Myelofibrosis with a Silver Lining
Take two aspirin, call me in the morning,
By Zhenya Senyak
You didn’t go to the big New York MPN Symposium.
Why would you?
If I didn’t have a daughter with a spare futon living on the Upper West Side and wasn’t given a press pass there’s no chance I would put my animals, my credit card and myself through the hassle to hear people say things I could better understand in print or on YouTube.
So when I ended up a week later back in North Carolina, I was surprised at how much fun it was, how many new perspectives I picked up. It’s a little bit like a rock concert. You can buy the CD but you miss the mosh pit and the electricity.
Here’s a report on the experience. Soon, enough you’ll be able to see the webcast on the CR&T and MPDfoundation websites, so I’ll try to give you some highlights from the narrow perspective of a an early MF patient who has declined treatment and is now trying to understand an optimum way forward.
When the story opens I’m on my way to see the doctor who first diagnosed my MF, the same doctor who is essentially hosting the Symposium that will take place two days later at a private club on 54th Street just off Fifth Avenue.
There is a kind of exquisite agony in riding the M-86 bus entering Central Park in the declining days of Autumn, waiting for traffic to clear so the bus can lurch another five or ten yards, cutting off buzzing yellow cabs and horn-blaring SUVs and BMWs with Jersey plates.
Through the window, pedestrians can be seen, freely charging through stopped traffic, talking and gesticulating to an invisible other in front of them, looking like a lunatic mob until the telltale ear buds or discreet antenna announces a different kind of insanity, the private cellphone conversation in full public view.
The contrast beween the fading Fall colors of the morningCentral Park forest, bordered in rough cut granite stone, and the tension within the stalled NYC bus is very great. We will never make it through the blocked intersection before the light turns red.
At the other end of the route, at the impossibly distant York Avenue stop on the East River, lie the towers of an American elite medical landmark, the spreading village of professional offices surrounding the stone and glass towers housing the glittering medical technology and labcoat wisdom of Weill Cornell, Columbia University, Sloan Kettering and New York Presbyterian Hospital.
Meanwhile, like a thick embolism, there’s a blockage in the road as cars feed into the single artery crossing Central Park. Ahead, Fifth Avenue where southbound traffic once headed for midtown and the Village is now securely parked in the intersection. Gridlock. Somehow, against all odds, the bus driver negotiates a path and with hissing brakes and a series of jolting, jarring surges gets us across on the journey to the East Side.
In one of the high towers on York Avenue sits the Sage of Hematology, the undisputed elder who bi-annually assembles medical high priests from distant places to forge common battle plans. From this place, for two generations, he has taught, healed, researched and published books and papers that have become the basis for a standard of practice. It would be hard to over-estimate the contributions and eminence of Richard T. Silver.
And almost impossible to imagine arriving late for our morning audience. For me, there are also other reasons to worry about this meeting.
It is the eve of another gathering, the 6th Annual Symposium on Myeloproliferative Diseases and I am about to end a two year journey that started from this place. If this damned bus ever makes it through.
It started like this:
Flashback: The Diagnosis
He is saying something profound, I know, this magical doctor in his little examination room on the third floor of New York Presbyterian. He’s small and balding, his voice is quiet, his manner friendly, familiar, his hands sure. He seems like a congenial wizard, filled with knowledge and secrets.
Soon my future will be spread out on glass slides before him to be read in the tea leaves of my stained bone marrow. I should focus, I know, but he has already delivered the punch line. Richard Silver has confirmed I have, myelofibrosis with myeloid metaplasia, and is now speculating I may never have had ET after all, but simply MF from the beginning. Why do I not find this line of thinking interesting?
I’m considering the bone marrow biopsy ahead, recovering from thelong bus ride and crosstown walk to get to this place, tasting the fact that the MF I simply suspected, based on graphs I produced of my CBC history over the past decade, is now a fact walking around the room on two solid, if fibrotic, legs.
The Silver touch
Why I wonder, with these numbers, do I not have an enlarged spleen. But I do. And Silver finds it, easily, and shows me how to breathe and where it is and how it feels when it is only 2 cm below the costal. For all his brilliance and international reputation, his manner is simple and friendly, like a kindly uncle I never had, and business-like without the slightest trace of rush.
It will be a while before he gets me a definitive report based on multiple blood tests (that turned my right arm black and blue) and the analysis of the bone marrow biopsy. Meantime he left me with a recommendation for a hematologist at Duke. He also gave me a copy of his letter to Leukemia summarizing some favorable results using recombinant interferon in the treatment of primary myelofibrosis. He recommends I start on pegylated interferon at a starting dose of 45 micrograms per week.
I did not follow Dr. Silver’s prescription to start PegIntron. And after a lengthy multi-day workup at the Duke hematology clinic, and consultation with my hematologist who discussed the fine line between ET and MF I declined to take Hydroxyurea as well.
More than reject medical advice, I rebelled against this early introduction of toxic chemicals and wrote widely within the MPD community of my decision.
My sole medication is a single aspirin daily. Not much of a defense against advancing MF but armor enough, I believed, against thrombosis or stroke. I continued regular CBCs with my primary physician, monitored counts, but saw no hematologist.
Now, two years later, I was about to see The hematologist.
We talked of his long and varied career, he showed me his photographs from the Brazilian jungles and Antarctic, his book Blood Morphology – published with a preface by the original definer of MPDs, William Damishek. And he talked about his role as principal investigator on Anagrelide, his continuing strong support of Interferon and his satisfaction with the turn-out for this Symposium. It was like a backstage meeting with a rock star before a performance to a packed house.
The Big Show
The big MPN NYC Symposium put on jointly by the MPN Research Foundation and the Cancer Research & Treatment Fund on November 2 was a show.
Awash in glittering credentials, dueling therapeutic options, descriptions of (yet more) promising clinical trials, and the quiet clink of heavy duty corporate sponsors, the Symposium was, in a sense, the opening act for another event, the international scientific congress that would take place the following two days at the foot of the Brooklyn Bridge. For most of us, it was the only event.
In the audience, 226 registrants sat at cloth-covered round tables facing a podium and twin screens on either side of the stage in the University Club conference room. Slides flashed, eminent hematologists, professors and clinical investigators spoke, findings were recited, points illustrated, all punctuated by applause. It was pretty jolly as people matched up faces and name tags with people they had only known through MPD lists, Facebook or MPNforum Magazine.
Getting a chance to actually hug Joe and Bonnie after long months following their ordeal – and love story https://mpnforum.com/2011/08/14/a-love-story/ – was worth the price of admission, the airport security checks, the crowded subways and that nervous breakdown of a bus ride.
The Big “D” …. A mild surprise to those of us who finally abandoned MPD and embraced the MPN banner is the the tenacious hold the term MPD held on the assembly. From the brochure itself promising a Symposium on Myeloproliferative Diseases” – to Dr. Jerry Spivak’s overt rejection of these diseases as neoplasms in any sense — the term MPD was gaily bandied about by speakers and patients alike in defiance of the World Health Organization nomenclature.
A One-Day Master Class
The organization of the day, however, was brilliant – opening with an overview of thrombosis, moving into a presentation of the genetic basis of MPNs, and following with treatment options, and alternative views of the natural history of these diseases. It concluded with Q&A to a panel of doctors and breakout sessions for each major MPN.
The structure gave the Symposium the hard edge of a one day master seminar.
Mostly, the formal presentations were a refresher course on the JAK2 inhibitors, the untapped power of interferon, the genetic roots of MPNs, and a series of mini-reports on therapeutic options, projects underway at various foundations (MPN Research Foundation, CR&T, and the NCI’s big Myeloproliferative Disorders Research Consortium) with a few side trips to new therapeutic targets like the bone-blood stem cell niche.
Ruxo and the elephant in the room
A main attraction of the symposium was Ruxolitinib. The only JAK2 inhibitor to have weathered the Phase III clinical trial, Ruxo is widely expected to be approved by the FDA next month. Dr. Srdan Verstovsek and Dr, Ruben Mesa presented findings that differed little from those presented at the ASCO meeting five months ago https://mpnforum.com/2011/10/12/ruxolitini/ , But they are like rock stars on tour and you don’t fault the Rolling Stones for doing Satisfaction, again,
There was an elephant in the room, hard to ignore. Only a few weeks
earlier Dr. Ayalew Tefferi’s (Mayo, Rochester) letter was published in the New England Journal of Medicine raising serious questions about the efficacy of Ruxolitinib. Tefferi reported that of the 51 Mayo patients who participated in the Phase I/II Ruxolitinib clinical trials 47 had discontinued due to disease progression, loss of response, or toxicity. Tefferi further reported “serious adverse events” including hospitalization following discontinuation, Additionally, 18 patients (35%) died and 5 patients (10%) had leukemic transformations. He also raised the issue of thrombocytopenia (platelet destruction) and worsening anemia.
While no mention of the Tefferi letter was made publicly, Verstovsek focused on the results of the large scale Phase III controlled trial, that followed the dosage and toxicitiy trials cited by Tefferi. Both the Comfort I trial in theUSand the Comfort II trial inEuropehad similar results in reduction of splenomegaly and improvement of quality of life. He also addressed the need to reduce Ruxolitinib dosage gradually in cases of discontinuation for any reason
(For an interview with both Verstovsek and Mesa with slides showing effects of Ruxolitinnib in its Phase III trial: https://mpnforum.com/ask-the-doctors/ )
An old workhorse spotlighted….Hydroxyurea
A surprise star of the proceedings wasn’t a shiny new designer drug but the old workhorse, hydroxyurea, hydrea Here Dr.Tiziano
Barbui and Dr. Jerry Spivak took strongly opposing positions on the innocuousness of Hydrea. At issue was the possibility of HU being leukemogenic over time, with conflicting papers and studies cited on both sides. The results seemed to be a draw, since Spivak, conceded, when appropriate and the literature supported such use, he would prescribe hydroxyurea. And Barbui agreed that, when combined with other drugs, the risk of leukemia is indeed increased. He would recommend hydroxyurea as a front line therapy for those patients who needed to be treated.
Ron Hoffman raising the question of standard of care for PV patients who require repressive therapy, compared Pegasys vs. HU, the subject of his new NCI clinical study. “Neither is innocuous, both have important side effects. The question is how does that translate to you.”
The real action began after lunch –
The buffet lunch – the lines for which, resembling the long winding corrals of a TSA security queue at LaGuardia, extended along the walls of both sides of the conference room – may have been the chief disappointment of the Symposium, Those fortunate enough to scarf up the offerings were rewarded with basic school lunch fare – pasta, sandwiches, chips, some greenery and a cookie. At least that’s what it looked like as successful buffet negotiators passed by with their food on display. By the time the last of us bellied up to the table all that was left were crumbs and scraps. But why complain? All New York City and its Sabrett Hot Dog and Soft Pretzel carts lay just outside the door,
The event kicked into interactive gear after lunch with the reading of questions from the audience followed by breakout sessions organized by MPN phenotype.
Here’s a sampling:
. “What is the proper aspirin dosage to reduce the risk of thrombosis or stroke?
Dr/ Babette Wechsler: “While it’s true there is no universal dose for anything, in the vast majority of cases a single low dose — ¼ of adult size — aspirin will inhibit platelet function as much as aspirin can inhibit platelet function.”
“Why are there no African Americans, Latinos or Asians at the conference?
Ron Hoffman: First, there is an admission fee and then you need access just to learn about the meeting from the Internet. The CDC has concluded the data just isn’t there, the epidemiology “is a mess.” In his hospital, bordering onHarlem and Spanish Harlem, “there is a reasonable distribution of MPD patients, Spanish speaking, Asians, African-Americans… medically underserved populations.”
“Do you recommend a regular bone marrow biopsy?””
Tiziani Barbui: “Last year we presented a paper. More than 1000 patients with ET had a bone marrow biopsy at diagnosis or shortly afterward without any treatment. We asked pathologists inItaly and at Mayo to review this bone marrow. ..hTey were able to recognize two groups of patients, 15% with early myelofibrosis and 85% with true ET. The two groups differed in terms of survival. ..It was very clear that the evolution toward MF and leukemia was higher in those classified as early MF. It is useful for treatment to know what is happening with the bone marrow at the beginning of these diseases.”
Jerry Spivak: “If I have a patient with the JAK2 mutation I’m not interested in doing a bone marrow for a couple of reasons. It’s expensive, it’s painful…and the patient always thinks I must have leukemia….A man with a high platelet count and JAK2 negative might be a different story. I do it on a patient basis.”
Ruben Mesa: ” The bone marrow gives us a unique insight into the illness, both into the type of diagnosis…is it going to behave like ET or early MF. Secondly the bone marrow can give us a window into the changes in chromosomes, changes in blast percentages, changes in fibrosis. So I do them at some periodic frequency. If we see things changing quite a bit, then we do it with greater frequency,”
Ron Hoffman: “It’s no picnic but less painful than a visit to the dentist. I think there are two standardized systems to diagnose ET, the World Health Organization and the British Committee on Standardization of Hematology and both require bone marrow. I see very little need to repeat a BMB in a periodic way…If you see changes, yes, but It is not our routine practice to sample every year or several years…because it hurts and I don’t think we’re getting significant information. We can do cytogenetics on peripheral blood. ”
Richard Silver: ” I tend to agree with Dr. Barbui. A BMB is mandatory in a diagnosis. It establishes a reticulin and collagen level and becomes a marker. We believe it is important to do a baseline. We find development of fibrosis can be capricious but I don’t think you have to do it on an annual basis. Jerry you seem to be in the minority..”
Jerry Spivak: “I recall that in the Polycythemia Vera Study Group 265 patients early on had fibrosis and it made not a bit of difference. People come to me waving their bone marrow slides thinking they’ve had the disease long enough to develop fibrosis. And I say, I don’t care. If your disease is unchanged nothing has happened. It means the fibrosis, if it’s there, isn’t bothering you…As a physician, I’m going to pick my times [when it is appropriate.]”
“Do you consider MF cancer?”
Jerry Spivak: “Of course not, it’s a reactive process, ultimately a stem cell failure that creates unstable genomic features. Fibrosis is a reaction to that. Treating the fibrosis won’t change that.””
Ruben Mesa: “Myelofibrosis, as Jerry says, is a secondary phenomenon but let us make no mistake. It is a chronic leukemia and it is a type of cancer. I wish that wasn’t the case and it’s why we labor so hard against this illness. How serious a cancer it is depends on the individual. For some people it could be just as serious and life threatening as other advanced cancers but for others it can be more indolent. Giving it that label, although accurate, doesn’t necessarily make your disease worse but it is clearly the correct way to think of the illness.”
Srdan Verstovsek: “I agree. There is no more to say. It is cancer, a malignancy and it shortens life expectancy in people and should be treated as such.
Ron Hoffman “There are a lot of different causes of fibrosis, the symptom we’re talking about in myelofibrosis is a hematological malignancy. There’s good data to support that in patients and in the laboratory. As manyof you unfortunately know, it is a serious illness. If you have an advanced stage of this disease you have very limited survival. So it is what it is.”
Before the Breakout Sessions
The working part of the Symposium ended with the breakout sessions, 75 minutes face to face with presenters, divided by disease types.
Before leaving the main conference room the co-sponsors David Boule for CR&T and Robert Rosen, MPN Research Foundation, talked briefly. (I missed David’s talk but at the end he announced the dedication of a new Richard T. Silver MPD Center as part of the Weill Cornell Medical Center.)
Bob Rosen, an MPN patient himself, is soft spoken. He presented the mission and history of the Foundation in a straightforward recitation of facts. As his list goes on for a few minutes, the full dramatic impact builds. In its 11 years, the Foundation has not only funded basic research to the tune of $8.5 million – it has been instrumental in creating research groups, tissue banks, genomic sequencing projects, environmental studies, and patient support systems.
One fact from Rosen’s presentation: A Foundation-funded Yale epidemiology study concluded there are 175,000 MPN patients in the U.S.
The break-out sessions followed a presentation and Q&A format. The only one I attended was the MF session chaired by Mesa and Verstovsek. (Barbui chaired the ET session, Spivak, PV.) The sense of déjà vue was strong since most of the slides and much of the presentation material had been covered earlier https://mpnforum.com/2011/10/12/ruxolitini/ and in Verstovsek’s morning presentation on JAK2 inhibitors and the JAK-STAT pathway.https://mpnforum.com/jak-stat-pathway-follow-the-yellow-brick-road/ But it’s ore than likely my flagging attention was caused by a combination of information overload, working way past naptime… and the slow digestion of a street vendor soft pretzel.
A question from a stem cell transplant patient who has been suffering from Graft Versus Host Disease questioning the on-going complications she experienced after having been cured snapped me out of it. The ambiguous nature of an MF “cure” through SCT was addressed with great subtlety by Ruben Mesa, particularly along with the on-going risk of GVHD. It’s an issue we need to look at. (Next month Marty Prager will take us through his stem cell transplant experience.)
After the show is over…
The return home to North Carolina was a 14 hour slog with a canceled flight, rerouting through Atlanta, providing ample time to reflect on the high stakes craps game we’re all playing. Now, that I have moved to the high risk category by virtue of age, an undeniable risk factor for thrombosis, what therapeutic conclusions could I take away from the day?
(1) Don’t medicate too early, that seems a consensus. Don’t wait too long is another consensus. The definition of too early and too late is weighed on the balance of discomfort and possible impetus to early leukemia on the one hand and premature death on the other. The image of Karl https://mpnforum.com/2011/07/07/remembering-karl-postjune/ is always before me.
(2) The JAK2 inhibitors are on to something, at least the possibility of holding the effects of MF at bay for a time. It doesn’t matter whether you are positive or negative for the JAK2 V617F mutation. These inhibitors work on the JAK-STAT pathway and while there are multiple JAK signaling enzymes the JAK2 enzyme is specifically involved in hematopoeisis. For a brief exhibit on the JAK-STAT pathway: https://mpnforum.com/jak-stat-pathway-follow-the-yellow-brick-road/ I’m JAK2 negative with minimal splenomegaly and stable counts. Way too early for JAK2 inhibitors.
(3) The interferons hold the promise of reversing fibrosis, affecting the marrow and the near certainty of providing miserable side effects until the appropriate dosage is arrived at. Silver pointed out that our suffering from viral infections like the flu are due not to the virus but the load of interferon, a naturally occurring protein – a cytokine – that is active in immune response. The interferon sweepstakes odds increase in your favor if you start early says Silver and become astronomically high against you if you wait too long. And then there are all the novel, highly experimental therapies now in the labs or early trials, TET2, MPLs, Exon !2. blood-bone stem cell niche targets…the list expands.
An option? For early MF, Interferon is still experimental and the others are not even available at the experimental level outside of clinical trial. Like Jerry Spivak said, we all have a right to our opinions, but no right to our facts. And the facts are just not there yet. Maybe Ron Hoffman’s MPD Research Consortium Pegasys vs HU trials will provide those facts. For now, it’s not worth the risk.
(4) Hydroxyurea is perhaps the most widely used cytotoxic substance prescribed for MPNs. It has generally acceptable side effects, will lower counts, but will not effect the progress of the disease and can compound the difficulty of treating progression to acute MF or leukemia. With the voice of Spivak ringing in my ears it’s easy to decline its use.
That, in 4000 words, is my version of The Symposium. There will be a more objective version via webcast at www.mpnfoundation.org and www.crt.org in a week or so. As to my personal conclusions, as before, I have no better strategy than an aspirin a day and watchful waiting. Difference is, now iI feel more confident it’s a path rooted in the best our MPN world can offer…so far.