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!