Kinected

A lot has happened since my last post:

•        Christmas
•        New Years
•        Birthdays (Howard Recombinant DNA Experiment #1 turned 3, and my wife had a birthday too)
•        4 Rounds of Rituxan

The Rituxan treatments have gone well, although I've had to deal with several failed IV placements (including 3 blown veins).  The only significant change in my blood counts so far has been a dramatic increase in monocytes as shown below, but this has me very excited.  It's believed that monocytes may mediate the antibody-dependent cell-mediated cytotoxicity (ADCC) by Rituximab, and a cursory analysis of my counts leads me to believe this may be the case.  Specifically, my monocyte counts increased dramatically after both Rituxan treatments were initiated (see highlighted areas).

I believe this increase in monocytes is directly correlated to the administration of the Rituxan as they begin to kill the hairies through antibody attack (see picture below).  The monocytes increase in numbers as Rituxan (RTX) is introduced into the bloodstream and then they level off as they morph into phagocytes and ADCC is evoked.  As you can see in the highlighted areas above, the pattern for this cycle (RTX #2)  is similar to the first RTX treatment in 2009, but the initial level of monocytes is much higher.  Given that my spleen is now 40% of its prior volume (no longer infiltrated with hairies), and the monocyte level is 9 times higher than when I started RTX treatment #1, I think this round may have a much bigger impact in reducing the hairy cell burden in my marrow aspirate!  

Monocyte Mediated ADCC

Starting in week 5 of RTX treatment #1, my neutrophil level increased dramatically as the monocyte levels began to top off.  Hopefully, the same increase will occur over the next few weeks.  If so, I think the response correlation with RTX treatment #1 will be another strong indicator of monocyte mediated ADCC.  It may take awhile for it to complete the job, but fortunately Rituxan's half-life is two weeks, so it will remain in my bloodstream for months and during that time > 99% remains in the peripheral blood looking for B-cells and hairies to destroy, so it's readily available for quite awhile as the layers of the hairy clumps are peeled away.

Then again, since neutrophils are the first to attack (neutrophils are microphages, ie: small eaters), they may be pulled out of the peripheral blood stream to mediate Rituxan-induced complement-dependent cytoxicity (CDC) and attach to C3b proteins -- causing a drop in their blood levels.  Perhaps the monocytes are being released into my blood stream in response to the transient decrease in neutrophils. Monocytes are held in reserve in the splenic red pulp for just such an emergency.  As the monocytes morph into macrophages (ie: big eaters) to mediate ADCC induced by Rituxan, the neutrophils are no longer needed as much and stay in the blood and increase in numbers as marrow function improves. 

I watched the Dr. Najeeb lecture series on the complement system, and now I'm wondering if an overzealous complement system response to Rituxan aggregates immune complexes (Ig's, anaphylatoxins like C3a, mast cell activation products, etc.) in the skin that lead to the non-itchy rashes often seen in patients who take Rituxan.  I had several during my first round in 2009.  This cycle I noticed a small dime-sized one on my left arm a couple days after the first round that's still there.  They're small patches that usually take 5 to 8 weeks to clear.

Here's a video on Rituxan's mode of action that covers direct cell death, ADCC and complement.  However, the video indicates NK cells are responsible for ADCC whereas I'm postulating that monocytes may also play a significant role.

Rituxan Method of Action

My fascination with GA101 continues to grow.  It's a third generation monoclonal antibody (mAb) that mediates ADCC 5 to 100 times more effectively than Rituxan.  Not only is this antibody humanized, but it's elbow region has been engineered to provide better cross-linking of CD-20 antigens, which appears to dramatically improve apoptosis (cell suicide) as stated in a citation from a prior post.  This mAb has now undergone Phase II trials in indolent/refractory non-Hodgkin's lymphoma with very good results.  I'm lobbying and anxious for in-vitro studies to occur in HCL. 

[Credit: Robert Marcus, Kings College Hospital, London]

Aside from that, I've become quite a gadget geek.  I bought a PS3 to support my http://folding.stanford.edu/ hobby and an Xbox Kinect for working out.  It's seems to be doing the trick too.  My creatine kinase levels went from 109 to 315 over the past week.  CK is an enzyme that's secreted when you workout and convert ATP to ADP to release energy.  The Kinect is an imaging sensor that allows you to play games without a controller.  It's truly amazing.  The technology is still in its infancy, but you can use it to workout and keep/manage all your workout metrics, and it provides real-time analysis of your form that's better than a personal trainer's.  I predict it will make P90x obsolete within a year, and I'm anxious for a yoga application to be released.  I'm hoping some yoga and regular stretching will keep things fluid in my marrow and increase the hairy clump surface area to volume ratio, but that's just a WAG.  I figure it can't hurt.

I'm so grateful and glad I'm participating in the NIH clinical trial!  Not treating my somewhat difficult case with Rituxan by monitoring MRD would probably have led to more Cladribine treatments and marrow suppression.  I think that my case shows that just blindly adding Rituxan at 6 months post-Cladribine and taking a wait-and-see approach by monitoring counts to determine relapse is risky -- especially for younger patients.  Rather, monitoring and treating MRD is the way to go, and right now, only NIH has the facilities to do that -- especially the hypersensitive PCR MRD test.  Likewise, NIH provides 2 8-week cycles of Rituxan to treat MRD -- something regular oncologists won't be able to justify to insurance companies until the NIH study is completed.

The family's doing well.  My youngest (8 mo's) is already cruising and lifting herself up on tables, and the eldest is starting to read and play computer games (Dora and Cat in the Hat).  I've had a couple weeks as Mr. Mom over the past month while my wife's been on travel.  The first time was a breeze, but the baby had an earache the second time, so things were a little more exhausting.  I've been working on Ka-band science downlink designs for future Deep Space Discovery Missions and the S-band command and telemetry link for the GEMS program.  Overall, things are going well.
Happy New Year, and here's to a fruitful 2011!

Prediction?...Pain!

After months of putting it off, I finally went to a new dentist last week.  He told me to see another endodontist to get a second opinion about the root canal and fistula that never resolved after the retreat 18 months ago.  The endodontist told me he's stymied, that it's not good to let the fistula linger because of possible bone damage, and to get the tooth (#14 molar) pulled.  Since the tooth extends into my nasal cavity, they may have to sew in some new bone to make it heal faster.  Once it heals, they'll install a post and a false tooth. 

Oh, and my dentist found a cavity under a cracked filling. 

The tooth extraction and filling cover the first week of December.  The following week, Dr.K is going to restage my progress in case they need to retreat with another round of Rituxan, which means another bone marrow biopsy (#6) on the 13th. 

My good friend Mr. T would like to have a few words:

Prediction? ... Pain!

The protocol has officially been ammended to allow two rounds of Rituxan for the delayed Rituxan cohort (the one that I'm in).  It's a simple one-line addition:  "Also may repeat for those with blood MRD six months after delayed Rituxan."  My flow was negative at 6 months post-Rituxan but has now been positive for 3 months, and will likely still be positive when I restage, so I'll probably receive another 8 rounds of Rituxan starting in January.   I'm very hopeful that this round may be even more effective than last year's since my counts are in good shape and my neutrophil level is much higher.

A high neutrophil count has been shown to correlate with improved antibody-dependent cell-mediated cytotoxicity (ADCC). In other words, the more neutrophils you have when you start Rituxan therapy, the more they can help kill the cells that are tagged with Rituxan. I'll be interested in seeing if I have another incidence of Rituxan-Related Late Onset Neutropenia (RRLON) at week 14 this time around.

I had a physical at my PCP on the 3rd.  Everything checked out fine.  My liver enzymes are holding steady at 22 for both the AST and ALT and my HDL is back up to 40 for the first time in 2 years!  I received 3 vaccinations:  tetanus, pneumonia, and flu.  I couldn't move my left arm for 4 days, but now I feel great.

Aside from that, I've been dabbling in some new favorite hobbies: studying organic chemistry, molecular cell biology, genetics and bioinformatics so that I can better understand some of the papers I've been reading on antibody research and lipid rafts.  I wish I could go back to school full time. 
(12/2/2010)  Tooth Extraction Follow-Up:  Had the tooth pulled.  Everything went fine, and the major bleeding stopped within minutes, although there was a very slow trickle afterward.  I'm hoping this means that there is continued improvement in my platelet count.  I was able to go without any gauze within 3 hours (probably sooner if I hadn't been so cautious).  There were several cysts (about 1 to 1.5 mm) that had formed at each root tip and had to be rigorously scraped off the bone after the roots were extracted.  The worst part was the high pitched squeal of the drill used to segment the root sections so they could be pulled individually.  1 day later, everything feels fine.  I just need to eat soft foods and avoid that side of my mouth for a few days.  In 2 to 3 months, I'll have an exam to verify the bone has grown back and then get a post installed.