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

 

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.

http://www.sciencedaily.com/releases/2011/06/110608195159.htm

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!

Later.
6/11/2011 update

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

http://www.medpagetoday.com/HematologyOncology/Leukemia/27009

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...

Hairy Cell Leukemia Trivia

Thought I'd put together a few trivia questions for those of you who want to test your hairy cell leukemia knowledge:

Questions:
1) What causes hairy cell leukemia?
2) Who discovered hairy cell leukemia?
3) In what year was hairy cell leukemia discovered?
4) Where was hairy cell leukemia discovered?
5) What is the formal name of hairy cell leukemia?
6) What protein is overexpressed on hairy cells and the main target of monoclonal antibody therapy?
7) What does the "CD" in "CD20" stand for?
8) Name the primary chemotherapies for hairy cell leukemia?
9) When is Pentostatin typically used in lieu of Cladribine?
10) What's the term for treatment with a monoclonal antibody (mAb)?
11) What is the primary mAb used to treat hairy cell?
12) What other surface proteins are also targeted in hairy cell?
13) Name a well known HCL immunotoxin?
14) Who is Ira Pastan?
15) What is the bacterial toxin used in HA22, and what's its origin?
16) What is the typical cause of fever after treatment with Cladribine (commonly misdiagnosed as "a mystery infection")?
17) What are the three modes of cell death mediated by Rituxan?
18) Who invented Cladribine?
19) Which is the more effective approach for administering Cladribine?
              5 day x 2 hour IV
              or 24x7 drip?
20) At what stage of cellular development is the malignant mutation of hairy cell believed to occur?
21) What is the median age of an HCL patient at diagnosis?
22) Is HCL more prevalent in men or women?
23) What type of cells are hairy cells from?
24) What is the average period of remission for HCL after Cladribine chemotherapy?
25) What percentage of patients receiving Cladribine have a complete remission, partial remission, and no response?
26) How rare is hairy cell leukemia?
27) What does MRD stand for?
28) Is there a cure for hairy cell leukemia?
29) The first case of patient/doctor genetic rights involved hairy cell leukemia and what university?
30) What's the life expectancy of the average hairy cell leukemia patient?
31) When should hairy cell leukemia be treated?
32) What is Hairy Cell Leukemia?
33) What is Bruton's Tyrosine Kinase (BTK)?
34) What Hairy Cell Leukemia (HCL) treatment options are available to multiply relapsed and refractory patients who don't respond to chemotherapy?

Answers:
1) Most cases of classic HCL have a BRAF V600E DNA mutation, caused by a photon from sunlight inducing an RNA translation error in a B-cell (a type of white blood cell) during replication.  This mutation is also common to 50% of melanoma cases, but in that case, it affects a skin cell.  The causes of other variants of HCL are unknown.
2) Bertha A. Bouroncle, MD
3) 1958
4) Ohio State University
5) Reticuloendotheliosis
6) CD20
7) "Cluster of Differentiation"
8) Cladribine and Pentostatin
9) When a patient's counts are so low or health is so weak that a less sudden drop in counts is needed; however, it is sometimes used if a patient doesn't respond to Cladribine.  Pentostatin is administered over several weeks whereas Cladribine is administered in 5 or 7 days.
10) mAb therapy
11) Rituximab (aka: Rituxan)
12) CD25, CD22
13) HA22
14) Head of NCI laboratory of molecular biology and immunotoxin development
15) Pseudomonas Exotoxin from Pseudomonas aeruginosa
16) Tumor Lysis (hairy cells dying)
17) Apoptosis (cell suicide), antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC)
18) Dr. Dennis Carson
19) Both are considered equally effective
20) Later in the differentiation process at the level of the germinal center B-cells, likely in the process of differentiating to a Memory B-cell (per Basso, et al, p.62, col 1).
21) 52
22) Men, by a ratio of 4:1
23)  B-cells, a type of lymphocyte.
24) Ten years.
25) 80%, 15% and 5% respectively.
26) HCL accounts for only 2% of diagnosed/reported cases of leukemia.  However, it may be more prevelant since it can remain "in-check" in many people without ever being diagnosed.
27) Minimal Residual Disease.
28) Not yet, but there are hairy cell clinical trials trying to establish a cure curve.
29) UCLA (link to court case)
30) The average patient will have a normal life expectancy.
31) In general, HCL should be treated when blood counts indicate one of the following conditions:
                 Platelets (PLT) < 100 K/uL
                 Hemoglobin (HGB) < 10 g/dL
                 Absolute Neutrophils (ANC) < 1.0 K/uL
       however, Dr. Michael Grever, in his paper "How I treat Hairy Cell Leukemia (Blood, 10/2009)" states the following:

                   "Therefore, I recommend that therapy be initiated when a declining trajectory predicts that the patient will reach a platelet count less than 100,000/uL or an absolute granulocyte count consistently below 1,000/uL."
32)  HCL is an uncommon, chronic, neoplastic (malignant) disorder of B lymphocytes (a type of white blood cell) that predominantly afflicts middle-aged men. The patient usually presents with pancytopenia (broad spectrum reduction in blood counts -- low platelets, low white blood cells, low red blood cells). In the U.S., there are 500 to 800 cases of HCL annually, representing just 2% of all leukemias. Although it is incurable, it is highly treatable, with an average remission of 10 years.
33) BTK is an enzyme that's critical to the maturation of B-cells.  Inhibiting it, with drugs like Ibrutinib, has proven to be a well-tolerated and effective means of targeting a variety of leukemias and lymphomas.  Clinical trials using Ibrutinib to target hairy cell leukemia in relapsed and refractory patients are now underway.
34)  Multiply relapsed and refractory Hairy Cell Leukemia (HCL) patients should consider the moxetumomab (moxe) clinical trial at NIH.  A majority of patients have achieved complete remissions and in many cases eliminated MRD.