Seeking advice for treatment of CLL

[strong-and-healthy]

Hi all

A close family member has been diagnosed with CLL (chronic lymphocytic leukemia). She is a 68 year old female and is experiencing fatigue and weight loss. We have been given the option of targeted oral medicine only (acalabrutinib) or medicines plus antibody drip (rituximab).

1 doctor is sure that only oral medication is enough and we don't need to treat it more aggressively. He's prescribed acalabrutinib 100 mg once a day initially and then increasing to 2 doses a day after checking blood reports. This is lifelong. He's saying we might have not needed to treat but for her symptoms of fatigue and weight loss.

Another doctor is advocating for acalabrutinib plus antibody drip (rituximab) 375mg 1 dose every 28 days for 6 months.

The Flow cytometry summary is - "examination of peripheral blood sample shows a cluster of lymphocytes (~ 63.7 % of all CD45 vs SSC gated cells) with the FSC falling in the small cell size. This lymphoid population comprises of ~46.4 % abnormal B-lymphocytes expressing CD19, CD5, CD 20, CD200, CD23 and kappa light chain. They are negative for CD43, CD11c, CD103, CD38, CD148, CD49d, CD123, CD25, CD10, lambda light chain and T- cell marker".

Please advise what would be the best line of treatment in such a case.

Secondly, 1 doctor has asked us to get a FISH blood test done, is this necessary?

Thank you for your help.

[AussieNeil Partner Administrator]

Strong-and-healthy,

Please appreciate that we cannot give medical advice. We do however, share experiences and provide references to evidence based information. This assists members to have more informed discussions with their doctors, so that they can better choose what's best for them. Our Pinned Posts section healthunlocked.com/cllsuppo... contains a wealth of relevant information for those with CLL. Most relevant to your family member is this post on the triggers for starting treatment: healthunlocked.com/cllsuppo...

I presume your close family member lives in India? Other Indian community members have shared how difficult it can be to find knowledgeable CLL specialists in your country. With respect to the suggested treatments, there are two basic approaches to treating CLL; fixed term combination therapy or maintenance therapy for as long as the drug is tolerated or resistance doesn't develop. The choice of which therapy is best can be influenced by FISH testing, but its main purpose is determining whether older chemo treatment will work. Those with 17p del CLL shouldn't be treated with older chemo drugs, but targeted therapy drugs, such as those recommended for your friend. Complex karyotype results from FISH testing also influence treatment choice.

Maintenance therapy with acalabrutinib is a standard therapy, but the recommended dose is 100 mg twice a day. Some members have been able to negotiate a lower dose once their CLL is considered under control - that is when lymphocyte counts are low to normal and other blood counts are close to normal or normal. We have over 1,400 previous posts about acalabrutinib/Calquence: healthunlocked.com/cllsuppo...

I wonder if you have correctly understood the suggested acalabrutinib plus rituximab (AR) treatment option? It's usual to give rituximab or the slightly better anti-CD20 monoclonal antibody treatment obinutuzumab, over 6 cycles of 28 days or about 6 months in combination with acalabrutinib and then continue the acalabrutinib treatment for at least another 6 months. AO is a standard combination treatment, AR is not, but I suspect it has been recommended to your family member, because rituximab will be cheaper than obinutuzumab. This recent post is relevant: healthunlocked.com/cllsuppo... It's usual to have dim CD20 with CLL, so being positive for CD20 means your family member should respond well to rituximab or obinutuzumab. The advantages of combination treatments are that the overall cost is lower, after successful treatment remissions can last many years, after which the same combination treatment, or an even better one which has become available during the period of remission, can be repeated.

There is additional testing besides FISH test results that can help with this decision. Your family friend is CD38 negative, so likely had a long period between her diagnosis (or when CLL began and was undetected) and needing treatment. If this was the case, then that would favour the combination treatment option, but other factors (co-morbidities, general state of health, etc. ) also need to be considered. Another important test is whether your family member is IGHV mutated. That's likely given she is CD38 negative, particularly if she had CLL for a long time before needing treatment and would also tend to favour the fixed term combination therapy approach.

Neil

[strong-and-healthy in reply to AussieNeil]

Thank you AussieNeil for that detailed reply.

Yes, I've checked the posts by others from India. There aren't CLL specialists here (or at least none that I could find). What is slightly confusing is we've been to 3 doctors and got 3 slightly different recommendation. It seems acalabrutinib at least covers all aspects and that's what we're most likely going to go with.

[AussieNeil Partner Administrator in reply to strong-and-healthy]

1) It's not unusual to have slightly different recommendations for CLL treatment, even from CLL specialists. That is more likely to happen when there are no particularly concerning markers.

2) The incidence of CLL in Asian countries is notably lower than elsewhere, mainly for genetic reasons.

Neil

[SofiaDeo in reply to strong-and-healthy]

Strong-and-healthy, There are commonly agreed upon "guidelines to treat" but as far as "which treatment to start with", there's not a huge consensus yet. There are 3-4 common starting protocols nowadays that, until there is more data, generally seem to be interchangeable. They all have pros & cons, so docs will vary a bit in their recommendations.

The only consistency I have noticed, is that it's impossible to predict who will have side effects, who won't, and whether or not a treatment works well. So don't spend a huge amount of time stressing about "where to start." Pick something, if it works without awful side effects, great. If it doesn't work well, or any initial side effects don't go away/calm down, consider changing.

[Skyshark in reply to AussieNeil]

It's usual to give rituximab or the slightly better anti-CD20 monoclonal antibody treatment obinutuzumab, over 6 cycles of 28 days or about 6 months in combination with acalabrutinib and then continue the acalabrutinib treatment for at least another 6 months. AO is a standard combination treatment, AR is not,

Acalabrutinib is taken as continuous maintenance therapy for as long as it's tolerated with or without the monoclonal antibody. All short duration treatments are Venetoclax based. Patients that respond well to Acalabrutinib have found they can take a few years drug holiday but there isn't a protocol for stopping.

[AussieNeil Partner Administrator in reply to Skyshark]

Skyshark, Thanks for your expansion on my answer.Strong-and-healthy, Here's a report on a clinical trial with an AO arm, confirming Skyshark's reply.

thelancet.com/journals/lanc...

Neil

[Nucleusman]

acalabrutinib works I am now in remission

[strong-and-healthy in reply to Nucleusman]

Good to hear! Hope it continues!! Would you mind my asking - how long have you been on it and are you still taking it?

[Nucleusman in reply to strong-and-healthy]

been on it 2 years believe it is for life- small price to pay. it is a form of chemo with less side eff cts but my only side effect intensive bruising and CLL tiredness

[Alpha66]

Really need a FISH genetic blood test to check for mutations ....some like P53 deletion rule out specific treatments as they are not effective. I'm on Acalabrutinib as I have a p53 deletion/mutation and after about a year my blood tests are in the normal range together with lymph nodes gone. Minor easy to manage side effects.

[AussieNeil Partner Administrator in reply to Alpha66]

Note that TP53 mutation testing is a separate test to FISH testing. Importantly, acalabrutinib and other BTKi drugs work well for those with TP53 mutated CLL.

[SeymourB in reply to AussieNeil]

AussieNeil -

TP53 and FiSH is confusing, because often the report says del17p/TP53. I think that what they mean by that is del17p or del TP53. But if we are negative on that FiSH, we could still have a mutation in TP53 that FiSH cannot sense, so the NGS (Next Generation Sequencing) TP53 test is still necessary. The latest NCCN Clincal Guidelines in the U.S. clearly specify TP53 NGS testing:

"INFORMATIVE FOR PROGNOSTIC AND/OR THERAPY DETERMINATION[d]:

• FISH to detect: +12; del(11q); del(13q); del(17p)

• TP53 sequencing

• CpG-stimulated metaphase karyotype for complex karyotype (CK)

• Molecular analysis to detect: Immunoglobulin heavy chain variable region gene (IGHV) mutation status

• Beta-2-microglobulin"

Often ignored is their requirement for an additional FiSH because MCL and CLL have overlapping Flow Cytometry:

"if flow cytometry is used to establish diagnosis, also include cytospin for cyclin D1 or fluorescence in situ hybridization (FISH) for t(11;14); t(11q;v) to exclude mantle cell lymphoma (MCL)."

I'm not sure what t(11q;v) is. I couldn't find a reference via PubMed or Google. The iwCLL Guidelines also recommend FISH for t(11;14)

The NCCN lists Acalabrutinib (continuous) plus Rituximab in Mantle Cell as an Other recommended regime for less aggressive induction as well as for maintenance therapy.

=seymour=

references:

The following guidelines can be downloaded after creating a free patient account. They are highly technical, and have tons of references cited to justify each part of the guidelines. They are updated several times a year as new study results refine aspects. In general, the CLL Clinical Guidelines still adhere to the 2018 iwCLL guidelines on most topics with occasional additional language nuances and additional advice.

nccn.org/professionals/phys...

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)Version 1.2025,

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

NCCN Evidence BlocksTM

Version 1.2025 — October 1, 2024

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nccn.org/professionals/phys...

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®

B-Cell Lymphomas

Version 3.2024 — August 26, 2024

[strong-and-healthy in reply to Alpha66]

That's good to hear Alpha66! Hope you continue quickly on the path to great health!

Would you mind my asking - are you still required to take 2 doses a day?

[Mahunny]

Your family member can request a 3rd opinion Virtual appointment with a CLL specific medical expert through the CLL Society website: cllsociety.org/

[strong-and-healthy in reply to Mahunny]

Thank you Mahunny, I'll check that out.

Edit : seems that's only for patients living in USA

[Mahunny in reply to strong-and-healthy]

so sorry. my only suggestion would be to see if there is something similar where you are that may offer services... I wish the best for your family member.

[AussieNeil Partner Administrator in reply to Mahunny]

Mahunny, unfortunately for those not living in the USA, the CLL Society's Expert Access program is not available.