Advances in MPN Knowledge from my conference notebook.
by Marina Sampanes Peed
(Ed.Note: Marina’s trademarked outline style has over the years proven invaluable to MPN patients trying to distill the essence of meeting. Join the ranks of her fans looking over her shoulder as she scribbles in her conference notebook.)
Will My ET/PV Progress to MF or AML?
Work is underway to identify prognostic markers to determine a patient’s likelihood of disease progression. At this time, we still don’t know.
MPNs are not static disorders. They mimic each other and other diseases. They all go through the JAK-STAT pathway.
Questions Remain: Biology is Complicated
We don’t know how and why the JAK2 mutation occurs.
We don’t know why some JAK2+ get PV, ET, or PMF.
Some people have JAK2+ with no signs of disease.
Mutated JAK2 levels (allele burden) do not always correlate with severity of disease. One can be in clinical remission with a high allele burden.
There is no specific diagnostic test for MPN.
The WHO definitions are not accurate (Spivak)
Women get the diseases earlier than men.
Men progress to AML more frequently than women.
New Gene Clues Indicate Transformation to MF
Danish researchers identified a unique 5-gene signature in patients with Primary Myelofibrosis and those with aggressive phenotype ET and PV who were transforming to Myelofibrosis. They used transcriptional profiling of whole blood to study the twenty most upregulated genes in Primary Myelofibrosis.
Five genes (DEFA4, ELA2, OLFM4, CTSG, and AZU1) were highly expressed in a subset of patients with “aggressive” ET and PV who were transforming towards MF. Because some of these genes are thought to be responsible for marrow damage in MF, this gene-signature may shed light on the pathogenesis and pathophysiology of Myelofibrosis development.
Mutation begins quite some time before diagnosis.
Transformed/mutated stem cells will out-perform normal stem cells and establish dominance.
Mutations occur during the disease evolution. Mutagenesis continues over time. It is unclear whether it is changing due to medication or natural evolution.
Somatic mutations in MPN: JAK2, CALR, and MPL. These mutations are mutually exclusive; but they share a key driver mutation (have the same downstream pathway).
Each mutation targets a different feature in the cell communication process. All target the proliferation signal (STAT). Regardless of the mutation, all communication runs through the JAK pathway. This is why the JAK inhibitors work with all three MPN.
These mutations occur randomly; only rarely occur in families. There could be some inherited pre-disposition for the mutation to occur.
JAK2 mutation is detectable in some people with “healthy blood.” This was discovered in a study for diabetes (December, 2014). Raises the question: what factors in microenvironment make the JAK2 mutation trigger MPN?
CALR: It plays a central housekeeping role in the body. All the mutations occur at the end of the gene and result in new enzymes. If we can create a new target for the mutation, then we can cure the disease. They are using CRISPR gene editing to study CALR.
About Treatments in General
All current therapies are poor at preferentially targeting MPN cells over normal cells.
Interferon-alpha shows success with 30% of patients experiencing molecular remission (JAK2-negative) in 4-5 years.
Combination treatments show best results – myelosuppression agent (Interferon-alpha, Hydroxyurea) with a JAK inhibitor (anti-inflammatory agent).
To suppress the immune system in 2 different ways (INFN and JAK inhibitor), there may be impacts we can’t anticipate.
Anemia from disease does influence life span. Anemia from a JAK inhibitor does not influence life span.
About JAK Inhibitors
JAK Inhibitors are very good at symptom reduction but they are not selective (they affect normal and mutated cells, causing issues with anemia, platelet counts, etc.), and they don’t eradicate the mutation.
JAK inhibitors affect other diseases because they affect the T-cells that go through the JAK pathways.
These likely have an effect on the course of the disease, but it is too early to quantify. But indications are they are more than palliative (Mullally).
People on JAK inhibitors are living longer, eating better, feeling better. It is possible that the inflammation suppression does alter the natural history of the disease.
Some JAK inhibitors have not made it through trial due to neurological issues, brain damage.
About Interferon-alpha & MPN
Interferon works best EARLY in the disease process. There is only mild success mid course, and no success when the disease is advanced and the bone marrow is sclerotic.
Pegylated Interferon is a drug of choice for younger women with ET or PV (Spivak)
Interferon benefits: spleen size reduction; blood counts under control; no hemorrhagic episodes; progression-free survival; and treats the fibrosis in absence of leukocytosis.
Interferon side effects: anemia, low platelets. Sometimes nausea, flu-like symptoms, depression can occur. Has caused pulmonary fibrosis. Most intolerance occurs with higher doses. Pegylation improves tolerability.
The Conundrum: High dose to achieve JAK2 mutation change OR low dose to reduce fibrosis and symptoms. Constant balance between toxicity and symptoms.
Promising Treatments in the Future
Gene editing has therapeutic potential. Hope to repair MPN mutations in hematopoietic stem cells. Research is now engineering most common mutations into normal HSC in mice to understand the mutations.
RECQL5: shows higher expression in JAK2+ patients. When this enzyme is inhibited, it kills the mutant cells.
CAR-T cells: used to kill B-cells. Could be used on CALR cells (selectively attack the mutant CALRs and leave the healthy cells untouched). With improved technology, CAR-T may be used in conditioning for stem cell transplant.
Imetelstat: a telomerase inhibitor. When chromosomes divide, the bottom part (telomerase) drops off; losing a bit of DNA. 36.4% of patients in trial had a positive response (decreased platelet counts, decreased JAK2 allele burden); 4 had complete remission. However, liver toxicity was significant and the FDA put the trial on hold for 10 months. 24 patients of the 33 discontinued the trial.
PRM-151: Recombinant Human Pentraxin-2 (a biological protein, also made in the liver). This protein inhibits change from monocytes to fibrocytes. MF patients have much less PTX-2 in blood compared to healthy patients (perhaps because of damage in the bone marrow). PRM-151 is administered as an infusion. In a study of 36 patients, 11 saw improvements with decreased fibrosis.
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