An update

Two months after the cessation of hostilities (against my CLL cells and with collateral damage to my gut), I seem to be doing about the same, which is feeling pretty good. I am back to work full-time (although I really only took two days off a week while doing the treatment), and cleaning up loose ends. It is a task made more difficult with having supervisors who are much more focussed on their own situation, ensuring that work flow continues unabated by anything foolish such as illness. And by supervisors who cannot let work go out, but are intent on sending work back again and again until it is not only polished, but fairly sparkles. And that is for the most routine of tasks, such as letters to incarcerated folks looking for someone to talk to (men get this task, for we have had a number of cases where these men, who are so hungry for interaction with women, that they become letter-writing pests).

On the other hand, my CLL continues to inhabit my body. I did not expect a complete remission from flavopiridol (Alvocidib). Virtually no one gets one; I think only one person in the entire history of clinical trials using the agent has achieved even a complete remission, let alone a molecular one. So it's a partial remission I've received. And that's just fine. With a response rate of only 50%, it's fortunate that I responded at all.

One excellent feature of flavopiridol is that when relapse comes (an average of 12 months over-all, and 9.4 months for 11q del folks such as myself), the regime almost always works just as effectively the second time around.

This leads me to conclude that perhaps our two-faced friend might be used effectively as a maintenance drug. I like to think of one dose a month being enough to keep CLL at bay for a long period of time. But no one is testing that treatment regime, which I think is unfortunate. Really, really unfortunate.

And my partial response may not be a terribly solid one. My counts improved nicely over the last two months, and my hemoglobin and platelet counts are near-normal. For that, I thank God.

On the other hand, my white count, after improving each week, has now tanked for whatever reason. I've not needed a Neulasta shot for the two months, but I am now skirting along near the magic 500 number. If my neutrophils drop below 500, I will have to get a shot. Not good.

What could be causing this? The worst possibility is that the idiotic decision I made two years ago to take FCR has ruined my marrow, and given me myelodysplastic syndrome (MDS) a terrible new chromosomal insult resulting from the combination of fludarabine and cyclophosphamide.

MDS is becoming more and more common, as a result of chemotherapy such as FCR. MDS is where CLL was 15 years ago; few treatments available, and none of them effective at all. Survival estimates range from a few months to a few years.

Funny MD Anderson never warns you of the possibility of a fatal complication from using their beloved FCR. It may be unfair, but it seems that certain docs there love FCR, dole it out like candy, and just brush away concerns from patients like so much dirt under a rug. Gotta push the drugs!

MDS usually appears as anemia, and then progresses to take out all lines of the myeloid precursors, resulting in neutropenia (what I have) and thrombocytopenia, in addition to anemia.

I didn't get more than four months remission from the FCR. Definitely not worth the potential price.

There are other possibilities to be considered with neutropenia after FCR. One could be acute myeloid leukemia, a very nasty leukemia (especially in folks who acquire it secondarily to chemotherapy), or something called chronic myelomonocytic leukemia (CMML). Or perhaps aplastic anemia (AA). (The NIH says of the latter, "Secondary aplastic anemia may be an unavoidable consequence of treatments such as chemotherapy.) Nice. Only in CLL it is now not necessary to have chemotherapy.

Or it could just be a benign problem. Some people never recover neutrophils after FCR. Meaning that they stay on growth factors such as Neulasta for as long as they a-last-a (sorry). That is a remote possibility, but it is a possibility.

I had a bone marrow biopsy (my 15th, for those keeping track). Dr. Kipps is worried enough about MDS that he is running a special test looking for tell-tale signs of the disease. He wasn't particularly worried about it before, since it turns out that flavopiridol can lower neutrophil counts (which I didn't think happened).

So, as usual with CLL, I just have to wait for the results. I am praying for the best, hoping for the best, preparing for the worst.

What a penalty for making the mistake of using the FCR candy. Death. Not good. When will MD Anderson learn that there are much better options than that? Ever? They developed it, I guess, so they want to use it, over and over again. I guess it's the 'invented here' mindset.

Neutropenia

Since my unfortunate decision to undergo FCR (fludarabine, cyclophosphamide and rituximab), my neutrophil count has hit rock bottom, and pretty much stayed there. In fact, the low white blood count was the reason I only did four of the normal six cycles.

The neutropenia improved since January 2009, which coincided with the end of the four-cycle treatment. In the spring of 2009, I was on neupogen or neulasta for several months, with the low point being reached when my absolute neutrophil count plummeted to 106, well below the dangerous level of 500.

I did not need neutrophil support in the late spring, summer, and fall of 2009. However, beginning in late November, my neutrophils have dropped to dangerous levels again.

My counts are buoyed by the colony support factors neupogen/neulasta, with each course lasting 2-4 weeks. However, it may be that I am now neupogen/neulasta dependent, which is dangerous. Dangerous because artificially stimulating the production of neutrophils can lead to myelodysplastic dysplastic syndrome (MDS) or even the aggressive leukemia acute myelogenous leukemia (AML).

I'm hoping and praying that this does not happen.

Other than boosting my level of exercise, I know of no way to increase the production of the stem cells that were damaged by FCR.

That is one reason I have soured on the idea of using FCR. A well-known (though I had not heard of it prior to researching marrow failure) side effect of fludarabine in combination is secondary MDS, more difficult to treat than de novo MDS.

Live and learn. Though the learning might be easier than the living, if things go against me.

Even without MDS, I am perpetually at higher risk for infection being frequently neutropenic.

Not a happy place to be in.

OTOH, the flavopiridol/Alvocidib is still apparently working, though the side effects associated with the drug has not. I am scheduled for the last treatment in this fifth cycle on Wednesday, February 3.

Vitamin Might Help Boost Neutrophil Counts

Anybody seen this one? This is an interesting idea. I tried reading the abstract of the paper itself and I must say I would not have drawn this conclusion, but I didn't read the full paper, so...

Niacinamide is a form of vitamin B3, and is generally found to be safe even in relatively high doses. Caution is called for, though. It's a good idea to check with the doc regarding the use of this or any other supplement. Also, the increase in counts is temporary (darn!). It may help us be safer from infections, though.

I hope there are more studies in this area. Neutropenia is a serious problem that (obviously) can kill.

The doses cited in the paper work out to between 750-1500 mg for a 165 pound man. The RDA is only 16 mg, so this qualifies as more medicine than supplementation. Also, niacin, the other common form of vitamin B3, has been linked to the growth of new blood vessels in the tumor. Tumors can't grow past a certain point without vascular support. This is true even in CLL, since lymph nodes need new blood vessels to grow, and increase microvascularization in the marrow has been linke to CLL progression.

Any comments?

**************
Vitamin B3 Fuels Neutrophil Production 2/23/2009

As the first line of defense against invading microbes, neutrophils
are the “foot soldiers” of the innate immune system. Upon release
from the bone marrow, neutrophils circulate in the blood for only a
few hours before homing to peripheral tissues where they survive at
most for 2 or 3 days. To keep up with the heavy demand for these
short-lived cells, a normal healthy adult produces approximately 10 to the 11th power
neutrophils each day and up to 10 times that number in the setting of
acute infection.

Cancer patients undergoing chemotherapy often experience disruptions
in neutrophil homeostasis, which places them at increased risk for
infection. The ability to boost neutrophil production with
recombinant granulocyte colony stimulating factor (G-CSF) has
revolutionized care for patients with chemotherapy-induced febrile (fever)
neutropenia. However, the molecular mechanism by which G-CSF induces
myeloid differentiation remains poorly understood.

A team of researchers at Hannover Medical School in Germany recently
reported a major breakthrough in neutrophil development that may have
important clinical implications. Upon binding to its receptor on the
surface of myeloid progenitor cells, G-CSF turns on an enzyme that
converts intracellular vitamin B3 (nicotinamide) into an activate
metabolite (nicotinamide monocleotide). The researchers found that
this is the rate-limiting step in a signal transduction pathway that
triggers granulopoiesis.

Addition of vitamin B3 or its precursor induced granulocyte
differentiation of cultured hematopoietic stem cells. Administration
of high doses (10-20mg/kg/day) of vitamin B3 to six healthy
individuals resulted in significant increases in neutrophil count over
a 7 day period and a return to physiological cell counts when vitamin
B3 was withdrawn.

These findings identify a new role for vitamin B3 in granulopoiesis
and beg for clinical trials to evaluate the use of vitamin B3 either
alone or in combination with G-CSF for the treatment of neutropenia.

Source

Skokowa J, Lan D, Thakur BK, et al. NAMPT is essential for the
G-CSF-induced myeloid differentiation via a NAD+-sirtuin-1-dependent
pathway. Nat Med. 2009;15(2):151-158.

Going on from here

Since my counts haven't recovered, we've stopped pretending that I'm going to get my fifth and sixth cycle of FCR. It has been rather stupid the way the infusion center has been handling it; I've gone in three straight weeks, been hooked up to the IV line, and then they draw blood, find out my counts are too low, then they apologize all over the past and are sad my counts are horribly low, etc., then I change plans and go into work. I should have gone in the day before, had a blood draw, then they could have called me

I go to the infusion center prepared with a giant bottle of Gatorade (2 liter), partially frozen to stay cool all day, a few of my 'Issac Asimov's Science Fiction Magazine', which I have been buying in bulk from e-bay. It's a lot cheaper than to buy the latest versions, so I save money. It's also interesting to read a magazine from the 1980s, when Reagan was still president, Islamic terror attacks weren't a problem, gas was $1.25 a gallon, when Asimov was alive, when I didn't have cancer....

The stories are timeless, though. There are some topical references of course (computers weren't as ubiquitious in the 80s, there was no internet, 'green' meant what you ate for dinner, and so on). But by and large, the stories remain quite readable and enjoyable. Asimov's is one of the primary place for future award-winning stories and authors to appear. Some are clunkers, of course, but many are enjoyable and a few outstanding.

It makes the time go by quickly and pleasantly. Sometimes my wife sneaks a treat into my backpack. This time, it was M&Ms. Thanks, Sweetie!

Getting back to the CLL... I see the local onc doc (who I guess is a hematologist, but who sees, obviously, few CLL patients) on Monday. We will discuss what to do from here. My guess is...nothing. I suppose we will track my counts for the next months, pray I don't get sick, and just soldier on until the inevitable happens.

My counts are truly terrible. My neutrophils were only 0.5 on February 2, 0.9 on the 9th, and back down to 0.6 on Wednesday the 20th. My platelets have never recovered either, but truth be told, my platelets haven't broken 100 since about 2006, when I had the high-dose methylprednisolone plus rituximab. (I was looking at some old test results I've kept, and my platelets shot up to something like 876 for one test, before settling back down to the low 100s, and then declining from there. Currently, they are in the low 70s. Everyone else besides the onc doc freaks at those numbers.

Oddly, my hemaglobin has remained decent. Below normal (what else is new) but decent. As I remember they are about 12.5 or so. Certainly no difficulties at this point in time with that.

My abdominal nodes are still there. I don't think they've changed one bit during the FCR. My other nodes have largely disappeared, which is nice. I HATE having nodes. I hate it. It's an ever-present reminder of my disease. I acquired the 11q deletion after the HDMP+R trial I as on in mid-2006. Not a pleasant thing to have. The abdominal nodes can be quite painful at times.

I have been tired, but that's something we CLLers always face. I have been trying to do a bit more exercise, since that is important for over-all health and can't hurt as I try to get my marrow to recover.

I see the CLL expert in San Diego in late March. I was supposed to have finished the six cycles by then, but obviously that's not going to happen. I want to ask about maintenance therapy. Many papers have suggested that rituximab, Campath, or Revlimid can be used to help prolong complete and partial remission. Sometimes, maintenance can even push a partial remission into a complete one. I'm not a candidate for Campath with my 'massive' abdominal nodes, and Rituxan would probably be nixed for that as well. Revlimid may be a possiblity, and since they've lowered the dose to 1/10 what they started out with, side effects have declined and tolerability has improved. This is my preference as of now.

I also am scheduled for a bone marrow biopsy in San Diego. I will pray that it comes out improved, or at least not gotten worse. It's going to be a stressful time, not only psychologically, but physically since the biopsies have gotten more and more painful as time has gone on. I hope I can get some pain medication this time!