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Of Knuckles, and of Getting Beat Up

Posted by Frederick Wasti
Sep 30 2012

[ Me ]

I have had arthritis for quite a few years. Most serious, I would say, was the arthritis in my left hip that required having an artificial hip replacement in May of 2011. And I do have some arthritis in my right hip, too, which has been gradually getting worse over time as well. However, I have had arthritis in my fingers and toes for a longer period of time, and it is the arthritis specifically in my fingers that is prompting me to bring arthritis up in the context of CLL here.

It has been a normal part of my life for some time now (literally for decades) to have a few finger joints that hurt. (Although it is not unusual for the thumb joints to develop arthritis, I so far have been spared that affliction.) I used to take Ibuprofen (Advil) to help calm things down when needed, but (in order to minimize taking too many medications at once, as well as to minimize the burden on my liver and kidneys during chemotherapy) I stopped taking Ibuprofen when I started CLL treatment. As it turned out, even if I had intended to continue taking Ibuprofen during treatment, I would have had to stop doing so when I started injecting myself with the "blood thinner" Fondaparinux anyway, since also taking Ibuprofen, one of the non-steroidal anti-inflammatory drugs (a.k.a. NSAIDs) that also tend to slow down clotting, would then pose a more serious risk of bleeding.

So, during my CLL treatment I have mostly just been living with (and perhaps grumbling about) the arthritis pain in my fingers. However, over just the last few months it does seem as if the finger arthritis has been accelerating, and has lately become too much to so easily ignore.

[ DIP = Distalinterphalangeal, PIP = Proximalinterphalangeal, MCP = Metacarpophalangeal, CMC = Carpometacarpal ]

What is most unusual about this recent arthritis (apart from the rate at which it developed and the intensity of the pain) is that it seems to be concentrated in the same four joints (the DIP and PIP joints) on the same two fingers (the middle and ring fingers) of each hand - therefore, it is more or less symmetrical from hand to hand (although the joints on the right hand do hurt a bit more those than on the left). The problem is that many of the things that the hands are used for do involve bending and/or stressing these joints.

Wondering if part of my treatment has been responsible for exacerbating my arthritis symptoms, I brought the issue up at Dana-Farber a few weeks ago, and Dr. Fisher said that Ofatumumab might possibly be responsible. He did point out that Rituximab (a more commonly used CD20 monoclonal antibody) is known to occasionally aggravate (but not cause) arthritis, and, after all, the pre-medications I receive before receiving either Ofatumumab or Alemtuzumab are all intended to try to head off as much as possible the various "irritations" such as these that such drugs can present to the body.

(Interestingly, Rituximab and occasionally Ofatumumab are sometimes prescribed for people with rheumatoid arthritis, but the type of arthritis I have is the more common osteoarthritis, and the cause of and treatment for the two types of arthritis are different.)

So, what could I do to relieve at least some of my arthritis pain? Because of the Fondaparinux injections I cannot use Ibuprofen or any of the other NSAIDs because of the danger of bleeding. Instead, I can more safely use Acetaminophen (Tylenol), but my experience with it is that it helps with arthritis pain only a little bit, and it does nothing for inflammation in any event. Dr. Fisher suggested the possibility of using a drug called Tramadol (trade name Ultram), which he could prescribe for me, but it is basically "just" a narcotic painkiller, so I have declined trying it so far.

So, currently I have been taking slow-release "arthritis strength" Acetaminophen (650 mg tablets) three times a day (and, on the days when I go to D-F for Alemtuzumab injections, my first Acetaminophen tablet of the day is the one that is part of my pre-meds). Acetaminophen does make the pain in my finger joints a little less sharp, so it is better than not taking it.

[ Me, too ]

So, that's my story regarding "Knuckles". Now, about "Getting Beat Up", which actually is a separate story:

Back during Part A, the infusions of high-dose Methylprednisolone and Ofatumumab left me feeling a bit "beaten up" and/or "washed out" for the rest of each day of treatment. Also at that time, the pre-medication of Benadryl made me very sleepy for quite a while each during treatment day. However, during Part B, Alemtuzumab, the drug that I've had most often (i.e., three days each week), has had almost no side effects on most treatment days (although, after developing hives on the way into Boston one morning in the second week of Part B, I've been taking Benadryl, Zyrtec, and Acetaminophen every night since in order to keep such allergic side effects away). Furthermore, taking Benadryl no longer makes me behave like a zombie - its sleepy/tiring effect has seemed to diminish as, I guess, I've maybe gotten more used to taking it.

However, the lack of side effects from Alemtuzumab no longer seems to be the rule. For several treatment days now (for the last week and a half, I would say), when getting back home, I have been feeling not just a little tired from the Benadryl, but also a bit "beaten up" and/or "washed out" as well. The effect is hardly severe - it's mild enough (at least so far) that it's really more of a surprise than a nuisance, but I suppose it's possible that it still might become more pronounced. On Friday I asked Dr. Fisher about it, and he said it's not unusual that a cumulative side effects of taking such a drug might increase over time. I guess it is reassuring to know that this recent change I've been experiencing is probably "normal", but it's also a little disappointing, especially where I had gotten used to Alemtuzumab causing almost no side effects each treatment day previously. Oh well...

My blood tests, meanwhile, continue to be "boring". The usual two graphs I have been using lately...

...continue to show that the total white cell count and the individual percentages of lymphocytes and neutrophils have each changed very little since the lymphocyte and neutrophil percentages changed so dramatically (forming nearly vertical lines on the graph) early in Part B. Furthermore, the total white count has been in the "normal" range for some time now, while the percentages of lymphocytes and neutrophils, while certainly far from "normal", are still quite favorable for the purpose of fighting ~lymphocytic~ leukemia.

But, as I've stated before, blood counts obtained from peripheral blood (i.e., the blood circulating in the systemic arteries and veins) is just looking at "the tip of the iceberg", since there can be much going on in the spleen, in the lymph nodes, and certainly in the marrow, that cannot be judged directly from peripheral blood, and, furthermore, such blood counts say nothing about what proportion of my lymphocytes happen to be leukemic ones. However, that's just where CT scans and bone marrow biopsies come in, and it just so happens that I did have a "cat scan" and a BMB routinely performed this past Friday (since it was then just halfway through Part B). I should have the CT scan results back early this coming week, although the full BMB results (especially the cytogenetics portion of the results) won't be available until sometime the following week. I am anxiously - but optimistically - looking forward to seeing all of the data from last Friday's testing, to be sure.

Categories: Leukemia

More of the Same...or Not

Posted by Frederick Wasti
Sep 11 2012

I continue to keep "plugging along" in Part B of my Dana-Farber clinical trial. On the first day of each 28-day cycle I receive an infusion of Ofatumumab (an "old friend" from Part A) and an injection of Alemtuzumab (new for Part B). On all the other days I receive just a "simple" Alemtuzumab injection. (Of course, every day's drugs are preceded by multiple pre-medications.) For Part B, we head into Boston and back three days every week, each Monday, Wednesday, and Friday (although last week, because of the Labor Day holiday on Monday, we made the trip on a Tuesday-Thursday-Saturday schedule).

Although my blood was drawn and tested every day we were at D-F during the first month of Part B, the blood is now (and for the rest of Part B) tested only on Mondays. However, after some rather drastic changes in my white blood cells at the very beginning of Part B, blood tests over the last several weeks have been pretty "boring". But it has not always been so:

Taking a look at how the percentages of my lymphocytes and neutrophils have changed during the clinical trial...

...shows that Part A (the area to the left of the vertical green line) caused the percentage of lymphocytes (the red line) to gradually but definitely decline while the percentage of neutrophils (the blue line) correspondingly increased. The same graph also shows that, in Part B (beginning with that green line, which represents July 9th, the first day of Part B), the slopes immediately and dramatically changed, until very quickly the lymphocytes approached zero and the neutrophils reached the upper nineties, whereupon the curves did then more or less level off. However, it is just that leveling off that has caused all of the recent blood tests to all seem, well, "boring".

Similarly, taking a look at changes in the total leukocyte count during the trial...

...shows that the total white cells count went from the upper fifties (in thousands of cells per microliter) down to about 5 or so (which is actually within the normal range) during Part A, and then the count has stayed there (more or less) throughout Part B.

However, in regard to being "bored" by all of the recent weekly blood test results, I do want to point out the following:

1. These blood test results may seem to be "boring", but they are also extremely gratifying, in that my lymphocytes have been ~greatly~ reduced (both the bad ones and, unfortunately, the good ones, too), while the all-important neutrophils have been allowed to rebound to normal numbers, and the total number of white blood cells has become quite normal (maybe even "low normal"). If anyone had told me that, after the four months of Part A and just a week or two of Part B, my white cell count would be normal, that my neutrophil count would be normal, and that my lymphocytes (including, of course, the leukemic lymphocytes) would be reduced to only 1% or 2% of my total while cell count, I would not have believed it - but that is just what has happened. (Amazing!)

2. It is well worth remembering that, at this point, since the above graphs illustrate all ~good~ news, ~any~ significant changes in the graphs would likely be ~bad~ changes, so, in that context, "boring" is certainly a ~good~ sign - <grin>.

3. These blood test results cannot show just what is going on with the proportions of the good (i.e., the normal, non-leukemic) lymphocytes and the bad (i.e., the cancerous) lymphocytes. In a sense, blood tests are really only looking at the tip of the proverbial iceberg. However, I am scheduled to have a bone marrow biopsy (which can provide information on what is going on with the lymphocytes and their production in my bone marrow) and a CT scan (which can provide information on the size of my spleen and lymph nodes, the "favorite hiding places" of leukemic lymphocytes) in just a few weeks (at the half-way point of Part B).

So, while the weekly blood test results may offer "more of the same" on Monday after Monday right now, hopefully whatever else might be going on within my circulatory and lymphatic systems, which cannot easily be detected by simple blood tests, but which might be observed in the upcoming CT scan and BMB, will all turn out to be positive. (After all, why go through the rest of Part B if nothing else further were going on, right?) Please stay tuned...

Categories: Leukemia

How Monoclonal Antibodies Work

Posted by Frederick Wasti
Sep 02 2012

In Part A of my Dana-Farber clinical trial, I had frequent (weekly) infusions of Ofatumumab, a monoclonal antibody. In Part B, I have very frequent (three times each week) injections of Alemtuzumab (also a monoclonal antibody), along with occasional (once a month) infusions of Ofatumumab. And, in Part C, I will again receive, although less frequently, both Alemtuzumab (twice a month) and Ofatumumab (once a month). So, it is clear that these two monoclonal antibodies are both important components in my treatment for CLL.

But, just what are monoclonal antibodies, and how do they work? And, perhaps more importantly, how are they different from the "usual" chemotherapy drugs? I'll try to cover the "what is a monoclonal antibody?" question in a future post, but I'd like to try to start answering both the "how does a monoclonal antibody work?" and "how is a monoclonal antibody different from the 'usual' chemotherapy drugs?" questions right here.

First, please keep in mind that "regular" chemotherapy drugs are very non-specific. In general, chemo drugs are designed to work on all rapidly dividing cells, and cancer cells are indeed rapidly dividing cells, so admittedly that does seem to make some sense. However, there are many other cells in the body that divide rapidly, too, such as skin cells and the cells that line the digestive tract, and they (as well as certain other sensitive cells) are also affected by "regular" chemo drugs. (As an example of this, hair loss due to chemotherapy is quite common, as we all know, and is due to actively dividing hair follicle cells in the skin being adversely affected by "typical" chemo drugs.)

Furthermore, many chemo drugs work their "magic" by interfering with DNA and/or RNA in actively dividing cells, and such "magic" can result in significant unintentional genetic side effects, even including triggering additional future cancers. (Of course, when someone is suffering from cancer, to fight it with a drug that might cause another cancer sometime in the future, in order to hopefully stop the current cancer in its tracks, is generally considered a fair trade-off.)

[I have previously covered some aspects of drug specificity and non-specific collateral damage (please see "Dr. Ehrlich's Magic Bullet" from 5/12/12 and "The Father of Non-Chemotherapy" from 5/22/12).]

However, monoclonal antibodies are, in comparison, very specific. They are still not quite perfect drugs (medical science is still searching for elusive perfect "magic bullets" for many, many diseases), but they do tend to target just certain cells having certain specific characteristics, and (ideally) have little or no effect on at least most other cells of the body. So, let's take a look at how monoclonal antibodies can be used to selectively kill lymphocytes as an entirely relevant example of this technology:

Lymphocytes, under a typical light microscope, appear to be more-or-less round cells having smooth surfaces. However, those apparent smooth surfaces are actually pretty "fuzzy", and much of that "fuzz" is due to the presence of large molecules either arising from or protruding through a lymphocyte's cell membrane. Scientists have determined which particular molecules are found on the surface of lymphocytes (and on other types of cells), and have named (or numbered) these molecules with numerical "CD" names. ("CD" stands for "cluster of differentiation".) Take a look at the schematic diagram of a B-lymphocyte below:

As you can see, a B-lymphocyte (the type of lymphocyte involved in CLL) has several types of CD molecules on its surface. Now, as it turns out, if you have a monoclonal antibody that can recognize and attach itself to, say, CD20 molecules, such attachments could easily interfere with the proper functioning of lymphocytes, either by interfering with cell signaling (as cells do normally "communicate" with each other biochemically), or by bringing about cell death either directly (by triggering the process of apoptosis, a.k.a. "programmed cell death") or indirectly (by otherwise simply interfering with important physiological processes, or by causing other cells to kill such "marked" lymphocytes).

Now, if you glazed over reading the above paragraph (as I did when I was proofreading it - <grin>), the important point to remember is this: If a monoclonal antibody attaches itself to one of a lymphocyte's many surface proteins, doing so will likely hurt or even kill the lymphocyte.

One of the advantages of using Ofatumumab for treating CLL (which involves only B-lymphocytes) is that Ofatumumab attaches itself only to CD20 molecules, and, since CD20 molecules are found only on B-lymphocytes, then only B-lymphocytes are killed when this attachment takes place. (Unfortunately, leukemic and healthy B-lymphocytes both have CD20 molecules, so it is obvious that using Ofatumumab does involve some collateral damage.)

While I do not have a video to share that shows how Ofatumumab kills B-lymphocytes by attaching to their CD20 molecules, I do have a link to a video showing how a similar monoclonal antibody called Rituximab (trade name Rituxan) does so - please click on the image below to view the video (in a separate browser window):

A couple of points related to this video:

1. Notice that it is not clear which of the three illustrated cell death mechanisms is/are actually at work once the monoclonal antibody attaches itself to the CD20 molecule. It could be any one of the three mechanisms, or maybe a combination of them, or perhaps it's something else not even known of yet. However, the bottom line is that the lymphocyte is killed, and that is the important thing in CLL.

2. Although the video happens to feature Rituximab (since it was produced by Rituxan's manufacturer, after all - <grin>), the monoclonal antibodies I am taking (Ofatumumab and Alemtuzumab) do act similarly. The biggest difference is that, while Ofatumumab also attaches to CD20 molecules, Alemtuzumab instead attaches to CD52 molecules, which are found on both B-lymphocytes and T-lymphocytes, so that, even though Alemtuzumab may be even more potent at destroying B-lymphocytes than Ofatumumab or Rituximab, the collateral damage from using Alemtuzumab is unfortunately also significantly greater.

Nowadays, the use of monoclonal antibodies for combating cancers, as opposed to the use of "regular" chemo drugs, is increasing. Of course, because different types of cancers involve different types of cells, and because each type of cell can have distinctive surface molecules, different monoclonal antibodies have to be used to attack different types of cancer cells, as illustrated in the image below:

Well, I hope I have provided here at least an introduction to how monoclonal antibodies work and to how they are fundamentally different from the "usual" chemotherapy drugs. As someone who is trying to avoid "regular" chemotherapy, I do have to say that I am certainly grateful for the development of such wonderful technology.

Categories: Leukemia