The One-Two Knockout

Good news for patients who don't respond to Cladribine. I found a study citation that shows that even for minor/non-responders to 2-CDA, complete remission after treatment with Rituximab was achieved.

A study at the University of Pisa, Pisa Italy, studied a cohort of 10 patients who followed a treatment regimen very similar to the one I'm in at NIH. Patients were first treated with a course of 2-CDA (chemo) followed by Rituximab 6 months later. Here's the study citation:

Purine analogues have dramatically improved the outcome of patients affected by hairy cell leukemia (HCL), although complete eradication of disease was achieved in few cases. The purpose of this study was to evaluate the role of Rituximab in eradicating minimal residual disease (MRD) in HCL patients after a pre-treatment with 2-chloro-deoxy-adenosine (2-CdA). Ten patients received four cycles of Rituximab after administration of Cladribrine. Before starting anti-CD20 antibody, two patients were in complete remission, six in partial remission and two showed no significant response to Cladribrine. All cases resulted IgH-positive. Median time from the last 2-CdA infusion was 5.7 months. Eight of 10 patients [four in partial remission (PR), two in complete remission (CR) and two unresponsive after 2-CdA] were evaluable for response. Two months after the end of anti-CD20 therapy, all evaluated patients presented a complete haematological remission. Moreover, Rituximab increased percentage of molecular remission up to 100% 1 yr after the end of treatment. Interestingly, in all cases but one, including those persistently polymerase chain reaction (PCR)-positive, semi-quantitative molecular analyses showed MRD levels lower than those found before Rituximab administration. Toxicity was very mild. The present results not only confirm the therapeutic effect of Rituximab, but also show its relevance in eradicating MRD in HCL.

The really great news here is that of 8 patients, 2 were non-responders at 6 months post-chemo, yet all achieved complete remission after treatment with Rituximab biological therapy, and the toxicity was very mild.

There is still plenty to hope for, and I'm glad I found the NIH study.

Plan B

A few months back I discussed how HCL thrives in the presence of a cytokine (cell signaling molecule) called tumor necrosis factor alpha (TNFa). Given my less than 3-sigma response to Cladribine, I thought it might be worth investigating foods and medicines that suppress the production of TNFa to help me bide my time.

I asked Dr. K (via e-mail) whether they monitor TNFa in the routine blood tests they perform. He said they used to but found the data to be not very meaningful. I assume this means there was too much variance in the data. I then asked him whether given the overall trend in my data, I'm considered a minor responder. He did not respond to that question.

I had read an article in Tallman and Poliak that discussed how TNFa reducing drugs given in parallel with 2-CdA improved response rates in HCL, so I did my own search regarding foods that lower TNFa and struck gold immediately.

As described in "Caffeine suppresses TNFa production via activation of the cyclic AMP/protein kinase A pathway", Horrigan et al, International Immunopharmacology, Vol. 4, No. 10-11 (October, 2004) pp. 1409-1417 -- coffee can suppress TNFa and thus may be helpful in suppressing the rate of cloning of HCL cells. The most caffeinated food (aside from sugar laden jolt and Red Bull) is restaurant prepared espresso. Here is the paper's abstract:

This study investigated the effect of in vitro exposure to caffeine, and its major metabolite paraxanthine, at concentrations relevant to typical caffeine consumption in humans, on lipopolysaccharide (LPS)-stimulated cytokine production in human whole blood. In addition, a role for the cyclic AMP/protein kinase A (PKA) pathway in the immunomodulatory effect of caffeine was investigated. Diluted whole blood (taken following >/=15 h abstinence from caffeine-containing food and beverages) was preincubated with caffeine or paraxanthine (10-100 microM) and stimulated with LPS (1 proportional, variant g/ml) for 24 h. The proinflammatory cytokines tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-12, and the antiinflammatory cytokine IL-10 were measured in cell-free supernatants. Whilst caffeine and paraxanthine had little or no effect on IL-10, IL-1beta, or IL-12 production, TNF-alpha production was suppressed in all individuals studied. The effect was statistically significant at 100 microM and consistent across seven experiments performed. Although not statistically significant, a similar effect was observed with paraxanthine. Caffeine (100 microM) also increased intracellular cyclic AMP concentrations in LPS-stimulated monocytes isolated from whole blood. Moreover, the effect of caffeine on TNF-alpha production was abolished by pretreatment with the protein kinase A inhibitor Rp-8-Br-cAMPS (10(-4) and 10(-5)M). To conclude, this study demonstrates that concentrations of caffeine that are relevant to human consumption consistently suppress production of the proinflammatory cytokine TNF-alpha in human blood and that this effect is mediated by the cyclic AMP/protein kinase A pathway.

I'm going to add one espresso a day to my morning routine in the hope that it will stop the strong cells from signaling further reproduction and infiltration of my marrow. With any luck, I might be able to tip the balance and hold off the stronger cells from reproducing while the chemo continues to take out the weaker ones. Then the Rituximab can come in and wipe out the cells that the chemo couldn't take out.

Foods containing Lutolein (a flavonoid) like celery, green pepper, and chamomile, also suppress TNFa. Other TNFa inhibitors include Nettle Leaf, and ECGC (found in Green Tea). Vitamin A also appears to help suppress TNFa production, which is also linked to the onset of diabetes ("Vitamin A may suppress type 1 diabetes", L. Crowley, Mar. 31, 2008).

I'll be adding all of these to my regular diet.

I wonder if previous studies of TNFa levels proved to be meaningless because diet can affect the levels. Without a controlled diet, studying TNFa levels may prove futile.

TNFa is also associated with demyelinating disorders such as multiple sclerosis and certain forms of tinnitus. Given the fact that Cladribine is effective in treating MS and HCL, I think a logical hypothesis is that Cladribine may somehow block TNFa signalling pathways, possibly by amplifying a protein kinase pathway. Perhaps in minor responders, there is a genetic difference which reduces this effect. A study of individuals who drank a V8-like beverage for 26 days showed they reduced their TNFa production by 34.4%.

Wish me luck!

Keep on Truckin'

I underwent chemotherapy (Cladribine -- aka Leustatin) four months ago and although 99% of the malignant cells in my peripheral blood have died off, my bone marrow response has been very slow. Dr. K wants me to remain on a one-month blood work follow up. As you can see in the graph below, my platelet count is still hovering around 100. I think that the count may be deceptively low because the platelets may be aggregating and fooling the FACS into counting what are multiple aggregate platelets as a single platelet. I'm going to ask Dr. K if he can order a peripheral smear slide examination (direct microscope examination by a pathologist) to see if this might be the case.

The good news is that my WBC, RBC, neutrophil and other counts continue to increase, although slowly. Some other counts, like Basophils, that were previously imperceivable, have now started registering.

Full disclosure -- I took 100 mg of grape seed extract (GSE) per day for a week back in June -- after my platelets had gone to 131, but before the next test showed them crashing back down to 100. Dr. K didn't have a problem with it (probably because he doesn't think it'll do anything), but given GSEs apoptotic effects on Jurkat leukemia cells, I thought it might also help destroy HCL cells too. The studies conducted by City of Hope indicated that GSE wouldn't harm healthy cells; however, I'm concerned that the GSE might have somehow knocked down my bone marrow's progenitor cell production. Still, there hasn't been enough data collected on GSE's effects in humans to know for sure.

I found an article addressing the efficacy of injecting Cladribine intravenously -- "Treatment of hairy cell leukemia with cladribine (2-Cda) by subcutaneous bolus injection: a phase II study," by Rohr et al, Annals of Oncology, 2002. I believe it is the basis for Dr. K's decision to use this method of administration in his clinical trial. The median time to failure for this approach is approximately 38 months. That sounds bad, but I think what it really means is that once a complete remission is achieved, it usually takes 38 months before any malignant cells are detected again. It may take much longer before the marrow and blood counts are affected, requiring a second round of chemotherapy.

Using this approach resulted in an overall remission rate of 97% (76% complete, 21% partial). Complete response requires the dissapearance of all evidence of disease, a return to normal peripheral blood counts, and the absence of hairy cells in the blood stream and the bone marrow. Time to failure is defined as the time between treatment start and progression, relapse, second tumor, or death, whichever occurs first. A partial response also requires a return of all blood counts to normal, but the reduction of cells in the marrow is somewhere between 50 and 99 percent.

PRs and CRs usually occur within 10 weeks after chemotherapy, so I'm bummed because it's been 16 weeks and my blood counts are still below normal and malignant cells, however slight, are still being detected in my bloodstream. That makes me part of the 5% considered minor/no response, so I'm glad I'm in the trial. Hopefully, what the Cladribine doesn't kill, the Rituxan I'm getting in October (once a week for 8 weeks) will.

(More at the bottom of this blog post...)

I've lost a total of 16 pounds over the last two months -- mostly excess fat. I'm down to 188 pounds and holding steady now. My endurance is great, but I have been feeling dizzy lately. I'm anxious for my next bone marrow biopsy in October and to get started on the Rituxan.

I also have a theory on what may have caused my leukemia. Several fellow HCLers have written to me noting that they are also RF engineers or hobbyists, wondering if there may be a common association between our line of work and the disease. A common factor in all of us is that we experienced high-power RF burns over 10 years ago. Likewise, electrical linemen also seem to have a slightly higher incidence of leukemia. Back in 1998, I received a 20 to 40 Watt RF burn at 137.5 MHz when a fellow engineer indicated he had turned off a transmitter but had not. When I disconnected the transmitter's output cable to reconfigure the system for another test, I received a severe RF burn on my hands that took several weeks to heal. In some people, RF burns may cause cellular mutations and induce HCL, but until some meaningful data is collected to prove this, I won't know for sure.

Regardless, bad things happen every day. You just have to accept it and keep on trucking.

KOT!

The Cost of Hairy Cell Leukemia

I reviewed all my insurance statements since my first doctor's appointment that led to my diagnosis and treatment for HCL. The total diagnostic cost billed by the doctors was $19250. Add the "virtual" cost of the NIH provided chemo at $5,000, the 1-month BMB at $1500 and the follow-on CBCs at $2000 along with $2500 for "progeny insurance" and the total is around $30260.

The insurance negotiated diagnostic costs came in at $4120 -- a $15,130 savings vice the doctor charges.

Given that I haven't submitted my "progeny insurance" claims yet, my total out-of-pocket (OOP) expense thus far is $2695. A savings of $42565, which may increase when I submit the other claims. My total OOP expense could be as low as $195. Not bad. Say what you want about insurance companies, but I'm grateful for mine. Without their negotiations and coverage, HCL would have left me bankrupt.

What I don't understand is why the initial doctors costs are so high compared to the negotiated costs. The variance between insured negotiated costs and uninsured non-negotiated costs is beyond reason. That the people who can afford it the least are left paying the most when their health turns for the worse is immoral given the large arbitrary cost fluctuations that exist between the insured and non-insured.

Following up on my last blog, my ALT and AST levels after going off Clonazepam were very good -- 24 and 28, respectively, so I've switched from Clonazepam to Gabapentin, which doesn't metabolize. I go in for my 4-month CBC tomorrow. I'll post the results once I get them.

3 Months Post-Chemo and Counting

It's hard to believe 3 months have passed since I underwent chemotherapy. I had my last blood tests on July 22nd, and the results were mixed. The good news is that about 99% of the malignant cells in my peripheral blood have been knocked down, and blood count-wise things are not getting worse (although I do have some questions about my T-cell ratios).

Each month the rate of reduction in the malignant cells has decreased by half. The first month 98% of the remaining hairy cells were destroyed, the second month 50% of the remaining hairy cells were destroyed, and the third month 25% of the remaining hairy cells were destroyed. I'm gonna go out on a limb and guess that this month 12.5% of the remaining hairy cells (of which there are very few) will be destroyed.

The bad news is that my blood counts aren't really that much better than last month. My white cell count is still about one-third of normal. Still, I've got 3 more months to improve, so I keep reminding myself I'm only halfway there. My liver function tests (AST and ALT levels) came back very high. I'm assuming this is because of the Clonazepam I've been taking to help me sleep, so I stopped taking it for the past week. I'll stay off it until I have my primary care doc do a liver function test next week.

I've lost about 16 pounds since chemotherapy. I simply can't eat enough while I'm at work to keep up with what my body needs. On the bright side, I'm back to working full days on some very interesting NASA science and technology satellites -- NuSTAR (to research the super-massive black hole at the center of our galaxy) and GLORY (to research Earth's aerosols, clouds and irradiance).

I'm really not too concerned about the low neutrophil count anymore. It seems to be slowly increasing, and from all accounts, I'm more susceptible to infections from germs already in my body than external pathogens. Christi, Claire and I went with our friends to the water park last week and had a great time splashing, sliding and playing in the water. I made sure to slather myself in sunblock spray to maintain my lovely pasty-white complexion. It's my sworn duty as leader of the Pasty Boyz.

The following charts show my blood count progress up to the last blood test:

Typically at 3 months, the WBC count is close enough to normal to warrant only testing the peripheral blood 3 months from now, but in my case, I need to go back in 3 more weeks (1 month since the last one).

On a good note, I can workout on my elliptical and exercise bike much more easily than I used to. About two weeks ago, I rode 20 miles on my exercise bike on interval training at about 75% of the bike's full resistance. I'm very anxious the get back to the Grand Canyon and see what I can do once my RBC recovers to a normal level.

Last June, I hiked an hour into the Canyon and it took me about two hours to hike back out. I had to stop and rest about every 200 feet to catch my breath and keep going up. At that point, I was already probably below normal on platelets, and I'm sure my red count was suffering too. Thank God my friends were there to share their water with me and keep me going.

It was exhilarating to make it out on my own two feet -- knowing that my friends were there to pull me through; but I was left wondering "How come it was so much harder for me than everyone else?" Certainly, sitting for 12 hours a day at work didn't help, but I kept wondering if something else was wrong. I wasn't really dehydrated, my legs just got tired really easily. Two days later, 4 people died when a medivac rescuing a hiker from the Canyon was trying to land and collided with another copter taking off from the Flagstaff Hospital. Without the right friends, that could have been me.

HCL and Secondary Cancers

A lot of the HCL blogs and discussion boards that I follow have patients who want to know more about secondary cancers, so I thought I'd do some more research into the subject.

An intensive study was conducted by NIH which examined the risk of secondary cancers in 3104 2 month + survivors of HCL. It found that the cumulative probability of a secondary cancer in 25 year survivors was 32%, but not everyone in the study lived that long. Most patients usually die of other natural causes first, but the finding is a major bummer for the younger than average patients like myself. Statistically, the mean follow up time with patients in the study was 6.5 years. Some died, some moved, some stopped participating out of apathy.
Standard incidence ratio (SIR) is a term used to compare the rate of a cancer among a particular group to the general healthy population; hence, for healthy average Joes, the SIR of a particular type of cancer is one. For HCL'ers, the SIR for Hodgkin lymphoma is 6.61 (6.6 times more likely to get it than a normal, healthy individual). The SIR for non-Hodgkin lymphoma is 5.03. Thyroid is 3.56. Lucky for me, the SIR for lung cancer is less than the normal population, coming in at only 0.63, but that's probably just due to the fact that people stop smoking when they find out they have leukemia -- a macroscopic trend which doesn't really transcend to individual risk reduction. Overall, the SIR for all secondary cancers over the HCL population is 1.24 -- or 24% greater than average.
In fact, HCL isn't the first cancer I've been treated for. I was treated for a basal cell carcinoma (BCC) in late July, 2007, so it's likely I've already experienced a secondary cancer from HCL even though it was treated prior to the official HCL diagnosis. BCC is a type of skin cancer which doesn't metastasize but can become disfiguring if left untreated. One of the nurses at NCI told me they tend to see more than the average number of skin cancers in patients with HCL. Be forewarned, I'm going to show you some pictures of my surgery below, so if you're squeemish, don't read on.
My BCC started as a persistent pimple on my left nasal ala -- mainly in the crease between my nostril and cheek. Over the course of several months, it gradually turned into a surface rash that sometimes bled when I showered -- cycling between healing and bleeding. At the time, my platelets were already down to the low end of normal, so this may have exacerbated the bleeding. Soon, I started feeling throbbing in the region and feared that veins to a tumor might be forming so I went in to get it checked out. With one look, my dermatologist knew she had to take a biopsy and sure enough the pathologist determined it was cancer.

As promised, here are the pre-close and post-close pictures from the Mohs surgery. Mohs surgeons are trained pathologists. This is required because the surgery is conducted in multiple phases to minimize cosmetic impact while ensuring that all the roots of the cancer are cut out. The surgeon uses a special dye to examine each sample of excised skin under a microscope and ensure that enough healthy margin exists at the edge of the cancer.

My surgery took 4 phases because it was rooted much deeper than anticipated. I was lucky that it was in the crease of my nose. The doctor did a great job, and most people can't even tell that I ever had surgery. It took extra long for him to cauterize my flesh and stop the bleeding, and he noted that to me when he did the surgery. That led to my Dr.'s appt. in October of 2007 which first noted that my platelets were at the low end of normal (140). Come to think of it, I think that's one of the reasons I demanded a CBC (or "the works" as I called it) at the time. Here's a link to a short video on Mohs surgery.

Anyway, I don't want to scare any of you HCL'ers out there, but you do need to be aware that you should take extra precautions, avoid the sun moreso than others, and live as healthy a lifestyle as possible after treatment.

My next blood test is in two weeks. I follow a lot of the discussion groups and many fellow HCL'ers who were treated at the same time as me are already in remission. I'm jealous but very hopeful that my blood tests will show significant improvement next time.

 

Numberz

I thought I'd share a few plots I've generated of my various blood counts. First, the white blood cell (WBC) count data. As you can see, the WBC was below the low end of normal prior to chemotherapy and is currently holding at ~1000 cells/uL. I've got a long way to go to get back to normal (the red line).








Next, the RBC counts. My red cells are also below the low end of normal but seem to be holding out. Based on the current trend in the curve, it looks like they may start to come back up soon.

Now for the some good news. My platelets are back on the rise, and they're the harbingers of recovery so this is a good sign.

But of course, the neutrophils have to put a damper on everything. Still, the rate at which they're declining is decelerating, so we should see a U-turn soon.

Lastly, the lymphocyte count is 30% of the low end of normal. Most of what's left (95%) are T-cells (that's what the report said). NK cells make up 4.5% and B-cells make up only 0.5% of the remaining lymphocytes. That's fine with me. It's a B-cell that mutated into a hairy cell and got me in this mess, so I'm not such a big fan of them anyway.