Thursday, 27 April 2017
Dr. Ruben Mesa
MPN patients still have significant unmet needs — particularly those with myelofibrosis.
Anemia is a multi=factorial problem due to several influencers: red cell production, red cell destruction, spleen activity, low EPO, iron, vitamin D, vitamin B, medication side effects. Hemoglobin can be limited by iron.
Treatments: how are they viewed by regulators? Insurance companies vary in the limits of treatment options.
Molecular features are important in determining the course of action.
What is the therapy?
Dosage: what is minimally effective dose by patient type? Variances by time of day or BID?
What are the expected benefits?
How long will benefits last?
What are known risks and side effects
How is therapy viewed by regulators?
What limits are placed on treatments by insurance?
Dr. Cecily Forsyth
Bone Marrow Biopsies: Yes? No? When?
She conducts a BMB on every MPN patient upon diagnosis along with a thrombophilia screen. The BMB identifies the MPN sub-classification and identifies known mutations at diagnosis. This forms baseline data for a chronic blood cancer that can evolve over many years.
Some MPN patients who are not JAK2+ at diagnosis go on to develop the JAK2 mutation.
Learning more about signaling mutations and epigenetic mutations that occur over time. The order in which the mutations occur may affect rate of progression and eventually therapy options.
Splachnic vein and portal vein thrombosis are typically caused by MPN. When the mesentery vein system is also affected, survival rate is very low (around 10%).
Is there an inflammatory response that triggers MPN or does MPN trigger inflammation? We know the JAK2 affects the endothelium.
Most people diagnosed with a myeloproliferative neoplasm receive the diagnosis over one year after symptoms begin.
Dr. Laura Michaelis
Risk assessment models for myelofibrosis (IPSS, DIPSS, DIPSS+) are based on historical data. The mean survival rates are imprecise and scare patients.
Other tests: MIPSS
GPSS shows molecular risk
“These tools have huge confidence limits.”
- Do not include use of ruxolitinib
- Do not adequately predict AML transformation
- Too dull for stem cell transplant decisions
- Not portable
MPNs are not linear diseases. Patients can be stable and quickly progress to AML. We don’t know why yet.
The panel of somatic mutations is still a work in progress, and is retrospective in development.
Still do not know all the gateways to progression.
The sensitivity of the assay is still an issue.
Most insurance companies will not pay for the testing.
Sometimes more information is simply confusion.
Patients are concerned about how the information may be used against them in insurance availability and pricing (health care and life insurance) and in employment decisions.
Dr. David Ross
The quality of pathology reporting varies wildly.
Descriptive reports are more useful than a diagnosis without specific description of what is seen to draw that conclusion.
The order of mutation acquisition and identification of cooperating mutations will help future diagnoses.
The mutation of JAK2C168 can mask the JAK2V617 mutation.
Complete Molecular Response: the allele burden of a mutation is below 1%
Signaling Somatic Mutations:
JAK2 CALR Type 1 CALR Type 2 MPLW515x
JAK2 & UPD9:
Triple Negative (JAK2, CALR, MPL):
10% have germline mutations that appear to be inherited, not somatic. Occur further down the gene than typical for somatic mutations.
Dr. Wendy Erber
Wrote paper published 2017 American Journal of Pathology, Guo, BB, et al.
Dr. Erber does not use the term “pre-fibrotic MF” because there is evidence to show transformation.
The megakaryocytes are larger than normal. They proliferate at 2-3 times normal rate and they don’t die.
She looked at genomes of the megakaryocytes.
The platelets may be the signal of changes in megs.
Dr. Kate Burbury
MPN Mutational Landscape:
MPN Myeloid Panel – includes exons and targeted locations of mutations
The number of somatic mutations strongly correlates with OS and transformation. There are some (5) known to be high risk mutations.
Can we use the mutational profile to treat and reduce the risk of progression?
This is likely possible as new targeted treatments are developed.
Known mutations in three types of proteins:
CALR mutations: CALR Type 1 and CALR Type 2 are different in ET and MF.
Type 2 is mostly in ET
CALR mutants bine and activate MPL. The mutation may be deletion or insertion.
The microenvironment affects the proteins and the mutations affect the microenvironment.
Extra information doesn’t always tell you what to do. And we don’t always know what it mea
Dr. Raajit Rampal
JAK2 inhibitors (Ruxolitinib)
Its efficacy decreases over time.
They don’t inhibit heterodimeric JAK-2
The mutations in de novo AML are different from post-MPN AML.
They are different diseases.
Ruxo and decitabine combined has additive value.
Dr. Andrew Grigg
Allografting for Myelofibrosis
There is a disconnect between primary myelofibrosis and secondary myelofibrosis.
TRM – Transplant Mortality
Risk of relapse post transplant is 40%
Selecting patients: TIMING is everything.
CALR patients tend to do better than JAK2
Decision to transplant is complicated and individualized.
= = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = =