Patients with asymptomatic lymphocytosis should not be referred to a haematology clinic unless they have a white cell count above a certain threshold, to avoid causing anxiety to patients and incurring unnecessary healthcare costs, say UK clinicians.
The research was published as an abstract from the British Society for Haematology 60th Annual Scientific Meeting, which was cancelled due to the COVID-19 pandemic.
Dr Peter Johnstone, from Barts Health NHS Trust, London, and colleagues looked at the outcomes of 93 patients after seeing that patients were being referred by their GP in increasing numbers with a raised lymphocyte count on routine full blood count but no symptoms.
They found that only 20 patients (21.5%) had a clonal population of cells, including a dozen cases of chronic lymphocytic leukaemia (CLL) and five with monoclonal B cell lymphocytosis (MBL).
Just two patients ended up requiring treatment after developing symptoms, and the team found that there was a clear difference in lymphocyte counts at presentation between those two patients and the ones who had no clonal populations.
“Our results will influence the advice we give GPs about referral to haematology clinics, with levels of 10–20×109/l perhaps being appropriate thresholds for detection of clinically relevant conditions,” they write.
The researchers say that referring only those patients with a lymphocyte count over a certain level could have several benefits as, while most will have no clonal population, those with a clonal population “are given a diagnostic label and often long-term follow-up”.
This, they note, “can negatively impact quality of life”. They say that the benefits of investigating and monitoring patients with MBL are “unclear”, especially as the rate of progression to progressive CLL is estimated at only 1%–2% per year.
In addition, immunophenotyping and follow-up clinic visits “carry a significant financial cost to the NHS”.
A Very Real Issue
Approached for comment, Francis Matthey, a consultant haematologist at Chelsea and Westminster Hospital, London, said that the study is “addressing a very real issue”.
Dr Matthey, who was not involved in the study, told Medscape News UK that, although it is “not that rare” for patients who have mild increases in lymphocyte counts in the absence of any other abnormality, it is “not uncommon” for GPs to refer them for further investigation.
He added that this is sometimes, “and I think often inappropriately, on the basis that they might have, say, chronic lymphocytic leukaemia, and then they refer it under the so-called two-week rule”.
He continued: “You see more and more of it now because, compared to when I first started as a consultant, it’s much more common for people to have blood counts done, for relatively little reason.”
Typically, blood counts may be taken as part of an annual cholesterol and blood pressure check, and that may be of “questionable” value, he said, when “they don’t need to have anything done about them other than be documented”.
In terms of lymphocyte count threshold recommended by the authors, Dr Matthey said that it seems “very reasonable”.
In his practice, he uses a cut-off of 10×109/l, assuming “the rest of the blood count is normal and…the patients are asymptomatic, and they don’t have any evidence of enlarged lymph nodes or enlarged spleen”.
He added: “Other people would use a lower cut off, but the point they’re making, which I think is very valid, is not just that this is a bit of burden on haematology but [also that] it causes, in some patients’ minds, a lot of worry”.
Dr Matthey agreed that patients can then often “wind up with a label”, pointing out that MBL “is just another way of saying it’s very low-grade CLL”.
“But we don’t want to use the word ‘leukaemia’, because it has an impact on people’s quality of life and anxiety, and may possibly impact upon insurance as well, which is something that is often forgotten about.”
To examine the long-term outcomes for patients with asymptomatic lymphocytosis, the team examined the records of all patients who underwent immunophenotyping at their centre between January 2013 and the end of June 2014.
To be included in the study, patients had to have been followed up for at least 5 years, have no pre-existing diagnosis of a lymphoproliferative disorder and no constitutional symptoms or cytopaenia at the time of testing.
Ninety three of 167 patients met the inclusion criteria, of whom 20 (21.5%) had a clonal population.
This included 12 with CLL, five with CLL-like MBL, one with splenic marginal lymphoma and two with B-cell lymphoproliferative disorders not otherwise specified.
Only two of the patients with clonal populations went on to have treatment, after developing symptoms 4 and 24 months after diagnosis, respectively. Of the remaining patients, nine had 6–12 monthly monitoring, three died from other causes, and six were lost to follow-up.
The team notes that the two patients who eventually needed treatment had initially presented with a lymphocyte count of >20×109/l, while all 73 patients with non-clonal lymphocytosis had an initial count of <10×109/l.
To investigate thresholds for lymphocytosis referral further, they sent a survey to haematology centres nationwide.
The 23 responses revealed that thresholds ranged from >3×109/l to >20×109/l, with the most commonly used 5×109/l and 10×109/l. Moreover, there was variation in the follow-up strategies employed and whether GPs had direct access to immunophenotyping.
New Cut Off Range
Dr Johnstone told Medscape News UK that they would next like to conduct a follow-up audit of their current patients to see whether, “if we implemented, say, a cut off of 10×109/l, how many that would remove, to give us an idea of what kind of saving we would be making”.
He said: “After that, we would be quite keen to discuss with local GPs to see whether we could implement a new cut off, from our work probably >10×109/l, although it would be up for discussion about where exactly we’d call the line”.
The team would then audit that “very carefully to make sure we’re not missing things, and with all the usual caveats that that is specifically asymptomatic, and purely lymphcytosis”.
He underlined that “if they have any kind of worrying symptoms or more than one cell line affected, than that’s a higher risk and we’d be more than happy to see them”.
Dr Johnstone noted that the issue of identifying patients on diagnostic tests with abnormalities of questionable prognostic significance is not confined to haematology.
“You can speak to any specialist probably in any different area and they’d be able to find you an example of something similar,” he said.
“As testing capacities increase, and the ways that we can test for things become more specialised, you can catch things theoretically earlier.”
While that is “generally a very good thing and certainly something we should be pushing towards”, the line needs to be drawn between catching “clinically significant precursors or high-risk individuals” for a given disease and “testing for testing’s sake”.
“I think that’s going to be an ongoing battle in all sorts of areas,” Dr Johnstone said, “and it’s one that we need to get right from both sides.”
While on the one hand, they want to offer patients with significant precursor states “the best possible care”, he said that “we want to be running a relatively efficient health service and we can’t test for absolutely everything”.
No funding declared.
No conflicts of interest declared.
BSH 2020: Abstract BSH2020-PO-044