Science & Medicine

The MPN Patient’s Dilemma

The MPN patient’s dilemma

Reflections on our current and future treatment options, drugs, genes, stem cell transplant, deadly delusions and the dawn of reason.

The reported attempt by a group of investors to gain rights to Sanofi’s fedratinib brings the MPN patient’s dilemma into sharp focus. The report surfaces after Zhaohui Ye at Johns Hopkins demonstrated CRISPR’s ability to clip out the JAK2 mutation in a human stem cell.

These two events – bringing back a failed JAK2 inhibitor and opening a new path to a cure —  are the prism through which we can clearly see the clash of the past and future in the practice of MPN medicine.  And the root of our dilemma as MPN patients seeking treatment.

Today, a decade after the JAK2 discoveries, the landscape of MPN therapy has expanded, become more highly populated…but remains fundamentally unchanged.  All around us we see both the benefits and limitations of treatment aimed at modifying the effects of our MPNs through development of some Magic Pill.

A deadly delusion

There is no Magic Pill, there is no free pharmaceutical ride.  To suggest the possibility is to promote a deadly delusion.

Every drug we take exacts a toll on our body.

There are claims for cures and semi-cures, for partial and complete remissions, but in the end a prescription for ET, PV, or MF remains a Casino chit that can only be cashed in at the craps table.  Treatment by one of the very few deeply experienced and skilled MPN specialists practicing worldwide might improve our odds but it’s still a gamble.

Precise and dependable long-term control of MPN blood line production, inflammatory cytokines and symptoms now, just as a half century ago, remains firmly out of reach for most of us.

We are never going to cure MPNs by treating the effects of this disease.   MPNs started with a stem cell mutation and will only be ended by repairing that mutation.

There’s a whole flock of new drugs in the development pipeline,medicne masked drugs that have crude and unpredictable epigenetic impacts on our systems, drugs targeting methylation, heat shock proteins, histone deactylases, telomeres, etc…plus the  multiple flavors of JAK inhibitors.  The sheer variety of approaches is indicative of our lack of certain knowledge.


We are never going to cure MPNs by treating the effects of this disease.   MPNs started with a stem cell mutation and will only be ended by repairing that mutation.  Everything else is a holding action,  partial, expensive, and limited.

Dealing drugs

There are times MPN patients simply need drugs to relieve pain or other symptoms.

The National Cancer Institute lists 30 drugs FDA-approved for MPN treatment!    It’s a bit of a stretch since virtually all drugs on that list are for post MPN blastic AML (Acute Myeloid Leukemia) or for Chronic Myeloid Leukemia.

The only readily recognizable drug on the list is Jakafi.  Our basic medicine cabinet of hydroxyurea and interferon didn’t make the cut. Neither drug has ever been FDA approved for MPNs.  (For an in-depth look at the interferons which are uniquely effective at certain MPN stages, please see the Interferon Papers.) 

But even Jakafi, the blockbuster FDA approved, kosher-for-MF wonder drug has unpredictable and unintended effects. jakafi label To reduce splenomegaly, relieve symptoms, improve quality of life, it’s been a bankrupting blessing to have in our medicine cabinets…but it doesn’t work for everyone, doesn’t work forever, doesn’t affect the underlying disease.  It does place us at greater risk of anemia and thrombocytopenia.  Jakafi’s current FDA-extended approval for PV patients seems more a triumph of creative research design than a major therapeutic advance.

The Sanofi Fedratinib story.

We all know the Sanofi fedratinib story by now, a mismanaged trial resulting in death and severe patient injury. It was a trial capped by a last minute crude corporate pullout abandoning Phase III patients weeks before a much touted FDA approval was anticipated.

Fedratinib was effective for some MF patients, specially for some for whom Jakafi no longer worked. And the deadly effects of Wernicke’s encephalopathy that affected patients was due to reduced thiamine uptake  something that could be monitored and easily remedied.  This inhibition of thiamine, as Incyte investigators reported, “appears unique to fedratinib and is not shared by marketed JAK inhibitors.” (Incyte’s Jakafi is the only marketed JAK inhibitor in the MPN space.)

So, why is fedratinib making a comeback?

One answer is we need it.  Here’s Teresa Blanda telling her story alongside one of our competent, compassionate MPN specialists, Dr. Catriona Jamieson of UCSD.

All the research and tweaking  by drug company labs may not cure MPNs but can produce powerfully beneficial drugs.  A case in point is CTI’s pacritinib, an oral tyrosine kinase inhibitor designed to inhibit JAK2 as well as another activating mutation, FLT3. It’s hard to know how effective pacritinib will be across a broad population or how durable its benefits will be but for now, for Teresa Blanda, “a clinical trial of one,” we can see and hear the immediate results.  It’s working when nothing else was.

Another reason?  Most likely motivation for the possible resurrection of fedratinib can be found in the composition of those working to bring it to market: the investors.  Having bet on a multi-million dollar large scale three phase international trial, why not salvage the investment by bringing out another $10,000/month drug.  It’s not a bad option, specially since there is a ready made niche for it.   Those of us whom Jakafi has failed are that niche.

Whether fedratinib becomes clinically available, or momelotinib, the old CYT-387, ends its long-delayed run up to market we already know neither one is the Magic Pill coming down the road.  There is no Santa Claus. At least not one popping down the chimney with gifts to reward good boys and girls.

Any drug addressing the effects of our MPNs carries a biological pricetag and comes with no guarantee.

And that’s the point.

The impact of one or more mutations in our hematopoietic stem cells is dazzlingly complex, involving multiple related systems, pathways and triggers turning on and off to the beat of individual genomic drums. In drug therapy there is no “one treatment treats all,” nor is there ”one treatment treats always.“

The answer lies not in addressing the effects, but the causes.  And the causes of MPNs, however devious they may be, lie way upstream where the pluripotent blood-producing stem cells reproduce and mutate.

The hope of gene editing

Drugs are the poetry and poison of MPN therapy, hopes, dreams and side effects in the palm of our hand.  Gene editing only offers a prosaic molecular scissor and gluepot.

Gene editing is potentially a means toward precise elimination of clonal disease. There are substantial scientific and technical issues to be resolved before a syringe-full of repaired stem cells can be successfully introduced into our veins.   But meantime there are other roles for gene editing in MPNs.  Like SCT.

The stem cell option and gene editing

For some — too old, too early, too late, too sick – SCT is off the table.  But if the timing and conditions are right and a matched donor available, we have seen how a stem cell transplant can return our friends to us and return them to a full, creative life.

SCT is like massive gene editing.  Traditionally, following preparation for receipt of a new, healthy blood-producing system by wiping out a deeply xenophobic resident immune system, donor stem cells — clear of the deadly mutation —  are introduced into our bodies.

Gene editing of our blood cells outside the body might ultimately provide a better option.  By repairing and re-introducing our own blood producing cells, gene editing by-passes the first step — carpet-bombing the immune system — and eliminates the need for a matched donor.  We ourselves are our own matched donor.

That’s a little down the road. In the meantime, gene editing may well find its first therapeutic MPN use in improving the condition of SCT patients by lowering the allele burden through ex vivo repair of mutated stem cells.

Until then, we have drugs. Thank God.

Until gene editing can improve targeting and demonstrate placement of replicable repair templates in clinical trial, we will need to rely on existing and improved drugs for symptomatic relief.  How long?

As Harvard’s Dr. George Church said, “Our ability to view and alter biology progresses exponentially…”  We have seen the first animal cures, the first excision of the JAK2 mutation from a human stem cell, the beginning of testing studies in loss-of-function mutations in hemophilia and sickle cell anemia.

But it’s only the beginning and meantime we remain dependent on reducing the impact of our MPNs with imperfect drugs.   Our reliance on drugs needs to be balanced with a realistic assessment gained in clear and open communication with our hematologists.

And if that discussion opens with the understanding that we simply don’t know what any MPN drug will do with any certainty, we have a chance to calibrate our expectations.  And good reason to monitor our treatment objectively

No alternative for relief

For symptomatic relief, for relief of pain, swelling, itching and all the rest we have no option but to reach for drugs, gratefully.  The physical long-term cost may be skin ulcers, severe anemia, thrombocytopenia, encephalopathy, toxemia, bleeding and worse but a life of symptomatic MPNs without palliative drugs is unsupportable.

For now,  until a radical shift in clinical practice can move from fighting small fires to extinguishing the blaze itself,  we are damned if we do and damned if we don’t.

And that is the heart of our dilemma. And the urge to bring gene editing to MPN clinical practice as quickly and safely as possible.

ZH sml
Take me back to the Contents

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Comments on: "The MPN Patient’s Dilemma" (3)

  1. Robert Baumeister said:

    Some great points there, Zhen! Gotcha on the GVHD with gene-edited auto SCT. This came out today:

    Looks like myeloablation with CD33/CD123 CAR T cells with an “auto destruct” switch is possible.

  2. Robert Baumeister said:

    Looking forward for the progress that CRISPR will bring to MPNs! I also have a question. You write this:

    “Gene editing of our blood cells outside the body might ultimately provide a better option. By repairing and re-introducing our own blood producing cells, gene editing by-passes the first step — carpet-bombing the immune system — and eliminates the need for a matched donor. We ourselves are our own matched donor.”

    No “carpet-bombing the immune system” means avoiding ablation (chemo, radiation) in autologous stem cell transplant with gene-edited autologous stem cells?

    • Thanks for the observation. Looks like I wasn’t clear. I was discussing SCT as a form of massive gene editing and the problem of tissue rejection and subsequent failure or GVHD.
      Two years ago I wrote a piece for MPNforum titled “Who goes there?” about the major histocompatibility complex. It’s worth revisiting for its view of the immune system. In our concerns over blood production we often ignore tightly related, mutually dependent systems.
      My point was, using our own repaired hematopoietic stem cells PCR’d ex vivo into significant mass we can in effect become our own donors

      The issue of destruction of the mutant JAK2 gene is another matter entirely, one that surely has to be addressed. I’m not sure every mutant gene has to be hunted down and repaired or destroyed. Many of us maintain stable allele burdens with no significant domination of the Jakv617f mutation for long periods of time. And while I don’t know the stats, my guess is a significant minority of us are heterozygous for the mutation as well as homozygous (meaning we are able to maintain one parental DNA strand clear of the mutation). Point is the gain-of-function and immortality conferred by the substitution of valine for phenylalanine in the JAK2 does cause instability but doesn’t follow a direct line to total domination. It’s certainly possible the effect of that and related mutations can be countered through some form of CAR-T if not direct repair. Needless to say, I don’t know and while some of this is hard science currently being implemented clinically much of it will remain in Buck Rogers/Dr. Who territory until the bench work and trials are done. Let’s talk about it when I get back from the gene editing conference in Boston.

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