Monoclonal gammopathy and serum immunoglobulin levels as prognostic factors in chronic lymphocytic leukaemia

[Yalokin]

"Immune dysregulation represents a dynamic process evolving during time, often towards hypogammaglobulineamia, especially therapy-related or during disease progression,8-11 and thus with a different subdivision over time. Nevertheless our study constitutes a ‘photograph’ at diagnosis of CLL patients and prognosis has been evaluated in this specific setting.

Prior studies reported an occurrence of hypogammaglobulinaemia in CLL patients ranging from 25% to 70%, but data still remain limited because of the heterogeneity of the examined cohorts, the small series and the inclusion of both treated and untreated patients.12-14

Here, we present data from our study of 1505 patients with newly diagnosed CLL regarding the occurrence of hypogammaglobulinaemia, IgG and IgM gammopathy and their significance in terms of survival and clinical and biological features of the disease"

Results

We retrospectively analyzed 1505 consecutive CLL patients from four different Italian centres diagnosed in the time span from 1987 to 2016. All patients had, at diagnosis, a baseline assessment including their serum Ig profile and immunofixation if a peak was detected at SPEP. Median age was 66 years old (range 26–96 years old), with a slight male predominance (52%, P = 0·589) and the median follow-up was 78 months (range 1–332 months) (Table I).

A total of 73 patients (4·8%) had IgM monoclonal gammopathy (IgM/CLL) detected by immunofixation with a restriction of the κ light chain in 70% and of the λ light chain in 30% of the cases. IgG monoclonal gammopathy (IgG/CLL) was found in 149 patients (10%) with an identical light chain restriction as in IgM/CLL (70% κ and 30% λ). In 88% of the IgG/CLL and 80% of the IgM/CLL cases the light chain isotype of the monoclonal paraprotein and the surface immunoglobulin of the CLL cells were the same (P < 0·0001). The remaining 1283 patients lacked paraprotein at SPEP or immunofixation. Among these, 1083 patients (72%) had normal Ig levels while 200 patients (13·2%) showed hypogammaglobulinaemia.

Clinical and biological characteristics of patients belonging to each of the four subgroups are shown in Table II.

Hypogammaglobulinaemia, the most frequent Ig aberration present at diagnosis in CLL (13·2%). After baseline assessment, in hypogamma/CLL group 42·4% of patients had reduced IgA, 52·7% had reduced IgM and 31·7% were deficient of all Ig classes. In this subset of patients, we evaluated if there was a specific threshold for Ig level under which patients had an inferior outcome and we detected it for IgA level.

CONCLUSION:

"Furthermore, beyond the well-known independent prognostic markers (e.g. IGHV status mutation, Binet/RAI stage, del17p), the presence of qualitative and quantitative Ig alterations does not have any impact on OS."

The post here:

onlinelibrary.wiley.com/doi...

[Yalokin]

Please note that the study includes the so-called "PRE-COVID" period.

[Yalokin]

Here are some other takeaways regarding IgA levels:

CONCLUSION: The prolonged clinical course of B-CLL is usually complicated by

hypogammaglobulinemia. Reduced survival was significantly influenced by low levels of

IgA (p=0.07). The intravenous administration of immunoglobulins could significantly

contribute to the reduction of infection frequency and improvement in the quality of life.

Are the results from 2001 yet? from here: onk.ns.ac.rs/Archive/Vol9/P...

They recommend an IgA infusion ???

How will IVIG raise IgA levels?

I think that the matter is being worked on, but as far as I know, a convenient stable form has not yet been invented.

These days I find strange contradictions in scientific publications.

[AussieNeil Partner Administrator in reply to Yalokin]

IgA is typically removed from IgG products, because otherwise there's an increased risk of reaction from the infusion. IgG products are used to support other health conditions besides CLL. Included IgA may not be a problem if you have CLL, or least an acceptable one. I know of one company working on bringing an IgA product to market.

Neil

[Yalokin in reply to AussieNeil]

Yes, yes. I also read that it is being worked on, but there is no ready product yet. They cannot achieve a stable product over time, as far as I remember (I read about it 2-3 months ago).

[SeymourB in reply to Yalokin]

Yalokin -

I think if both IgA and IgG are low, giving IgG is an attempt to help. Not much gets through to the mucosa, but it does make it into the surrounding tissue.

=seymour=

[Yalokin]

Here, the same difference in conclusions: This study concluded that both reduced and elevated levels of IgG and IgA at diagnosis are important prognostic markers for infection in CLL. It was also concluded that IgA is a marker of disease progression and survival

From here: medivizor.com/blog/SampleLi...

[SeymourB in reply to Yalokin]

Yalokin -

We should emphasized "At diagnosis". Quite a few things will eventually develop to more severe levels. If they exist at diagnosis, that's when it's a bellweather sign of poorer outcome.

We should also note that at the time these papers covered, chemotherapy was the only thing available to most of them. Many patients might have faired better on targetted therapies.

=seymour=

[Yalokin in reply to SeymourB]

See this from my other post. You might be surprised.

link.springer.com/article/1...

[SeymourB in reply to Yalokin]

Yalokin -

That's an excellent paper, with many excellent references to guidelines that I have saved for later. The paper's goal was to show that hemo/oncos fail to monitor infections and Ig therapy adherence to guidelines.

I'm not sure what I would be surprised about, except that so few Europeans (and I suspect Americans, too) get antibody titres before and after important vaccines. Medicos are almost clueless in knowledge of immune function on a practical level.

=seymour=

[HopeME in reply to SeymourB]

Seymour

I’m curious do you see an immunologist? I don’t but I’m strongly considering requesting access to one. It seems like it would be time well spent for a CLL patient

Best,

Mark

[SeymourB in reply to HopeME]

HopeME -

I do. She's board certified in both allergy and immunology. She admits that she sees mostly children and allergy patients, though.

Besides ordering IgG, IgM, and IgA tests that your hemo/onco may not order, they can also test your Ig levels to specific vaccines before and after the vaccine. Usually, they do it for pneumococcal pneumonia.

She got me SCIG therapy a few years ago based on failed titres for pneumovax23 vaccine, and several long sinus infections. that blocked my ears. I stopped it near the start of the pandemic, becuase I felt masking and handwashing by the general public was helping reduce my risk, and I wanted kids who are born with immune dysfunction to have access to Ig.

Since then, I've gotten one serious bacterial sinus infection during my bout of COVID. I would say that an ENT is also a key specialist to have on your payroll. They can confirm infections by cultures, and can peer into the darkness better than a GP can.

I wish there were more immunologists familiar with CLL, though. Perhaps a university clinic is better to shop.

=seymour=

[HopeME in reply to SeymourB]

Helpful information. I’ve never had testing of any titres and I’ve never had much in the way of infections but my IgG is low around 400. My concern is that I didn’t get up to date on vaccinations prior to starting BR treatment in 2018. When I switched to Dana Farber after treatment at another hospital I caught up on vaccinations but I was still within a year of receiving R so I wonder if they were effective? I’d like to know where I stand but my doctors haven’t felt the need to test given I haven’t had any significant infections. The criteria that a patient needs a history of infections has always been perplexing to me as it seems a preventative approach would be more appropriate.

Best,

Mark

[morepork]

Fortunately in my case, despite having lived with hypogammaglobulinemia across my 3 measured IG's for approximately 15 years (IgA 0.3), and also being 17p deleted (which used also to be thought to predict an 'inferior outcome') I have so far avoided any serious infections. CLL seems to have such variables in each of our individual cases. 😊

[Yalokin in reply to morepork]

and what is your TP53 gene status?

[SeymourB in reply to morepork]

morepork -

It's great to hear that you've done well! Maybe you could share your hygeine methods.

I did better during the lockdowns, because of masking and increased handwashing.

But we should also consider our ability to fight hospital acquired infections. Despite the fact that hospitals have quality standards, specific types of infections happen more often there. I hope this has improved since the pandemic, but I wouldn't be surprised if it actually got worse due to staffing problems and pandemic fatigue. In addition, if you're sick enough to be hospitalized, you are likely more vulnerable to infection. Tooth brushing while in the hospital makes a difference in incidence of pneumonia, especially for ventilated patients:

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

Finally, antibodies are not the be-all end-all of immune function. Some of us inherit better versions of genes for innate and complement immunity, and some get slightly worse ones. We're a long way from having an immune system functional assay that looks at antibodies, T-cell function, innate function, and complement in a holistic way. The research is just not there for much of that yet.

In the mean time, clean air and clean hands can make a huge difference.

=seymour=

[AussieNeil Partner Administrator in reply to SeymourB]

With respect to hospital acquired infections (nosocomial is the medical term), in one discussion with a nurse in the oncology ward, he shared that they had seen a marked drop in the incidence of Vancomycin Resistant Enterococcus faecium (VRE), when they began using dedicated equipment to monitor patient's pulse and blood pressure, rather than wheeling around a shared unit: en.wikipedia.org/wiki/Enter....

Neil

[SERVrider]

My history seems to bear this out; Everything started with progressively falling platelet levels spotted by my GP in regular diabetic blood sampling. I was referred to the haematologist. She did more detailed blood sampling and found extremely low IgG, IgA and IgM levels so referred me to the Immunologist. He started me on SCIG replacement. About a year later, I had splenomegaly and enlarging neck lymph nodes so a biopsy was done of a node and that indicated CLL. A BMB was done and that confirmed CLL. I am now on continued SCIG replacement and acalabrutinib.

[Yalokin in reply to SERVrider]

I'm off to the mountains in a bit, but I'd be interested to know what markers your CLL had that determined the low immunoglobulin levels early on.

Take care. Be healthy!

[HMBradley53]

I have Hypogammaglobulinemia and have been worried about also having CLL do you think a person who has Hypogamma should be worried about CLL????

[Newdawn Administrator in reply to HMBradley53]

No I don’t Bradley and I think that’s the danger of joining a site like this based on a shared but not linked issue. It sounds much more likely that your lupus could be the culprit in your hypogammaglobulinaemia as it’s a feature of the condition. This article is a bit complex but explains things very comprehensively.

rheumatologyadvisor.com/hom...

Hypogammaglobulinaemia can be a primary or secondary acquired condition as in CLL and people with the primary deficiency have it quite separate from any automatic association with CLL;

‘Primary hypogammaglobulinemia results from primary failure of the immunologic mechanism, which can vary from the complete absence of immunoglobulins due to agammaglobulinemia to normal immunoglobulin levels with altered function.’

You may have primary or secondary hypogammaglobulinaemia and again it’s well explained in the article I linked.

Best wishes to you but please don’t cause yourself unnecessary fear by erroneously linking your low IgG’s with the causation from CLL because it’s very different. Maybe it’s a concern you need to discuss with your immunologist to put your mind at rest.

Newdawn

[HMBradley53 in reply to Newdawn]

Thank you ! My immunologist said mine is from my autoimmune diseases and my sister also has it and hers is from having stomach cancer and the treatment and still interesting that we both have it

[SERVrider]

Funnily enough, on the day the haematology registrar told me that the lymph biopsy indicated CLL, I bumped into the immunology consultant and told her of the diagnosis. We had a few, unscheduled, minutes together in her office and she said "Perhaps that was it rather than CVID (common variable immunodeficiency) all along".