Monday, November 9, 2015

Metabolic Rewiring in Hairy Cell Leukemia

Here's a link to an interesting article on "BRAF-V600E Metabolic Rewiring and Reprogramming."

BRAF-V600E is the mutation present in nearly 100% of the classic form of hairy cell leukemia (and is also common in 50% of melanoma cases).

The metabolic cycle shown in the diagram may imply that a diet which promotes ketogenesis (such as a high protein, low-carb diet), may promote BRAF-V600E/MEK1 binding and tumor cell proliferation.

I'd be interested in understanding how levels of HMGCL compare between patients and whether there is a correlation to treatment success.

Interestingly enough, an HMGCL antibody has been produced in rabbits:

I wonder if such an antibody could be used to safely regulate HMGCL levels during treatment and reduce cell proliferation. 

A common mistake a lot of people initially diagnosed with HCL (including myself) make is to assume that HCL is like solid tumors and feeds on sugar.  They then follow a low carb diet, which in turn causes the body to invoke ketogenesis to metabolize fat and protein.  In so doing, they promote cell proliferation instead of starving the HCL. 

This is the mistake I made when being treated.  I wonder if it is one of the reasons why I did not respond as quickly as others to treatment during chemotherapy and my first round of Rituxan.  I stopped the diet before my second treatment of Rituxan and ultimately got a complete remission.

Just remember, "liquid cancers" aren't like solid tumors.  Follow a balanced diet, and let the medicine do its job.

Saturday, March 22, 2014

Trial Announcement for Multiply Relapsed Hairy Cell Leukemia Patients

Multiply Relapsed HCL Patients:
If you're a multiply relapsed HCL patient looking for a non-chemotherapy treatment, consider the Moxe clinical trial at NIH.  This is a Phase 3 trial.

Results from the Phase 1 trial indicate there is no toxicity, a complete remission rate of 57%, and a majority of those patients were able to eliminate all signs of malignancy. These results are superior to many other non-chemotherapy treatments for relapsed HCL. Check out the webpage or call Dr. Kreitman at 301-648-7375.

Here's a great link for patients that explains the trial and how the drug works.

"Moxetumomab is a nonchemotherapy treatment that can produce MRD-negative complete remissions where patients have a chance to be free of disease for a long duration," he explained. "We have patients who have been free of MRD for more than 5 years now on moxetumomab, and more than 10 years on the parent drug, BL22."

Here's a link to the clinical trial protocol details.

This referral letter explains the trial to doctors looking for treatment options for their multiply relapsed and refractory HCL patients.

Wednesday, July 3, 2013

Hairy Cell Leukemia: A Pleasant Surprise...

It's been a week since my restaging appointment at NIH.  Those of you in the trial know the routine:  CBC bloodraw in Phlebotomy, MRI and ultrasound in Imaging, then bone marrow biopsy and aspiration (my tenth) in Out-patient Procedures.  Get an X-ray and EKG in between those appointments. 

Waiting for results over the past week was nerve-wracking.  I got the CBC results that day.  My platelets were down slightly.  All white counts were normal, but looked like they were trending down too.  Red counts were fine, and they had certainly been pulling their share during all the recent hikes I've taken. 

Recovering from a head cold, I thought maybe that could account for the slight dip I perceived in the platelets and neutrophils.  Last year, 18 months after my final Rituxan treatment, my bone marrow aspirate came back slightly positive (.08%) for HCL.  At the time, Dr. K indicated that it might come back negative in a year, but I didn't think it would.  I assumed the cells would double every 3 weeks, and I'd have 60 to 80 weeks before I would need to be retreated.  Enough time to maybe let me get into an inhibitor trial and avoid chemo, which suppressed my marrow much longer than expected when I was first treated.  Thinking about going back for retreatment and the possibility of another chemo was starting to wear on me. 

Well, I'm pleased to report that both my peripheral blood and bone marrow aspirate flow results were negative for hairy cell leukemia - providing further data to show that using Rituxan to treat minimal residual disease (MRD) may allow the body to get an upper hand in keeping the disease in check.  In my case, chemo didn't get me into a partial or complete remission (CR), and a first cycle of Rituxan at 6 months post chemo to treat continued HCL infiltration allowed me to get a short-term CR.  A year later, when MRD first appeared, the second cycle of Rituxan had the opportunity to knock out what remained.

I've been in CR ever since that final treatment, and now there's no evidence of HCL at all!  My body is keeping it in check and appears to have eliminated the small amount that was detected last year.  Although the PCR lab was never able to clone my hairy cells to perform the hyper-sensitive MRD test and determine if HCL is completely eradicated from my body, I'm elated that I appear to have the upper-hand at this point.  The only supplement I take is 1000 IU of Vitamin D in the winter.  My diet is relaxed and normal, just no junk food or soda.  My ultrasound tech said my liver was now "textbook" and no longer fatty like it was when I was first diagnosed.

I couldn't have gotten to this point had I not participated in the NIH trial for newly diagnosed HCL patients.  I'm eternally grateful to Dr. K, Rita and the fantastic team at NIH.

Wednesday, June 5, 2013

Hairy Cell Leukemia: Making an Impact...

About 2.5 years ago, I blogged regarding a new drug I read about and brought to the attention of the Hairy Cell Consortium.  It's a Bruton's Tyrosine Kinase (BTK) inhibitor known as PCI-32765, and was inspired by a rare disease known as XLA, in which the body doesn't produce B-cells due to a BTK gene defect.  Developed to treat NHL, when I read about it, I thought the underlying mechanism warranted investigation for treating HCL.

Here's a link to the post:

Well, the email describing the mechanisms and potential of the drug that I sent to the Hairy Cell Consortium had an impact.  They performed in vitro studies of the drug, and it was found to be highly effective in stopping HCL proliferation!
Clinical trials using this drug to treat relapsed and refractory Hairy Cell Leukemia patients are now underway at The Ohio State University Medical Center (Go Buckeyes!!!) and The Karmanos Cancer Institute in Detroit Michigan!

The drug goes by the trade name Ibrutinib.  Let's hope it lives up to the potential I anticipated in my post back in 2010!  Seems like our arsenal and options are really piling up.  Translational medicine and targeted therapies are taking off, and will hopefully make chemo a distant memory someday soon. 

On a personal note:    Back in April, I went on a 5 day trek to the Royal Arch Loop of the Grand Canyon South Rim with some friends from work.  It was awesome!  The second to last day we hiked 13 hours in 80 degree weather and ran out of water, so we banded a team of 5 together for a 3-hour night hike down to the Colorado River to collect 40 liters of water for the rest of the team (9 of us altogether), so we could hike out the next day.  Awesome!  5 years ago, I couldn't climb 13 steps without stopping to catch my breath.  The last day of the Royal Arch trek, I hiked 4000 feet vertically with 32 pounds on my back for over 7 miles and felt fantastic!!!

I go for my annual re-staging at NCI/NIH on June 26th.  Wish me luck...

Elves' Chasm

Rappelling down a canyon wall

The Ravine to Royal Arch Creek

The Royal Arch!

Desert Blossom

Toltec Beach on The Colorado River

Night Hike and Water Filtering Mission

Sunday, January 20, 2013

It's Been Awhile...

It's hard to believe my last post dates back to July, 2011.  So much has happened since then.  Shortly after my last post, I experienced a significant drop in a type of white blood cell known as neutrophils, which I attribute to an effect known as Rituxan-related late-onset-neutropenia (LON).  I quickly recovered with the help of the expert staff at NIH, where I am being treated.  The neutrophil count of 700 that I alluded to in my last post was just the beginning.  I dipped all the way down to 0 but recovered quickly with the help of neupogen (aka: Neulasta), a hormone that induces the marrow to produce neutrophils.  Everything worked out fine in just a few days.  I'm grateful for everyone at NIH who treated me and helped me recover.  They are fantastic!

Otherwise, I've been working hard and just enjoying life.  Great progress has been made with respect to early treatments using Vemurafenib  (aka PLX-4032), the BRAF V-600E inhibitor that targets the mutation specific to nearly 100% of hairy cell classic cases.  UVA rays from sunlight induce the mutation (the same one that causes 50% of melanoma cases).  In other words, the cause of hairy cell leukemia is sun exposure.  A refractory patient in Germany was the first I know of to receive Vemurafenib, and now a patient in England -- an incredibly courageous individual who has seen more hardship over the past two years than I can imagine.  He's a pathfinder and an inspiration to many of us.  Both patients had given up hope of achieving a meaningful remission with the known chemotherapies (Cladribine, Pentostatin, and Bendamustine) and tried the Vemurafenib as a last hope.  I believe one of them got down to a platelet count of 10 (out of 160,000) when he started treatment.  This new drug appears to be working well -- melting away the refractory hairy cells, and also is being investigated to treat papillary thyroid cancer, which is also associated with the BRAF V600 mutations (thus probably caused by excess UVA exposure). 

NIH is preparing to start a trial in March, 2013 for refractory and relapsed patients that will investigate two other BRAF V600 inhibitors to treat HCL.  I will post a link to that trial and protocol when it becomes available.  Interested individuals should contact Dr. Kreitman at NIH. He always welcomes direct calls from patients (see his number in the blog sidebar). 

Personally, everything is well with me.  My counts are still great, and I had a peripheral blood flow cytometry test last week which was negative for hairy cells.  My last bone marrow biopsy was in June, 2012.  The core was negative for hairy cells, and the aspirate only showed 0.08% hairies, if I recall correctly.  I've started rowing 2 to 4 miles every day and hope to join a local rowing club soon.  The only daily supplement I take is 1000 IU of Vitamin D in the winter and early Spring.

I continue to highly endorse NIH for both new and refractory/relapsed patients.  The Cladribine + Rituxan trial has had a 100% remission rate for new patients (over 70 now), which is amazing.  I know I'd be in a very different position right now had I not received both rounds of Rituxan when I did -- to treat minimal residual disease instead of relapse.  My participation in the trial made all the difference in the world between achieving a CR (complete remission) and being among the 20% of patients who do not with just standard chemotherapy. 

All first time HCL patients should call Dr. Kreitman at NIH to discuss treatment options and submit research samples before proceeding with treatment, regardless of whether they decide to seek treatment at their local hemoncologist or NIH.

Just one more thing:  Here is a link to 15-year-old Jack Andraka's TED talk.  At 3-cents, his carbon nanotube antibody-based sensor (patent pending) costs 1/26000th that of the $800, 60-year-old ELISA test for pancreatic cancer and is 100 times more sensitive.  The possible applications cover a broad spectrum -- from water contamination to HIV detection, and will improve the lives of billions.  He's showing us that innovation can bridge the gap between providing services and cutting costs.  Glad Intel and the school systems are still supporting and promoting science fairs.  This is one helluva return on investment!!!

Happy New Year to All!

- Jon

Here are some articles related to the BRAF V600E mutation and HCL Classic:

The BRAF V600E Mutation in Hairy Cell Leukemia

BRAF Inhibition in Refractory Hairy-Cell Leukemia

Thursday, July 7, 2011

Hairy Cell Leukemia: Mission Accomplished!

I was going to call this post "A Little Bit of Everything", but fortunately my plans have changed! 

I did it!, or should I say "Dr. Kreitman and The NIH Trial to Treat First Time HCL Patients did it!"  All of my tests are now negative:  peripheral blood flow (looks for hairies in your veins), bone marrow and most importantly bone marrow aspirate (the liquid in your bones where cells develop) are all negative!  I couldn't have done it without the NIH trial.  If you recall, it's taken me a little over two years to get here. 

The initial treatment with Cladribine only led to a partial remission, and I still had 30% bone marrow infiltration and positive blood flows at 6-months post-chemo (November 2009).  At that point, I had my first Rituxan treatment (8 rounds over 8 weeks).  I achieved a complete remission (CR) 6 months later, in May 2010, but still had hairy cells in my bone marrow aspirate (a value not included in determining CR).  That 1st CR was short lived.  The cells in my aspirate continued to proliferate and upon restaging in December 2010, my bone marrow infiltration was back up to 5% and the peripheral blood flow showed .04% hairies.  Although my complete blood counts (CBCs) were at remission levels, the marrow infiltration indicated it was no longer a CR and positive flow results for hairy cell indicated minimal residual disease (MRD), so I was retreated with Rituxan for the second and final time in accordance with the trial's protocol.  This latest treatment wiped out the hairies in all areas to undetectable levels.  I'm not completely out of the woods.  Time will tell if this is a durable remission, but one thing's for sure:  The combination of Cladribine and Rituxan did what Cladribine alone could not without waiting for relapse or subjecting me to multiple rounds of chemo.

Although I've wiped out the hairies, I have one more minor hurdle to jump.  As I discovered and wrote last year, there is a documented phenomenon that occurred in 20% of lymphoma patients, who received combined chemo and Rituxan therapy, known as Rituxan-related late onset neutropenia (LON).  The nadir (low point in counts) typically occurs 14 weeks after the last dose of Rituxan when the counts dip to about 660 (average).  The effect lasts for about 4 weeks.  I noticed a similar effect happened to me after my first Rituxan treatment and blogged about it then.  You'll also recall that I've been interested in seeing if it would happen again.  Well, it happened again!  My 6-month CBC (16 weeks after my last Rituxan dose or 24 weeks after I started this cycle) indicates that my neutrophils are at 750.  Although it appears to be slightly later by 2 weeks, I don't get CBCs often enough to say whether the low-point occured at 14 weeks or not. 

Still, it is statistically in keeping with the findings of the lymphoma study.  I believe I've discovered and am the first documented case of this occuring in an HCL patient.  Time will tell as my recovery and other patients are studied.  I expect to be at a remission level in 3 weeks, when I have my next CBC.  So technically, I'm not in a CR until the neuts jump back up, but I don't really care.  Everything else is in great shape.  Based on my first experience and knowledge of RTX LON, I consider it a nuance that will quickly recover; however, I won't be surprised if the duration of this neutropenia is slightly longer than the first time.

So far it's been a great summer.  My youngest daughter, who was born a year after I was first treated, started walking on her first birthday and can now say the letters in her name.  My 3-year old is doing great and having lots of fun with her garden and playing in the sand and taking swim lessons.  We recently headed up to Lancaster, PA to visit Dutch Wonderland and the Thomas the Train event at Strasburg railroad in our new Swagger Wagon (a Honda Odyssey). 

The sun and I have also come to terms.  I'm going to wear sunscreen and s/he's going to lay off me for awhile.  Likewise, I've set up a portable 60 Watt solar panel array to charge all my mobile devices and run my low power electronics to pay her/him hommage.  Yes, I'm a gadget geek, but if the power ever goes out, I'll still have my iTunes!  I also just bought a kayak and will be taking lots of late afternoon trips on the Potomac this summer.

Yippeekayay !!!

Friday, June 10, 2011

All Hail Ra

I know it's been too long since my last post!

I've got lots to discuss and I'm short on time right now, but I wanted to share an interesting "Science Daily" article that I just found.

It states:

The researchers demonstrated that B-cells are deficient in one of the main DNA repair pathways, known as Nucleotide Excision Repair. This pathway repairs a lot of different DNA lesions, including UV-induced damage and chemical adducts (e.g. from air pollution and cigarette smoke). Their model therefore explains why strong UV exposure (e.g. unprotected sun bathing) is the number one environmental risk factor for lymphoma and also supports the evidence that exposure to air pollution and smoking are also risk factors.
Dr Nouspikel said: "Lymphoma is one of the ten most frequent cancers in adults in the UK, and the third among children. If we want to come up with efficient strategies for prevention and therapy, it is crucial to understand what causes it. The novel mechanism we have discovered potentially accounts for the development of many different types of lymphoma. It may also explain why strong exposure to sunlight is the main environmental risk factor for this cancer."

This supports my theory than sunlight may cause mutations (specifically cytosine deamination to uracil in RNA) that cause HCL!  Likewise, it reinforces my hypothesis that the reason they can't sequence my hairy cell DNA is because there is a mutation in my DNA corresponding to the primer they're using which the DNA repair enzymes either failed or don't attempt to repair.
I've got lots more to talk about, like mcl-1 inhibitors and new data at 15 weeks after my last Rituxan treatment that supports my Rituxan-related late onset neutropenia (LON) hypothesis, but it'll have to wait until I have more time.  I'm still waiting to get my latest flow results.

There was a huge Coronal Mass Ejection (CME) 2 days ago that spanned half the surface of the sun and is headed our way, so wear sunscreen!

6/11/2011 update

Wow!  Just one day later, one of my fellow HCL'ers (shout out to Vincent) found this announcement:

It states that HCL has been narrowed down to a single common gene mutation, BRAF V600E.  BRAF is a gene most widely known for its involvement in melanoma.  This is groundbreaking, and since the leading cause of BRAF V600 mutation is excessive sun exposure, gives further credence to my hypothesis that sun exposure is a leading cause of HCL.  All these studies are starting to add up and reinforce that hypothesis.  It also means that clinical trials with BRAF V600E inhibitors like PLX-4720, which are highly active in treating melanoma, are warranted in patients with refractory and relapsed HCL.  Perhaps a PLX4720-assisted Cladribine / GA-101 trial in refractory and relapsed HCL'ers is in the future...

Here's the published study.

These findings may lead to the development of mouse models for HCL research: 

"On the basis of our findings, it should be feasible to develop murine models of HCL by activating the RAS–RAF–MAPK signaling pathway in specific B-cell subpopulation."

"Strikingly, a T→A transversion occurring at position 1860 of the messenger RNA RefSeq NM_004333.4 and resulting in the V600E variant was found in samples from all 47 patients with HCL..."

I'm hypothesizing that the transversion is sunlight induced.  It will be interesting to see if research related to the first study I cited can determine whether DNA excision repair related to BRAF V600 is inactive during certain stages of B-cell maturation (specifically en route or at the germinal center stage).

It's all coming together.  Needless to say Eddie Vedder's "Hard Sun" is going to be the backup soundtrack for my next bloodcount video...