Straight scoop on ASH, MPN drugs, clinical trials and credible scuttlebutt.
That reports of trial results, new meds, scientific breakthroughs and all the rest come out of ASH is undeniable. But this is another year of therapeutic drought for MPNs. There’s an El Nino brewing out there in the ocean of pharmaceutical R&D but it will be a while before it yields something new for us to reach for in our medicine chests.
So, it’s probably useful to pass along a sense of what this giant scientific/medical circus is really like in case you think it takes place in a sterile operating theatre environment of quiet work and professional consultation.
For what it’s worth, I’ll share my sense of the leading MPN drug and clinical trial contenders at the end. But if it’s objective data-based information you’re looking for head for the MPN Research Foundation’s new website. John Crispino’s flawless analyses might already be up there. Then there’s Ann Brazeau’s elegant MPN Advocacy and Education that features news and their hot-off-the-press MPN A&E Newsletter. David Wallace’s PV Reporter has a great search engine for this stuff as well as a sprinkling of ASH news and videos. The gold standard for serious review would be the ASH site where you can access and download abstracts about any med that interests you. And if you really want to dig into clinical trials there’s always the offical FDA clinical trials site.
Unless you have a sense of an ASH meeting, reading reports of results and upcoming trials without the context might give you a totally wrong impression. So let’s have at it.
To be honest, the ASH annual meeting is a massive contradiction. It’s totally chaotic and tightly organized, both stimulating and fundamentally exhausting.
Stage this monumental event in a tourist destination like Orlando — spread out like a theme park across Central Florida— and add the hordes of weekending kids and anxious parents pouring into the clogged city arteries and hotel lobbies, jostling long lines of dispirited jet-lagged physicians waiting for taxis, shuttles, limos to get them out of the airport and into their hotels and you have all the ingredients for a bad case of shin splints and mind-numbing confusion.
And that’s all before the actual event starts.
ASH is always staged in these Convention Center catacombs built by Chambers of Commerce to attract mega-events to fill hotels and restaurants in town. These airline hangars of buildings are silos joined by endless carpeted hallways, criss-creossed by stairs and escalators that lead to monstrous lecture halls. Registrants are urged from event to event through signage, guides, and conflicting printed schedules.
During ASH, the available floorspace is covered with 20,000 or so hematologists tramping along in a Tower of Babel murmur of conversation and complaint. The sight of these international specialists hauling backpack, rollerbags, briefcases and ASH-logoed shopping bags, rushing to the next meeting, a quarter mile across the hall up two flights, is bewildering.
Why? If it’s about learning, a few hours reading a scientific paper with a cup of coffee by your side would be far more efficient and reduce America’s carbon footprint. For authors, reporting on current research that appears in posters in crowded ASH halls could be more easily, efficiently done in the scientific journals, including ASH”s own Blood.
But ASH isn’t about all that. It’s a celebration, a gathering, a kind of Burning Man event for distinguished scientists and physicians, a shopping mall for science and technology. It’s a chance to renew acquaintances, give birth to a research project, sample an unrelated branch of hematology, advance one’s status and career, while taking a break from an often backbreaking routine.
The Poster Hall, Exhibits and People
Nowhere are the contradictions of ASH more evident than in the Poster Hall. Here long and sober research pays off in competitive peer acknowledgement by granting scientists the privilege of displaying their results in black and white and color to their colleagues. While there is clear interest in some posters, this is not a gallery given over to hushed viewing.
The Poster Hall in which extended graphic abstracts are hung up for view seems to be both an honor and consolation prize for those not making an oral presentation of a research finding. For viewers, it can be a trial to crowd around a difficult to read poster, dodging physicians and students juggling paper plates of crackers and cheese, beer or wine, and the inevitable ASH tote bag..
Chances are the Poster’s primary author is nowhere in sight to handle questions. Basically the room is papered with abstracts blown up to fit a large piece of glossy paper tacked to a display board. And the festive spirit of an ASH gathering is everywhere evident.
The Exhibit Hall, a Temple of Commercial Celebration, is colorful and lively, shades of marketplace everywhere, with free giveaways of pens and clips and Cracker Jack toys with lines of doctors queued up for coffee, ice cream or a savory crepe. Except for the Incyte booth, mostly given over to Jakafi, there’s not a high level of MPN support on the Exhibit floor. Between brightly lit and well designed sleek exhibits promoting some drug or other, I found the large and sparkly Gilead Booth.
I asked about Momelotinib. No one heard of it but they scanned my badge and promised to get someone back to me.
Now that Gilead is sitting on 30 plus BILLION dollars in cash reserves based on its Hep C drug added to its HIV revenues it’s not surprising it’s not covering a troubled MPN drug that’s unlikely to achieve the status of Gilead’s blockbuster stars. I checked on Imetelstat at the Janssen booth and came up empty. CTI was no better. I asked two very well dressed professional guys at the booth if they had any information about Pacritinib. Blank stares. One thought it might be a German drug.
Still, to be fair, I didn’t go to the Exhibit Hall to learn anything. I mostly wanted to connect with some friends and tour the attractions.
There is something to be said for the opportunity to meet friends and colleagues in a single location during a compressed time period But not much. I saw Jason Gotlib (Stanford) with his wife at the airline terminal waiting for a cab or shuttle downtown. Not enough time to connect or an environment to schmooze. One friend I rarely see is fellow tarheel David Wallace (PV Reporter). It would be hard to miss him since we were Press Room neighbors. (Ah, the ASH press room with bottomless samovars of Starbuck’s French Roast and a rock solid wi-fi.) Found David collaring hematologists, showing up at the CREATE seminar and catching up on his meeting notes.
Srdan Verstovsek and Ruben Mesa were at the CREATE gene therapy seminar they had helped sponsor… but we didn’t have much opportunity to chat I met Richard Silver — another CREATE sponsor — on the third floor outside the Tangerine theater for a presentation by Qaseem Kasim on the use of gene therapy to knock back a kid’s terminal leukemia. That presentation had been moved to another time and location. We talked briefly, not nearly long enough, since he had been up since 5 AM on an EHA teleconference.
A good random meetup: I saw Ronald Hoffman (Mt. Sinai) outside the 4:30 MPN genetics presentation about to start. He was talking to a tall, soft-spoken courteous gentlemen, Francsico Cervantes (University of Barcelona).
After Ron left we had a chance to talk a bit. It was a great pleasure to have a simple conversation with this courtly, quiet and deeply knowledgeable MPN hematologist without amplified soundsystems, PowerPoint slides or illustrated lectures.
Ayalew Tefferi (Mayo Clinic) walked up to us, talked briefly about a new oral JAK3 drug, shook hands, and briskly headed into the hall where he was scheduled to present some significant MPN genetic findings. Actually, his presentation was a practical scientific high point of the meeting for me.
After delivering his detailed presentation of multiple MPN mutations tracked in an extensive gene panel, he opened the discussion for questions. “How do you see the applicability of all these data?”
“ If it’s just TET, I say don’t worry about it. If it’s ASXL-1 maybe worry about it a little and come back and see me in a month. But basically we can use these data to help decide whether or not and when to recommend stem transplant. Thats a reasonable response isn’t it?”
And yes, it was. After all the deeply technical explication and intense detail of proving out scientific theses, after the sacrifice of mountains of mice to play out scenarios of immune response to inhibitors and all the rest, there is this one clear idea.
The doctor facing the MF patient who’s not high risk — when nothing is guaranteed — faces the choice of prescribing drugs, clinical trial or SCT. Now with an extensive gene panel he has an additional simple tool to aid his decision making process.
It’s no small matter for the doctor or the patient. Patients can sicken on clinical trial and physicians have no definitive way to determine when to pull the trigger. Delay and it may be too late to opt for stem cell translant. Thank you, Dr. Tefferi. That’s the kind of clarity we can take to the bank.
I decided to follow just a few drugs. — Pacritinib. PRM-151, Imetelstat and a nod to an interferon/ruxo combo.
Pacritinib, another JAK inhibitor, is a long-overdue alternative to Jakafi It’s also probably the drug longest in the pipeline. CTI will likely file an NDA in 2016 based on Phase III results. It could be a boon for patients too anemic or thrombocytopenic for Jakafi. It could be the back up we’ve been waiting for after the grave failure of Sanofi’s Fedratinib and the fumbling progress of Gilead’s Momelotinib. Alessandro Vanucchi presented a paper at ASH reporting reductions in spleen volume and symptom burden in intermediate and high risk MF. “These data presented at ASH 2015 are important and clinically meaningful, said Vannucchi, “as they demonstrate pacritinib’s potential to achieve treatment goals across intermediate or high-risk patients with myelofibrosis, regardless of baseline characteristics including starting platelet count.”
PRM-151 with its fibrosis busting pentraxin has been in limbo since last year’s ASH. Since Bristol Myers took over, injected a wad of cash and some urgency, the drug is moving on to new trials. Srdan Verstovsek, the chief investigator for the Phase II trial, is both upbeat and realistic about PRM-151. “I am very happy to see the continued benefits in patients with myelofibrosis remaining on PRM-151, including reductions in spleen size with longer treatment,” said Verstovsek “Many of these patients had failed multiple other therapies, and PRM-151 has given them new hope for the future.”
“What’s changed,” he says, ” is patients are stable, some on it for 72 weeks [note: erroneously reported as 70 months in earlier edition] nd doing well.” Voncille Fryou, MF patient on the trial, agrees. ‘PRM-151 does work, I’m living proof and so are my BMBs done every 3 months for over 2 yrs. Is it still working now? When I saw Dr V in Oct two years ago, he was more excited about PRM-151 than any other drug I ever heard him speak of… But there’s no drug here that works forever and I have been through them. I’m afraid the drug is starting to fail me.” You can read her detailed PRM-151 clinical trial experience here.
Imetelstat is still worrisome,. Yes Janssen and its deep pockets, skilled labs and aggressive marketing is behind it. The drug snapped back from the clinical hold placed by the FDA but remains dangerously toxic unless carefully monitored. The mode of action may be the most worrisome thing about this drug that seems to have so much potential. It’s coming off a small clinical trial with controversial results but as one investigator put it, “It has earned a chance to prove itself in clinical trial. ” That’s true. The question is should we subject ourselves to its effects so long as we have other options?
One possibility, when we need treatment and have no further options to control myelofibrosis, may be an interesting trial now recruiting in Chicago, alisertib, an aurora kinase inhibitor.
Aurora kinase inhibitors aren’t new and have not had a strong performance record in clinical trial. The aurora kinases A and B control cellular mitosis during division and are found to be overexpressed in many cancers. Inhibiting this kinase has been the goal of much research in the past 20 years. This trial, headed up by Brady Stein at Northwestern, is very small (24 patients) with yards and yards of exclusions (NCT02530619) This is a dose de-escalation trial, aimed at controlling megakaryocytic expansion.
Based on a quick study, the rational looks something like this. Abnormal hematopoietic cells, specially megakaryocytes, stimulate fibroblast production resulting in replacement of blood producing tissue in the marrow with collagen fibrosis. Targeting the mutant megakaryocyte by inhibiting the aurora kinase should expand the number of chromosomes in the cell beyond its ability to reproduce. That seems to be the general idea anyhow and it has been highly successful in mouse populations, killing the megakaryocytic progenitor.
In general dosage and toxicity Phase One clinical trials are our worst therapeutic option. But if you have no other option and are in the Chicago area it might be worth considering with your hematologist. One other trial site is reportedly going to open in Florida. This trial will test the efficacy of inhibiting the AK in ever small doses of the inhibitor alisertib,
And of course there’s interferon, given a recent boost by Hans Hasselbalch’s presentation at ASH of his findings that combination therapy of interferon and ruxolitinib had produced 100% complete responses in 75% of patients. The ASH abstract is here and an earlier paper on combo therapy use in PV is here.
There are other options on the back of the stove like PD-1 checkpoint inhibitors that boost the immune system by lowering the ability of the PD-1 protein on cell surfaces to fend off T cells. PD-1 blockade with drugs like Keytruda, and Opdivo, are being used with various cancers including multiple myeloma. There is a myelofibrosis trial at MD Anderson that is currently recruiting.
But nothing holds nearly the promise — or poses as many development challenges — as gene therapy through gene editing and mobilizing T Cells through immunotherapy,. For that, look in on the CREATE seminar in progress.
Coming up: A major research paper based on work done by two MPN hematologists and their colleagues is finally making use of the 23andMe MPN database. A couple of years back over a thousand of us spit in tubes and mailed them in to support this research effort. That paper, we’ve heard, is currently in final editorial rvvisions…23andMe had no comment…The John Mascarenhas encyclopedic summary of myelofibrois treatment options that surfaced at ASH, “Looking forward: Novel therapeutic approaches in chronic and advanced phases of myelofibrosis,” will appear, in full, in the MPN Quarterly Journal in January.