MPNforum Magazine

Rochelle Moore’s first report on this month’s 4th Annual Florence-Miami MPN Patient Conference appeared in a Facebook Page,  Myelofibrosis Private Support Group. Her notes were so complete, spontaneous and useful, we asked her to adapt them for MPNforum. 

Other Mutations…Notes from the Miami Conference

by Rochelle Moore

Last month Jeremy Smith reported on an upcoming MPN Miami Patient Conference. I was able to work out my schedule to attend along with my daughter, Beth, a college senior science student who is also my driving partner. (It was a 2600 miles [4184 km] round trip drive!)

It was an excellent conference organized by Dr.  Ayalew Tefferi, with many top MPN experts from both Europe and US speaking. Held at the Lois Pope Life Center, University of Miami Miller School of Medicine, Dr. Tefferi  organized this event to be free of any drug sponsorship. Rather, the conference was supported by an unrestricted education grant from the Terner Foundation. Mary Terner had been a patient of Dr. Tefferi. Dr. Tefferi was also intent on this being a patient-caregiver interactive time with the doctors. He said, “We will give you all that we know and are able to share, and I want ALL of your questions to be answered.”

A repeated theme running through the day was “Other Mutations.” Whether describing the action of the disease, testing for clearer prognosis risk or identifying therapeutic targets, you could feel the excitement of the doctors in the progress of research to understand the disease better on a molecular level in order to come closer to controlling it. And that excitement and progress can only translate to Good News for the MPN community!

After each talk there was Q & A panel time – often even the doctors asked each other questions. It was good to see their desire to continue learning rather witness a “doctor’s ego,” as too many have experienced in their medical journeys. I am excited to share the encouraging and hopeful information we learned by giving you a copy of my notes:

*Credit belongs to Robert Baumeister for investing in my prep prior to the conference toward understanding significant current research, during the conference toward relevant questions to ask, then as an MPNforum associate editor, encouragement and instruction toward the writing of this story.

Dr. William Vainchenker, Villejuif, France — (for those who enjoy research science) Although the JAK2 mutation is the phenotypic driver of the disease, it is not sufficient alone to cause the disease; JAK 2 needs something else- the cytokines, based on which receptor (MPL [TPO] receptor, EPO receptor), And other mutation. MPNs require differentiation and proliferation.

For example, the cytokines are capable of inducing fibroblasts. The further along in the disease, the more mutations. Those with MF, have more mutations than those with PV or ET.

Regardless of your MPN mutation JAK2 activation occurs on the same pathway, what is important is what type of signaling mutation is going on as he believes future research will lead to therapeutic targets according to: signaling mutations, epigenetic mutations, and spliceosome mutations.

Therapeutic potential of interferon in MPNs: Interferon has an impressive hematological and molecular response, while currently JAK2 is difficult to target because it is indispensable for normal hematopoiesis, Interferon targets “leukemic” stem cells and works directly in immune system.

Dr. Vainchenker responded to my question about his thoughts on the efficacy of the upcoming combination therapies (Pi3k + RUX inhibitors, HSP90 + RUX inhibitors, etc.) by saying that these combos and others will “do better” at controlling the disease because they hit the disease more fully along the pathways where it is activated. However, he believes the future will eventually be in a more specific mutation inhibitor.

Finally, at the end of the Q & A with Dr. Vainchenker, Dr. Tefferi asked if he wanted to give us a taste of what is coming in with regard to a CALR vaccinatiuon without divulging any secrets, but just enough to “keep us in suspense.” So while we were all sitting on the edge of our seats waiting for his response, he quietly shook his head and had nothing he could say yet. Too bad, but the thought of a CALR vaccination in the works is certainly exciting!

Dr. Alessandro Vannucchi, Florence, Italy — (Prognostication) It is possible that the JAK2 mutation and the CALR mutation come from two different hematopoietic progenitor cells. With the discovery of CALR, there remains 15% unknown mutations in ET and 10% in MF.

If negative for JAK2, MPL, and CALR = triple negative. CALR type 1 mutation = better prognosis; CALR type 2 mutation = very similar in prognosis to JAK 2; Triple negative = poor prognosis.

There is increasing evidence that allelic burden does matter There is a direct relationship between allelic burden and amount of hemoglobin; the higher allelic burden = lower platelet count, more symptomatic, larger spleen, greater risk to progress. When Jak2 is below 20% you likely have ET, if above likely PV. Many are diagnosed with ET based on 2012 criteria, but may really have “masked PV.” Even more important, subclonal, or second/next generation sequencing to discover what other mutations you have may have a strong impact in clinical application independent of IPSS or DIPPS plus scores. The clinical relevance is significant in that a new “high molecular risk” category has been characterized that will contribute to a refined prognostic score.

For example, knowing the full molecular sequence can identify patients who will most benefit from SCT. Interpretation of this score is still an art that needs to be discussed carefully with your doctor. ASXL1, EZH2, SRSF2, IDH1/2 are important marker mutations that identify likelihood of progression. ASXL1 has particularly been “dependable” in identifying progression. Mayo Medical Lab and Dr. Vannucchi’s lab in Florence have already begun this 25 gene panel testing  in ET and PV.

Dr. Tefferi said, “This is a new era. I can’t tell you how important this is.” Vannucchi said he agreed 100%. Beginning with his own patients, Mayo Medical Lab is absorbing the cost of the testing as research until it becomes commercially available as a service to patients and their doctors, however, it will take time to become more widely available. Design of a trial is in the works using molecular testing.

I had an opportunity to ask Dr. Vannucchi a few questions during a break and he revealed that he has a CALR antibody that he is working with pre-clinically in his lab! He believes Pi3k is a good target in MPNs; he also has 4 patients on the combination Pi3K inhibitor, BKM120 + RUX/Jakafi and they are doing very well! And, he should begin another combination Pi3K inhibitor + JAK inhibitor trial using Everolimus soon!

Dr. Francisco Cervantes, Barcelona, Spain – (just a couple highlights) We are learning that leukocyte counts are important in that higher counts = higher platelet interaction and platelet activation. Wrestling with the question of whether exposure to cytoreductive drugs, like anagrelide or busulfan, or hydroxyurea, increases leukemic risk for ET patients.

Dr. Ayalew Tefferi, Rochester, MN— (organizer of this event) Considerations for treatment in MF: 1) Age 2) DIPPS score 3) Mutations His study and Vannucchi’s study of molecular risk progression were performed independently and have been confirmed. Dr. Barbui asked: Do mutations (bad ones) make already high risk patients at a higher risk? Tefferi and Vannucchi:  Absolutely yes. Dr. Tefferi echoed what Vainchenker said about needing more than JAK2 to activate and proliferate disease, and that immune structures affect and activate disease. He also said who we are in terms of our germline/preexisting molecular structure dictates how mutations behave and affect us.

Dr. Tefferi actually said Jak inhibitors do have an effect on the disease so the “punch is not so hard.” “Obviously Jakafi is a very useful drug.” “My goal is remission and cure. Let’s pursue those treatments.”

He and Vannucchi are working to get objective molecular data.

Dr. Stephen Nimer, University of Miami, FL – (our host – previously was 20 yrs at MSK) Interferon may lessen transformation and reduce allele burden. JAK 2 allelic burden goes down and leukemic blast phase goes up during progression.

Repeated theme: Something more is going on than JAK2 upregulation. Studying role of TKIs in MPNs. Looking at drugs to effect epigenetics where the transfer of genetic information from one cell to another is performed outside the DNA and actual modifications in the DNA can convert back to normal or lose their identity and become easier to target. Looking at drugs that inhibit DNA methylation. TET2, IDH1/2 are involved in methylation and turn genes back on.

So the exciting news about this research is that an IDH1/2 enzyme inhibitor was given to leukemia patients and very recently reported in a meeting in San Diego that 5 of 7 patients are in CR. Dr. Tefferi was visibly excited, and said, “Unbelievable! I did not hear this yet! There is hope!”

There was a break after Nimer’s talk and all the doctors crowded around him to hear more! They work on specific next generation mutation inhibitors, and are excited about this potentially promising future. For example, Tefferi asked Nimer is ASXL1 an actionable target. Nimer’s answer: not alone, but enzymes in the PRC2 complex are targetable, and talked about UTX and UTY inhibitors that oppose EZH2 and ASXL1.

In 2014, we can report on 20 year survival in remissions, a clear indication that transplantation  offers effective, curative therapy for MF. The oldest patient  transplanted at our Center was 78 years, a retired orthopedic physician who said he was used to taking risks. However, you should definitely discuss quality vs quantity life issues based on your specific situation. =======================

Dr. Joachim Deeg, Fred Hutchison, Seattle, Washington – (on SCT) JAK inhibitors are useful to shrink spleen before a transplant. In fact there are survival prolongation studies on prior JAK inhibitor use. Relevant, but not included factors in current classification to determine who to transplant: severity of fibrosis, extramedullary disease, spleen size (taking out the spleen may improve survival), cytokine profile, duration of disease, and mutations.

The less advanced the disease at transplantation, the better the chance for  a successful transplant. Future studies will need to show whether patients with CALR mutations should be  transplanted.  The more advanced the disease at transplantation, doubles the relapse issues not related to transplant. CALR mutation – and low risk category, may not need to transplant.

“In 2014,” said Deeg, “we can report on 20 year survival in remissions, a clear indication that transplantation  offers effective, curative therapy for MF.”  Oldest age he has transplanted: 78, a retired orthopedic physician who said he was used to taking risks. You should definitely discuss quality vs quantity life issues based on your specific situation. Molecular data and non-transplant manifestations (such as JAK inhibitors) are considerations when looking at transplanting.

Regarding Imetelstat: During the final Q & A time, Dr. Tefferi finally agreed to make some comments about Imetelstat. He is very cautious about what to say to the public since the FDA clinical hold.  Two Imetelstat patients were in the audience and Dr. Tefferi encouraged them to speak. One patient had been a post PV MF and is currently still in complete remission with nothing but praise for what this drug has given her. The other patient spoke in tears about having been in CR as well, but recently his counts have returned to abnormal and neither he nor Dr. Tefferi has an answer as to why. The patient said he still feels good and he is very confused, and Dr. Tefferi said he is puzzled as well, but they will figure this out together. The patient is now considered CI (clinical improvement).

Dr. Tefferi said he wants to know all experiences with Imetelstat – both good and bad. He said, “Imetelstat is still the only drug to give CRs/PRs for MF (high risk). It works fantastic for 20% of patients and not as fantastic for 80% of patients who were on it.” He also said the FDA’s concern is for the ET patients (low risk) trial regarding the persistent low grade toxicity.

For me, this conference held out hope and encouragement in multiple ways. I was greatly encouraged by the spirit of the doctors reporting; their openness to report the latest research and their eagerness to discover the mechanics of the disease in order to find a way to control or cure it gives great hope.

These brilliant scientist researchers, many who flew in just for the day and had little sleep, found it valuable to talk with a handful (about 60) patients and caregivers and answer all of our questions. No one was in a hurry, no one avoided a question. They are coming to similar conclusions about the other mutations and are beginning to better understand the molecular architecture of the MPN. We can take encouragement in all of these realities that better medicine, better disease control, and ultimately a cure is in an ever nearer future.

Take me back to the Contents © Rochelle Moore and MPNforum Magazine, LLC, 2014. Unauthorized use and/or duplication of this material without express and written permission is prohibited. Excerpts and links may be used, provided that full and clear credit is given to MPNforum.com with appropriate and specific direction to the original content.