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An Initial Look at Some CLL Initialisms

Posted by Frederick Wasti
May 02 2013

Any discussion of Chronic Lymphocytic Leukemia is replete with sometimes confusing (and sometimes even misleading) terminology, with the actual terms often found "hidden" behind abbreviations, acronyms, and/or initialisms, which may simply (or probably complicatingly) add to the confusion.

As an aside, I should first point out that "acronyms" are not exactly the same as "abbreviations", and that "initialisms" are different, too. Basically, an abbreviation is any shortened form of a word or group of words, but acronyms and initialisms are both more specific and more restrictive.

An acronym is an abbreviation usually formed from some or all of the initial (and occasionally other) letters of a series of words or syllables, and is pronounced as if it were a word by itself. An initialism is also an abbreviation formed from some or all of the initial (and occasionally other) letters of a series of words or syllables, but is not pronounced as a word by itself. All acronyms are, of course, abbreviations, just as all initialisms are abbreviations, but not all abbreviations are either acronyms or initialisms.

[And, by the way, in the image above, if you didn't happen to know, "TNT" is an initialism for three of the syllables in "Trinitrotoluene", while "radar" is an acronym for "RA(dio) D(etecting) A(nd) R(anging)", and, if you're unfamiliar with the acronym "WYSIWYG" in the image above, it's a computer programming abbreviation for "What you see is what you get" and is pronounced as "wiz-ee-wig" - <grin>.]

Examples of "simple" abbreviations (i.e., non-acronym and non-initialism abbreviations) are "lb" (for pound) and "oz" for ounce -- note that neither is specifically made up of initial letters (although one initial letter happens to be used for "oz"); that neither abbreviation is ordinarily pronounced as spelled (i.e., one does not usually say "ell-bee" for lb, nor either "oh-zee" or "awz" for oz); and that such abbreviations are usually pronounced by vocally substituting the original unabbreviated word(s) that they were derived from (i.e., one says "pound" for lb and "ounce" for oz).

Examples of initialisms are "FBI" (for Federal Bureau of Investigation) and "CIA" (for Central Intelligence Agency). Note that neither initialism is pronounced as spelled (i.e., one usually does not say something like "fib-bee" for FBI, or "see-ah" for CIA) - one pronounces each by separately pronouncing the initial letters in each (i.e., one usually pronounces FBI as "eff-bee-eye" and CIA as "see-eye-ay").

Some more computer programming humor:

Examples of acronyms are "NATO" (for North Atlantic Treaty Organization) and "NASA" (for National Aeronautics and Space Administration). Note that each is generally pronounced as if the letters in the acronym made up a new word (i.e., one usually pronounces NATO as "nay-toe", and NASA as "nas-suh"), and one does not usually pronounce them as if they were initialisms (i.e., one does not generally say either "enn-ay-tee-oh" or "enn-ay-ess-ay").

Thus, you can see that abbreviations can include acronyms and initialisms, and that all three terms ~might~ be formed by using initial letters from multiple words, but all three terms are otherwise somewhat distinct.

Therefore, for a more relevant example, "CLL" is an abbreviation for "Chronic Lymphocytic Leukemia" that is, more specifically, also an initialism, but it is not actually an acronym. Simple, eh?

But I digress...

Well, most of the terms to be discussed here (and in a follow-up blog entry) (e.g., "Chronic Lymphocytic Leukemia" and "Minimal Residual Disease") are often abbreviated to initialisms (e.g., "CLL" and "MRD") but such abbreviations are not acronyms. Still, to get back to my original point, the terms used in discussing CLL can sometimes be confusing and even misleading, sometimes even more so when abbreviated.

A prime example of a CLL term that is confusing and/or misleading is "Complete Response" (to treatment), or "CR". Quoting from the "CLL Topics" web site:

"For starters, 'CR' does not mean what you think in means if you are talking plain English. If you are new to the world of oncology research, you may be forgiven for thinking 'complete' means - well, complete. Duh. And that if you get a 'CR' remission, you are home free because your response to the therapy in question is complete. (Not!) 'CR' just means that your blood counts look normal at the end of the therapy, [and] you do not have any swollen lymph nodes bigger than 1.5 cm that can be felt by your doctor poking around."

Remember that a ~complete~ (as in "total") positive response to treatment is really next to impossible in CLL:

With solid cancer tumors, the ultimate goal of treatment is to remove or destroy all of a tumor before any of its cells have spread (i.e., metastasized) to other locations in the body. For example, the words a solid tumor patient wants to hear (and that his medical team would like to provide) are "it looks like we got it all". However, with blood cancers such as leukemia, there is no simple way to "get it (or them) all", since the cancerous blood cells have already "metastasized" (so to speak) - they have already been distributed by the circulatory and lymphatic systems throughout the ~entire~ body.

In the specific case of Chronic Lymphocytic Leukemia - CLL - there is no known treatment regimen that will succeed in killing all of the leukemic lymphocytes. For many CLL patients (the ones with favorable leukemia cell genetics), a half dozen monthly rounds of the "gold standard" FCR treatment will reduce their CLL to very low levels, and they may often remain "in remission" (not cured, though) for several (and, in some cases, many) years. That is what is typically referred to as a Complete Response - the patient is not actually cured, but the disease is still relatively undetectable.

However, in the case of CLL patients with a chromosome 17p deletion in their CLL cells, treatments such as the FCR "gold standard" don't work well -- 17p-deleted patients treated with FCR usually have only partial treatment responses that don't last for very long. (This is, of course, why yours truly is in a clinical trial at Dana-Farber that is aimed specifically at 17p-deleted participants.)

While I likely would not have benefited very much, or for very long, from "gold standard" FCR treatment, my own clinical trial treatment (High-dose Methylprednisolone, Alemtuzumab, and Alemtuzumab) would seem to have given me a so-called Complete Response to treatment - i.e., it ~seems~ as if my leukemic cells are "gone" (since they have been reduced to a level below the level of detection), and I "do not have any swollen lymph nodes bigger than 1.5 cm that can be felt by [my] doctor poking around".

Actually, what constitutes a Complete Response to treatment in CLL involves a fairly specific set of criteria. According to the latest (2008) set of formal international standards for what is required for a Complete Response in CLL, there are five criteria which have to be met, and I'll consider each one of these as it relates to my own situation:

1. "Absence of lymphadenopathy > 1.5 cm, hepatomegaly, splenomegaly, and constitutional symptoms"

The first three "big words" refer to enlarged lymph nodes, an enlarged liver, and an enlarged spleen. An enlarged lymph node is further defined as being one more than 1.5 cm (about 5/8 of an inch) in size. A "constitutional symptom" is a generalized body symptom that indicates that there is something "wrong" with the body, but is not by itself specific enough to indicate just what is "wrong". Examples of constitutional symptoms include fevers, headaches, chills, lethargy, and any other "general" symptom of less than perfect health.

In my particular case, my lymph nodes (judged both by palpation and from CT scans) have been greatly reduced - a few abdominal lymph nodes (in CT scans) appear to be slightly enlarged, but, in general, my lymph nodes are mostly "sub-centimeter" in size, as characterized by the radiologists who had read my more recent CT scans. My liver has never been reported as being enlarged, and, while my spleen was previously judged as being a bit enlarged (perhaps 16 cm instead of the "normal" 11 or 12 cm), the consensus now is that my spleen is just a bit difficult to measure (some of us have more bean-shaped spleens, easy to measure on a CT scan, while others, such as yours truly, have lobular spleens that make their measuring more of an art than a science), and so perhaps it is not all that large after all (?).

As for constitutional (and other) symptoms, I am basically feeling pretty healthy right now. I do have some arthritis symptoms that bother me frequently each and every day, but they are not directly related to CLL (although they may have been aggravated by the ~treatment~ for CLL). I still battle seborrheic dermatitis on my face, but that is not really a constitutional symptom, since it can be attributed to my currently (intentionally) skewed and therefore weakened immune system. Overall, I do feel pretty good - I feel "well". I do admit to some issues involving stamina (or lack thereof), but this is not overly debilitating, at least for this retired person (but I can see that it could be more problematic for a younger person).

So, I would say that, overall, I do more-or-less meet the first CR criterion, although perhaps not completely.

2. "Normalization of CBC (neutrophils > 1,500/µL, platelets > 100,000/µL, hemoglobin > 11 g/dL)"

It is good that some specific measures to judge the "normalization" of a person's complete blood count have been provided, since treatment for CLL always involves some skewing of blood cell counts - i.e., an intentional, desirable reduction in lymphocytes is common to most treatments for CLL (as it certainly has been so in mine). However, the above numbers for neutrophils, platelets, and hemoglobin indicate relatively normal (or at least minimal) levels for each of these blood parameters, as compared to the lower numbers for each that are typically found in someone badly impacted by CLL, where the aggressive production of CLL cells in the bone marrow has crowded out the normal production of red cells, of platelets, and of other white cells.

My last neutrophil count, before starting treatment at Dana-Farber, was about 500 per microliter, and, in fact, was one of the reasons for me to start treatment a little over a year ago. Since the trial began, though, my neutrophil counts...

...have consistently been above (and usually way above) the criterion of "> 1,500/µL".

My platelet counts, while below 100,000 per microliter before treatment started, have generally (although not always, and not overwhelmingly) been above 100,000...

...throughout the clinical trial. (In case you're wondering, that one big spike above occurred during the time that I was fighting pneumonia at Brigham and Women's Hospital.)

As for hemoglobin (the reddish oxygen-carrying pigment in red blood cells), my blood tests have never, either before or during treatment, ...

...fallen even close to 11 grams per deciliter. (In fact, I don't even include 11 g/dL on the vertical axis of my hemoglobin graph, above.)

3. "Lymphocytes < 4,000/µL"

This criterion, of course, has to be of prime concern in what is called Chronic ~Lymphocytic~ Leukemia, right? And, I do have to admit that my lymphocyte counts had always been well above 4,000 cells per microliter, at least between the time of diagnosis and the start of the clinical trial, and that they had risen slowly during that time to almost 50,000 per microliter, but that, once the trial got underway, they fell dramatically, and have remained very low ever since:

Looking more closely at the lymphocyte counts just during the trial, ...

... it can be seen that my lymphocyte counts had dropped below the 4,000 per microliter criterion before the end of Part A, and then plummeted at the start of Part B to what looks like "zero" on the graph for Parts B and C because of the scale - actually, they usually have been counted at about one or two dozen cells per microliter throughout Parts B and C, which certainly meets the criterion of "< 4,000/µL"!

4. "Minimal residual disease (MRD) < 1 CLL cell per 10,000 leukocytes"

A test for Minimal Residual Disease is not routinely performed, as it is more complicated - and thus more expensive - to perform than any of the "usual" blood tests. Furthermore, it makes no sense to routinely perform such a complicated and expensive test, designed for detecting tiny traces of CLL cells, when simple blood tests indicate that there are likely to be ~huge~ numbers of CLL cells present. Therefore, an MRD test is generally carried out only when it seems as if a clinical trial participant is nearing the point of reaching a Complete Response, in order to quantitatively demonstrate that the trial has been successful. (Because such a level of proof is not required when treating a CLL patient who is not participating in a clinical trial, MRD testing is generally not performed at all for such non-trial patients).

While MRD testing can be performed on peripheral blood taken from a vein, its significance is generally more emphatic when it is performed on tissue from a bone marrow biopsy (because, while CLL lymphocytes are also found in the blood and in the spleen and lymph nodes, it is in the ~marrow~ that they do most of their damage, by crowding out other blood cells). The current "state of the art" working standard of "< 1 CLL cell per 10,000 leukocytes" (which can also be stated as "less than 0.01% CLL cells per sample of leukocytes") is lower than it used to be at one time, due to improved methodology, but it will likely become even lower still as technology increases the level of sensitivity for measuring MRD so that lower and lower levels of CLL cells can be detected.

I have had four MRD tests, three performed on my bone marrow tissues and one on my peripheral blood. Here is a graph of my MRD results:

It's not a particularly clear graph, as it is from a scan I made from a printout from D-F, of a previously printed report that was faxed to D-F from the testing lab (Esoterix Genetic Laboratories of NYC). (While D-F routinely performs nearly all patient blood testing internally, MRD testing is so specialized that it is usually carried out only at certain dedicated facilities.) So, I created the following graph in Excel, to make things a little easier to view and (hopefully) to understand:

The vertical axis represents the percentage of CLL cells found in a tested sample of all white blood cells. The horizontal axis represent time, encompassing the dates of my four MRD tests.

What might seem unusual if you study the graph axes carefully is that the vertical axis is not linear - it is arranged logarithmically, so that both very large and very small quantities can be easily shown on the same graph. To demonstrate the usefulness of using such a logarithmic vertical axis, I also created an MRD graph using the same data, but with a linear vertical axis instead:

Note that this latter MRD graph cannot easily show numbers close to zero -- the line representing the 0.01% test sensitivity limit and the curve connecting the 9/28/2012 and 11/9/2012 testing dates are both "squished down" onto the bottom of the graph, seemingly right on the horizontal axis, yet they are not actually equal to zero.

Since the above "silly" graph is not very useful for referring to in the following discussion, I'm inserting the previous logarithmic graph once again right here:

My MRD tests were performed on four samples: on marrow from 7/16/2012, at the end of Part A; on blood from 8/13/2012, at about one-third the way into Part B; on marrow from 9/28/2012, at about the midpoint of Part B; and on marrow from 11/9/2012, shortly before the end of Part B. [I also had a bone marrow biopsy back on 3/14/2012, which was the "screening day" for acceptance into the trial, but - not surprisingly - there was no MRD test performed on my marrow tissue at that time, since it was all too obvious that I had ~plenty~ of CLL cells back then.]

My first MRD test was performed at the end of Part A, on 9/28/2012. I certainly knew that bone marrow tissue was being tested for various things at that time (since I was certainly ~fully~ aware that I had a bone marrow biopsy taken from my hip on that date - <grin>), but I did not find out until later that, from MRD testing, I had approximately 6 CLL cells for every 100 white cells (5.96%) in my marrow at the end of Part A. Since 5.96% is a whole lot more than 0.01% (the current sensitivity level of detection for MRD), it must have been quite apparent to my hematologist/oncologist, Dr. David Fisher, and to the Primary Investigator for the clinical trial, Dr. Jennifer Brown, that - not surprisingly - the trial had not finished doing its job on my CLL. I have to assume that this result was to be expected at the end of Part A, but that an MRD test probably still had to be carried out, as a required "milestone" test for the end of Part A, likely according to the trial's protocol.

I also did not know (until later on) that my blood from 8/13/2012 was also tested for MRD. I suppose that, even though I was not scheduled for a bone marrow biopsy for a few more weeks after that date, it was probably a good idea to see how my blood was doing for CLL cells early in Part B (which had already shown dramatic and immediate changes right at the start of Part B). The results of this MRD test did show that at least my blood had already achieved MRD status, since it had tested at less than 0.01% CLL cells. You can easily see this plotted on the MRD graphs above (except for that "squished" graph with the linear vertical axis), where there is a point for the percentage of CLL cells on 8/13 plotted beneath the 0.01% MRD test sensitivity level horizontal line.

[You should also find, if you haven't spotted this already, that the curve connecting the MRD test points does not run through the point for 8/13 -- this is, of course (and you've probably already figured this out), because this test was done on ~blood~, and it is really only the MRD ~marrow~ tests that are truly significant -- nonetheless, it must have been gratifying to Drs. Brown and Fisher to see that at least my blood had reached MRD status early in Part B.]

I had another bone marrow biopsy, and an MRD test run on it, at the intended approximate midpoint for Part B, on 9/28/2012. [I say "intended", because, while Part B was supposed to be six months long, I achieved MRD status after about "only" five months of Part B, and so I "was graduated" from Part B to Part C about one month early.] This MRD test produced results that were of the "pretty darned good news" variety - I was measured as having only 0.02% CLL cells, ~almost~ (but not quite) down to the level of sensitivity for MRD testing.

Shortly after the time that the third MRD test results came back to D-F (it does take a few weeks for such test results to be returned), I had started developing a "pretty good" rash (neither "pretty" nor "good", actually) over much of my body (see the blog entry for 10/23/2012, "A Rash Decision", for all the gory details). I did send an email at that time (on 10/23) to each of the members of my D-F medical team, since I was concerned that it had been suggested that I might have to end my participation in the clinical trial "merely" because I had recently developed a "little" rash here and there (and everywhere). In an email reply from Dr. Brown on 10/24, she said, "I hope to continue you on the protocol, and the goal is to continue until the disease is not detectable. Would be very surprising if the rash is from the protocol therapy as opposed to the antibiotics.". I "lucked out" on both parts of her reply - I was indeed able to continue in the trial, eventually achieving MRD status (see below), and simply switching from Bactrim to Mepron for my antibacterial medication seemed to help with the skin rash.

My last MRD test was performed on a marrow sample obtained on 11/9/12. Ordinarily, I would have been scheduled to have a bone marrow biopsy and MRD test at the end of the six months of Part B, but they were done a bit early because (I assume) it was felt that there was a good chance that I may have reached MRD status a bit early. The results of the testing showed that, indeed, I then had less than 0.01% CLL cells in my marrow, which is about as close to "cured" as can be proven with the current level of MRD technology. (I was, of course, ~not~ really "cured" - undoubtedly I still had zillions of CLL cells in my body, but at least the number of them was low enough that they were no longer detectable.)

Well, I'm approaching the end of this blog entry pretty shortly (and I know that you're probably reading that with some relief - <grin>), but I would just like to point out a couple of foibles involving the above MRD graphs (the ones with logarithmic vertical axes, not the silly one with a linear vertical axis):

1. Note that there is actually no "zero" on the vertical axis scale. Each division on the axis is ten times greater than the division below it, and is also ten times smaller than the division above it. So, the scale goes from 10% down to 1%, then to 0.1%, then to 0.01%, and then to 0.001%, and, if it continued further, it would go down to 0.0001%, and then to 0.00001%, and so forth, and - well, here is the interesting part - it could never possibly reach zero. Ever! Interesting, eh? (Well, at least ~I~ think so - <g>.)

2. Both Esoterix Genetic Laboratories and I "fudged" a bit in plotting the results for 8/13 and 11/9 on the graphs. Since a level of 0.01% of CLL cells, which represents a level of one CLL cell for every 10,000 white blood cells, is the lowest level of CLL cells that possibly can be detected currently, and Esoterix "found that it could not find" (<grin>) any CLL cells in my blood at that level of test sensitivity, all Esoterix could say is that my CLL cells were "< 0.01%" of all of my white cells. But, just how do you plot "less than 0.01%" on a graph? Well, you can't (at least not with a point). So, when Esoterix - or when I - plotted a point for "< 0.01%" (which we each did twice, once for the blood test on 8/13 and once for the marrow test on 11/9), we had to "fudge 'em". I don't know exactly what value Esoterix used to represent "< 0.01%" on its report graph, but I will admit to using "0.005%" for my "< 0.01%" points - however, that was just a wild guess -- "< 0.01%" could mean "0.009999%", ~or~ it could mean "0.0000001%", which are certainly very different from each other (and I am hoping it is more like the latter than the former - <smile>).

5. "Bone marrow biopsy shows normal cellularity, lymphocytes < 30%"

OK, that's the final criterion required for meeting the Complete Response (CR) standard. Certainly, "normal cellularity" ought to be an ideal worth achieving. And, when one thinks about it, "lymphocytes < 30%" sounds pretty logical, too - since the normal percentage of lymphocytes (compared to all of the white cells) in blood should typically be between perhaps 20% and 35% or so, then (assuming that the rates of production of each type of white cell in the marrow are all equal to each other) (which they're not, but let's let that detail "slide") a normal percentage of lymphocytes in the marrow might be as much as 30%.

Well, amongst my most recent bone marrow biopsy results, from 11/9/2012, the "cellularity" was reported, in highly technical terms (<grin>), as "OK". (Really.) Looking back at the BMB results from 9/28/2012, the "cellularity" was also reported as "OK". So, I guess one can safely assume that my bone marrow's cellularity is currently "OK" - <smile>. The results from 11/9 for "lymphocytes" was "3%", and, from earlier, on 9/28, as "12%". So, I guess one can then assume that my marrow lymphocytes have made up well under 30% for some time now. So, I guess I passed the final criterion "with flying colors".

Well, that just about completes this blog entry. I have (at least partially) explained about MRD, and I have demonstrated that I have achieved MRD status and have also ("more or less", but mostly "more") achieved CR status. However, I do have more to say about what MRD really means; and then there are still the "PR", "PD", "SD", and "PFS" initialisms to cover; and then there's the "three R's" of "Remission", "Relapse", and "Refractory", which will involve another "see-are" term, "Complete Remission" (which is ~not~ usually abbreviated as "CR"); and...

Well, I guess I still have some more blog entries yet to come then... (<smile>)

Categories: Leukemia