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!

Rewind...

I had a clinic appointment yesterday and got my FACS and BMBx results:

Peripheral blood flow is unchanged over the past 3 months and holding at .04% hairies.
Aspirate flow is at 4% -- up from 2% last May.
BMBx immunostaining shows 5% infiltration.  That means I'm no longer in remission.

It could be that my aspirate and blood flows always had hairies, but they were just masked by Rituxan until it detached from the cells and flushed out of my system.  Still, the Rituxan treatments had an effect.  Prior to Rituxan, my bone marrow infiltration at 6 months post-chemo was 30%.  Now it's just 5%.  Likewise, my blood counts are now about the best they've been since treatment started and they got a real boost after the Rituxan treatments.

The protocol calls for another round of Rituxan treatments at 6 months post-Rituxan if the peripheral blood flow is positive, so I'll be going in to NIH next Tuesday to get some more aspirate drawn for the PCR lab, then I'll start the first of 8 more Rituxan treatments (1 a week for 8 weeks) in the early afternoon.

The basic gist is this:  given that my hairies' DNA doesn't bind to the baseline PCR primer used for the hyper-sensitive MRD analysis (and any variants they may have tried), my HCL genome is likely mutated from the norm such that they don't die as easily as most, even though they have more than 100,000 CD20 antigens and bind really well with the Rituxan.  The exact nature of the mutation is still not known.

Since I was slow in responding to Cladribine and didn't get a knock-out punch from Rituxan, I wonder if the assumed mutation affects lipid raft function and restricts the biochemical reaction associated with hairy cell apoptosis and antibody-dependent cellular cytotoxicity (ADCC), but there's no way to know that for sure (for now anyway).  Likewise, the high and fairly steady flow in the aspirate leads me to wonder if there is a significant physiological change or maturation of the cells as they move from the aspirate into the marrow and peripheral blood that makes the pb and marrow cells easier to kill (a more normal lipid raft structure)?  Regardless, the prevailing theory is that the hairies in the aspirate are clumped together in a ball and the Rituxan can't peel away enough layers of the onion to eliminate them completely.

In any case, I'm hoping this round will provide more of a wallop since the bone marrow infiltration is less than before.  Still, at 4%, the aspirate flow is the same as when I started Rituxan treatments in November of '09, so it's anyone's guess as to what we'll see a year from now. 

Til then, I'll keep pushing the rock!

Merry Christmas to all and a Happy New Year too!

Restaging

Monday was a busy morning for restaging at NIH:
        1) 17 vials of blood at 7 am
        2) 45 minutes in the MRI hotdog chamber at 8 am (sounded like I was surrounded by a swarm of helicopters)
        3) Ultrasound at 9 am.
        4) Bone Marrow Biopsy at 10 am.
        5) EKG at 11
        6) Back to work at 1

I should get my FACS results for the bone marrow aspirate and peripheral blood in a couple days.  The good news is that ultrasound of my spleen shows that it now measures 10 cm.  That's down from 13.4 cm at diagnosis, and means the overall volume at diagnosis was 2.4 times what it is now -- comparitively large although a spleen size of 13.4 cm isn't abnormal for a tall man.  This bodes well for having delivered a fairly strong punch to the hairies.

The bone marrow biopsy was the most pain-free so far, but mine was still done by hand -- not the new bone marrow drill that gets the job done in just 10 seconds.  NIH started using the drill recently, but they didn't have any bits left from the initial order, so I'll have to wait until next August (biopsy #7)  to see if the drill is as fast and painless as claimed.

My CBC results were very good.  The WBC is back up to 3.74, platelets are up to 139 and ANC is at 2.5.  There is no sign of any fat in my liver and my AST and ALT are still great at 20 and 30, respectively.

We're assuming the FACS will be positive, so I'm scheduled for a clinic appointment next Wednesday and will start my second round of Rituxan on the 28th -- 8 cycles over 8 weeks.  When I'm done this round, I'll have received 16 cycles of Rituxan over the course of 16 months.

I'll post my FACS results as soon as they come in.

Hairy Cell Leukemia: I Want a New Drug ...

I want a new drug... 

Okay, maybe not yet, but it looks like there are lots of new potential candidates for treating HCL that still have yet to be explored.  Two posts ago, I mentioned a new third-generation antibody that has the potential of being 5 to 100 times more powerful than Rituxan but hasn't been used to treat HCL yet.  I'm hoping some preliminary in-vitro studies will be conducted soon.

Today, I found another one -- a Btk (Bruton's tyrosine kinase) Inhibitor, PCI-32765, that is currently in Phase I clinical trials in patients with B cell malignancies (specifically Non-Hodgkin's Lymphoma).  Btk is an essential signalling factor needed for the development of  B-cells.  By inhibiting it, the Btk protein production is blocked and B-cells can't develop.  The inspiration for developing the drug was born from a disease, XLA, in which B-cells are absent from the peripheral blood because Btk is not produced due to a Btk gene defect. 

What's great about this drug is that it's a pill, taken orally, that inhibits Btk production and thus B-cell production.  Since HCL is a B-cell malignancy, I've asked the Hairy Cell Consortium if they are familiar with the drug and whether it may be a candidate for a Phase 1 trial to treat relapsed and refractory HCL patients.  I'll let you know if they respond. 

"This is a very selective compound for B-cells, and it could represent an important alternative to rituximab therapy for the treatment of B-cell NHL. Other obvious applications include autoimmune disorders such as rheumatoid arthritis and lupus, and Pharmacyclics also has strong preclinical efficacy with PCI-32765 in these disease models," said Dr. Mark Genovese, Professor of Medicine and Co-Chief of the Division of Immunology and Rheumatology at Stanford University Medical Center and member of Pharmacyclics' Scientific Advisory Board. [Taken from Pharmacyclics Press Release dated April 13, 2009]


Wouldn't it be great if we HCL'ers could knock out minimal residual disease (MRD) and then take a pill as maintenance therapy so that we'd never have to worry about it ever coming back?  Even better if it could act as the first-line therapy someday and eliminate the need for chemotherapy altogether (and side-effects like increased secondary cancer risk and impact to T-cell counts), or provide  a new treatment alternative for patients with HCL-V (the variant form of HCL that doesn't respond as well to Cladribine).

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.

A New Hope

Good news!  The latest FACS results from blood taken on September 30th indicate no change in the peripheral blood hairy cell burden or the percentage of lymphocytes that express the hairy cell phenotype (characteristics).  This gives more credence to the hypothesis that the positive FACS results are due to the Rituxan monoclonal antibodies (mAbs) detaching from the residual hairy cells and clearing my system.  The hairy cells may have always been there, but now they are no longer masked by the Rituxan and are once again detectable by FACS.  The important point is that the percentage of hairy cells in the blood remained unchanged at .04%, so the malignancy is not dividing/growing in numbers.  We'll continue to monitor over the months to come, but given that the results are identical to those from 4 weeks ago, I'm very hopeful.

Here's a video of my latest bloodcounts.  Please excuse the melodramatic soundtrack,  I was just indulging in some creative publishing ...
In other news, I'm very excited about a drug I found while researching the relationship between lipid rafts and anti-CD20 monoclonal antibodies.  It may have significant potential in treating HCL -- perhaps 5 to 100 times greater potency than Rituxan.  Pursuant to my inquiries, HCL investigators, who were previously unaware that the drug existed, are now performing detailed analysis of its potential in treating HCL that could lead to some preliminary in vitro laboratory studies.  If all goes well, it may be used in a Phase 1 trial to treat HCL patients who otherwise would have to resort to palliative treatment options.  Maybe several years down the road, it will also become part of the standard arsenal in treating this disease. 

We HCL'ers are fortunate to have so many options and doctors who are willing to listen to and pursue our questions.  It's a good feeling to know that in some small way we can help fight the war on cancer and not be its victims.

Double Trouble

The tumor load in my peripheral bloodstream doubled over the past 3 weeks.  I had a FACS done on August 31st, and the report indicated the percentage of hairy cells increased to .04% from .02%. If the cells are really doubling every three weeks, then I'll have an appreciable burden (around 1%) by January.  Currently, about 5% of my lymphocytes are hairy cells.  I just got the flow results today and haven't talked to Dr. K yet about what it all means.  Still, I've asked to have another flow on Sept. 21st.  If the burden doubles yet again, then I'd like to get another bone marrow biopsy in early October to see if the cells are back in the core.

On the bright side, my counts are continuing to improve, so at least the hairy burden is currently low enough so as not to significantly impair my marrow function.  My WBC is at 4.03, my neutrophils are at 2.6 and my platelets are at 141 -- an all time high since treatment.  I'm still hopeful that I might be able to get another Rituxan treatment while the overall burden and clump sizes are low.

I've read some interesting articles on leukemia using fat as fuel as well as fatty acid involvement in hairy cell membrane morphology.  A study demonstrated how drugs that inhibit fatty acid oxidation may sensitize leukemic cells to drugs that induce apoptosis.   I'm very interested in finding out whether there is a relationship between fatty acid oxidation, body mass index (BMI) and the effectivity of Cladribine.  If one could show that people with lower BMI respond better to Cladribine chemotherapy, then perhaps general approaches to reducing BMI prior to treatment with 2CDA could result in better outcomes for all patients.  My crazy brain at work.  (Afternote:  Turns out there is a basis for my query regarding a correlation between BMI and chemotherapy, although it's not directly related to HCL.  A study of childhood leukemia patients showed that patients with high BMIs were less likely to respond to chemotherapy.  While the theory reported is that cancer cells sequester in body fat, I have my feelings that cellular membrane factors may be involved as well.)

Time to go exercise...

(More random thoughts, 9/9/10) I've been reading about cellular plasma membrane structures called "lipid rafts."  Although these structures are readily observed in cultured cells, they have not been observed in live cells, and their existence in live cells is considered controversial; however, I wonder if hairy cell filopodia (aka villi -- the fine hair-like projections of hairy cells) are actually extrusions of cytoplasmic material from lipid rafts which have large cholesterol concentrations (remember -- hairy cells have high cholesterol content).  I read an abstract from a study entitled "Lipid Raft Disruption Prevents Apoptosis Induced by Cladribine."  It indicates that although leukemic test cells completely absorb Cladribine, disrupting the lipid rafts inhibited the flow of calcium ions through the plasma membrane and reduced the apoptotic effects of Cladribine.  Although the study used ALL cells, I wonder if this is a reason why Cladribine doesn't work well for some HCL patients (the lipid rafts are disrupted or vary in some way that prevents proper biochemical flow to induce apoptosis).  Still, the study probably used cultured cells, so it's hard to know if it applies to live cells.  I'd like to get the full article and learn more about the causes of lipid raft disruption to find out if there are things that can be done to make Cladribine more effective for all patients.  Who knows, maybe this is a factor in HCL-V, and figuring out a way to open the ion pathways will make Cladribine effective in that variant of the disease too.

Similarly, treatment with interferon-alpha has been shown to reduce HCL cholesterol content and villi length.  This would support my theory since lipid rafts are assumed to contain large amounts of cholesterol.  Reducing the cholesterol content of the lipid raft would reduce its area and correspondingly, the amount of material extruded to form the villi would be reduced -- resulting in shorter villi.  I don't know why I write this stuff.  Aside from the fact that I'm desperate to kill these hairy bastards, I suppose I'm hoping a grad student will take it on as a project or at least comment on its plausibility.

(Even more random thoughts, 9/10/2010)  This is kind of cool.  I just found an abstract for a study entitled "Microvilli structures on B lymphocytes: inducible functional domains", which states:  "We also discovered that depletion of cholesterol, using b-methyl-cyclodextrin, lowered the number of microvilli, indicating that intact lipid rafts are required for their expression."  This applies to the microvilli of normal cells, but it is in keeping with my hypothesis regarding unusually large lipid rafts as the source of the filopodia (aka villi of hairy cells.  Perhaps my hypothesis is right.  Now if only I could win the lottery and fund my own studies...

Interestingly enough, there is a patent for a formulation of Cladribine that uses b-cyclodextrin as the soluble agent in lieu of the original benzyl alcohol and propylene glycol cosolvent soluble agent combination.  This is a similar compound as that referred to in the paragraph above (Both β-cyclodextrin and Methyl-β-cyclodextrin (MβCD) remove cholesterol from cultured cells) and it's used to deplete cholesterol and reduce the number of microvilli on B lymphocytes.  If hairy cell villi are indicative of lipid rafts, and lipid rafts are necessary to allow ion flow and induce apoptosis, then perhaps this formulation of Cladribine is slightly less effective than the original version.  I'd like to know which version of the drug I was given.  If b-methyl-cyclodextrin acts as a lipid raft disrupter, then maybe the original formulation is more effective in patients with variant lipid raft function.

(9/11/2010)  I found another great article:  "CD20-mediated apoptosis: signalling through lipid rafts," which seems to imply that in order for Rituxan to induce apoptosis, it must cross-link CD20 proteins that are located in separate lipid rafts.  My initial thought was "does this mean that if your cells have fewer rafts or if the rafts are too large, the drug will be less effective?" and this thought turned out to be mirrored in the final thoughts of the study report: "Finally, it will be important to test the prediction that the size or abundance of lipid rafts in B-cell membranes is a contributing factor to the susceptibility or resistance of patients to CD20-mediated B-cell depletion."  This study's findings resonate a common theme with the other studies I've referenced regarding the involvement of lipid rafts in apoptosis.

Much of this report seems to read as if the high cholesterol content of the cells is necessary in order to allow the calcium ion flow needed for apoptosis to work properly.  This would indicate that going on a low-cholesterol diet during therapy to try to starve the hairies may be counter-productive.  Since the underlying apoptotic biochemical process seems to be the same for Cladribine induced apoptosis as it is for anti-CD20 induced apoptosis, maybe cholesterol gets synthesized into other chemicals during apoptosis -- causing the hairies to suck in more cholesterol from the peripheral blood as they try to survive.  Maybe this explains why my blood cholesterol dropped precipitously during Cladribine chemotherapy (HDL went from 30 to 18 in a matter of days, LDL went from 90s to  high 60s).  I'm guessing that partial apoptosis biochemical processes started and consumed cholesterol, but the calcium mobilization was inhibited so as the cells survived, they consumed more cholesterol from my peripheral blood to reconstitute themselves.  Ultimately, many of them died after six months (went from 80% bone marrow infiltration at 1 month post chemo to 30% at 6 months) probably due to DNA damage and slow but sure calcium mobilization, but too many survived.

I found another article which reinforces and provides further detail on the involvement of cholesterol in B-cell apoptosis: "Cholesterol depletion inhibits src family kinase-dependent calcium mobilization and apoptosis induced by Rituximab crosslinking."

Hmmm....does this mean I should eat Ben and Jerry's Vanilla ice cream during therapy?  Of course not, fat and cholesterol are different substances.  Maybe shrimp is a good compromise -- low in fat, but high in cholesterol.  Leukemia is so paradoxical to the conventional mindset.  This is interesting because studies in many solid tumors (like prostate cancer) show that cholesterol depletion aids in apoptosis.  The differences between leukemia and solid tumors are fascinating.  Time to go watch Woody Allen's "Sleeper" -- turns out chocolate cake is good for you after all...

(9/18/2010)  I got a great reply from the "Hairy Cell Consortium" regarding some questions I had regarding lipid raft research for HCL:

My e-mail to them read as follows:
      Given the findings of the following studies:
          "CD20-mediated apoptosis: signalling through lipid rafts"
          http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1782791/pdf/imm0107-0176.pdf

          and

         "Lipid raft disruption prevents apoptosis induced by Cladribine"
          http://www.ncbi.nlm.nih.gov/pubmed/16730061

          isn't it possible that lipid raft disruption may play a
          significant role in why these drugs
          are are not effective for some patients?
          Why isn't there more research to characterize
          HCL lipid rafts and determine the role that lipid
          rafts have in the disease?

Here's their reply:
 
         Dear Mr. Howard:

        
         The question that you pose about the potential
         importance of "lipid rafts" and response to therapy
         in hairy cell leukemia is excellent. To our knowledge,
         the characterization of "lipid rafts" in hairy cell
         leukemia has not been published. In contrast, lipid
         rafts have been explored in chronic lymphocytic leukemia
         by several investigators. The presence of lipid rafts has
         been correlated with response to cladribine as well
         as response to monoclonal antibodies in vitro. The
         monoclonal antibodies that have been studied include
         both Rituximab and Alemtuzumab. Since both of these
         agents may have some benefit in this disease, all patients
         have not responded. It would be interesting to
         correlate the responsiveness to these agents as well
         as to the purine nucleoside analogues. This is the type
         of study that might be conducted within the Hairy Cell
         Leukemia Consortium. Your question has merit
         because it might provide predictive biomarkers to
         determine who will and will not respond to these agents.

       Regards,
       The HCL Consortium Team

This response made me very happy.  Hopefully, they'll perform some studies.  Who knows, maybe the research will not only provide predictive biomarkers but ways to tailor the structure of antibodies to conform to variances in lipid raft size and placement that fall outside the range accomodated by the current antibodies' structures.