An MPN conference in Estoril, Portugal
-by Robert Baumeister and Rochelle Moore
Portugal in late October has balmy temperatures, clear skies, and a bright sun. The ideal weather is accompanied with a light breeze drifting in from the atlantic ocean like the consummately choreographed dance. It is the perfect place to go this time a year as are all opportune and exemplary performances. It is not surprising that the organizers (ESH, European School of Haematology) of this conference, The 6th International Conference on Myeloproliferative Neoplasms, have now chosen this location twice for their bi-annual gathering of MPN experts.
Despite these apparent incentives it was the list of speakers present at this gathering that convinced us to go. Names of researchers that, if one follows the MPN research are the “all stars” of the field: Barbui, Green, Levine, Pahl, Skoda, Vannucchi, Crispino, Cross, Hoffman, Constantinescu, Mullally, Villeval, Kralovics, Barosi, Méndez Ferrer, Prchal, Harrison, Skoda, Spivak, Mesa, Kröger, Jamieson, Cervantes, Cazzola, Van Etten, Silver (in no order of relevance and not exhaustive). With few exceptions – everybody was there. To have them all in one place for three days discussing the latest MPN research exclusively, was too sweet an opportunity to miss for a patient and a caregiver who thirst for breakthrough discoveries.
The MPN scientific community does not use meetings like the ESH Conference to break important scientific news. The organizers managed to get an agreement with ASH (American Society of Hematology), the premiere hematological conference of the year, so researchers could present unpublished data, however, scientific breakthroughs are reserved for ASH (Abstracts are published online November 6; ASH Annual Meeting is held December 6-9). Knowing that such breakthroughs are customarily reported at the major conferences (ASH, EHA – European Hematology Association) we tempered our expectations.
As complete outsiders to the scientific community we were impressed with Dr. Anthony Green’s offer to talk to us prior to the conference. It was the perfect introduction to the event, giving us a better understanding of his work presented at the conference regarding the relevance of the order of the acquisition of mutations in MPNs and research on the connection between the CALR mutation and the activation of the Jak Stat pathway.
Green let us in on what he expected to be interesting and important presentations. We mentioned that patients often wish for more cooperation and agreement among the researchers. Green had a different take on the issue. He described it as “healthy competition,” though he said there is much collaboration among the scientists. It is essential for scientists to make discoveries and get papers published and this gives a sense of competition, but as Green mentions, it makes the research go faster.
Some of the scientific leaders were accompanied by senior – though surprisingly young by age – members of their research teams as networking and “inspiration” was the purpose of their stay One mentioned the potential presence of “sharks in the room” while refusing to let us in on the latest findings. However, some were selected and gained the experience of presenting their abstract or poster at an important MPN conference. These team members clearly understand the privilege they hold in being a part of science-breaking research with a leading expert in the field.
We were very happy to meet Dr. Angela Fleishman, one of our friends from an MPN forum group she researches MPNs in her own lab (http://www.mpnlab.org/) at the University of California, Irvine. She has helped us and other patients with general questions about the disease or upcoming trials. She was one of the ten who received an MPN Research Foundation Challenge Grant awards this year.
It was a delight to sit with Prof. Dr. Heinz Gisslinger has been working as a clinician with the drug interferon for 30 years. This is what he says about the drug and the new form in trials now: The side effects are dose dependent. The first came in convincing patients to agree to take a drug with such side effects. He saw the TKIs come for CML, which were not effective for MPNs, and the development of the Pegelated versions of interferon. He now mostly prescribes Pegasys because it has a little longer half-life, which can mean fewer side effects. But he and his colleagues saw that interferon was very active in ET and PV early MF.
Now there is the so-called “Austrian interferon (AOP2014).” This version has an even longer half-life, so it can be taken every other week. It is currently in Phase 3 clinical trials. He says the drug will be the first approved interferon, to his understanding in 2017, and it will move interferon first line. He believes the drug to be very active without as many side effects. When considering side effects, he points to two: 1) the potential to provoking autoimmunity disorders in patients with pre-existing autoimmunity disorders, so this side effect is considered patient dependent and 2) mood disturbances is the other important side effect to consider, which he says is dose dependent. He believes that it is important to slow down disease activity, shrink the spleen, and improve symptoms, and in his vast experience, interferon has been shown to do this.
Ron Hoffman presented his preclinical findings on the combination of a nutlin 3 inhibitor (a small-molecule inhibitor of p53-MDM2 binding) and Interferon. He discussed moving cells out of dormant or quiescent states, or silent states (with interferon), and the combo with the nutlin 3 inhibitor is selective for MPN progenitor and stem cells, not normal cells, thus a reduction in malignant cells was seen. Then he mentioned that a clinical trial of single agent nutlin 3 inhibitor (RG73388) will start early 2015.
It was also mentioned by Heike Pahl and others that Novartis will start a triple combination clinical trial of a CDK 4/6 (LEE011) inhibitor in combination with Ruxolitinib and pan PIM inhibitor (LGB321).
Dr. Ross Levine presented his view on the role of the Jak Stat pathway in the MPNs and presented a type II Jak inhibitor (CHZ8689) that inhibits the Jak Stat pathway when there is resistance to type I Jak inhibitors and also reduces the allele burden, basically hitting the Jak2 more specifically and harder. When we asked what he thought patients should be excited about: “I think what’s the most encouraging thing for patients is that there has been an explosion of knowledge, approaches, and an increasing number of people interested in MPNs. More than anything patients should be extraordinarily encouraged that now there are a tremendous number of people who are very interested in this disease and understanding it and treating it better when ten years ago there were very few people working on it, and that to me is the most exciting fundamental issue.”
Levine acknowledged there was a great deal of biology presented, but also interesting data on targeting specific molecules that may not have been thought about before, and for example targeting DNA pathways or stem cells. He also suggested that in many cases these novel approaches may be most useful in combination with a lot of the drugs we already have on hand whether it be interferons or JAK inhibitors or other agents saying, “The challenge is not that we don’t have some drugs that have efficacy, the problem is we don’t have the level of efficacy that we’d like to see.” So, he said moving forward the question is how to move from drugs that have good results treating some aspects of the disease to something more dramatic, and he is hopeful that some of the preliminary results seen at this meeting would be quite promising. Further good news he said is that the FDA and other regulatory agencies have become more interested in the question of how we can design better trials.
Regarding the question of interferon, Levine says the challenge with this drug is that it takes a long time to work, we do not a great understanding why some patients have very significant responses and other patients don’t, and for some it is a difficult drug to take. On the other hand, he was more encouraged from data in this meeting with the possibility of combination studies where less of the drug can be used, patients can potentially get off sooner, the combination of drugs could synergize, and so the patient would not be on chronic substantial doses for years. He referred to what Hoffman suggested regarding getting the cells out of dormant or quiescent states, and if this is the goal, his hope would be that perhaps an initial phase of interferon followed by other agent, and if this should benefit we could have a winner.
Dr. Stefan Constantinescu is another co-recipient of a 2014 MPNRF Challenge Grant with the abstract, “Mechanisms of Sensibility and Resistance of MPN Hematopoietic Stem Cells to IFNα Therapy” (http://www.mpnresearchfoundation.org/2014-MPN-Challenge-3A-Villeval-3B-Pellegrini-3B-Constantinescu). During his interview with us talked about Jak2 activation and potential therapies. He explained how the pathological function of the jak 2 mutation is also activated all the time by other active/driver mutants and the current challenge that it is impossible to treat properly because you need to get rid of the mutated clones (whatever they are because all the drivers eventually activate Jak2) by increasing the current Jak 2 inhibitor doses so high to kill off the mutant clones which would affect the normal blood formation or activation of Jak 2 by cytokines.
So Constantinescu’s team (and others) are trying to understand on a molecular level how the Jak 2 activation pathway is different when it is driven by a mutation or a receptor or perhaps in other defects because, again, he stressed, they all rely on Jak 2 super activation. But if there would be a different confirmation of change required, for example a myelo-stemic change in the kinanse domain that would be common for many ways to activate Jak2 abnormally, then the specialist in screening for drugs could select for one of those kinds of regions. In other words, if they can find out how the pathologically activated Jak kinase is different, then they can target that pathologic activation. He shared that groups are trying screenings, but it is too early to talk about specific molecules. He hopes in a few years progress in the area of the pathologic forms of Jak 2 activation and not the normal cytokine response is better understood.
There seem to be some “high tech” problems designing these new Jak inhibitors as Dr. Stefan Constantinescu discussed specific issues with the design of these new molecules and his colleague Dr. O. Silvennoinen used new and faster supercomputing to simulate the binding mechanism of such molecules. It is fascinating stuff, but one can only wonder how many people in the audience understood a question relating to the “second pocket in the pseudo kinase domain.”
Lucia Kubovcakova from Dr. Radek Skoda’s team presented an abstract that showed the hypothesis that Interferon and the Jak inhibitor, Ruxolitinib, antagonize each other does not hold. The combination in her mouse model had good effects on counts and spleen though no reduction of allelic burden was observed.
Finally, we had the privilege of interviewing the SCT expert, the very personable Prof. Dr. Nicolaus Kröger. He walked us through what is important to consider in SCTs. Of utmost importance is experience. He said it is not related to drugs, protocol, and guidelines, that any center can use or follow because in the end you need the entire team to be experienced, very well trained and professionalized. This is known as the “center effect,” which directly relates to experience and the number of transplants by the hospital.
The differences with having an MPN and transplanting vs another disease are the severe bone marrow fibrosis, which affects the microenvironment and good niche needed to build back good hematopoiesis, and a huge spleen causes trouble with engraftment of cells. With regard to risk, while it is important to weigh, SCT is the only procedure that can provide a cure. So Kröger says one must very well balance risk and benefit. The new opportunity that molecular typing provides can detect patients who may have been Int 1, for example, but have the mutations that make the risk actually higher, so SCT may be more heavily weighted in such a case.
The professor said the field of stem cell transplantation is moving quite rapidly. In past conferences, only disease specific risk factors were discussed (IPSS, cytogenetics, blasts, etc), but now transplant specific risk factors, such as donor availability, and patient risk factors like age and comorbidities are all considered to develop an individualized treatment in order to gain the most benefit and avoid both non-relapse mortality and relapse. There are many options to modify the conditioning regiment for example, for example adjusting the level of conditioning or GVHD (Graft vs Host Disease). Some GVHD is desirable because it also means GVLE (Graft vs Leukemia Effect). Those with no GVHD often relapse, so sometime it may need to be induced a little. Jak inhibitors are used to improve patient specific disease factors, such as reducing the spleen, reducing constitutional symptoms, gaining weight, and thus lowering therapy related complications. These methods are evolving and improving now and moving forward into the future.
The ESH MPN conference had a workshop-like character. After a speaker gave his/her presentation, there was a time for Q & A during which the other researchers/clinicians raised potential considerations to further explore the research presented as well as to further understand the methods used. This united effort and collaboration to understand the fundamental biology and solve the MPN puzzle was impressive to our lay person eyes.
We could feel the progress in the air, hear it in their voices, and see the light in their eyes. These experts are not only “all stars,” of the MPN field, but they are people of high character. Their interactions with one another, and their personal behavior and integrity are of the utmost quality. We were a part of a conversation and were able to then witness one expert clinician bringing a hematologist to an expert SCT doctor to receive much needed help for a patient who required individualized treatment. Several doctors sought help for a particular patient.
While there was much mingling and networking by researchers and clinicians before, during, and after the conference – this conference provides a unique opportunity for them to interact exclusively with colleagues in MPNs – they generously and warmly took the time to speak with us. This spoke volumes to us regarding the motivation behind their work. We spoke to each interviewee of the 1000s of patients in the Facebook forums who we interact with daily and eagerly await hopeful news from their findings. And we passed on our gratitude for their incredible efforts and continued encouraging progress.
It is with gratefulness that we acknowledge MPN Forum, and Zhenya Senyak in particular, for providing us with the access and encouragement to cover this exciting conference, and the ESH staff for providing us with press credentials, and for their exemplary organization.
(All photos by Rochelle Moore)
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