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.

Benefits of NIH Hairy Cell Leukemia Trial Participation

I've read a lot of bulletin board posts with various insights regarding participation in the NIH Trial for Newly Diagnosed HCL Patients so since I'm participating in the trial, I thought I'd offer my own.

While I have the advantage of living close to NIH, I've been in touch with many patients who have had to deal with the logistics of participating in the trial from all over the country.  Here are many of the trades people make when considering trial participation:

Trade #1:  Can I afford to travel to or stay at NIH for 8 weeks of Rituxan treatments?
         Fact: You don't have to.  Rituxan can be administered by your local doctor.  You only need to travel/stay at NIH for the first week of chemotherapy treatment.  NIH will send the Rituxan to your local doctor and coordinate the administration free of charge.

Trade #2:  My local oncologist can provide the Cladribine and Rituxan combination, so there's no need to participate in the trial.
         Fact: While local administration of the Cladribine/Rituxan combination is becoming more common,  most insurance will only cover the cost of 4 weeks of Rituxan.  By participating in the NIH trial, you'll receive up to 16 weeks (2 cycles at least 6 months apart with 8 weekly rounds per cycle) of Rituxan free of charge.  Most insurance companies view the free NIH-provided Rituxan and expected increase in remission as a major cost-savings and will cover the entire cost of local Rituxan administration (local Dr. time and facilities costs).  Since Rituxan effectivity is dependent on the size/radius of the remaining clumps of hairies, long-lasting remission and eradication is much more likely with 8 cycles per treatment than with 4.  Independent adminstration of Rituxan without monitoring minimal residual disease (MRD) in a clinical trial setting does not provide an effective means of treating the disease.  Once the trial is completed,  local oncologists will be provided with the most effective combination therapy treatment.
      
Trade #3:  The trial doesn't provide any major advantage.
          Fact:  Prior trials in Italy combining Rituxan and Cladribine resulted in a significant increase in complete remissions and elimination of minimal residual disease (MRD).  It is believed that this may increase the duration of remission, which is being studied by the NIH trial.  The NIH hyper-sensitive MRD test is able to detect 1 hairy in 1 million mononuclear cells -- 100 times more sensitive than a standard FACS.  This is a significant advantage -- allowing Rituxan to be administered at a point when it will be most effective.  This also means that Rituxan will only be administered if it is necessary.  Only NIH can perform this test!
                    Whereas most doctors aren't proactive in following their patients and wait until blood counts   indicate the need for re-treatment, Dr. Kreitman will actively study your progress and treat the earliest signs of MRD, which may possibly increase the duration of your remission (one of the hypothetical effects being studied).

Trade #4:  There are risks associated with Rituxan.  Cladribine is highly effective in most patients, so I'll do that for now and only take Rituxan later if it becomes necessary.
          Fact:  Data indicate that 40% of patients relapse after only 10 years of single-drug chemotherapy.  To prevent significant bone marrow suppression, it's desired to limit a patient to two treatments of purine analogue chemotherapy (Cladribine or Pentostatin).  The prevailing theory is that Rituxan is most effective when used in conjunction with a purine analogue so that the clumps of hairies are unclumped/diffused prior to administering it (being studied by the trial).  This allows Rituxan to destroy the individual hairy cells immediately instead of slowly peeling the outer layers of the hairy clumps (resulting in a direct additive effect vs. a percentage of the remaining load).  Don't lose this advantage by deferring Rituxan treatments until after chemotherapy is no longer viable.  One look at my ANC plots (see prior posts), and you can see I owe my overall strong response to the Cladribine/Rituxan combination.

Trade #5:  I can't afford to travel to NIH.
        Fact:  A lot first-time patients deal with the cost/benefit trade-off of travel to NIH, and rightly so.  Once accepted into the trial, NIH will cover the costs of all subsequent travel for the patient (spouses and children are not covered).  Angel Flight and the Air Charity Network offer flights to patients in financial need.

Trade #6: I can't afford accommodations while at NIH.
       Once admitted to the trial, NIH will provide free accommodations through their in-patient hospital.  While qualifying for the trial, you may need to spend two nights at a local hotel.   Current rates for the Bethesda Marriott are approximately $139/night.  You'll find that the current commercial rates are often better than the NIH negotiated rates, so ask for both.

The best way to make a fully informed decision is to gather as much information as possible.  Dr. Kreitman is always available and will quickly respond to your questions.  Email him at kreitmar@mail.nih.gov.

.