Science & Medicine

TSR — Autumn reflections 2021

Science Short Shots…

The List of Good Docs changes hands

Stem Cell Transplant –  the Chimaera

Asheville –birthplace of MPNforum

New York Times writer on her MPN journey

Science Short Shots...


Normal life span with PV new research from Silver et al. in Leukemia…

GVHD and Jakafi…. One of the most common steroids used to treat Graft Versus Host Disease cease being effective in about  50% of patients…The FDA approed ruxolitinib (Jakafi) as a second line therapy after failure of systemic therapy. The overall response rate in clinical trial (NCT03112603) for rux was 70% vs 57% for the best available therapy. Duration of response was 4.2 months for Jakafi vs 2.1 months for the BAT arm.

In the past decade for MPN therapy we’ve had the same basic trio of drugs available to us.. Hydroxyurea, interferon, and Jakafi (the first two of which, not approvedf for MPNs by the FDA, available off label only. That slim forumlarly, .with slight variations from newcomers, has been it — despite billions of dollars invested by drug companies in Jakafi lookalikes. Research into the genetic roots of our MPNs was stifled as labs and universities chased the JAK2 inhibitor pot of gold.

But now it’s really a new era. Molecular research, whole genome sequencing, single cell tracing, genome wide micro-arrays and the introduction of new gene editing capabilities has already resulted in discovery of dozens of mutant genes contributing to MPN progression as well as successful intervention in other hematopoietic cancers. MPNs are complex because of the early acquisition of driving mutation and mu;tiple cellular mutations during the long latency period — 20-40years in most cases before symptomatic eruption and diagnosis…But we now have CRISPR, the immunotherapy tools — and clinical proof — that early genetic testing and intervention can stop MPN in its tracks. It’s already been done with sickle cell, multiple myeloma and CLL the most common blood cancer Meantime, the interferons are available to us and highly effective under the right circumstances and we have palliative drugs and meds to inhibit proliferation. And we have a community of committed researchers, patient advocates and each other for support while waiting for a breakthrough. ..Our role as patients: Follow the research, partner with our docs, keep informed, and maintain the realistic hope that we’ll still be here when MPN is not.

.All COVID vaccines are not created equal… This new one gets under your skin.

According to the LA TImes:   Data collected from 18 states between March and August suggest the RNA based vaccine   Pfizer-BioNTech vaccine reduces the risk of being hospitalized with COVID-19 by 91% in the first four months after receiving the second dose. Beyond 120 days, however, that vaccine efficacy drops to 77%. ….Meanwhile, Moderna’s vaccine was 93% effective at reducing the short-term risk of COVID-19 hospitalization and remained 92% effective after 120 days.

Meantime, India announced approval of the world’s first DNA COVID-19 vaccine, ZyCoV-D,   61% effective when tested against the DELTA variant. ZyCoV-D is delivered via three “shots”  under the skin through a high pressure stream of fluid that punctures the surface. Reportedly the vaccine  is both less painful to administer and far more stable to ship and store.   Under development since the 1990s, DNA vaccines were in restricted use since they need to make it all the way through the cell to the nucleus to be effective. The under-skin application just needs to get to the cytoplasm and its pathway is both quick and rich with antibodies.  Both the RNA and DNA vaccines  target the virus’ Spike protein to inhibit attachment to cell receptors.

The New England Journal of Medicine reported on the Israeli booster progam and the waning effectivenss of the Pfizer vax.   “In early June, fewer than 20 cases of Covid-19 were confirmed ….and approximately half of those cases were diagnosed in persons who were returning from abroad. At that time, the number of active severe cases reached approximately 20. By the end of August, more than 10,000 confirmed cases were being detected daily, and more than 600 persons with severe cases were hospitalized.

Several causes are possible for the high levels of transmission of the delta variant, including the increased infectiousness of the variant,3 waning vaccine-elicited immunity,2,4 and heightened immune evasion by the variant. Of these causes, the latter two directly contribute to a decrease in vaccine efficacy. An analysis of the Israeli data with respect to the outbreak of the delta variant indicated a high degree of waning immunity.

Mutations are the engine that drive MPNs. It’s an engine that chugs along for the life of the cell, building on every cell division. The long  process of evolution writes its creations with keystrokes of tiny errors.  Each typo a mutation.  Every cell division, piles up small changes in the resulting daughter cells.  A jumbling of the DNA alphabet of CGTA bases — cytosine, guanine,thymine,  adenine… a deletion or insertion, a transposition, a frame shift.

With each human cell duplicating its 3 billion base pairs every time it splits, likelihood of a typo here and there is inevitable.Over the lifetime of a  cell 1.7 mutatons are acquired per cell divsion….An additional 0.7-3.9 cell divisions per year provide a competitive advantage to the MPN -producing JAK2 v617f mutant over native or Wild Type blood producing stem cells. Mature blood cells can have hundreds of mutations.

Here are some  random numbers from a recent paper that present a new perspective on MPNs.  The JAK2v617f mutation – the prime driver of MPN – emerges early on, frequently  in the womb and early childhood…. There is a long –30-40 year – latency period before diagnosis and treatmentFor the slowest growing mutant JAK2 clones it takes an estimated 40 years for the mutant cell fraction to reach a 1% allele burden, which is about 10 years before diagnosis… Say the authors. “With sensitive technique detecting up to 1 in 10,000 aberrant cells,it would have been possible to detect mutant Jak2… 10 to 40 years before disease presentation..”.. ….

Addressing the early eruption of the JAK2V617F clone decades before its dominance and major impacts on the hematopoietic system would change the MPN treatment paradigm from disease control and palliation to eradication.”

The key is very early diagnosis – expansion of genomic testing in early childhood and adolescence when MPN predilection is suspected or appears as a familial germline feature. Early diagnosis and gene editing are the most promising avenues to finally cure MPNs. Currently, late and crude diagnosis based on m clinical tests, CBC and blood morphology encourage limited, delayed treatment of advanced MPN disease. As a result, for some of us the only survival option is complete hematopoietic system replacement through stem cell transplantation..

The List — the end and beginning of an era.

Inroducing Ben Hansen new editor of the List of Patient Recommended Physicians.  Ben was raised among the cornfields of Iowa, but decided that was too much stimulation, so he traveled Europe and Asia before trying to make a living banging on keyboards. He plays chess and the harmonica, badly. Today marks his first turn at the helm of the List.

Ellen Jaquardt.  For a most of a decade Ellen has been working quietly in the background, building the List from a few names to a global spanning collection of over 400 good docs. The results of her work are open to all, without charge, and the MPN community came in force. Over 200,000 visits, downloads of recommendations, conversations with recommending patients, new relationships, second opinions and new healthcare partnerships grew out of the List.  And always, behind the scene, was Ellen. We don’t know much about her. We know she has advanced botanical degrees, is a Hoosier defending native plants and a warrior fighting invasive species. On Facebook we’ve seen her remodel rooms, undertake large scale DIY projects with her husband, Hank, but that’s about it.  She has always been there for us when we needed her. We have no good way to acknowledge her unselfish service to our community beyond simply saying Thank you.  Ellen, you’ve a made a significant difference in many lives.

To produce the physical List of Patient-Recommended Doctors takes a ton of documentation, fact checking and computer wizardry.  Here’s a parting  description from its normally silent editor.

Ellen:Handling the List for the last ten years has been a testament that old dogs can learn new tricks. I’m not particularly good on computers, but Zhen’s encouragement and nudging had me learning WordPress (honestly, I’m still not clear what html is, but turns out you don’t really have to understand it to make it work), how to do tricky transpose pastes in Excel, and all kinds of new-to-me computer skills to make and update the List. It’s been a great run, but other volunteer activities are taking the fore, like being president of the Indiana Native Plant Society and of the Monroe County – Identify and Reduce Invasive Species group. I’m happy that Ben has stepped up to handle the List updates and given his very real computer skills I’ll bet the List is going to have significant improvements going forward. T

“Thanks for all of you who have recommended your doctors – you made the List what it is.”

Stem cell transplant — a reflection on creation of the chimaera

There is an essential contradiction built into the stem cell transplant decision. Clearly it is the young, the less burdened with myelofibrosis or other blood cancers, who will do better on this journey.  And are the most reluctant.   A high risk, end stage MF or AML patient often has little choice.  But for the intermediate-risk, relatively healthy patient with progressing disease, SCT means trading a potentially manageable MF for the unknown rigors, restrictions, and risks inherent in stem cell transplant.

It is not an easy decision.  No one comes out the other side through the same door they entered.  Life is permanently altered — often miraculously better, sometimes terribly worse.

In this bid for renewed life, there is one assured death. Destruction of one’s native blood-producing system, of one’s core immune system, a necessary passage to make way for the life giving blood-producing stem cells provided by a generous donor.  Eradicating the patient’s own blood-producing capability has life changing implications.

Once the donor cells are introduced  and find their way into the bone marrow, the patient’s transformation begins.

Every blood cell, eventually, will have new DNA.  The patient has become the Chimaera, the mythic creature made of parts from different animals.Soon every cell in the patient’s body will be washed in new blood carrying nutrients, oxygen, carting off wastes, exchanging gases and fluids, bearing warriors prepared to do battle with foreign invaders.

In this transformation is both hope and danger. The river of donor blood carries its own gene-driven disease fighting capabilities, including T-cells searching out pathogens by brushing up against every cell in search of alien proteins. Thus the donor cell that brings new life will also attack those patient cells that appear to be foreign.  Graft Versus Host Disease can be minor and even helpful as well as serious and life threatening.  The close match of donor and patients — Human Leukocyte Antigens, the gene sequence coding for the signalng system on the cell surface– is designed to minimize this collision of cultures.

Integration of the Chimaera into the labyrinth of our multiple biologic systems is the beginning of new life. Happy Birthday!

My Asheville, North Carolina — a reflection on the birthplace of MPNforum

Western North Carolina, my adopted country. I left California to come East under extraordinary conditions. Near the end of the dot com boom.  My mother died. My house burned down. George Bush was elected President. It all happened in the space of three weeks.

The country I came to was magical. Homeless, SAMSUNG I was on a tour, on my way from someplace else to some other place when I first saw Asheville.  It was the merging of Woodstock and Berkeley, .two poles of my youth, it was mountains and three rivers. I had come home to a place I never saw before,.

Dualiaties and contradictions. Asheville, the town Thomas Wolfe couldn’t wait to leave, is a half mile high Appalachian valley, in the foothills of the Blue Ridge and Smoky Mountains.  Tucked in the western  corner of North Carolina, the town neighbors Tennessee and South Carolina, a few hours from Atlanta. Although Conferederate during the War between the States, there was a strong Union sentiment in town and the neighboring Madison county.  Knoxville, up the road,  was Union-held throughout the war.  And although Asheville was never much of a slave holding state – no plantations,  small scale tobacco and black dirt mountain farms – it became a major slave trading market in the last days of the war as Southerns fleeing Northward on the French Broad River brought with them slaves to sell.

These dual streams, slavery and freedom,  wild landscape and the Chamber of Commerce, South and North, characterize Asheville to this day. A liberal town set in a solid Baptist core, changing rapidly under the impact of a surge of outlanders, its old Southern charm is garlanded with gated communities and condos, luxury hotels, boutique food chains and busking street musicians..

My home in West Asheville,  a small yellow bungalow, nearly 100 years old, is on a long rise above the River Arts district. A village that used to be called Sulphur Springs before it was absorbed into Asheville, West Asheville is in that intermediate stage between seedy auto repair and parts shops and pricey coffeehouses and upscale restaurants. Local tailgate markets and sustainable, organic foods predominate. Teddy Roosevelt visited here once. F. Scott Fitzgerald lived here briefly. His wife, Zelda, died in the fire that burned down the Sulphur Springs Hotel.

Autumn 2021 serves up another dualtiy.  Peaceful golden light in the midst of a pandemic and furious political divisions.  It’s late enough in the year for the mosquitoes to be mostly gone,  the weather is warm and moist, afternoon thunderstorms often a possibility, fireflies at night as darkness thickens over the lawns and street and gardens.r

The final contradiction.   It is out of all this that MPNforum was conceived and  born,

in this place far removed from  any connection to myeloproliferative neoplasm there are likely few or no others with the disease within easy driving distance.  Not an MPN specializing hematologist in town, mountain or valley..

Almost all  my engagement with MPNforum, with its thousands of patients, doctors, researchers, and caregivers,  has been viewed through the window of my computer, monitor on a desk in West Asheville,  Nearby a dog wating for a walk and a parrot loudly complaining much of the time. The overhanging Blue Ridge Mountains a towering witness in the background

A New York Times writer on her MPN journey.

(Editor’s Note: There is some truth to the reporter’s claim that WHO’s reclassification of Myeloproliferative Disorders (MPD)  Neoplasms (MPN) as a blood cancer impacted funding for research. A much bigger impetus however was the FDA’s approval of Incyte’s ruxolitinib, its billion dollar myelofibrosis drug, in 2011. Marketing success of Jakafi triggered a multi-billion dollar tsunami of lookalike research, acquisitions and clinical trials as drug companies competed for a piece of the action. ) If the linke takes you to a NYT paywall, try this:

Thank you!

With special thanks to Carlos Garces,  Helen Iden,  Jeremy Smith, Avraham Dworsky, Trisha Margeson, Mary Cotter and, of course, Ellen Jacquart, for continuing support of MPNforum publications.

Looking for something?

The new and expanded LIST of MPN Patient Recommended Physicians… 

To get to the MPNforum Magazine iSummertime 2021 Issue with the MPN Symptom Assessment form, and Dr. Nicolaus Krogers paper on Survival Odds after Stem Cell Transplant plus links to the full MPN Clinic Index and Responses, HERE.

For last month’s issue on Mutations, inflammation and research that turned MPN diagnostics on its head go HERE

The current issue of the MPN Quarterly Journal has much more on the mutations affecting us.

For a quick check up on your own progress, there’s both the MPN Symptom Assessment Form and the Myelofibrosis prognostic scoring tests on the MPN MAGIC site.

You can always find Back Articles and Issue Covers with links at The Catalog page:

If you’re really stuck go to Google, type in MPNforum: followed by a description of what you’re searching for.  Or write us at Always good to hear from you.

MPNforum, PO Box 17142, Asheville, NC 28816
Donations to MPNforum are not tax-deductible

© MPNforum, LLC ,, and the MPNforum Quarterly Journal 2021. MPNforum are licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Reproduction is permitted provided full and clear credit is given to authors and with appropriate and specific direction to the original content.

Comments on: "TSR — Autumn reflections 2021" (2)

  1. Janet Cardenas said:

    Wish I could read the article in the New York Times by Ruth Fein Revell, but I don’t have a subscription.

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