Tuesday, July 14, 2009

MBL v CLL

I have beavering away at the chapter I promised to write and have completed this section on monoclonal B-cell lymphocytosis. The references are not yet complete but if anyone particularly needs them, they will be ready in a day or two, so ask.

Monoclonal B-cell lymphocytosis

Having defined CLL as a lymphocytosis with a characteristic immunophenotype it became clear to CLL specialists that early stage CLL was apparently getting commoner. In fact, apparent fluctuations in the incidence of CLL have been occurring for a long time. In the nineteen fifties and sixties several studies reported incidences in excess of 6 per 100,000 [5]. This was in the days before immunophenotyping when any lymphocytosis over 10 x 10^9 per microlitre of relatively appropriate morphology was designated CLL. From our own experience we can be sure that we misdiagnosed many patients during this period and in our work as a reference center we have recognized that these types of mistakes were not rare. Immunophenotyping has excluded the majority of interlopers and as a result the perceived incidence of CLL fell between the nineteen seventies and nineteen nineties. Sgambati et al [6] reporting on statistics from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) Program described a fall in incidence rates for CLL for white males from 4.2 per 100,000 to 3.2 per 100,000 between 1973 and 1976 while the rate for white females fell from 3.8 to 2.6 over the same period. The rates for those of African-American, Hispanic or Asian origin were much lower.

Exactly how many cases of CLL are collected depends on how assiduous is the collection. Simply relying on death certificates or hospital admissions will miss all those early stage patients that never progress and never require treatment. Between 1984 and 1988 Cartwright et al [7] enlisted the help of hematologists performing blood tests for one third of the population of England and Wales to register every new diagnosis of CLL. The annual incidence was 5.54 per 100,000 with a male to female ratio of 1.95. There was no temporal variation, but a threefold difference between districts. Racial differences could not explain the discrepancies, though districts where the disease was commoner tended to have more old people. What was noticeable was that the disease was apparently commoner where the hematologists took a special interest in the disease, suggesting that such specialists would be more likely to make the diagnosis with relatively low lymphocyte counts that less obsessed doctors might pass as normal.

Guidelines for the diagnosis of CLL were published in 1988 by a National Cancer Institute Working Group (NCI-WG) [8] and in 1989 by the International Workshop on CLL (IWCLL) [9]. The former required a lymphocytosis of >5 x 10^9/L but the latter a lymphocytosis of >10 x 10^9/L. This confusion was removed by the 1996 guidelines published by the NCI-WG [10] which settled on a lymphocytosis of >5 x 10^9/L but has been further complicated by the 2008 guidelines published by the IWCLL [11] which raise the threshold to a B-cell lymphocytosis (rather than a total lymphocytosis) of >5 x 10^9/L.

In 2002 Rawstron et al [12], using four-color flow cytometry of the dregs of blood samples taken for other reasons, discovered that 3.5% of the population over the age of 40 harbors a population of cells immunophenotypically similar to those of CLL and this has been confirmed by others, who emphasize that marginal zone lymphoma also exists in this pre-clinical form [13]. The prevalence of such cells rises with age, to 7.7% of people in their seventies. Recently the group from Salamanca, Spain, using a more highly sensitive multicolor flow technique have suggested that as many as 12% of the population over the age of 40 have a small population of CLL-like cells in heir blood [14].

An International Working Group [15] has designated this condition as Monoclonal B-cell Lymphocytosis (MBL) and laid down diagnostic criteria (Table 1). Of course, this new entity did not suddenly appear in 2002, and the International Group also reported on previous sightings of the condition under such names as ‘smoldering CLL’ and ‘benign monoclonal B-lymphocytosis’.

Rawstron et al [16 NEJM 2008] have reported on the relationship between MBL and CLL. Among subjects with a normal blood count, the prevalence of MBL was 78 in 1520 or 5.1%. Because the samples were taken from anonymous subjects no follow-up was possible. In such patients the B-lymphocyte count could be as low as 0.015 x 10^9/L and none were higher than 1.2 x 10^9/L (normal range: 0.025-0.49 X 10^9/L). Another cohort, who did have a lymphocytosis (lymphocyte count >4.0 x 10^9/L) could be followed up. Of 2228 such individuals, 309 had MBL (13.9%) and 185 of these had sequential monitoring for between 0.2 and 11.8 years (median 6.7). While in most cases the lymphocytosis was stable or regressive, in 51 subjects (28%) there was progressive lymphocytosis; in 31 to a lymphocyte count of >30 x 10^9/L. Among the 51, other features of progressive CLL, predominantly lymphadenopathy, developed in 28 (55%) while 13 (25%) required chemotherapy a median of four years after the initial diagnosis. The estimated rate of progression to CLL requiring treatment of MBL with lymphocytosis was 1.1% per year; about the same rate at which monoclonal gammopathy of undetermined significance (MGUS) transforms to myeloma.

The only factor among those examined that predicted progression was the absolute B-lymphocyte count. Those with B-lymphocyte counts below 1.9 x 10^9/L seldom progressed, while of those with a B-lymphocyte count of greater than 4 x 10^9/L, more than half had progressed at 10 years follow-up. There were 62 deaths among the 185 who were followed up; the majority had died from an unrelated cause, but 13 had had progressive CLL, although CLL was mentioned on the death certificate of only four.

Although MBL only seldom transforms to CLL, almost all cases of CLL were once MBL. Taking advantage of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, Landgren et al [17] were able to identify among 77,469 healthy adults 129 subjects who eventually developed. Of these, 45 had available pre-diagnostic cryopreserved whole blood. Using flow cytometry and molecular techniques they were able to identify an MBL clone in 44 of the specimens.

The new definition of CLL and its relationship to MBL will change clinical practice. One of the consequences would be a demand to monitor cases of MBL with flow cytometry to check on B-cell numbers. Shanafelt et al [18] have addressed this problem by re-evaluating 459 Rai stage 0 patients in view of the new guidelines. They found that 190 patients would be reclassified as MBL. By studying the likelihood of progression they determined that a threshold B-cell count of 11 x 10^9/L was necessary for the condition to progress to clinically significant CLL. This equates to an absolute lymphocyte count of 20 x 10^9/L. The fascinating corollary is that CLL should not be diagnosed until the absolute lymphocyte count consistently exceeds 20 x 10^9/L. This would obviate the need for expensive flow cytometry measurements for follow-up patients. For those more conservatively minded, their study found that the current CLL definition threshold of a B-cell count of 5 x 10^9/L equates to an absolute lymphocyte count of 11 x 10^9/L. So much for progress over the past 35 years.

15 comments:

Anonymous said...

Hi Terry
Would you please right me the reference number 13?
Thank you!

Anonymous said...

Terry
Would you please write me reference #13? Thank you!

Terry Hamblin said...

This reference was omitted from the final article but I think it was Nieto WG, Almeida J, Romero A, et al. Increased frequency (12%) of circulating CLL-like B-cell clones in healthy individuals using a high-sensitive multicolor flow cytometry approach. Prepublished online May 6, 2009;doi:10.1182/blood-2009-01-197368 Accessed July 3rd 2009.

or possibly this one

Nieto WG, Teodosio C, López A, Rodríguez-Caballero A, Romero A, Bárcena P, Gutierrez ML, Langerak AW, Fernandez-Navarro P, Orfao A, Almeida J; Cytometry B Clin Cytom. 2010;78 Suppl 1:S24-34.
Non-CLL-like monoclonal B-cell lymphocytosis in the general population: prevalence and phenotypic/genetic characteristics.

Anonymous said...

Terry
I have asked you before the same question but really, out of sympathy, I beg for your answer again. I trust you so much. I am obsessive about one issue: I have MBL (CD5neg; CD20+; CD11c) - stable, assymptomatic, normal levels of immunneglobulins, no cytopenias, total lymphocytes count even decreased over these last 3 years since diagnsosis. My questions:
1)I had an occupational accident with a HIV positive person (I work in a hospital here in my country)...it was not that serious...basically his saliva into my eyes...anyway, I have been tested several times up to 9 months after the accident. I took a RNA PCR along with a p24 assay after 35 days from the accident. ALL negative! After that I have been tested by using Antibododies (only) Assays up to 9 months after the accident. Wouldn't I be able to produce antibodies having MBL? I am mentally sick since I started reading about immunodeficiencies related to CLL or other Lymphomas.
2)In your opinion, ALL indolent B cell lymphomas show significant demage of the immune system? I am a married man and I have to trust in my sero status regarding viruses.
3) Once you told me that problems in the "marginal zone" should not be a problem regarding antibody response. You told me it was a CLL problem. Why is it like that?
I am so sorry and ashamed for asking you that, but if I ask it to an infectious disease physician he/she would not know what MBL is so someone with your expertise should help me a lot more.
Stay well! God bless you!

Terry Hamblin said...

Even with MBL you would certainly make anti-HIV antibodies if you had really been exposed to the virus. CLL is a particular disease much given to immunodeficiency and the same is not true for marginal zone lymphoma, where increased antibody production is more likely, especially in the early phase. Nobody is really sure why CLL is so different, but it is something to do with the CLL cells suborning the role of antigen presenting cell from CD14+ dendritic cells.

My advice would be to put this out of your mind and be reassurred. I know that it is difficult. Your final alternative would be to test for HIV again with an RT-PCR test.

Anonymous said...

Terry, thank you!
About the HIV issue, I would like to put it out of my mind. Did you mention to go for another RT-PCR just for "psychological" reasons or do you think it is clinically necessary after all the testing I have gone through?
I will follow your advice. To hear from a specialist (instead of going for another RT-PCR) would be ok for me.

Terry Hamblin said...

I would only have another test if you can't put this out of your mind.

Anonymous said...

Terry, I promise this wil be my last post...in your opinion, in case I try my best to put it out of mind, do you think I will be negligent with myself if I do not go for another PCR? I really donot want to take another test. I want to put it all this to an end.

Terry Hamblin said...

No you would not be negligent. I am convinced that you are HIV negative.

Anonymous said...

Terry, thank you. I also believe I am not infected. Deep inside I know it after so many tests.
Just a theorical thought: talking about EARLY CLL patients (it´s not my case I know) who have not needed any treatment...would you only order standard serologies (the one that looks for antibodies only)instead of RT-PCR in case they've had some kind of contact of HIV, Hepatitis C, B, etc? I know they may not respond to vaccines but regarding "live viruses", wouldn't they respond differently?

Terry Hamblin said...

I suspect that MBL with CLL markers would be safe, but how far into early CLL remains safe is an open question that no-one has investigated.

Anonymous said...

Terry, so I REALLY want to tell you this is the last one. You help me a lot. Again, out of sympathy...
Are you really ok with my option of putting it out and NOT going for another RT-PCR and live my life?

Terry Hamblin said...

REALLY.

Anonymous said...

Terry, I know I might be annoying you. Last one I promise. A
As I am not a native English speaker (sorry, I am so ashamed to ask you this), so has your "REALLY" meant that you are OK if I do not get tested again by RT-PCR?

Terry Hamblin said...

I am OK with it.