Regular readers will have often heard that around 30% of those diagnosed with CLL never need treatment. So how is it determined whether you fall into that category and if so, what's the best way to monitor whether your CLL/SLL becomes no longer asymptomatic?
For the former, we havethe CLL-IPI, the Chronic lymphocytic leukemia international prognostic index: a systematic review and meta-analysis
The chronic lymphocytic leukemia international prognostic index (CLL-IPI), which combines 5 parameters (age, clinical stage, TP53 status [normal vs del(17p) and/or TP53 mutation], IGHV mutational status, and serum β2-microglobulin) to predict clinical outcome in chronic lymphocytic leukemia (CLL) patients was first published in 2016.1 The utility of this prognostic tool has been confirmed in independent validation studies across countries and in different practice settings (ie, academic medical centers, national population-based cohorts, and clinical trials).2-7
There's also CLL-WONT covered in this paper; Identifying patients with chronic lymphocytic leukemia without need of treatment: End of endless watch and wait?
* More than half of patients with low to intermediate risk CLL-IPI and CLL-WONT may safely end specialized follow-up
* Survival was similar and time to infection was longer in patients ending specialized follow-up compared to those who continued
That the" time to infection was longer" makes sense when you appreciate that even the precursor to CLL/SLL, Monoclonal B-cell Lymphocytosis (MBL) compromises your immune system. So visiting a hospital to see your specialist unfortunately does put you at increased risk of contracting an infection.
I've noted that some of our deemed low risk UK CLL members have their CLL monitored by their GP. Given CLL/SLL is deemed an orphan disease in the USA and Europe to encourage research and drug development, it's not something GPs/PCPs see all that often and even oncologists that don't see many CLL patients can struggle to keep up with the fast changing improvements in treatment options. An Australian Leukaemia Foundation survey determined that a GP would typically see about half a dozen lymphoma cases (CLL is the most common adult Non-Hodgkin's Lymphoma), in their entire career!
So if you are deemed to have low risk CLL/SLL, this is where your knowledge of CLL/SLL becomes very important in ensuring your long term health and why it makes sense to track your critical blood test results; haemoglobin and platelet counts and lymphocyte doubling time, as well as being observant about other changes in your body and health. You'll be able to advocate to obtain a referral to see a CLL specialist based on references from information posted here on the latest management and treatment guidelines.
We have plenty of excellent maintained pinned posts that will help you live long and well with a CLL/SLL diagnosis: healthunlocked.com/cllsuppo...
With respect to when treatment is deemed necessary, there are two main guideline documents in regular use, the USA's NCCN CLL guidelines (for which there are physician and patient versions) and the internationally used iwCLL guidelines, both of which are maintained by top level CLL/SLL specialists/researchers. The NCCN guidelines are more regularly updated; with the most recent updates in November 2023 and March 2024 for the patient and physician version 3.2024 guidelines respectively. The iwCLL guidelines document was last updated in 2018. The triggers for starting treatment are closely matched, with the NCCN guidelines more up to date with regard to including newer treatment options and providing guidance on which treatment is more suitable, based on test results also used for determining the CLL-IPI risk rating.
The NCCN guidelines state that "Indications for initiating treatment include severe fatigue, weight loss, night sweats, and fever without infection; threatened end-organ function; progressive bulky disease (enlarged spleen or lymph nodes); progressive anemia or thrombocytopenia; or steroid-refractory autoimmune cytopenia.
63 Absolute lymphocyte count alone is not an indication for treatment in the absence of leukostasis, which is rarely seen in patients with CLL."
The iwCLL guidelines includes the use of lymphocyte doubling time as an indication for starting treatment, which is not mentioned in the NCCN guidelines. "Progressive lymphocytosis with an increase of >=50% over a 2-month period, or lymphocyte doubling time (LDT) 30 x 10^9/L may require a longer observation period to determine the LDT. Factors contributing to lymphocytosis other than CLL (eg, infections, steroid administration) should be excluded."
See: When will I need treatment? Is Watch and Wait still the best option with newer treatments?
The good news for those treated with targeted therapies, is that due to the improvement offered by these, there's a need for Reassessing the Chronic Lymphocytic Leukemia International Prognostic Index in the era of targeted therapies
* The CLL-IPI retains prognostic value for PFS, but its impact appears diminished in predicting survival with targeted drugs.
* Improved survival with targeted therapies vs. chemoimmunotherapy underscores the need to reevaluate prognostic tools amid treatment shifts.
Note particularly the good news that; "Targeted therapies showed enhanced outcomes over chemoimmunotherapy, highlighting their effectiveness across various risk groups."
Neil
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Thanks Neil for all the efforts you put in to keep CLL patients informed. Today I was watching the All in podcast which is one of my favorite channels on YouTube. I heard David Friedberg talk about AI aiding in gene editing and finding new cas proteins that may be able to target cancerous cells more accurately. The details were a bit above my head. I was wondering do you see potential for that helping new treatments for CLL and attacking cancerous b cells? Or is that more only for solid tumor cancers?
Leukaemias are much easier for research studies than solid tumours, because it's so much easier to sample how the blood tumour is responding to a trial drug. The challenge with CLL, is that there are many tumour growth drivers, compared to many other cancers. (The first targeted inhibitor therapy, imatinib, was approved for Chronic Myeloid Leukemia (CML), because over 90% of the time it's caused by one genetic driver.) However, I would think that repairing mutated or deleted TP53 or unmutated IGHV would be good targets for genetic repair for those with these CLL drivers.
Great article. Loved the 2nd key point at the end. " Improved survival with targeted therapies vs. chemoimmunotherapy underscores the need to reevaluate prognostic tools amid treatment shifts."
Yes thank you Neil even though much is over my head too. I did come to that same conclusion when I decreased my monthly surveillance to every 3 months with my Local Oncologist & to semi annual/annual with my CLL Specialist. I still request any healthcare provider to put on a mask & many act like its such a foreign request but I don’t care how far they have to go to get one lol. If my Hairdresser can place me in a separate room & require any braider to wear one why would a Whole Hospital act weird about it🤣😂😆
I got sick 2X over the year I’ve been on BTKIs, its just that the first infection took 3 months for me to get antibiotics on my own while my team just watched me decline. The second time it happened was when we increased the dose but this time I called 4 doctors, 2 Oncologist, Primary & ENT. Prompt treatment worked the best for me & I will push for that each time.
All my doctors are so fascinated by my lab numbers but this bone pain is quite severe & no one seems the least bit concerned about that. Ortho & I believe that weight loss will help & I pray it does because I do not want to stop this treatment. Its working miracles even on just half dosage.
I will never give up but its been hard😢My new Rolling Walker
Hi Neil. Reading this in my work break so only skimming. So is it saying that people with low level CLL in long term Watch and Wait need not have blood draws or be monitored? Admit that this frightens me a bit. I no longer travel for a face to face appointment with my consultant but admit that my 6 monthly blood tests with phone call and the availability of a specialist nurse make me feel much safer. Plus the few times I have needed advice (covid, chickenpox etc…) they’ve been a great help. My own GP is excellent but during Covid he said I was fine to work (front facing hospital ward) whereas my consultant immediately said no.
Will it be a choice? I feel a bit concerned. Knowing I’m monitored and can ask questions if necessary (not often) makes me feel secure. My knowledge of CLL is ever increasing but I still like to know I’m monitored by people who specialise in the field.
Peggy, the post's purpose was to alert everyone of this trend away from specialist oversight for low risk patients. Blood tests are low cost and regular blood testing should not be abandoned when we have a diagnosis of CLL/SLL or even the precursor MBL. What we need to assure for our best health, is that if we end up potentially losing the oversight of our specialist, then we need to insist on:
1) Having a knowledgeable review of scheduled blood counts
2) Regular physical examinations for signs of increasing nodal or spleen involvement, etc.
3) Prompt referral back to a CLL specialist should there be any sign that our blood cancer might be on the move.
So I totally agree that we need to maintain prompt access to those who specialise in our blood cancer. GPs/PCPs should be aware of their lack of expertise in CLL/SLL etc., and be prepared to support this specialist access. Blood testing is highly automated, but I gather it's fairly common practice for pathology labs to have a pathologist review key results that are out of their reference range and add a note drawing this to the attention of the ordering physician. I would strongly recommend that everyone keep a copy of their blood test results and look for such notes, or indeed any out of range results. Then if they can't reassure themselves that these are expected (e.g. a lymphocyte count outside the reference range is a given with this diagnosis), they should be supported in having these results explained to their satisfaction by someone with the appropriate medical training and experience.
Thanks Neil. I will remain under my specialist as long as I possibly can. My GP is lovely but admits that he has gained knowledge from me. Initially with the injections he said that I did not need pneumonia etc…. But as soon as I was referred I was told to get them straight away. In UK now it’s very hard to actually get to see a GP. Indeed they are referring so much to the pharmacies that I fear they will soon be unable to cope under the strain.
Thanks Neil for the article, but I don’t know if I would feel comfortable not seeing my specialist at least once a year. I am currently asymptomatic with low lymphocytes burden. But it is reassuring to check with my oncologist at least once a year. I usually schedule my regular physical six month later. So I get my blood checked every 6 months by one or the other.
I have to say that I would be nervous with my current GP monitoring my CLL. The one I had when I was diagnosed - yes, I would be comfortable. Interestingly, the one who diagnosed me is a physician’s assistant but was always much more invested in my health than my current GP.
My current GP flipped out when she saw my latest blood test results. I believe my ALC at the time was around 90k. I explained I had just seen my CLL specialist and he was not concerned. Nothing I said was taken into account. She sent a message to my CLL specialist and he had me come in just to reassure me all was well.
So, if people early on in their CLL journey or those with low risk CLL are seeing their GPs for follow-up, while it may make sense to the bean counters, I foresee a lot of miscommunications and chaos developing.
Not every patient with CLL regularly reads HealthUnlocked/CLL. Should they? Of course.😊 But for those that don’t and for GPs who don’t keep up with new developments in CL, we may well see the uninformed leading the uninformed.
I also just had a GP decide my son (who is 32) has dementia. He presented with pain and sleep disturbances, a text book case for GERD for a person with Down Syndrome. She opted for dementia.
Thanks for posting this article Neil. I stumbled across a secondary reference to it (usnews.com/news/health-news... and came here to see what others thought.
When "The patients were told they didn’t need to bother with follow-up for three years", then most would certainly worry less about the seriousness of their disease. Get some immunizations and call me in three years doesn't seem serious to me.
Since specialists won't treat without symptoms, perhaps this is the way to go. it would certainly bring down the medical cots...
My dad was diagnosed with CLL in his mid-70s and never needed treatment (he passed away at 88). In his early 80's he went to a Veterans Administration facility for the first time to get a free check up. The doctor reviewed his medical history and said to my dad that he sees my dad has CLL. My dad was confused, he had forgotten he had it. He was getting periodic checkups at his local clinic, but since he had so many different appointments each year (follow ups for his heart bypass surgery, colon cancer, and blood clots), he lost track of what he was being seen for.
Since you wrote this post, Neil, and shared the latest evaluation of the CLL-IPI that is titled "Reassessing the Chronic Lymphocytic Leukemia International Prognostic Index in the era of targeted therapies", the ASH journal, Blood, has also published an article related to that study that asks whether it's time for a new prognostic tool for CLL.
As you noted, improved outcomes for those with CLL who are treated with targeted therapies have led to a closer examination of the CLL-IPI.
Just to recap, the study by Langerbeins et al, "evaluated the chronic lymphocytic leukemia International Prognostic Index (CLL-IPI) in patients with CLL treated first line with targeted drugs (n = 991) or chemoimmunotherapy (n = 1256)."
KEY POINTS:
"The CLL-IPI retains prognostic value for PFS, but its impact appears diminished in predicting survival with targeted drugs.
Improved survival with targeted therapies vs chemoimmunotherapy underscores the need to reevaluate prognostic tools amid treatment shifts."
Petra Langerbeins, et al; Reassessing the chronic lymphocytic leukemia International Prognostic Index in the era of targeted therapies. Blood 2024; 143 (25): 2588–2598. doi: doi.org/10.1182/blood.20230...
The second article, by Francesco Forconi discusses the findings and significance of the Langerbeins et al study. It's titled "Time for a new prognostic score in CLL?"
Forconi notes the timeliness of the study and highlights that "all prognostic scores need reevaluation as standard therapies change".
Although new targeted therapies have significantly improved outcomes for those with CLL, especially survival for those with high and very high risk CLL, Forconi concludes that, until "extended observation and a better understanding of how to combine new targeted drugs . . make it possible to identify the best prognostic factors of OS [overall survival]", the CLL-IPI is still a useful prognostic tool.
Here are a few excerpts from that article:
"Langerbeins at al also demonstrated that the improvement gained using targeted drugs instead of chemoimmunotherapy on OS was particularly evident in the CLL-IPI high- and very-high-risk groups,"
"The better understanding of the main biological “drivers” of CLL, namely BCR and BCL2, and how to target them therapeutically has led to a significant improvement of the treatment strategies in CLL"
"The current most appealing strategies include those combining BCRi with BCL2i,8-10 which were given to only 26% of the patients in the trials considered by Langerbeins et al, or BCL2i with anti-CD20 antibodies. However, concepts are rapidly evolving, and the period of observation of patients having received BCRi or BCL2i or their combinations remains short in a condition like CLL, where survivals can be measured in decades."
"Also, the new clinical trials with BCRi plus BCL2i combinations or BCL2i plus anti-CD20 antibody combinations will tell us if these therapeutic approaches may find a different indication for the CLL with unmutated IGHV (U-CLL) or mutated IGHV (M-CLL). U-CLL and M-CLL carry distinctive cellular origin, biology, epigenetics and genetics, and clinical behavior.6 Therefore, prognostic algorithms may need to be generated separately in these 2 types of CLL. Only extended observation time and a better understanding of how to combine new targeted drugs will make it possible to identify the best prognostic factors of OS."
Francesco Forconi; Time for a new prognostic score in CLL?. Blood 2024; 143 (25): 2561–2562. doi: doi.org/10.1182/blood.20240...
This is another of those 'watch this space' topics
Thank you CllerinOz, How marvellous to have confirmation that in a condition "where survivals can be measured in decades", "that the improvement gained using targeted drugs instead of chemoimmunotherapy on OS was particularly evident in the CLL-IPI high- and very-high-risk groups". (My emphasis)
Specifically, to reiterate what you quoted,
""Langerbeins at al also demonstrated that the improvement gained using targeted drugs instead of chemoimmunotherapy on OS was particularly evident in the CLL-IPI high- and very-high-risk groups."
"The better understanding of the main biological “drivers” of CLL, namely BCR and BCL2, and how to target them therapeutically has led to a significant improvement of the treatment strategies in CLL"
"The current most appealing strategies include those combining BCRi with BCL2i,8-10 which were given to only 26% of the patients in the trials considered by Langerbeins et al, or BCL2i with anti-CD20 antibodies. However, concepts are rapidly evolving, and the period of observation of patients having received BCRi or BCL2i or their combinations remains short in a condition like CLL, where survivals can be measured in decades."
The Danish study in your post has been republished in the latest edition of Blood Advances along with a related article written by Philip A Thompson who is now at the Peter MacCallum Cancer Centre in Melbourne, Australia.
Titled "Ending endless follow-up for low-risk CLL?", it makes some important points including the following:
a) The identification of a low-risk group of patients, for whom intensity of sFU could be attenuated, would free up scarce resources for patients with more pressing health care needs and "a robust model to reduce pressure on specialist health care systems would be of great interest to health policy markers worldwide". The Danish system reported above makes an "ideal test case".
b) There are a number of implementation risks:
"First, the prognostic models used require analysis of genomic data (fluorescence in situ hybridization and IGHV somatic hypermutation analysis) that are not always readily available, with CLL-IPI particularly heavily weighted toward these 2 parameters.
Secondly, as discussed, there are numerous factors not contained within these models which were considered by the study team before discharging patients and this may be difficult to replicate by general hematologists who see fewer patients with CLL.
Third, prospective communication with the patient’s primary health care provider (PCP) in such a system is surely critical to its success. This provider-to-provider communication is important to ensure the PCP is adequately educated regarding both findings that should prompt re-referral, as well as the unique preventive health care needs of patients with CLL, given that even early-stage CLL is associated with increased risk of infection and other cancers, particularly skin.8 This underscores the need for coordinated health maintenance activities, which would need to be implemented by the PCP, including vaccination (eg, pneumococcal pneumonia, COVID-19, influenza) and other cancer screening (especially skin).
Finally, when implementing such a practice, patient and other stakeholder satisfaction should be monitored and considered. Regarding this, one wonders whether a shared-care arrangement, where some more limited sFU, rather than complete discharge from sFU, may provide greater patient and PCP satisfaction." (my emphasis)
Philip A. Thompson; Ending endless follow-up for low-risk CLL?. Blood Adv 2024; 8 (16): 4447–4448. doi: doi.org/10.1182/bloodadvanc...
That's a timely addition, given some newly diagnosed members are being handed back to their GP/PCP for monitoring. The points about implementing vaccinations and skin care in particular certainly will need improvement in the UK!
"This underscores the need for coordinated health maintenance activities, which would need to be implemented by the PCP, including vaccination (eg, pneumococcal pneumonia, COVID-19, influenza) and other cancer screening (especially skin)." (My emphasis)
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