HIGHLIGHTS & ODD BUT INTERESTING INFORMATION
by Marina Peed
(Editor’s note on looking over Marina’s shoulder: Marina Peed takes fast, accurate notes. She’s shared her conference reporting in MPNforum before and was part of the team tapped to share impressions at the Joyce Niblack/Mayo Clinic Conference- 2013. Here, just hours after the Conference, are her rough notes, a mini-MPNclinic.)
Are mutations which activate JAK2 a hallmark of all MPN patients?
The mutation occurs in a single blood cell, after birth, that takes over all blood production instructions.
JAK2 mutation is the heavy foot on the gas pedal that stimulates production
What about those who are JAK2 negative with MPNs?
The causes of the disease are probably very similar; probably have other mutations like JAK2 exon 12 mutations, or loss of function mutations in LNK, negative regulator of JAK2.
LNK is the gene that puts the brake on blood production.
Even if you eradicate JAK2, the TET2 mutations persist.
- The JAK2+ cells can continue in some EPO-independent colonies
- Patients who evolve to acute leukemia lose JAK2 positivity
- More mutations seen in poor responders to IFNa
Now doing more Whole Exome Sequencing to identify MPN Alleles*
So far, sequenced 40 exomes from MPN patients and sequenced members of 2 families with high penetrance MPN *to find familial predisposition locus.
Q: With so many other mutations, is important for patients to know if they have any of them?
How does someone with PV know if they have the TET2 mutation?
A: The JAK2 mutation is the primary one we look for. It indicates a clonal stem cell disorder.
Use clinical signs & JAK2 mutation in MPN diagnosis. Not part of the prognosis process.
The TET2 and LNK and other mutations are still in the work of research labs.
Some day, labs may run all these but not yet.
With modern treatments, life expectancy for ET and PV is quite good. Knowing about the mutations not so important.
With MF, the mutations are more important because the disease is unstable.
- Will take months to years to find true “drivers” which cause MPN versus “passengers” along for the ride.
- Hard to determine which mutations are important relative to MPNs – need to look for recurrence (in larger number of MPN patients)
- Many mutations may not be specific to MPN, but might be seen in other leukemias like MDS, AML
- AML after MPN is a different disease from de novo AML. Need different therapeutic approaches.
- JAK2 is activated in all MPN patients, regardless of mutation.
- What mutations occur with AML so we can work to prevent transformation to AML?
- Are there cooperating somatic mutations?
Perhaps it is the presence of other mutations that determine whether you have ET, PV, or PMF.
Interferon may be the best treatment to control the proliferative aspects of PV.
- INF plus JAK2 inhibitors and other drugs for symptomatic relief.
- In 2012, treat for clinical response, not for molecular response to avoid toxicity.
Anemia has been documented to cause thinking problems from mild to severe.
Q: Parameters for when transfusions are appropriate?
A: RBCs carry oxygen from lungs to the rest of the body. Different people can tolerate different levels of Hgb.
Don’t want anyone going below 7.0 – organ distress… don’t get it if above 10.0
8.0 is the average.
Q: How can Anemia be treated?
A: Anemia is considered significant when Hgb <10.
Danazol, Procrit, Thalidomide…
Some investigational agents are also underway, like Pamolidomide.
General Q&A of all the Doctors:
Q: When to use JAK2 inhibitor?
A: Jakafi is good for people who are symptomatic of the disease.
Not to be used if have not symptoms, or anemia only.
Q: When the spleen is enlarging, what is going on?
A: Extra-medulary hematopoiesis – the cells implant and tries to take over blood cell production.
Results in ineffective hematapoeisis.
Q: If a spleen is large and painful, does that mean it’s producing lots of good blood?
A: Not necessarily. No correlation between size of the spleen and its blood production.
Q: How often to get BMB?
A: The BMB tells us if there is scarring (fibrosis), the cytogenetics, how it appears (blasts)
Is it being done for diagnosis, baseline measure.
Repeat when we want to see if the therapy is improving the disease.
Repeat when looking for signs of progression.
Someone in 30s or 40s who presents with ET needs a BMB for baseline.
= = =
Dr. Susan LeClair did a great presentation on the most important information & measures we need from our lab work.
CBCs: the time of day impacts blood counts. Try to get your CBCs done around the same time of day for more accurate comparison over time.
These are the indicators Dr. LeClair would track on her labs spreadsheet (with explanations that follow):
WBC ANC HGB MCV MCH RDW PLT Uric Acid LDH
Reference Range/Interval: reflects what 95% of all the people in my area should have – population based. RR will change by methods used in each lab.
Value: you want to track your personal changes
Dr. LeClair shared why the Hemoglobin count is far more accurate than Hematocrit:
Hemoglobin (Hgb) – concentration of oxygen carrying protein
Can quantify the hemoglobin that has oxygen and the hemoglobins that do not or cannot
Remains consistent regardless of cell size.
Men have different RR than women. RR also varies by age and location (e.g., altitude)
Hgb count is lower in the evening.
Hemoglobin – issues in over-production
More cells make the blood more viscous (e.g., jello w/a lot of fruit compared to plain jello)
Hematocrit (HCT) is calculated from the MCV (avg red cell size – mean cell volume) MCV x RBC
Our red cells vary widely in size
RDW: red cell distribution width – tells the variability of the size of the red cells
If all cells consistent in size, RDW = 10ish
If cells vary wildly in size, RDW = 14ish
If the RDW is increasing, the HGB is decreasing
Q: What’s the difference between Blasts in peripheral blood vs. Blasts in BMB
A: Differential – everyone has up to 5% blasts in bone marrow.
As fibrosis worsens, more blasts in the blood.
When more than 20% blasts in marrow, it’s acute leukemia
Blood cells grow in the bone marrow likes grapes on a vine.
The blast counts mean different things if patient has MF, MDS, or CML…
Q: How do we choose a BMT center? Does more disease-specific knowledge matter?
A: It can be confusing. Get different answers because the results are less than optimal and different centers approach from different angles.
Look for centers that have done transplants for MF patients because many issues post-transplant are specialized for MF. Conditioning pre-transplant and measurements post-transplant.
MF SCT Specialists: MDACC, Hutchinson, Mayo, Dana Farber
Q: Impact of too much iron (ferritin) from chronic transfusions?
A: We get more iron from blood transfusions than we get from diet. It impacts the blood values.
There are 3 meds that reduce iron (iron-chelating agents), but they are very expensive and have side effects. A lot of PR around these meds (highly profitable for pharma).
There is a big difference between progression of the disease and losing a response to a treatment.
Progression is when you get worse from your baseline.
When treatments are not as effective as they used to, that is losing response. Then need to adapt the treatments.
© Marina Peed and MPNforum.com, 2013. Unauthorized use and/or duplication of this material without express and written permission from this blog’s author and/or owner is strictly prohibited. Excerpts and links may be used, provided that full and clear credit is given to Marina Peed and MPNforum.com with appropriate and specific direction to the original content.
Comments on: "Marina’s notes" (3)
You are amazing in many ways, Marina. Peace, hugs and prayers………………Kathy
Thank you for sharing your notes with us.
Wow, you took MUCH better notes than I did, Marina! I was too busy eating all the snacks they kept putting out for us. Thanks for sharing these….