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Decimation [Not One Step Back]

Posted by Frederick Wasti
May 31 2013

I have previously pointed out that, unlike with solid tumor cancers, a complete cure with most forms of leukemia is not a generally attainable possibility. And, even with solid tumors, the use of the word "cure" is not overly common, and the term "remission" is instead often applied, at least for a period of time, after an apparently successful set of treatments.

In achieving MRD status after five months of Part B in my Dana-Farber clinical trial, I would also have achieved a CR, which is a Complete Response to the experimental treatment protocol involved in the trial. However, would I be in "Remission" or not?

A remission could be defined as "the absence of disease activity in patients with a chronic illness". In a sense, that sounds about the same as what a Complete Response indicates. Now, I'm sort of new at having cancer treatment (leukemia treatment), so my knowledge of the differences between the terms may be a bit shaky, but, as I see it, here are the essential differences:

I believe that the term Complete Response can be applied at one instance of time, without necessarily implying that the Complete Response would last indefinitely. On the other hand, a Remission implies that the absence of disease has occurred over a period of time, and may (hopefully) continue for a longer period of time.

Furthermore, I believe that the term Remission can be applied in all cases of apparently successful cancer treatments, while the term Complete Response is more likely to be used in the experimental setting of a clinical trial.

[But, I could be wrong about the above two distinctions...]

There also happen to be specific types of remissions. In the case of many cancers, a patient can achieve a Complete Remission (which is not generally abbreviated as CR -- CR is usually reserved for Complete Response). A Complete Remission could be defined as "the absence of active disease, with no evidence of disease as indicated by imaging, such as CT and/or PET scans, and sometimes [especially in leukemia] by bone marrow biopsy". (There is a suggestion of long-term freedom from disease in the use of this term, but there are, of course, no guarantees.)

Especially for leukemia there is an additional type of remission (with an even more stringent requirement to achieve), and that is Molecular Remission, which could be defined as "a complete remission with no evidence of disease in the blood cells and/or bone marrow using sensitive chemical tests (such as PCR testing)". Note that a Molecular Remission is not only a specific type of remission, it is also a specific type of complete remission.

[By the way, "PCR" stands for "polymerase chain reaction", and I won't get into explaining it here, but, if you are interested in what it entails, you might check out the description of it on Wikipedia ( http://en.wikipedia.org/wiki/Polymerase_chain_reaction ) or in an online article titled "What The Heck is PCR?" ( http://people.ku.edu/~jbrown/pcr.html ).]

An attempt to prove a Molecular Remission is more likely to occur during (or at the end of) a clinical trial than in a "regular" leukemia treatment. Unlike in established protocols for treating leukemia, where demonstrating a "regular" Complete Remission is "good enough", in clinical trials it is necessary (or at least highly desirable) to prove that there are no detectable traces of disease, as part of "proving that the experiment was a success".

I would suggest that MRD status is akin to Molecular Remission status, except (I believe) that MRD status implies a chemically tested apparent absence of disease at one point in time, while (I believe) a Molecular Remission perhaps implies that the absence of disease might be durable.

[Remember, though, that, once again, I could be incorrect about the above distinction - Heck, not only am I "not a doctor", I don't even "play one on TV" - <grin>.]

It is too easy to dwell on what is ~not~ true about a Complete Remission and about a Complete Response - i.e., it is too easy to emphasize that neither necessarily represents a complete ~cure~. That is to say, the disease may end up "coming back" (because it really never actually left at all, but was merely greatly diminished to where it could not easily be detected). Instead, it could be positively emphasized that, while a complete ~cure~ may not actually have been achieved in a particular case, greatly lowering the population of disease cells (CLL lymphocytes in my case) to a very low number probably means at least a longer period of time may transpire before the disease does possibly end up returning.

However, despite the admonition I offered in the above paragraph, I would like to take a look here at just how many (or how few) CLL cells may still exist in my body (or, at least, at how many may have existed a few months ago when I achieved MRD status).

Remember that, at the current "state of the art", MRD status is reached when fewer than 0.01% of CLL cells exist in a population of white blood cells tested. That is to say that, at a detection sensitivity level of 0.01%, less than one in 10,000 white cells could be a CLL cell. But just how many cells does that actually represent? How many CLL cells might I still have in my body? Well, let's do some math and find out:

First, let's say that the average adult body contains about five or six liters of blood (males more towards six or a bit more, females more towards five or a bit less). Let's then say that I probably have six liters or a bit more in me, since I'm a "bit above average sized male" (<grin>), but let's just call it six liters for simplicity.

Then, let's take a look at how many white blood cells in total I might have in me. Ordinarily, white cells could normally make up as much as 9,000 to 10,000 or as few as 3,000 to 4,000 per microliter of blood. (The D-F blood test printouts give 3.8-9.2 x 1,000 cells per microliter of blood as the normal range.)

What's more important for the calculations here is just how many white blood cells do ~I~ have per microliter, and not what the average number would be. However, the good news is that most of my recent tests show that I typically have about 6,000 white cells per microliter, entirely within the normal range. And, I am pleased to say that my white cell counts have been within (or at least very close to) the normal range since last summer,...

and, furthermore, that this is something that had not been true for quite a few years...

(While, in the above historical graph, I have not labeled the start of the clinical trial, it must be pretty obvious as to just where on the graph that treatment did begin, right?)

So, back to the math: Since there are 1,000,000 microliters of blood in a liter of blood (since a microliter is one-millionth of a liter in quantity), and since I have perhaps about 6 liters of blood in my body, multiplying 6 liters times 1,000,000 microliters per liter would suggest that I have about 6,000,000 (six Million) microliters of blood in me.

Then, taking my recent estimated average of 6,000 white cells per microliter (and it did happen to be very close to that on Wednesday, at 5.9 thousands of WBC per microliter), and multiplying that by my total estimated blood volume of 6,000,000 microliters, would mean that I have roughly 36,000,000,000 (36 Billion) total white cells in my body.

[And, speaking of Wednesday's test results, I am very pleased to report that the results were all still ~boring~, which is to say that they still have not changed very much for several months now, which is certainly a case of "no (new) news is good news".]

Now, remember that the level of sensitivity of my MRD tests is 0.01% CLL cells per WBC, or one CLL cell for every 10,000 white cells. At that threshold, we would multiply the approximate 36,000,000,000 WBC in me times the threshold of 1 CLL cell per 10,000 WBC, which would mean that the sensitivity threshold level would represent that there could be 3,600,000 CLL cells, or 3 1/2 Million CLL cells, in my body.

However, as I pointed out previously, there were no CLL cells detected in me at that sensitivity level, so we really don't know just how many CLL cells I actually have. However, as I also pointed out previously, it seems as if Esoterix Genetic Laboratories of NYC, which performed each of my MRD tests, in order to display the ambiguous "less than 0.01%" quantity on a graph, used perhaps 0.005% for a data point - at least I will admit to using 0.005% for plotting "less than 0.01%" on my own version of the MRD results graph.

Well, ~if~ I did have 0.005% CLL cells in a sample of WBC at that time, that would mean that I had ~half~ the threshold number of CLL cells in my body. So, for 0.005%, I would have had 3,600,000 CLL cells divided by 2, or 1,800,000, or 1.8 Million CLL cells, in my body.

Now it's pretty obvious that 1.8 Million CLL cells is ~not~ zero CLL cells, IT'S A WHOLE LOT BETTER than the number of CLL cells that I must have had before treatment was started, when I had ~not~ six thousand WBC per microliter ~but~ almost sixty thousand, when lymphocytes made up ~not~ one or two percent of my WBC ~but~ about ninety percent, and when leukemic lymphocytes made up ~most~ of my lymphocytes. I guess my CLL cells have been ~DECIMATED~ during my treatment.

HOWEVER, when one is discussing the killing of disease cells, for example, the act of "decimation" is a good thing, right? (Well, it's maybe not so good from the point of view of the cells being killed, but, in CLL, it is the survival of the ~rest~ of the body cells, and ~not~ the survival of the CLL cells, that is most important - or, at least, that's what the rest of my body cells have "decided" - <grin>.)

The use of the word "decimation" often implies something negative, since, in typical modern usage of the word, it is generally intended to be almost synonymous with "annihilation" or "obliteration", words that certainly usually have a negative connotation. Modern usage is for the verb "annihilate" to mean "to destroy completely; to reduce to nonexistence", and for "obliterate" to mean "to do away with completely so as to leave no trace; to wipe out, rub off, or erase". Actually both of these words are more extreme than the modern usage of decimation -- the verb "decimate" now usually means "to inflict great destruction or damage on; to reduce markedly in amount", which doesn't sound quite as destructive as do the other two almost-synonyms, does it?

Nonetheless, I started thinking about the word "decimation" and how it has changed over time. A couple of millennia ago, back in the days of the Roman Republic and then in the Roman Empire, decimation did not mean what we now usually intend it to mean. [Of course, there actually was no English word "decimation" back then because there was no English language back then, but I am referring to the ~concept~ behind the word in Latin.]

Interestingly, the derivation of the word "decimate" is from the Latin word "decimus", meaning "tenth", which in turn is from "decem", meaning "ten", and the original use of the term "decimate" was to mean "to punish (often by killing) every tenth person". [The actual Latin word for "decimate" was "decimare", while the Latin for "decimation" was "decimatio", so it's pretty clear from whence both the Latin words and then eventually the English words ultimately arose.]

However, the original concept of decimation was actually a far cry from what we usually mean in modern English when we say "decimate" -- what we now intend to suggest is essentially the opposite, where we might now "decimate" by wiping out or destroying at least nine tenths or more of something, perhaps (and not intentionally) leaving a tenth or less surviving.

Apparently the first use of the concept of decimation stems from the practice in the ancient Roman Legions, where one tenth of a mutinous or cowardly legion might be ordered to be beaten to death by the other nine tenths. The unlucky tenth was "chosen" at random, so that, while all or perhaps only some members of a legion might have been guilty of some sort of poor behavior in the eyes of their leaders, "only" one tenth of a legion would actually receive the severe punishment of decimation.

However, because of the random uncertainty involved in deciding just who the victims would be, and because of the fact that the "lucky" nine tenths had to put their own comrades to death by stoning them or by beating them with clubs (which were certainly more "personal" ways to kill someone than the "modern" military method of impersonally shooting someone by firing squad, employing rifles fired from a short but "emotionally safe" distance away), ~all~ legionaries must have felt some punishment. Certainly it must have felt more traumatic to all-too-personally kill ones fellow soldiers, even for soldiers that were probably already hardened to easily kill enemy soldiers or slaves. In addition, clubbing or stoning was probably not the most humane way to die either (an understatement, to be sure), and it was probably not considered an "honorable" way to die from a soldier's point of view (nor was it intended to be, I suppose) - I would imagine that a legionary would rather die by the sword than by clubs or stones.

I do have my doubts about not only the unfairness but also the overall effectiveness of the use of such a harsh and arbitrary punishment -- I can see that such an intensely negative form of punishment might not always have had a positive effect on military performance, to say nothing of its effect on morale. [I am reminded of the joke (the humor of which depends upon an awareness - on the part of both the teller and the listener - of the ineffectiveness of arbitrary negative reinforcement on human behavior) of the pirate captain who warned his crew, "And the flogging will continue until morale improves".] Furthermore, it seems quite short-sighted militarily to "decimate" (in the original sense) ones own soldiers, reducing the strength of a legion by one tenth (although any leader who would have imposed such a punishment might have argued that he would rather command nine tenths of a legion of willing soldiers than a legion full of less than stalwart warriors).

In any event, despite its severity, and despite its notoriety even two thousand years later, the concept of decimation in the Roman Legions was apparently not frequently carried out (although I suppose that the threat would have been always present for legionaries to consider in the back of their minds). Of course, modern knowledge of ancient Roman military customs is quite sketchy, due both to the amount of history that has been lost to us, and to the embellishment and other distortion involved in what was recorded for people to read back then - and to read today, two millennia later in time. I should add that we have our own modern distortions to consider as well, since much of our collective knowledge of Roman history is gleaned from the reading of books (and "History is written by the victors"), and (especially for non-historians) learned from the viewing of popular movies about ancient Rome that are (quite intentionally) not always as factual as documentaries would be. ("Never let facts get in the way of a good story.")

In any event, the actual logistics involved in decimation, when applied to an entire legion, probably went something like this: Since a typical legion (commanded by a legate) would have several thousand men in it, it was probably impractical and rather unwieldy for the unfortunate one tenth to be selected and then executed en masse. A legion was generally composed of ten cohorts, and each cohort in turn was made up of several centuries (each of which, despite the name, was often composed of somewhat less than 100 men). For decimation, within each century (the leader of which was a centurion), the soldiers were divided up into groups of ten, and each group of ten had to draw lots, and the unfortunate loser of the lottery was then put to death by the other nine. (No, I don't know either what was done in the likely frequent event that the members of a century did not add up to an exact multiple of ten, but I'm sure that the centurion in each case would have dealt with such irregularities in some sort of arbitrary and capricious manner.)

As far as I know, it was thus exactly or approximately one-tenth of each century that would have been killed as a result of decimation. I have occasionally thought that it might have been simpler, since there were ten cohorts in a legion, to "simply" have a lottery to decide which cohort would be put to death by the other nine cohorts. However, besides the fact that this might have been logistically a bit awkward to carry out (especially so if the lottery-losing cohort decided to fight back against their impending punishment), I can also see that doing so would have lost "the personal touch", since the soldiers killing the unfortunate lottery losers would have been killing men that they probably felt less connected to -- rather than knowing them each by name, they probably would have known them only by the (Roman numeral) number of their cohort.

My hasty and simplistic idea also would have been awkward in a couple of other ways: First, the cohorts were generally arranged in numerical order, from Cohort I (made up of the best soldiers) to Cohort X (made up of probably the least experienced soldiers and/or soldiers lesser in some other way), and I can imagine that the legate would not likely be disposed to dispensing capital punishment to one of the more valuable cohorts. Then, although the cohorts in earlier Roman history were essentially equal in size to each other, sometime during the first century CE the first cohort in each legion was doubled in size, which would have made it quite problematic to kill any one cohort in its entirety, since none of the ten cohorts would then be made up of one tenth of the legion.

The historian Polybius provided the following description of decimation from the 3rd Century BCE, in the early days of the Roman Republic: "If ever these same things happen to occur among a large group of men, the officers reject the idea of bludgeoning or slaughtering all the men involved. Instead they find a solution for the situation which chooses by a lottery system sometimes five, sometimes eight, sometimes twenty of these men, always calculating the number in this group with reference to the whole unit of offenders so that this group forms one-tenth of all those guilty of cowardice. And these men who are chosen by lot are bludgeoned mercilessly."

Historically, it does seem that Marcus Licinius Crassus, a Roman general, and one of the three men, along with Julius Caesar and Pompey, who shared power in the First Triumvirate, during the First Century BCE, when Rome was in the process of transitioning from a republic led by the Senate to an empire ruled by an Emperor, did carry out decimation perhaps at least twice. [As an aside, I might mention that Crassus, due to successful large-scale real estate transactions and development, which were made extremely profitable by government policies that he had personally helped influence, became the richest man ever in Rome, and probably one of the richest men in all of history.]

During the two year period from 73 to 71 BCE, there was a serious slave revolt led by the slave Spartacus (and, yes, if you've seen any of the Spartacus movies or TV series and thought it was all fictional, well, there was indeed such an important man in Roman history). At first, the revolt was not too worrisome to the Senate in Rome, since it was confined to the southern parts of the Italian peninsula. However, as Spartacus and his slave army started advancing towards Rome, the Senate "enlisted" Crassus as a General, authorized to organize and equip an army (all of which he personally paid for) to march towards the forces of Spartacus to save the capital city of the Roman Republic.

Eventually Crassus and his army were victorious over Spartacus and his army, but victories did not come quickly at first. Once, during one of the earlier battles against the slave forces, when part of his army dropped its weapons and fled, Crassus resorted to invoking decimation on some of his army. While one in ten soldiers were killed by some of the others, the rest of his army was forced to watch what the historian Plutarch described as "many things horrible and dreadful to see". And, although I am still skeptical of the value of decimation in improving morale, historian Appian of Alexandria reported that the will to fight by the Roman soldiers against the slave revolt did greatly increase, since Crassus had proven that "he was more dangerous to them than the enemy".

At one other time, Crassus had ordered a large group of soldiers to circle around behind Spartacus' army, and to remain there (without attacking) until Crassus had first launched a frontal assault. However, the leaders of the group felt that they then were in a position that was just too good to not attack from, and disobeyed Crassus' orders to stay put. Crassus then imposed decimation upon the group and its leaders as punishment for disobedience.

As the battles started to fall in favor of the Romans (at least partially because reinforcements from other parts of the Roman territories had arrived to bolster the Crassus forces), things started to get desperate for the slaves. In one battle, when Spartacus furiously led a group of slaves towards Crassus, and got so close to him that two of the personal centurions guarding Crassus were killed, events finally started turning against Spartacus, and he ended up being killed, and 6,000 members of his slave army were taken captive by the Romans. Crassus had all of the 6,000 slaves crucified at intervals all along the Appian Way from Capua to Rome, a distance of perhaps 100 miles, and then, as a final warning to anyone else who might be considering insurrection against the might of Rome, he ordered that their bodies not be taken down when dead but be left to rot on the 6,000 crosses, as an example of just what can happen to the enemies of Rome (perhaps especially so if they happened to be rebellious slaves).

[By the way, the Appian Way (i.e., the Via Appia) was not named for historian Appian of Alexandria, but for Appius Claudius Caecus, who, early in the Roman Republic, built the first portion of this major Roman highway running "up and down" the Italian peninsula, as well as building the first aqueduct in Rome, not surprisingly named the Aqua Appia.]

During one scene from the 1964 film Fall of the Roman Empire, a group of cowardly soldiers were lined up along the edge of a bridge, and, using a seemingly less common means of decimating, an officer on horseback pushed every tenth man off the bridge.

Although there are historical records of a number of instances of decimation throughout ancient history, some are not universally accepted as being factual, or are now characterized as having been at least partially embellished.

One example of such a controversial account centers around Mauritius, the leader of the Theban Legion (named so for being garrisoned at Thebes in Egypt, which also happened to be where Mauritius was originally born). As the story (or legend) goes, in the 3rd Century CE, the legion (of 6,000-odd men - one account of it even claims that it included exactly 6,666 soldiers) was ordered by the Emperor Maximian to proceed to Gaul (now France) in order to aid another legion there. Along the way, at the town of Agaunum (in present-day Switzerland, and now known as the town of Saint Maurice-en-Valais) the Legion had been ordered by the Emperor to accomplish a task (and accounts have disagreed as to what the task actually entailed), and the Theban Legion (which, according to Christian versions of the events, was made of entirely of Christian soldiers and officers, including Mauritius) refused to obey. The Emperor then ordered that decimation be carried out, and it was, but the Legion still refused to carry out the order. In an extreme use of the concept of decimation, the Emperor then demanded that decimation be carried out repeatedly until the entire Theban Legion had been totally destroyed.

In recognition of the story/legend by the Christian Church, Mauritius (also now known as Maurice) and three other leaders were canonized as saints, and the Legion is now referred to as the "Martyrs of Agaunum". Maurice is still considered a saint in the Roman Catholic, Eastern Orthodox, and Coptic Christian churches. The famous town of St Moritz in Switzerland is named for Saint Maurice. [There is quite a good article about Maurice and the Theban Legion in Wikipedia ( http://en.wikipedia.org/wiki/Saint_Maurice ), if you'd to like to learn of all the various accounts of their exploits.]

[Interestingly, I think, is that a statue of Saint Maurice, the oldest surviving image of him, from the 13th Century CE, in the Cathedral of Saints Catherine and Maurice in the German city of Magdeburg, depicts him as a black African knight. And, having been born in Thebes, in Egypt, it is very possible that Maurice was indeed an ethnic black African. In any event, the statue is considered to be one of the oldest reasonably realistic depictions of a black African in European art.]

Decimation may have also been employed by the military in more "modern" times.

A general in World War I named Luigi Cadorna, famous (or notorious) for his seemingly rash and overly aggressive tactics, was in command during a half dozen Italian campaigns, all of which ended in disaster. The most serious defeat under his "leadership" occurred at one battle at the town of Kobarid in Slovenia in 1917, although, at an enquiry into the debacle after the war ended, Cadorna "claimed that he had no responsibility for the defeat, despite fleeing to Padua during the battle and abandoning the entire Italian Second Army to its fate". [I might mention here that it was the defeat at the Battle of Caporetto (as the town of Kobarid is known in Italian) that was described by Ernest Hemingway in "A Farewell to Arms".]

Cadorna apparently blamed everyone but himself for such failures, and Cadorna allegedly ordered decimation to be carried out on what he considered to be the most ineffective units, although such allegations are still controversial. Nonetheless, even if he did not actually order any such decimations, he did dismiss hundreds of officers for "their" failures, and some of them (the leaders of what he considered to be the most cowardly units) were apparently executed by his order. Furthermore, under his command, "one in every seventeen Italian soldiers faced a disciplinary charge in the war, and 61 per cent were found guilty. About 750 were executed, the highest number of any army in the war."

The movie Paths of Glory (1957) was a depiction of the true story of three French soldiers during World War I, who were executed for mutiny, which was by itself, not unusual, except that they were executed "in the spirit of decimation" (as I would characterize it). After a series of unsuccessful attempted attacks against the Germans, a frustrated General Paul Mireau blamed the failures of his tactics on the cowardice of his soldiers, and ordered that 100 soldiers be selected, to be tried, and, of course, to then be found guilty and executed for cowardice, although he was then talked into reducing the number down to three - one from each company of soldiers involved - by a General Georges Broulard.

In Paths of Glory, Kirk Douglas (who also starred as Spartacus in the film by that name) played (in what I feel was his best ever acting performance) one "Colonel Dax", who had led the futile French attacks in question (but only after protesting to his superiors about the suicide nature of what his men were to be ordered to do). Then, after General Mireau's three scapegoats had been selected, Colonel Dax (who was supposed to have been a lawyer before the war) volunteered to be the trio's counsel for the court marshal. Needless to say, the three men - two personally selected by their own company commanders for dubious reasons, and the third selected by lottery, but who ironically had previously been commended for bravery on two occasions - were all found "guilty", and they were executed by firing squad the next morning.

And then it was "And now back to our War, already in progress"...

[Interestingly (I think), Paths of Glory was not shown in France for quite some time after its release everywhere else. Apparently the French government put pressure on the film's distributor (United Artists) not to release the film in France, but eventually, after 18 years, it did end up being shown there in 1975.]

Antony Beevor, in his book Stalingrad, written about the history surrounding the fierce battle for the city during World War II, described one occasion where a Soviet commander carried out a form of decimation on a group of deserters, by first having the soldiers line up at attention in a single line, and then walking along the line and shooting every tenth man until he finally ran out of ammo for his pistol.

For just one more example of decimation from World War II (but I honestly don't know if it is totally fictional or is based on any actual history), we will turn to a new short film, aptly titled DECIMATION, that was shown for the first time at the Seattle International Film Festival just this past Monday evening (Memorial Day, May 27, 2013).

From the film's web site: "Set in 1942, Decimation finds 10 Russian soldiers who have been accused of cowardice on the Eastern Front and are being temporarily imprisoned. A Red Army General decides to utilize the ancient Roman punishment of decimation where 1 soldier is drawn at random and the other 9 serve as his executioner. The men are notified of their punishment at dusk and by dawn they will either meet their maker or be forced to take a friend's life before returning to the front line. The film chronicles the men’s last traumatic hours before the execution, revealing the horrors of war, their collective experiences, and their dreams for a normal post war life. (12 Angry Men meets All Quiet on the Western Front.)"

Now please allow me to digress just a bit more. (You've been very polite so far about my "modest" digressions -- at least I haven't heard anyone complaining so far, and, if you're still reading this far, you're obviously a very patient person - <grin>.)

In much of my discussion so far of ancient Rome and the practice of decimation, I have used a number of images for illustration. However, if you've ever paid much attention to still or film images of ancient Rome, you may have seen the letters "SPQR" prominently displayed, such as in the image below:

"SPQR" was not a Latin word, per se (although our expression "per se" is in fact made up of two Latin words). Rather, "SPQR" is an initialism. (It is not an acronym, of course, since it is pronounced in English by pronouncing its letters, as in "ess-pee-kyu-arr", and not as if it were a word itself.)

"SPQR" is an abbreviation for, in Latin, "Senatus PopulusQue Romanus", which translates most literally as "The Senate and the Roman People" or, alternatively, as "The Senate and the People of Rome".

Rome was founded circa 750 BCE, and at first was governed as a kingdom, but then, as it grew, it did transition into the Roman Republic, circa 509 BCE. The Republic was ruled by the Senate (theoretically representing all Roman citizens) and various other (usually) elected officials, such as Consuls, Praetors, Censors, and Tribunes. While Censors and Tribunes had their greatest authority within Rome, the Praetors and the Senate exerted much of their authority over and through the military out in the provinces. The Consuls generally had the greatest authority of all, both within Rome and without.

Obviously the Senate was an important branch of the Roman government, and the initials "SPQR" proclaimed its authority, and the authority of the Roman citizens, both in the Roman Republic, and later on in the Roman Empire.

It is difficult to say exactly when the transition from Republic to Empire - ruled by one (or sometimes two or three) almost absolute leaders as well as by the Senate - took place. A series of changes were ultimately involved, but I think the changes could be said to have taken place during the latter part of the 1st Century BCE, with the transition having been completed in 29 BCE with the supremacy of Octavian, who in 27 BCE accepted the title of "Augustus" or "Exalted One", given him by the Senate.

While the first few Emperors did not claim to be monarchs, and generally considered themselves to be leaders of a republic, over time the Roman Emperors consolidated power for themselves, which meant that less power was vested in the Senate, and in the populace through elected officials. Nonetheless, the initialism "SPQR", for "The Senate and the People of Rome", was still proudly displayed as the symbol for the Roman Empire.

I think it is interesting that, in modern Rome, "SPQR" can still be seen displayed, and not just in or on historical buildings or monuments.

First, I should point out that the coat of arms for the City of Rome (above) prominently features "SPQR", to which a cross has been added.

However, I should also point out that, to some modern Italians, "SPQR" actually stands for "Sono pazzi questi romani", which translates as "Those Romans are crazy".

In any event, "SPQR" does appear on many mundane objects of infrastructure in modern Rome, such as on rubbish barrels, ...

...and on manhole covers, ...

[And, by the way, that's the Roman Coliseum across the street in the image below.]

...and on water valve covers ...

However, while such displays of "SPQR" might bring a chuckle or two to the viewer, I would point out that Rome ~should~ rightly be proud of all of the many civil engineering advances that were developed in ancient times during the Republic and the Empire, and which still are so important to support life in the modern urban center that Rome now is.

Such pride in civil infrastructure can be seen in many other cities of Europe, of course, such as in Paris, ...

...and in London, ...

...and across the Atlantic in many American cities, ...

...and across the Pacific in New Zealand, ...

...and in Japan, ...

...where apparently some of the most artistic manhole covers can be found.

Here in Massachusetts, where Boston, the undisputed HUB of the (Entire) You-nah-verse is located, there are many examples of Boston Water Works manhole cuh-vahs and water valve cuh-vahs -

[However, I should point out that, since Boston is indeed the Hub of the (Entire) Universe, Boston area residents do ~not~ have an accent -- rather, it is the ~rest~ of the world that has accents.]

Some of these proud displays of modern urban infrastructure can be seen around many famous Boston landmarks, such as outside the Dana-Farber Cancer Institute, and that quickly brings me back to my CLL story. (Some seque, eh?) So, please allow me to digress from my previous digressions and maybe get back to the topic of DECIMATING leukemic lymphocytes, OK?

I have previously pointed out that, in the MRD graphs prepared by Esoterix Labs and by yours truly, there had been a bit of "fudging" employed in order to plot a data point for "less than 0.01%". (To properly plot "less than 0.01%" for any date would require, not a dot, but a line, located directly above that date on the horizontal axis, and which would start immediately below 0.01% and then run straight down vertically until it reached zero.) As you already know, Esoterix plotted a dot at, or in the neighborhood of, 0.005%, and I have already confessed to using 0.005% for my own dot.

However, considering that "less than 0.01%" on these MRD graphs is "unknown territory" (i.e., "terra incognita" in Latin - <grin>), why can't we suggest that it might be something other than 0.005%, such as, say, only 0.001%, eh? In other words, there is more than one possibility for what the bone marrow biopsy MRD tests' line might actually be like once it dips below 0.01%. How do these two possibilities look like in the following graph? Which would you prefer?

I don't know about you (well, yes, I actually do know a little bit about you, because you're willing to expend a lot of energy following this blog, and, since it's not likely for my scintillating prose, it must be out of concern for my little battle against CLL), but ~I~ like the sound of 0.001% better than 0.005% (and, of course, even more so than 0.00999999%, which would also qualify for "less than 0.01%").

Now, while 0.001% does sound good (since it represents even ~more~ DECIMATION than 0.005%), do I have any evidence to possibly support wishing for a CLL level of 0.001% (which could also be expressed as having only one CLL in any sample of ~100,000~ white cells)? Well, yes, I do. It's not evidence in the form of proof, exactly, but it still is a plausible possibility.

Let's try an experiment:

Let me make up an imaginary, hypothetical MRD graph for an imaginary CLL patient. Let's call him Johannus Q. Publicus (the "Q." is probably short for "Que"). Let's say that he is being treated for CLL. (Yes, "CLL" could also mean "200" in Roman Numerals, although "200" would probably be better expressed as "CC" -- however, we're talking about leukemia here, OK?) Then, let's just say that he has MRD tests performed approximately once a month for a few months of treatment. OK?

Now let's say that, on 7/10/12, Johannus had an MRD result of 10%. Then, a month later, on 8/9/12, he found that his MRD result had dropped to one tenth of that, down to 1%. And then, on 9/8/12, he found that it had done the same thing again, dropping once again to one tenth the previous value, all the way down to 0.1%. And, once again, on 10/8/12, he found that it had dropped to one tenth the previous result, and was then way, way down to 0.01%. And finally, in the test for 11/7/12, he found it had dropped once again to one tenth of what it had been before, and it then measured only 0.001% (just like for me - well, maybe - <g>).

OK, let's put the above data points on an MRD graph -- it would look like this:

Do you notice that, since his treatment "decimated" (more in the modern sense of the word) his CLL, cutting it to one tenth of its previous value each month, his MRD results end up forming a perfectly straight line? Yeah, I'm sure you did, right? Now, I want to point out that this is because the vertical axis on the graph is logarithmic, and not linear. (If the vertical axis were linear, the curve would not be straight, but would be, well, "curvy".)

Now the above straight line on a vertically logarithmic graph is ~very~ significant. You may remember from my last blog entry, when I pointed out that, on a logarithmic axis graph, "both very large and very small quantities can be easily shown on the same graph". That is one neat feature of such a graph. However, what we have just done here with our little experiment is to demonstrate that such a graph will also display a logarithmic death curve (or decay curve) as a straight line.

I should point out here that, if Johannus' numbers had dropped by the same amount each month (e.g., "10", to "8", to "6", to "4", to "2"), his numbers would have formed a straight line on a "regular" linear graph, but a "curvy" line on a logarithmic graph. However, in our little experiment, Johannus' numbers dropped in a ~logarithmic~ fashion - dropping by 9% (10% minus 1%) over the first month interval, by 0.9% (1.0% minus 0.1%) the for the second month, by 0.09% (0.10% minus 0.01%) for the third month, and by 0.009% (0.010% minus 0.001%) over the fourth one-month interval. Such results would be "curvy" on a linear graph, but would form a perfectly straight line on a logarithmic graph. However, let me just demonstrate how Johannus' logarithmic decay numbers would appear if we plotted them on a linear graph, just as a comparison:

Now let's, once again, look at his results plotted on a logarithmic graph:

Oh, WAIT !!! -- NO !!! -- that's not ~his~ graph, that actually could be ~my~ graph, where it is suggested that maybe my last "less than 0.01%" result could even be as low as 0.001%. Do you notice how such a graph forms (almost) a straight line? Well, the really, really, really ~BIG~ point I am trying to make here is that suggesting that my "less than 0.01%" result could really be 0.001% is ~not~ just a wild, hopeful wish -- it is approximately what would be ~expected~ if my CLL death curve followed a logarithmic decline all the way to the last MRD result (which is ~exactly~ what it was doing done previously, before it entered "terra incognita", right?). WOW!!!

Well, I know I "had to put a lot of chalk on the blackboard" to try to prove that such a wish is not only possible, but might even be (almost) probable. Nonetheless, it would be quite a likely occurrence ~IF~ my CLL cells have continued to die off at a logarithmic rate since 9/28. Now, is that interesting, or what? Well, ~I~ think it is. (<smile>)

Well, earlier in this blog post I demonstrated how to calculate just how many CLL cells I might still have in my body, both at the MRD sensitivity threshold of 0.01% and at a possible "less than 0.01%" level of 0.005%. Well, the question that now could be asked, now that I have shown that it is entirely realistic to suggest that my "less than 0.01%" level might actually be something like 0.001%, is this: Just how many CLL cells might there be in my body if my MRD level is actually 0.001%? Fortunately, since you and I have already slogged our way together through the basic calculation process already, all we have to do is make just one additional little calculation, as follows:

Since having an MRD level of 0.01% CLL cells per WBC means that I could have 3,600,000 CLL cells, or about 3 1/2 Million CLL cells, in my body, and since 0.001% is one tenth of 0.01%, then all we would now have to do would be to divide 3,600,000 by 10 (or, identically, multiply 3,600,000 by one tenth), which would give us an estimate of "only" 360,000 CLL cells in my body. [Or, alternatively, we could have used our previously estimated 0.005% MRD level, which would be five times 0.001%, which would allow us to divide 1.8 Million by five to get the same answer of 360 thousand CLL cells in my body.]

Well, admittedly that ~still~ sounds like a lot of CLL cells, but having a little more than one third of a Million CLL cells would definitely be better than having a little more than 3 1/2 Million CLL cells, right? And, as pointed out before, ~any~ of these MRD results would be hugely better than the Gazillion CLL cells I had in me before starting treatment.

~That~ is DECIMATION.

[And I don't ~ever~ want to take even one step back...]

Oh, just one final point for me to make: As I pointed out in my previous blog post, "note that there is actually no 'zero' on the vertical axis scale" (on a logarithmic graph axis). Well, this would be good news indeed for Johannus Q. Publicus, since there is no "zero" available in the set of Roman Numerals (but which there ~is~ in the Arabic Numerals that we use nowadays). So, if Johannus ever possibly were able to "decimate" his CLL cells all the way down to zero, he would never be able to label it as zero on his MRD graph, to which he would probably say (in Latin, of course) "Bummer!". Or, maybe not. [But I digress...]

  

Well, "That's All, Folks" (for now...)

Categories: General, Leukemia

Decimation [entry in progress]

Posted by Frederick Wasti
May 27 2013

I'm working on a blog entry "as we speak", but I've got "quite a ways to go" before it'll be online.

In the meantime, just a note on scheduling: Although today, Monday, May 27th, would normally be a "Dana-Farber Day" for us, because it's Memorial Day we will not be going this week until Wednesday the 29th. So, the (hopefully) usual "boring" lab results will not be posted until later in the week.

In the meantime, I'm working on a rather long story about "Decimation" - or maybe I'll end up calling it "Decimated". Or something... Please stay tuned.

Categories: Leukemia

Interim Report

Posted by Frederick Wasti
May 14 2013

Just a quick update -

Yesterday was a ~long~ day at Dana-Farber - it was an "Ofatumumab-infusion-as-well-as-the-usual-Alemtuzumab-injection" day (which fortunately now occurs only once every eight weeks - the other visits to D-F in between are for quick Alemtuzumab injections only).

The good news is ~boring~ news -- the blood tests still keep showing no significant changes from visit to visit in Part C. I guess ~boring~ can be a good thing, eh? :-)

Categories: Leukemia

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