Path towards diagnosis

[travisgf87]

Hi all,

I'm a 37 year old male in the USA. I'm married with a nearly 1.5 year old son. And.... I think I will likely officially be part of this club soon...

I have a mild case of ulcerative colitis for which I need regular blood counts tests(diagnosed in 2009) but no other major health issues other than anxiety.

First red flag was lymphocyte count of 5.4 in June of 2024. GI doctor not concerned said repeat in 3 months. Everything else was normal.

In early September I tested positive for covid but felt better within a week and did my repeat CBC. Lymphocytes count still high (5.2) and total WBC 14.3. Neutrophils also a bit high but everything else normal. Sent results to PCP this time as anxiety started to build. She suggested it was reactive to covid and said retake CBC in 1-2 months along with peripheral smear to check the cell structure. Well, I waited about 3 weeks and as anxiety grew I wanted to check the smear for reassurance everything was normal. Lymphocyte count was 6.0 this time and WBC 12.8. neutrophils back to normal and everything else normal. The blood smear showed "lymphocytosis with reactive features." No other comments. No reference to small mature cells or smudge cells or recommendations for follow up testing. PCP felt confident it was due to having covid recently. Made sense but I was still anxious.

Last month I asked more questions and PCP did an "e-consult" with Hematology to help ease my anxiety. The hematologist also felt CLL was unlikely in someone my age with my history and likely reactive as the smear showed. He suggested a repeat of CBC and if count remained over 5 to do flow cytometry.

Took the repeat yesterday. Lymphocytes up to 7.3 now and WBC 13.9. I left a message with my PCP about getting in to do the flow cytometry.

Feeling pretty anxious and discouraged. Never expected I'd be dealing with CLL but it seems likely to me.

Is it typical to have a peripheral blood smear apparently show no signs of CLL, to indicate reactive, but still be CLL? Having trouble understanding that part, yet lymphocyte count keeps going up. From what I read I thought the smear is done first and while not enough to diagnose CLL it gives a pretty good idea of either CLL or normal/reactive and then flow cytometry is done to confirm if malignancy is suspected.

Hoping for some thoughts from the group! Thanks!

[Spark_Plug]

travisgf87, Although you haven't been diagnosed go here {cllsociety.org/newly-diagno... High quality trusted information.

Doctor Goggle is not your friend.

You're going to need more test results to know anything definite. Try to relax, I know we all roll our eyes at that one but, try.

Ask your hematologist how many CLL patients the treat on a regular basis percent wise. Not all professionals are equal.

[travisgf87 in reply to Spark_Plug]

Appreciate the link and advice, thanks! And yes haven't been able to relax for a few months now. Unfortunately, that is even more difficult now. I know it won't change anything but still...

[AussieNeil Partner Administrator]

Welcome to our community Travis,

Hopefully, you won't end up a full member, but if that does happen, you've found a great place for support, where you'll learn ways to live out a normal life expectancy. It's what CLL specialists are increasingly saying can be the case with the recent dramatic improvements in treatment options.

The odds are certainly against you being diagnosed with CLL, with the median age of diagnosis being around 70, but we do have some members around your age or even younger. CLL is a very heterogeneous illness, so how it becomes apparent varies considerably. Smudge cells being present in a blood smear is a fairly good indicator that CLL is present, but Flow Cytometry is the definitive test. This test checks for a monoclonal population of lymphocytes and if that's found, the specific pattern of Clusters of Differentiation 'CD' cell membrane proteins is checked to determine what type of lymphocyte neoplasm (blood cancer) is causing the high lymphocyte count (lymphocytosis). If CLL is confirmed, several different prognostic tests can be done to give some guidance on how long before treatment may be required. The strongest predictor is IGHV mutation status, with mutated IGHV indicating an indolent, slow growing variant. Those with unmutated IGHV generally require earlier treatment, but the treatment revolution means that anything you read that's older than 5 years old is usually incorrect. If you want to learn more about CLL before you get your flow cytometry test result, this post will keep you busy reading; healthunlocked.com/cllsuppo...

Neil

[travisgf87 in reply to AussieNeil]

Thanks for the info, Neil! Everything I've been reading suggests that smudge cells are always present in CLL and are a characteristic finding. However, I also read the percentage of smudge cells can be an indication of prognosis. I haven't seen anything showing CLL can present without any smudge cells. Have you heard of this? I'm wondering if this is possible and if so, could it indicate a more aggressive illness?

[AussieNeil Partner Administrator in reply to travisgf87]

My pathology lab does a manual check (blood smear) whenever any of my CBC/CBE/FBC (same test, naming varies by path lab) blood test results are out of range. That's been pretty well every one of my 200+ blood tests since my diagnosis. I regularly, but don't always see the comment "smudge cells present". More smudge cells present is a good sign, indicating the CLL cells are more fragile/vulnerable, per this Mayo Clinic report, but given other member reports, I doubt the accuracy of reporting regarding the presence of smudge cells from pathology labs can be relied upon as a prognostic measure, which is a pity.

Using Smudge Cells on Routine Blood Smears to Predict Clinical Outcome in Chronic Lymphocytic Leukemia: A Universally Available Prognostic Test

mayoclinicproceedings.org/a...

The median percentage of smudge cells was higher in patients with the mutated immunoglobulin heavy chain gene than in those with the unmutated immunoglobulin heavy chain gene (31% vs 13%; P=.02). Patients with less than 30% smudge cells had a median time from diagnosis to initial treatment of 72.7 months, whereas the median time from diagnosis to initial treatment in patients with 30% or more smudge cells was not reached (P=.001).

If you are diagnosed with CLL, your earliest prognostic indicator will be whether your CLL is CD38 positive or negative in your flow cytometry results. CD38 negative CLL correlates with a long time in watch and wait and around a 60% chance of being IGHV mutated.

Neil

[travisgf87 in reply to AussieNeil]

Good information thanks. How reliable are blood smears actually then? I thought they often were a pretty dependable first sign or indicator of either having CLL or not. Seems that may not entirely be the case. Since mine only showed "reactive" my assumption (and apparently that of my PCP and Hematologist) was it kind of ruled out CLL. Until the last CBC showed the ALC increasing again...

[AussieNeil Partner Administrator in reply to travisgf87]

The Mayo Clinic abstract noted that of the 200 lymphocytes and smudge cells sampled from the each of the 75 early and intermediate stage patients in their study, "The median percentage of smudge cells was 27% (range, 4%-72%)". Blood tests are by default automated unless your doctor asks for a manual count or the pathology lab procedure is to check out of range results with a manual count, which requires a blood smear. To perform a manual white blood cell differential, the pathologist counts and categorises 100 white blood cells by type (neutrophil, basophil, monocyte, eosinophil and lymphocyte, where they are roughly outnumbered 1,000 to 1 by red blood cells and 100 to one by platelets in a healthy specimen, With your "lymphocytes up to 7.3 now and WBC 13.9", about half of the 100 white blood cells will be lymphocytes, but bear in mind that in a healthy lymphocyte count, about two thirds are T and NK lymphocytes and a third B lymphocytes. So assuming you do have CLL, roughly 10 of the white blood cells inspected are likely to be healthy B cells with around 40 CLL cells. If your smudge cell count is in the lower part of the range (quite likely given you are yet to be diagnosed), a smudge cell might not be noted in your blood smear sample. (4% of 40 is 1.6 cells.)

Neil

[travisgf87 in reply to AussieNeil]

Thanks again Neil! You are a wealth of information and I appreciate you taking the time to explain this and help me make sense of it. In other words it's possible that given my (relatively) low count a smudge cell was not identified in the sample of cells that were reviewed.

Are reactive lymphocytes (or "lymphocytosis with reactive features" as noted in my smear) also associated with CLL?

[AussieNeil Partner Administrator in reply to travisgf87]

This is probably one of our best posts about reactive lymphocytes: healthunlocked.com/cllsuppo... As you can see, it's complicated. Try not to overthink matters and endeavour to patiently wait for that flow cytometry test result.

[travisgf87 in reply to AussieNeil]

AussieNeil the overthinking and waiting is proving to be difficult for me! My mind is going in many directions, most of them not good unfortunately.

It makes sense that one can't distinguish between types of lymphocytes (whether they are B, T, or NK cells) using only a microscope and that is where flow cytometry comes in. But a pathologist can tell reactive lymphocytes from CLL B cells, correct? My understanding is that reactive lymphocytes have unique morphology and size compared to CLL cells which are monomorphic in appearance. Following this logic, in my case what may have happened is the pathologist only saw a few reactive cells in their slide and moved on, unfortunately missing the CLL cells? And that's why the smear only noted "lymphocytosis with reactive features"?

[AussieNeil Partner Administrator in reply to travisgf87]

I'd say you are overthinking the reactive lymphocyte comments, particularly given you noted that your "PCP felt confident it was due to having covid recently."

With CLL, an early lesson worth learning is to not over-react to comments made in pathology reports, but look for trends. We get to have many more blood tests and scans than our healthy peers and one consequence of this, is that we are more likely to see mention of something which usually turns out to be benign and of no consequence.

Neil

[travisgf87 in reply to AussieNeil]

Yes, and the hematologist on the "e-consult" also said given my age and history, and particularly since the smear showed reactive features of the lymphocytes he felt it was very unlikely to be CLL. But you're saying that the reactive lymphocytes could be completely unrelated to the CLL cells and was more of an incidental finding?

[SpringerBella in reply to AussieNeil]

Could you explain further the following , particularly the derivation of healthy vs CLL cells:

With your "lymphocytes up to 7.3 now and WBC 13.9", about half of the 100 white blood cells will be lymphocytes, but bear in mind that in a healthy lymphocyte count, about two thirds are T and NK lymphocytes and a third B lymphocytes. So assuming you do have CLL, roughly 10 of the white blood cells inspected are likely to be healthy B cells with around 40 CLL cells.

[AussieNeil Partner Administrator in reply to SpringerBella]

SpringerBella, I was attempting to illustrate the approximate number of CLL cells and hence the probability of there being smudge cells in a blood smear from someone with what might be early stage CLL.

It's virtually impossible to distinguish the different lymphocyte types under a microscope, which is why flow cytometry immunophenotype testing is used. That works by using specially made fluorescing monoclonal antibodies that lock onto the varying CD markers on the different lymphocyte cell membranes. The total lymphocyte count and the percentages of the different lymphocyte types can vary throughout the day and in response to infections and vaccinations. By measuring the different colour intensities for the CD markers being looked for, counts of healthy and monoclonal B cells can be determined, along with counts of natural killer (NK) and T cells. B and T cells can be differentiated by whether they express CD19 (B cells), or CD3 (T cells). T cells are further differentiated into helper (CD4) and cytotoxic (CD8) expressing T cells. Likewise, we can count the number of monoclonal CLL cells, because "CLL has a characteristic immunophenotype, expressing CD5, CD19, dim CD20, dim CD22, CD23, bright CD43, dim CD45, dim to negative CD79b, dim CD81, CD200, and dim monoclonal surface immunoglobulin. This characteristic immunophenotype allows a definitive diagnosis and the ruling out of another leukemia or lymphoma."

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

When we develop CLL, the monoclonal B cells keep increasing, while the other lymphocyte counts change only a little. The T cell CD4:CD8 ratio often changes as CLL progresses, because CLL drives an increase in CD4 T cells, fostering a tumor-promoting microenvironment, but that change is dwarfed by the growth in CLL cells.

With the SLL expression of CLL/SLL, the CLL cells preferentially stay in the nodes, spleen and bone marrow and the lymphocyte count stays around normal. That's why SLL is usually diagnosed by flow cytometry testing of a node biopsy. (My lymphocyte count was just within the normal range when I was diagnosed, but there were enough CLL cells in my blood for a flow cytometry test to determine that I had CLL /SLL. A couple of years later, my lymphocyte count had increased so that I met the criteria for CLL.)

Neil

[SpringerBella in reply to AussieNeil]

As you might guess, I am still trying to make sense of my CLL diagnosis from April 2024. Currently, W&W. I will be returning to hematologist in February, subsequent to updated CBC. I became confused with the Flow report (April), which characterized abnormal B-cells @ 20.5%. Hematologist indicated that he does not utilize that percentage. His explanation echoed what you have described, specifically, the "normal" lymphocytes tend to stay in the normal range; any increase in the ALC is due to proliferation of the abnormal B-cells. The April flow report shows CD4:CD8: 1.3. (Yes, there were smudge cells seen on initial diff.) Thanks for the thorough explanation. Your expertise and commitment to educating CLL patients is much appreciated.

Carol

[SofiaDeo in reply to travisgf87]

You don't get the diagnosis from a smear. A pathologist looking at smears, is looking for abnormalities, but can only guess. While the guesses can be very good, if a patient has a "classic" presentation of something, in real life things don't always appear as a textbook example.

You are immediately post Covid, and we don't yet know for sure how long folk's bloodwork may be "abnormal" after this infection. I'm not speaking of Long Covid, just, the normal exhaustion your system has gone through after an infection. Your immunity has recently taken a hit, and there are other viruses and bacteria floating around you may be reacting to. There have been abnormal geographic events in various places around the world, there are unusual chemicals & other irritants in the air, water, soil that one may be reacting to.

You don't mention where you are, so I couldn't guess what might be a major irritant. I know I got lung irritation from wildfire smoke, construction dust, and a leaky toilet seal letting hydrogen sulfide sewer gas into the house several years ago. It looked like I had an infection, but I didn't. Is it possible there is something environmental causing an irritation?

[travisgf87 in reply to SofiaDeo]

Thanks for the response, SofiaDeo. I understand the diagnosis comes from flow cytometry, I just expected that if it was likely to be CLL (or even suspicious for it) the smear would have indicated some sort of abnormality, smudge cells, the "classic" small mature cells with dense chromatin, etc. It seemed to me "reactive" was the opposite of what one would expect to find in possible CLL.

I have had covid at least twice. Most recently last September. Wouldn't have expected covid to still be my issue with this now but to your point it's all relatively new and who knows what repeat infections do. As I mentioned in my OP I do have an autoimmune illness (ulcerative colitis) as well. Rheumatoid arthritis also runs in my family and I've noticed joint pain in my ankles and knees particularly after sitting for long periods. Could it be related? Maybe. Wish I had definitive answers. The speculation and uncertainty is tough!

[DanBro1 in reply to AussieNeil]

AussieNeal, you sent me to WordHippo.com to look up 'heterogeneous': "Characterized by a varied distribution of particles or components, very complicated or detailed". Mrs. Miller, my late high school English teacher, would have been very proud of you.

[Zweistein]

I was recently diagnosed with CLL and with hindsight I had blood counts similar to yours about 2 years ago but did not investigate further as the doctor thought it was likely from my previous covid infection. In the meanwhile my lymphocytes more than doubled until November 2024. Since then I saw several doctors and ended with three blood tests in intervalls of about 1 month, all measured in different labs. The first one had 20% smudge cells, then one 8% and now one that shows no smudge cells but had CLL markers on the b lymphocytes. It is natural that you are speculating on the basis of a normal blood count. I did the same and had a hard time until I got the official result from flow cytometry . To my surprise the confirmation of the suspicion was a relief as there are worse lymphomas than CLL. Though one decade older than you I am in a similar situation like you. We got married last year and my wife is pregnant. What helped me a lot were the conference videos on YouTube about CLL from 2024 and some of the latest publications. Have a look at this paper:

onlinelibrary.wiley.com/doi...

With Ibrutinib there is no difference in overall survival compared to the general population for more than a decade and then the plot ends as it runs out of data. And combination therapies reduce the chance of BTK inhibitor escape mutations:

youtu.be/A2Ly_WRVSH4?si=XaJ...(Not working as expected?)

I am optimistic to live for decades with CLL.

[travisgf87 in reply to Zweistein]

Thanks zweistein, appreciate the response and the information.

Are you currently being treated? Or in watch and wait?

[Zweistein in reply to travisgf87]

Watch & wait. My lymphocytes are at about 10 and I am in Binet stage A, RAI 0. So I am still at the beginning of my CLL journey. Until last week my situation was like yours. You are not alone.

[Lovely67]

Hi Travis,

I can understand your anxiety. Even if you have CLL, you will likely lead a normal life due to advancement in medical field and field of CLL. I highly recommend you start healthy diet and regular exercise if you don’t already do that. Even a brisk walk for 30 minutes every day counts as very good exercise. Go with whole wheat diet with less red meat and more focus on chicken and fish and whole grains. Reduce processed foods like white bread, sausages, cookies and reduce sugar intake and reduce/eliminate sodas. This will help you a lot and most likely delay any medication for CLL for many years. Doctors don’t say much about diet but processed foods, less exercise and overweight will advance CLL even further. More importantly relax and enjoy life but take care of diet and exercise. All the best.

[travisgf87 in reply to Lovely67]

Lovely67 thank you for your reply. I've already gone down the rabbit hole of "what-ifs" (what if I have all the worst markers, what if it turns into Richter's, etc.). Doesn't help anything I know but I already have health anxiety and the unknown and uncertainty is what it thrives on! I do try to walk daily but I definitely could improve on processed foods and could stand to lose a few pounds

[Baz209]

Again, its waiting for what you're told by your doctors. But, it's possible that at your age it could be Monoclonal B cell lymphocytosis, (MBL). It does not typically cause symptoms and is not a type of cancer. However, in rare cases, high-count MBL may progress to chronic lymphocytic leukemia (CLL). MBL does not require treatment, but a person may need regular blood testing to monitor their lymphocyte levels. When I was at MBL, it also said CLL type phenotype.

[travisgf87 in reply to Baz209]

Thanks Baz209 appreciate the response. I wondered about that as well. I was reading some information about MBL on this site. Seems that's also very rare if under 40. I wonder, can it still be MBL, though, if the lymphocyte count continues to rise and is now over 7? Seems it would be around 5-6 and stable over time but I'll be the first to admit I have a lot to learn!

[Baz209]

The best advice I can give is wait for confirmation and take it from there. Otherwise, you'll just end up a nervous wreck. Once you get the results, then do your research, and don't go along the lines of "boosting your immune system" because some herbs will probably produce /replicate the unwanted cells. This is my own personal experience.

[travisgf87 in reply to Baz209]

Appreciate that, thanks. The waiting is not easy and "a nervous wreck" pretty much sums up my current state! Lol

[Baz209 in reply to travisgf87]

Keep us here updated, lots of great people around.

[SeymourB]

travisgf87 -

Reactive lymphocytes are not an indication for CLL. They're an indication for infection. Usually, they're T-cells. Lymphocyte counts even vary with the time of day. The same sample sent to 2 different labs can return different counts. Small increases like yours can be deceptive.

pmc.ncbi.nlm.nih.gov/articl... A Deep Learning Approach for the Morphological Recognition of Reactive Lymphocytes in Patients with COVID-19 Infection Bioengineering (Basel). 2022 May 23;9(5):229

"Recent observations of the morphology of cells circulating in blood found the presence of particular reactive lymphocytes (COVID-19 RL) in some of the infected patients and demonstrated that it was an indicator of a better prognosis of the disease."

pubmed.ncbi.nlm.nih.gov/372... Systematic Evaluation of Hematologic Parameters and Blood Smear Findings in Patients With SARS-CoV-2 vs Other Viral Respiratory Infections Am J Clin Pathol. 2023 Oct 3;160(4):331-334.

"The most common peripheral blood abnormalities were anemia, thrombocytopenia, absolute lymphopenia, and reactive lymphocytes."

CLL patients do get reactive lymphocytes because we also get a lot of infections.

COVID can also cause smudge cells:

pmc.ncbi.nlm.nih.gov/articl... Blood cell morphology and COVID-19 clinical course, severity, and outcome J Hematop. 2021 Jul 5;14(3):221–228

"The most frequent PBS change among COVID-19 patients were smudge cells (67.4%), giant platelets (42.7%), atypical lymphocytes (36%), and schistocytes (27%) (Table 2 and Fig. 1). Other blood test findings are shown in Table 3. "

I hope this puts your mind at ease some until your flow cytometry results arrive.

=seymour=

[travisgf87 in reply to SeymourB]

Thanks for the reply SeymourB

Do you make anything of the fact that the smear only stated "lymphocytosis with reactive features" and there was no mention of smudge cells or the "classic" CLL type cell (small, nature with dense nucleus and clumped chromatin)?

[Zweistein in reply to travisgf87]

Hi travisgf87,

you have to wait for your results from flow cytometry. I recently had 3 manual blood counts in a row (company doctor, general practitioner, hematologist), all evaluated in different accredited labs and the results were very different. What is a smudge cell for one laboratory is an atypical b lymphocyte for another. And the classification of atypical lymphocytes as reactive and neoplastic was also not reproducible. There are several possible reasons for elevated lymphocyte counts, even over a longer period of time. Have you had your CRP levels checked?

[travisgf87 in reply to Zweistein]

Hi Zweistein no, I've only had the CBCs, a CMP a few months back, and the peripheral blood smear.

[SeymourB in reply to travisgf87]

When they say reactive features, they mean that you have an infection. Infections can cause lymphocytosis, too, and that's why they mention reactive features.

The lack of other language that might indicate CLL is not a sure thing that you don't have CLL, but it's certainly evidence that they don't suspect CLL or want a flow cytometry to eliminate that possibility.

There's no rush. CLL grows slowly even in agressive cases. Wait a few months and re-do the CBC and differential. If the lymphocyte count climbs, then they'll probably order flow cytometry if they haven't already.

Best of luck.

=seymour=