MPNforum Magazine

 

December 7, 2003.

 Frank C., Sunday Brunch, Hotel Coronado, TripAdvisor

Three guys are sitting around breakfast at the swank Hotel Del Coronado in San Diego.

The packed and noisy dining room, crowded with hematologists attending the 45th Annual Meeting of the American Society of Hematology (ASH) seems hardly the place to be hatching dramatic plans. And yet there they are animated, scrawling notes and sketches on scraps of paper and napkins, exchanging views and gestures while their coffee grows cold.

Hematologists themselves, they are running late for the first session but the project taking shape under their hands draws all their attention.

Birth of a dream

What if research centers around the world collaborated on MPN research? Basic MPN research. And then collectively ran small investigator-sponsored clinical trials to test the science.  No drug companies would be involved as sponsors at this stage. If the science translated into an effective therapy for MPNs, there would be time and reason enough for the pharmaceutical giants to engage in costly, complex clinical trials.

That breakfast took place two years before discovery of the JAK2 mutation, in the dark ages of MPN applications of molecular biology. The first full fruits of the Human Genome Project, the first sequencing of the human genome, had been only roughly completed just three years earlier. But the seed had been planted.

Dr. Ronald Hoffman and his associates at the table, Dr. Tiziano Barbui (Bergamo, Italy), and Dr. Steven Fruchtman (Mt. Sinai, New York) are all deeply experienced in the myeloproliferative disorders, the MPD science and clinical practice.  They’re all laden with credentials and credibility.  Ron Hoffman, for example,  past president of ASH, then chief of the hematology/oncology sections at the University of Illinois Medical School, he published original research into the origins of myeloproliferative neoplasms…part of a publishing output that would grow to over 400 papers in scientific journals.

Considering professional jealousies among labs and institutions, the rush to publication by scientists and academics  and the turf wars over research funding for MPNs — this little backwater complex of related clonal blood diseases — it’s hard to see how their idea could work.  And yet the concept of bringing together international institutions and laboratories, scientists and clinical investigators into one great cooperative consortium inflamed the imaginations of the three doctors.

In the following days and weeks a small organizational flaw that might ultimately weaken the structure of MPD-RC was written into its blueprint. Although the new collective effort would ultimately rely on patient participation, no MPN patients were part of the Consortium. No MPN patients would be at the table.

The foundation of this bright new concept of cooperative medical and institutional medical research would follow the old top down model of providers on the one hand and consumers of services on the other.

It’s in that setting, on a sunny December morning in San Diego, between orange juice and coffee, that the MPD Research Consortium — MPD-RC — was born.

There was an important step necessary to translate these sketches and concepts into reality: Organization.  And here, several months later,  fate stepped in to take a hand.

On the snow-choked frozen streets of his Chicago neighborhood, Hoffman would occasionally run across Robert Rosen, a friend with polycythemia vera. Rosen firmly believed the cure for MPDs lay in basic science and practical research translating that science into drugs that could be tested in tissues and clinical trial.  He had put his money into the establishment of the MPD Research Foundation.

Hoffman outlined his idea to Rosen and the need to start getting commitments to implement it. To do that would take money to organize the project, airfare and lodging to bring scientists and hematologists from distant labs together.  One of the earliest investments in science made by the MPD Research Foundation was an organizational grant for $30,000 —  shortly to be increased to $60,000 – to get the MPD Research Consortium organized and qualified to apply for grants.

Buttressing the idea of an international consortium of science and clinical practice,  four other world class institutions joined the original group from the University of Illinois, Mt. Sinai, and Bergamo:  Weill-Cornell, Georgetown, University of Utah and San Matteo.

Dr. William D. Merritt…another lucky break.

Ron Hoffman applied for an MPD Research Consortium grant from the National Cancer Institute. On the receiving end at NCI, was William Merritt, PhD. In January 2006 he was a newly arrived program director at NCI’s  Cancer Therapy Evaluation program. The timing for MPD-RC couldn’t have been better.

Merritt  came to NCI  in 1998 serving as Scientific Review Officer.  With a PhD degree in biology from  Purdue University in 1975, Dr. Merritt did his post-doc training at the prestigious German Cancer Research Center, Heidelberg, Germany and the Cell Biology Department at Yale University Medical School.  His  research and academic background in cancer therapy plus his focused work in stem cell transplantation and hematological malignancy neatly fit MPD-RC’s niche.

Beyond that, Merritt was committed to collaborative and translational research in fulfillment of CTEP’s mission. He was a perfect fit to take the lead in guiding the MPD-RC grant proposal through ultimate funding after the peer-reviewed evaluation process.

The result: In 2006, less than three years after breakfast at the Hotel Del Coronado, the NCI awarded a $20 million grant to the new consortium, then sited at the University of Illinois. Five years later, NCI doubled down on its bet and approved another $20 million in renewing the grant.

The formal purpose: Advance basic and clinical research for incurable blood disorders by coordinating, facilitating and performing basic and clinical research investigating the genetic and cellular mechanisms of the Philadelphia Chromosome (Ph) negative myeloproliferative neoplasms (MPNs). The ultimate goal: Develop novel therapeutic strategies to improve the management of patients with this type of diseases.

It was the largest grant for scientific research ever made by the NCI. The MPN Research Foundation’s $60,000 investment in Ron Hoffman’s dream paid off many times over.

Interest in the MPN Tissue Bank. 

While  the MPD-RC progress in bringing scientific studies to practical conclusions would prove to be frustrating and painfully slow, a core MPD-RC program, the tissue bank, funded by the Centers for Disease Control, provided immediate and significant assistance to researchers looking for biomarkers to gauge effectiveness of drugs or help uncover hidden pathways of MPN disease.

The Tissue Bank has “about 12,000 tissue specimens from approximately 1000 patients,”says Rona Weinberg PhD, adjunct professor of medicine at Mount Sinai. Her lab, the MPD-RC tissue bank, is located at  the New York Blood Center.  Samples, according to Weinberg,  are kept in small vials in a liquid nitrogen oxide environment at about -150 degrees Celsius.  “We have found a way to keep some tissues viable by adding a chemical. It’s similar to adding anti-freeze to a car radiator.”

Patient tissue samples are taken at various times during clinical trial for review, to determine efficacy of meds and to discover potential biomarkers that might be useful in identifying new drug targets. “The process,” says Weinberg, “follows all protocols for human experimentation, including patient consent and oversight of the Institutional Review Board.”

The tissues are available on request to all researchers and not restricted to MPD Consortium members. Researchers simply email requests, fill out an on-line form that is then reviewed by the Ethics Committee prior to approval.

Eight years later…. the scorecard.

Fast forward to 2014 to look back at MPD-RC’s key achievements…and challenges in the eight years since the first NCI grant was awarded.

Populating its clinical trials has been one of MPD-RC’s key challenges.The inability of MPD-RC to populate its clinical trials has led to carryovers, unexpended funds allocated to clinical trials. Another challenge is to produce tangible therapeutic results.  Testing unsuccessful novel concepts and applications of meds that are subsequently withdrawn by the manufacturer might look like a squandering of financial and personal resources. But performing basic scientific and clinical research, the raison-d’etre of MPD-RC, often leads to dead ends.

While enthusiastic about work in progress and optimistic about ultimate success in several areas, Hoffman regrets the inability of the MPD-RC to communicate the value of the Consortium to MPN patients and ”…to engage them in participating in our trials in greater numbers.”

Part of that problem may be the MPD-RC website which is the main public portal to the Consortium’s programs. A quick look at the dated and neglected MPD-RC website tells most of the story.  Much of the site was put up in 2006 and 2007 and is devoted to promotion of the Consortium’s clinical trials. Since there’s not much reason for a patient —  or hematologist for that matter —  to visit that site it’s a bit like a tree falling in a forest when there are no ears to hear.  It doesn’t make much of an impression.

The MPD-RC also suffers from the obvious lack of clear, meaningful communications with the MPN patient community in other areas as well.  While the most egregious example might be that dysfunctional website it’s more basic than that.   In none of the MPD-RC programs has there been provision for patient input or review and very little patient-directed outreach.  While there is a commitment to turn that around, the ultimate challenge is to produce results.

 Costs, clinical trials, studies and current projects

The NCI total investment of $40 million in MPD-RC’s MPN programs is impacted by the imposition of a 69.5% overhead rate (Facilities & Administration) that is applied as a multiplier to direct costs. These indirect costs, through a complex funding formula, account for about 35% of the grant total. 

 …the final judgment will be made not on how cost-efficient the effort is but the real impact of the total investment.

it’s not overhead costs that ultimately matter.  Every organization has development, infrastructure, salaries, equipment, travel, etc. costs. And in the case of an international consortium of over 40 centers, run out of a high-rent district like Mount Sinai’s,  those costs can be extraordinary.  This is about science and collaboration and the final judgment will be made not on how cost-efficient the effort is but the   real impact of the total investment.

How has the work of the MPD Research Consortium impacted the lives of patients over the past eight years of its existence?  What are the actual and prospective impacts?

The hope of clinical trial…

Clinical trials, the proving ground for MPD-RC research,  have a special place in the hearts of MPN patients. After all, this is the road that, one day, the miracle drug that will wipe out the chaos of our clonal disorder will come down.

But problems come down that road a lot more often than miracles.

Faced with symptomatic advancing disease – often, myelofibrosis – our toughest decision has to be clinical trial or stem cell transplant.

Clinical trial for the MPN patient may be an option for relief or extended survival. While it is free of most direct costs to us it may come at a high price for the hope it offers. Toxicity of experimental drugs – immediate or long-term  – is largely unknown as we have seen from two well-publicized MPN clinical trials this past year, Sanofi’s Phase III fedratinib trial and Geron’s imetelstat.  Regardless of company size or reputation, regardless of “proven” safety profiles, experimental drugs can turn out to be toxic short term or long. Or disqualify us for alternate therapies.

The other cost we face is the passage of time and the possible progression of our MPN or deterioration of our health during the course of the clinical trial.  In some cases clinical trial can cause a lost opportunity for other therapeutic interventions like stem cell transplant.

Early phase clinical trials, those  testing dosage and toxicity of experimental drugs,  are a risky crap shoot.  Late phase clinical trials, using matched groups with a control arm,  involve a toss of a coin to determine whether we get the possible miracle drug or the sugar pill.

Faced with occasionally extravagant claims for Complete Response from drug companies and respected specialists, evaluating the risk/benefit of any particular clinical trial versus allogenic stem cell transplant has to be the most serious and intensive work done by MPN patients with our hematologists.

Enter the MPD-RC

In this environment, MPD-RC should be our natural ally. In a world where so few know much about myeloproliferative neoplasm conditions, MPN patients and caregivers are normally isolated. We’re disconnected from both the medical world and, except for the minority of us hooked up on-line, often unaware of options.

Arrayed on the other side is a formidable force of drug companies, insurance companies, and medical institutions – powerful, organized, with deep pockets. Some may be motivated to serve us out of passion and compassion but all have commercial interests in providing products and services to us.  Not MPD-RC.

The MPD-RC, funded by the National Cancer Institute of the NIH, stands apart. Essentially,  it should be free of commercial interest in pursuing science and testing theories and products.

Its mission frequently requires clinical trial of experimental drugs. While MPD-RC has not been as successful as commercial entities in populating its trials with MPN patients– nor in realizing game-changing results from the trials it has conducted–its trials are varied and to some extent successful.

Note: There is a separate branch of the MPD Research Consortium, the MPD Clinical Consortium although all activities were commonly referred to as MPD-RC projects.

The MPD-RC clinical trials

There’s a shopping list of current MPD-RC clinical trials on-line, 11 of them here on Clinical Trials. gov.

Two are active, six are recruiting and two have been terminated. One trial was terminated due to toxicity and lack of response (Avastin in MF), the other aborted when the drug company could no longer supply the drug (Clopidogrel).

One active trial, CEP-701 (Lestaurtinib) in myelofibrosis is very long-standing.  Ron Hoffman’s lab has been working with this JAK2 inhibitor since 2008, three years before Incyte’s ruxolitinib (Jakafi) received FDA approval.  Dr. Srdan Verstovsek at MD Anderson terminated his trial of CEP-701 in June, 2012 reporting very high rates of Serious Adverse Effects due to toxicity.

The Pegasys versus Hydroxyurea in PV and ET trial generated considerable interest when first announced 2010. Even though it has failed to fully populate – it is still recruiting – there are active participants in both arms of the trial. One compounding difficulty might be the prospect, for a patient, of traveling to Mount Sinai in New York City for testing etc. only to  discover he or she is on the 500mg of HU twice daily arm of the trial.

Two other trials are of special interest to MPN patients: The combination trial of ruxolitinib and decitabine for blast phase MPN or AML, announced earlier this year,  as well as the not yet listed Nutlin trial – see MPD-RC Milestones, below, for Dr. John Mascarenhas’ comments on both.

Some MPD-RC milestones in MPN science and exploration

The actual immediate impact of this enormous investment and passage of time on the health and well-being of MPN patients has been, at first glance, negligible. Even eight years from the starting gate, it may just be too early in the process.   No one is waiting for a genie to pop out of the MPD-RC bottle.  Part of the Consortium’s work with the Tissue Bank has undoubtedly yielded important results…but those results are mostly if not entirely shielded for now by research protocols and confidentiality agreements.

“How do you quantify the opportunity for investigators to come together, to work collaboratively in a unified fashion…”

Dr. John Mascarenhas, one of the key drivers of the MPD-RC program at Mt. Sinai understands. “It would be hard to quantify the important impacts of this program right now. How do you quantify the opportunity for investigators to come together, to work collaboratively in a unified fashion, to formulate concepts and translate them as a team?”  He was  able to reel off several examples easily.

Decitabine and ruxolitinib — new clinical trials.  At one of the annual MPD-RC meetings a presentation from Dr. Ross Levine’s group at Sloan Kettering of mouse studies showing the value of a combination of decitabine and ruxolitinib led to several centers taking up the study at different international sites. These clinical trials have an Investigative New Drug designation from the FDA. The MD Anderson’s study of the combined drugs is focused on Acute Myeloid Leukemia NCT02257138 but is not yet recruiting.  The MPD-RC trial NCT02076191 of the same combinatorial drugs  is currently enrolling patients at eight sites so far.

”Our collaboration,” says Mascarenhas, “isn’t simply from lab to clinic. Because we treat patients there’s an accumulation  of tissue banked before and after clinical trials.This allows investigators to access results and perform deep analyses to gain more insight.”(Note: these are tissues derived from blood, spleen, bone marrow biopsies, etc.)

Beyond building a critical mass of understanding through collaboration, the MPD-RC does have to its credit several completed projects. One, the MPD-RC clinical trial examining reduced intensity conditioning in stem cell transplant compared outcomes among patients receiving stem cells from related and unrelated donors. www.clinicaltrials.gov as #NCT00572897. The results, demonstrating poorer outcomes in the unrelated arm due to graft failure surprised no one, but could lead to re-evaluation and new transplant protocols.   A new Consortium trial, MPD-RC 114 is exploring the use of ruxolitinib prior to transplant testing whether reduced splenomegaly, improved performance and reduction of inflammatory cytokines might mediate GVHD issues and help the engraftment process.

The MPD-RC’s Professor Dr. Heike Pahl (Freiburg, Germany) is working on the genetic basis of altered gene expression, specifically the mechanism by which JAK2 mutation impacts the overexpression of transcription factor NF-E2 and PRV-1 in polycythemia vera.   Dr. Josef Prchal’s (Salt Lake City) work on the genetic basis of PV and Dr. Anna Rita Migliaccio’s (Mount Sinai) work on growth factor signaling area are well advanced MPD-RC projects.

Finally on direct patient benefit and clinical trial,  there is Nutlin.  A protocol for a Nutlin-3 clinical trial is nearing completion.  This will be MPD-RC 115 and will be focused on PV patients with HU intolerance/resistance or Pegasys intolerance/resistance or both and will be a phase I/II trial with this novel oral agent. “This is a very exciting trial,” says Mascarenhas, “and a direct result of translational laboratory work by the Hoffman laboratory published in Blood.  FDA approved the IND and MPD-RC  hopes to open this trial before the end of 2014.”

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Looking ahead…finding the missing patient 

While the process of discovery and the translation of scientific findings and testing through to delivery of an effective drug is necessarily slow, that other driver of MPD-RC’s programs — MPN patient support — can be rapidly energized. In the heat of forging this massive consortium and administering reviews and grants, that component has been clearly neglected.  The impact on populating MPD-RC trials is only the most direct indicator of the lack of visibility MPD-RC has among MPN patients.

It looks like all that is about to change. This summer Dr. Ruben Mesa (Mayo Clinic-Scottsdale)  — familiar to many MPN patients through his extensive videos, writing,  patient advocacy work and appearances at patient events, announced new MPD-RC patient outreach programs, including a new twitter resource @MPDRC.

Along with Ron Hoffman, John Mascarenhas and the Mount Sinai administrative group, Mesa is part of the executive team for Project Six (the clinical trial arm) or the MPD-Clinical Consortium.  “The logistics of running these trials,” said Mesa, “requires coordinating both the Mount Sinai Medical Center in New York as the main hub and Mario Negri Sud, based in northern Italy,  that acts as a main clearinghouse for these studies for the EU.”

“Ruben Mesa has been essential in spearheading social and scientific media initiatives,” said Mascarenhas, “and is the chair of the membership committee with emphasis on engaging the many institutions involved in the MPD-RC and assisting the central office with communications and personalized interactions with each member site”

But time for the visionary MPD-RC project may be running out.

Aside from the Center for Disease Control grant to fund the MPN Tissue Bank, $40 million has been invested by the NCI in the MPD-RC so far.  While significant work is being done, nothing so far has emerged from the Consortium labs to be translated into drugs that would benefit MPN patients.  Beyond that, private sector research at a small fraction of that investment has produced dramatic results. For example,  discovery of the Calreticulin mutation, occurring commonly in JAK2-negative MPN patients, was announced last year by two laboratories. This discovery has already produced an international flurry of papers. studies and preliminary trials.  (The MPN Research Foundation’s support of Robert Kralovics’ discoveries is reported to be $300,000.)

Summer 2016 the MPD-RC NCI grant is up for renewal.  And in the current environment an additional $20 million grant for basic MPN research will not be an easy pill to swallow without some hefty proof of near-term benefit.

MPD-RC founding director Ron Hoffman set himself and his associates an extraordinary mission for the Consortium. While passionate about the concept and optimistic about current and future activities, he is hardest on himself for not yet achieving an unlikely immediate goal. “Our greatest failure,” said Hoffman in response to a direct question “is that we have not to date identified drugs or treatments that can cure all patients with MPNs. We can cure some patients with stem cell transplantation but only a minority are eligible for this type of therapy…The commitment to cure all MPN patients is the overall mission of all the efforts of the MPD-RC.”

-Женя

 –

MPD-RC Centers

 

Name	Principal investigator
Belfast City Hospital Belfast, United Kingdom	Mary Frances McMullin, MD
Columbia University New York, NY	Mark Heaney, M.D.
Cleveland Clinic Cleveland Ohio	Yogen Saunthararajah, MD
John H. Stroger Hospital of Cook County Chicago, IL	Rose Catchatourian, MD
Duke University Medical Center Durham, North Carolina	Murat O. Arcasoy, MD
Emory University Atlanta, Georgia	Elliot F. Winton, MD
Geisinger Cancer Center  Hazelton, PA	Harsh Gandhi, MD
Georgetown University Medical Center Washington D.C.	Craig Kessler, MD
Guy’s and St. Thomas’ NHS Foundation Trust London, United Kingdom	Claire Harrison, MD
Heart of England NHS Foundation Trust Birmingham, UK	Joanne Claire Ewing, M.D.
Assistance Publique-Hopitaux de Paris (AP-HP), Hopital Saint-LouisParis, France	Jean-Jacques Kiladjian, MD
Johannes Wesling Klinikum Minden, Germany	Martin Griesshammer, MD
Johns HopkinsBaltimore, MD	Jerry L. Spivak, MD
Mayo ClinicScottsdale. AZ	Ruben Mesa, MD
Mount Sinai School of Medicine New York, NY	Ronald Hoffman, MDJohn Mascarenhas, MD
Northwestern University Chicago, IL	Brady Stein, MDJohn Galvin, MD
Ohio State University Columbus, OH	Rebecca Klisovic, MD
Ospedale San Martino Genova, Italy	Andrea Bacigalupo, MD
Ospedali Riuniti de Bergamo Bergamo, Italy	Alessandro Rambaldi, MD
Oxford University Hospital Oxford  United Kingdom	Adam Mead, MD
Princess Margaret Medical Center Toronto, Canada	Vikas Gupta, MD
Roswell Park Buffalo, NY	Eunice Wang, MD
San Matteo HospitalPavia, Italy	Gianni Barosi, MD
Chaim Sheba Medical Center Tel Hashomer, Israel	Arnon Nagler, MD
Rush University Medical Center Chicago, IL	Jamile Shammo, MD
Sloan-Kettering Institute for Cancer Research New York, NY	Raajit Rampal, MD
Stanford University School of Medicine Stanford, CA	Jason Gotlib, MD
The Palo Alto Clinic Palo Alto, CA	David Leibowitz, MD
Universita Cattolica del Sacro Cuore Rome, Italy	Valerio De Stefano, MD
University of Chicago Chicago, IL	Olatoyosi Odenike, MD
Universitätsklinikum Freiburg Freiburg, Germany	Nikolas von Bubnoff, MD
University of CambridgeCambridge, UK	Anthony Green, MD, PhD
University of Florence Florence, Italy	Alessandro Vannucchi, MD
University Hospital Aachen Aachen, Germany	Steffen Koschmieder, MD
University of Illinois Chicago, IL	Damiano Rondelli, MD
University of Kansas Medical Center, Westwood, KS	Yacoub Abdulraheen, MD
University of Maryland Baltimore, MD	Maria Baer, MD
University of Pennsylvania Philadelphia, PA	Elizabeth Hexner, MD
University Hospital of Ulm Ulm, Germany	Konstanze Dohner, MDRichard Schlenk, MD
University of Southern California Los Angeles, CA	Casey O’Connell, MD
University of Utah Salt Lake City, UT	Josef Prchal, MD
Wake Forest University School of Medicine, Winston-Salem, North Carolina	Dmitry Berenzon, MD
Washington University School of Medicine, St. Louis, MO	Stephen Oh, MD, PhD
Weill Cornell Medical Center New York, NY	Richard T. Silver, MD
New York University School of Medicine New York, NY	Judith Goldberg, ScD
Mario Negri Sud Chieti, Italy	Giovanni Tognoni, MD
New York Blood Center New York, NY	Rona Weinberg, PhD

 

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