Monoclonal B-Cell Lymphocytosis (MBL)

by Hank George, FALU, CLU, FLMI

Have you ever heard of this condition?

Is it in your underwriting manual?

It should be!

This short paper is intended to provide underwriters with what they need to understand and assess monoclonal b-cell lymphocytosis (MBL)…

… which is essential because if you haven't encountered MBL as yet, rest assured that you will.

Note: if you have not as yet seen one of our more recent vintage CE (continuing education) courses, this is the format and style we use in those courses.

We hope you will agree with companies enrolled in our program that this is the ideal approach to assure both comprehension and retention.

The following statements by two leading MBL investigators indirectly reflect the urgency of recognizing MBL in an underwriting setting:

"It is crucial to minimize unneeded psychological discomfort caused by labeling individuals with laboratory abnormalities and/or low risk clinical features as having leukemia."

Stefano Molica, MD, et al.
Hematologica
96(2011):277

"Once an individual acquires this 'label', insurance might become more expensive or unavailable. Informing subjects with screen detected MBL of their status could cause anxiety or the unintended consequences of employment or insurance discrimination."

Neil E. Caporaso, MD, et al.
Cytometry Part B: Clinical Cytometry
78B(2010):S115

In other words, physicians are discouraged from telling patients that they have a potentially life-threatening hematological disease when they are diagnosed with MBL.

For this reason:

  1. Any number of – for want of a better term – obfuscating labels may be used for MBL by their physicians.
  2. Applicants will thus be disposed to answer NO to questions about having cancer or leukemia, and may give the same response for "blood disorder" if MBL is represented to them is merely a "laboratory" abnormality.

If we are to identify MBL, in many cases it will be because we recognize the circumstances under which is it apt to be discovered and the ways in which physicians will follow up with these patients.

What is MBL?

It is "…an asymptomatic hematologic condition defined by the presence of monoclonal B-lymphocytes detected in the peripheral blood of persons who do not have chronic lymphocytic leukemia (CLL), other B-lymphoproliferative disorders (BLPD) or underlying conditions such as infections or autoimmune disease."

You K. Shim, et al.
Centers for Disease Control, Atlanta
Cytometry Part B: Clinical Cytometry
78(2010):S10

In other words, these patients have B-lymphocytes with some or all of the features of chronic lymphocytic leukemia but do not satisfy the diagnostic criteria for CLL or any other B-cell neoplasm. [Rawstron and Bennett]

What is meant by "monoclonal"?

Monoclonality refers to originating from a common progenitor cell with all cellular molecules identical to those of the cell of origin. It is a distinguishing feature of a neoplastic process.

Normal B-lymphocyte populations are polyclonal in origin.

Does the presence of a monoclonal cell population inherently equate to having a malignancy?

No.

The term "malignancy" is meant to characterize a disease process capable causing significant harm – in most cases, potentially death – to the host organism. As you will see further on, the discovery of monoclonal B-cells in lesser concentrations has not been shown to confer these risks.

Which disorder most underwriters are acquainted with (and see periodically) is quite similar in this regard to MBL?

Monoclonal gammopathy of uncertain significance (MGUS).

Like MBL, MGUS is often referenced by physicians using terms which downplay its significance as a precursor of a fatal disease (myeloma).

Lymphocytosis

What is lymphocytosis?

An excess number of lymphocytes

What is the difference between relative vs. absolute lymphocytosis?

Relative lymphocytosis is present when the % of lymphocytes in a white blood cell differential count is larger than defined by the normal range. The typical normal range for lymphs is 20-40%.

40% lymphs on a CBC differential would have relative lymphocytosis.

Absolute lymphocytosis is determined by multiplying the % of lymphs in the differential count times the total WBC count. The normal range for the absolute lymphocyte count is typically between 1000 and 4000 cells per cubic millimeter (m³) of blood.

A person would be said to have absolute lymphocytosis if the absolute lymphocyte count exceeded 4000 cells/mm³.

Clinically, only the absolute lymph count is used to identify potentially significant lymphocytosis.

What are the potential causes of absolute lymphocytosis?

Please see Table 1:

Table 1: Causes of Absolute Lymphocytosis

Reactive

  • Viral infections
  • Other infections
  • Drug hypersensitivity
  • Heavy smoking
  • Acute stress (transient)
  • Acute hypoxia (transient)
  • Asthma attack
  • Pulmonary embolus
  • Myocardial infarction

Neoplastic

  • Monoclonal B-cell lymphocytosis
  • Chronic lymphocytic leukemia
  • B-cell lymphoma
  • Hairy cell and prolymphocytic leukemias

Grove. British Medical Journal. 338(2009):1562

What is meant by "reactive lymphocytosis"?

Lymphocytes become activated by (react to) a variety of stimuli, leading to excess manufacture and thus higher numbers in the peripheral blood.

Reactive lymphocytosis rarely lasts more than 3 months, is almost always polyclonal and T-lymphocytes typically predominate. The vast majority of cases are due to viral infections.

How is monoclonal B-cell lymphocytosis (MBL) detected?

Using a laboratory procedure called flow cytometry, which distinguishes lymphocytes by type and origin (mono- vs. polyclonal); and provides an accurate measurement of the size of any clonal lymphocyte population.

In recent years, more sensitive flow cytometry techniques have allowed us to distinguish tiny monoclonal cell clusters. As you will see, this has lead to the most important distinction in assessing the risk associated with MBL.

What % of patients referred for assessment of absolute lymphocytosis are found to have MBL?

In this context – clinical referral, as distinct from population screening – between 10% and 13% in various studies. [Caporaso, Rawstrom and Bennett]

If only for this reason, it is imperative that underwriters get sufficient information on all cases of clinically-evaluated lymphocytosis.

Do MBL patients have lymphadenopathy, splenomegaly and/or other findings associated with CLL?

No. By definition they are asymptomatic and only diagnosed on the basis of further evaluation of abnormal CBC findings. [Hasserjian]

MBL vs. CLL

Is CLL a prevalent form of leukemia?

Yes.

It is the most common leukemia in the US, representing 34% of new leukemia diagnoses.

Approximately 15,000 new cases are diagnosed annually and over 100,000 persons are thought to be alive with CLL at any given time. [Lanasa]

Is CLL curable?

No…however, it is often quite indolent in its clinical course.

Because the incidence of CLL rises steeply with age, this indolent behavior means that many elderly CLL patients die with…not of…CLL (a phenomenon we see far more commonly in older age prostate cancer patients).

What are the latest criteria for the diagnosis of CLL? [Monica]

The International Workshop on CLL made a major change in the criteria for the diagnosis of CLL in 2008. This change was necessary because of the emergence of MBL is a newly-defined condition.

This change was to use the absolute B-lymphocyte count – rather than the absolute total lymphocyte count – at the threshold of 5000 μL as the basis for diagnosing CLL.

How does this differ from MBL?

MBL is diagnosed when the CLL-like absolute B-cell count is < 5000 μL.

Is there any minimum threshold below which the absolute count of CLL-like B-lymphocytes is not, technically, MBL?

No. We will put this point in perspective a bit further on when we distinguish between "low count" vs. "high count" MBL.

How has this change in the definition of CLL impacted the prevalence of CLL?

"…up to 40% of patients previously categorized as affected by CLL have been reclassified as MBL subjects…"

Lydia Scarfo, MD
Laboratory for B Cell Neoplasia
San Raffaele Scientific Institute, Milan
Seminars in Cancer Biology
20(2010):384

What complicating effects does this change in CLL diagnosis have for us?

  1. Undoubtedly a substantial share of applicants who were originally diagnosed with CLL – but would now be properly said to have MBL – will nevertheless be presented to us as having a leukemia diagnosis
  2. Companies offering coverage to elderly applicants with CLL will want to rethink their guidelines now that the 40% of "best cases" will henceforth no longer included in the CLL population.

Is CLL always preceded by a preclinical MBL phase?

According to experts, "virtually all" CLL cases do go through an MBL phase. [Goldin, Landgren]

How long before a diagnosis of CLL is preclinical MBL detectable?

In studies done so far – remember, MBL has only been recognized as a condition for a few years – MBL has been documented up to 6.4 years prior to CLL diagnosis. [Rawstron]

Is MBL more common in persons with a family history of CLL?

Yes.

The risk in this context is held by most experts to be between 2-fold to as much as 7-fold increased, with the best evidence suggesting it is probably 3-4 times greater. [Matos, Rawstrom and Yuille, Scarfo, Shim]

Thus far, the only non-neoplastic disorder associated with an increased frequency of MBL comorbidity is hepatitis C and the presence of MBL appears to correlate with more advanced liver disease. [Fazi]

MBL also appears to be 1.3 to 2 times more common in men than women. [Shim]

MBL Subtypes and their Implications

"…MBL seems to be a melting-pot containing several entities, identical in terms of phenotype but with extremely different risks of leukemia development…"

Scarfo, Op. Cit.

What are the two subtypes of MBL?

  1. Clinical ("high count") MBL – which comes to medical attention due to assessment of lymphocytosis on a CBC.
  2. General population ("low count") MBL – which is rarely if ever detected in a clinical setting because absolute lymphocytosis is not present and therefore flow cytometry is not done.

What is the significance of general population ("low count") MBL?

What few studies have been done to date suggest that this "impairment" is quite common at older ages, almost always remains stable and rarely progresses to clinical ("high count") MBL or overt CLL. [Caporaso, Ghia, Scarfo]

Another way of looking at this is that MBL without absolute B-cell lymphocytosis should be considered little more than an incidental finding made possible by highly-sensitive flow cytometry and having negligible significance to the patient. [Dagklis]

How common is "low count" MBL?

In a Spanish study using highly-sensitive flow cytometry to screen apparently healthy persons, 12% at ages over age 40, > 20% over age 60 and 75% who were at least 90 years old had this condition. [Shim]

While an Italian study showed lower prevalences, nonetheless 9% of subjects over 60 and nearly half by age 90 satisfied flow cytometric criteria for MBL. [Scarfo]

Is there a threshold at which the absolute B-cell count is likely to increase over time, putting the patient at risk for CLL?

Yes.

The threshold appears to be between 3,000 and 3700 per μL. [Rawstron, Rossi]

Based on this, one might characterize monoclonal B-cell lymphocytosis as representing a continuum of three distinct entities:

  1. General population ("low count") MBL – with little or no apparent clinical significance
  2. Clinical ("high count") MBL – a preleukemic disorder
  3. CLL – an incurable malignancy

What % of patients with clinical ("high count") MBL are likely to progress to CLL?

In one study, 34% eventually met the criteria for CLL. [Hasserjian]

Overall, between 1.1% and 2% of these patients progress to CLL each year. [Rawstron and Bennett, Scarfo]

Should MBL patients be monitored periodically?

Experts appear to agree that general population ("low count") cases do not require any further follow-up whereas clinical ("high count") MBL should be monitored with CBCs and B-cell counts every 6 to 12 months. [Caporaso. Hasserjian, Scarfo]

Do we have any information as yet on outcomes in clinical MBL?

Several small studies have been done over rather limited durations:

  1. A Chinese study followed subjects for 45 months. These investigators concluded that MBL has a low probability of progression and that overall survival is does not differ from what has been reported in many studies for early, asymptomatic CLL cases (the very ones which would now be classified as MBL). [Xu]
  2. A Spanish study followed 35 MBL cases for over 70 months. There were no deaths due to CLL. [Florensa]
  3. Marti et al tracked 8 "large count" MBL cases for 10 years, after which 4 died (one from CLL), 1 survivor was diagnosed with lymphoma and another developed splenomegaly and lymphadenopathy similar to that seen in CLL.

There was considerable heterogeneity in these small studies and at this point the long-term prognosis in clinical ("high count") MBL remains largely unknown.

Underwriting Considerations

General Population ("Low Count") MBL:

We are unlikely to see general population ("low count") MBL for reasons already discussed.

In the rare situation where it is discovered in a clinical setting and the subject seeks coverage, we would be inclined to take a liberal approach if the applicant is age 70 or over.

At younger ages, with a corresponding longer life expectancy, it could be argued that the evidence is as yet insufficient to completely disregard this finding and then underwrite accordingly.

Our greatest concern here is for critical illness (dread disease) cover, where the clinical ambiguities of this relatively newly-recognized disorder could put carriers at risk for claims…depending in part on their impairment definitions and whether or not they extend coverage in any premalignant contexts.

Clinical ("High Count") MBL:

This is definitely a premalignant blood disorder.

Because of its similarities to MGUS and the fact that both MGUS and MBL have the potential to culminate in incurable cancer, we would be disposed to approach MBL in much the same way we currently underwrite MGUS.

As a rule of thumb, the younger the applicant is when clinical MBL is discovered, the more conservative our action would be.

References

Caporaso. Cytometry Part B: Clinical Cytometry. 78B(2010):S115

Dagklis. Blood. 114(2009):26

Fazi. Cytometry Part B: Clinical Cytometry. 78B(2010):S61

Florensa. Medicina Clinica. E-published May 9, 2011

Ghia. Blood. 116(2010):22

Goldin. European Journal of Clinical and Medical Oncology. 2(2010):119

Hasserjian. Surgical Pathology. 3(2010):907

Lanasa. Immunology Research. 49(2011):269

Landgren. The New England Journal of Medicine. 360(2009):659

Marti. Cytometry Part B: Clinical Cytometry. 78B(2010):S83

Matos. British Journal of Haematology. 147(2009):339

Molica. Hematologica. 96(2011):277

Rawstron. Cytometry Part B: Clinical Cytometry. 78B(2010):S19

Rawstron and Bennett. The New England Journal of Medicine. 359(2008):575

Rawstron and Yuille. Blood. 100(2002):2289

Rossi. British Journal of Haematology. 146(2009):64

Shim. Cytometry Part B: Clinical Cytometry. 78B(2010):S10

Xu. Leukemia Research. 33(2009):1619

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