I don't think experts understand or can entirely explain MPN disease progression. Nobody can predict who will progress, how fast, or to which diseases. MPNs were largely ignored until the early 2000s when they were reclassified as cancers. Some experts can't even agree on the reclassification.

As we all know, the mutations cause the bone marrow "factory" that produces healthy blood cells in the right numbers to go haywire. ET typically starts off with just the platelets being high and gradually going up. If you live long enough, more types of blood cells start going wonky. But most patients would have to live well beyond a normal life span for things to get that bad. A few will be unlucky and experience progression.

As I understand it, the only cure is bone marrow transplant, which is often deemed more risky than the disease. Drugs in the interferon family (besremi and ruxolitinib) MAY reverse disease progression and lead to remission, but too early to say. All the other treatments just manage cells for a time, sometimes decades. They may stop working for some people. Again, nobody knows why.

The really hard thing to deal with, as people here post about so often, are the myriad side effects of both disease and drugs. The list goes on and on from migraines to hair loss to blood clots to mouth sores to diarrhea to constipation to leg aches to foot pain to gout to weight gain to fatigue. A few folks have no symptoms, look great, and are running marathons, so it's easy to for the rest of us to wonder if this is all in our heads or if we're just great big babies.

I would say that the psychological effects of an MPN, especially living with the unpredictability for the rest of your life, is its biggest challenge.