Stable, so far

Two plus months from my last FCR cycle, my marrow is damaged, but I am doing OK in spite of that. I've managed to avoid infections (knock on wood) and am working and carrying on a relatively normal existence.

I still have low platelets, low WBC, am neutropenic, but as of the results of the last blood test I've seen shows, the hemaglobin has come back and is now in the 12.5 range, which is a lot better than the 7.9 range I was in last fall.

I see Dr. Kipps later this month. I'll have a BMB and get his usual thorough exam. I know I have not had a molecular remission, nor a complete remission, since I still have enlarged nodes. We will see what kind of partial remission I'm in.

One unfortunate note is that we are dealing with a sick dog. He has been diagnosed with hemangiosarcoma, which is a cancer of the blood vessel cells. He has a massive spleen that could rupture with fatal results at any time. We've been offered surgery with the hope he may live another few months, but since he is 16, has an undetermined secondary mass in his stomach, we probably won't put our old guy through that.

Spring has come early again to Sacramento, with the fruit trees blossoming with all vigor.

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.

It's Official...I'm off FCR

I met with the local onc doc at UC Davis, and she told me there was no point in continuing to wait while my marrow struggled to make neutrophils. They have just not recovered from the fourth cycle in January.

She said she would schedule an MRI to check the abdomen. However, I know the nodes never were significantly reduced by the FCR, though I did have a response even there. Just not enough.

My response in the blood/marrow was good, I guess, though I have been mired in neutropenia land for almost two months.

Knock on wood and prayers...I have not been sick with an infection, though every tiny cut gets infected and it takes forever to resolve them. I have been dealing with gastric problems for years, and that has not improved either.

I also with have a bone marrow biopsy next month with Kipps. I will see how terrible my marrow is.

After a nice eight-year really non-eventful life with intermediate risk CLL, my cancer has not been kind to me at all.

On the positive side, the number of trials for CLL continues to increase, and there are a number of theories out there that sound really promising. I just don't know if I'll be around to get to try any of them...

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!

FCR Ain't a Happening Trip Right Now

I'm out of the FCR treatment now because of low counts. This is a problem for many, since fludarabine can damage the marrow. Many people don't get beyond the fourth cycle, the local onc doc says.

As memory recalls a year ago, one famous CLL doc at MD Anderson told me when I got a second opinion, 'younger' patients such as myself (now 58) don't have as rough of a time as older patients do, and I should have no problem completing the full six cycles.

I have had two different courses of therapy before, so that might account for the difficulties I'm having now.

I am going back yet again next week to see if my counts have recovered enough to have the next two cycles, but to be honest, I'm losing interest in FCR.

The problems with fludarabine are legion, and eventually they will sell the drug to clean out wheel bearings only. It's way too hard on the marrow, it is so immunosuppressive that they have to irradiate the blood they give you, for fear that the few stem cells you'd ordinarily (or potentially) get in a transfusion would start re-populating your bone marrow, giving you a bad case of mis-matched transfusion leading to all sorts of problems. That's why, though, it is a good drug to give prior to a stem cell transplant.

The various docs who have opined that FCR could cure CLL are, of course, wrong. When one looks at a survival chart, there is no plateau, no levelling off of the death spiral for CLL patients.

We must look elsewhere for potentially curative regimes. FCR ain't it

I did not get in to the lumiliximab trial after all. They have enrolled only one person at UC Davis. I developed a cold or upper respiratory infection and I was booted out of the trial.

However, my CLL has gone into overdrive, with a projected doubling time of only three months. Therefore, I was offered standard FCR or rituximab plus revlimid. I was really hoping for a second enrollment in the ISF 35/Memgen trial at UC San Diego under Dr. Castro, but there has been a long delay. It is just now enrolling.

(The thing they are most excited about are the 17p del CLL patients. The results so far have been promising, and the theory that a few cycles of Memgen followed by FCR might result in decent remissions for this hard-to-treat population.)

So I'm disappointed that I didn't get into a trial, but I'm more disappointed that I did not have the option of going on the ISF-35, multiple injection trial.

FCR+L Trial

A lot has happened since my last post. I've been trying to get into the FCR+L trial since May, and I finally am supposed to start on Sunday, September 22, 2008. (There is a wrinkle; I've just developed a cough, so I need to have that checked out before I start the trial).

I was notified on Thursday that I have been randomized to be in the arm of the trial that includes the lumiliximab. Lumiliximab is a CD-23 antibody. It works in a fashion like rituximab, but the CD-23 marker isn't as good of a target.

The difference is that the CD-20 marker is a transmembrane protein; it pokes part of itself outside of the lymphocyte, and keeps the 'tail end' inside of the cell, in the cytoplasm I would assume. The way these markers work is they are the 'eyes and ears' of the cell, sensory organs if you will. The marker detects a signal outside of the cell in the microenvironment, and then signals inside of the cell.

Being a transmembrane molecule, the CD-2o marker is a robust one, hanging on the the cell (in large numbers, in the thousands), resisting falling off and becoming useless. The CD-23 marker, unlike the CD-20, is much more easily dislodged from the cell, and a detectable fraction of the markers are found in the microenvironment. This makes the CD-23 marker less effective at killing CLL cells.

The hope the company who is pushing this MoAB through clinical trials is that it will enhance standard therapies. Small studies have suggested that this is true; the complete remission rate with FCR+L is higher than plain old FCR.

I am scheduled to start the study this coming week at the University of California, Davis Medical Center. Although I've gotten all of my treatment so far from UC San Diego, I opted for UCD this time because the trial protocol they offered me allowed either MRIs or CT scans. Anyone who knows me knows that I dislike CT scans because of the amount of radiation, which raises the risk of secondary malignancies, a complication CLL patients are already at higher risk for.

The secondary reason is that I live in Sacramento, and this will mean not having to fly down to San Diego for follow-up visits and all six cycles, assuming I would get that far.

As far as my general health goes, I am fading, but not at a fast clip. My biggest problem is my anemia. I am in the 8.8 range at last test, and this is not normal. Even the government will pay for Epogen if the hemo rate is below 10.0, which I am.

My other numbers are terrible, but sort of holding steady. WBC at the 200,000 range, platelets (always a problem for me) at about 75, and the red blood counts, as I've mentioned, a continuing problem.

My latest test should be on my fax machine when I get home tonight, so I should know if I need a transfusion in the next day or two.

My biggest problem right now is this cough I can't get rid of. Dr. Hamblin believes I should wait before I start the trial, and I am inclined to agree with him.

I think I got this latest infection (I've been remarkably infection-free even with terrible numbers, until this year, and I've had three infections since January) from using a neti pot. This is a device that allows you to pour salt water from one nostril into the other, draining stuff and supposedly keeping you clean. However, I made the mistake of just using tap water, which is not sterile. I usually boil the water, but just forgot.

This cough has now settled into my chest. Well will see what happens.