwhelmed you with information without the ability to determine what's relevant. It's not smart enough to do that, but you can see that it has found the same study reports that Skyshark and I found.

With respect to the second paragraph, beginning "The study also noted that venetoclax has a molecular weight of 868.44 which was hypothesized to limit its passage through the tight junctions of the BBB.", as Skyshark has noted, the ease of crossing the blood brain barrier (BBB) decreases as the molecular weight increases. So BTKi drugs can fairly easily pass the BBB, venetoclax less so and monoclonal antibodies should find it really difficult - just as those study reports I mentioned concluded.

Neil