Science & Medicine

ASH 2016 – Top Takeaways by Top Docs

It’s a bit like getting dispatches from a war zone. Reports from the front lines. The unfolding battle scene makes more sense when looked at through the eye of commanders in the field.  Through private conversations, emails, and formal statements some of our most trusted, senior hematologists and scientists shared their impressions of ASH San Diego news with MPNforum readers.  Here are the written statements or summaries of those impressions from Jerry Spivak, Richard Silver, John Crispino, Serge Verstovsek,  John Mascarenhas, Ruben Mesa, Claire Harrison and Brady Stein.  

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Dr. Jerry Spivak

Dr. Jerry Spivak, MD, Johns Hopkins

The pace of scientific progress is deliberate and incremental, and the MPN research, both basic and clinical, reported at the recent annual ASH meeting conformed to this behavior.


Prchal on deregulated X factor in PV and ET
Most notable to me from a basic science perspective was the report from Josef Prchal’s laboratory about deregulated X chromosome gene expression in with PV and ET patients. Importantly, the X chromosomes had more overexpressed genes than the 46 autosomes in women PV patients, one of which could facilitate continuous JAK2 activation. This fits with the observation in mice that deletion of Xist (the gene responsible for X chromosome inactivation in women since only one X chromosome is needed) results in an aggressive MPN, and with our recent observation that women with PV deregulate different genes than men.
It could also explain the differences in clinical behavior of women with PV compared to their male counterparts, despite lower expression of JAK2 V617F. It is good news that differences between men and women with PV, both genetic and clinical, are finally starting to attract attention, although we have been emphasizing this for over a decade. Unfortunately, the message hasn’t reached everyone, considering that this important abstract was not deemed significant enough for platform presentation.
The clinical abstracts largely involved “filling in the blanks” with respect to combining ruxolitinib with other treatments like chromatin-modifying agents or bone marrow transplantation, as well as its effects in the community practice as opposed to the idealized atmosphere of a clinical trial. Importantly, in an observational, “real life” PMF study, ruxolitinib achieved response rates comparable to those seen in phase III clinical trials and 10 mg BID was identified as the appropriate starting dose.
Transfusion-dependence and delayed initiation of therapy were two causes for an inferior response to the drug; ruxolitinib was also tolerated well in PMF patients greater than 75 years of age.

HU v, PEG for PVUnfortunately for PV, we continue to be treated to comparisons between hydroxyurea (HU) and pegylated interferon (or HU and ruxolitinib), since HU is considered the “gold standard” for PV treatment without a shred of evidence to support the routine use of HU or of any other chemotherapeutic agent for that matter. The initial results of the MPD-RC prospective trial of HU vs pegylated interferon, which showed no difference, can only be considered preliminary given the small number of patients and limited observation period.

A novel agent, sotatercept, an inhibitor of proteins involved in bone destruction, which was found unexpectedly to promote red cell production by an undefined apparently nonerythropoietin-related mechanism, was examined in anemic PMF patients. In this phase II study, the drug was administered subcutaneously every three weeks and 36% of the subjects, all women, responded with a hemoglobin increase, durably in some with continued therapy. Much more needs to be learned about this drug, particularly whether plasma volume shifts as opposed to a true increase in erythropoiesis are involved since the hemoglobin increments achieved were more rapid than is seen with erythropoietin.

The promise of Pacritinib, an inhibitor of a variety of tyrosine kinases, was its potential usefulness in PMF patients with low platelet counts. This year’s ASH abstract presentation indicated that it was effective in reducing splenomegaly and alleviating symptoms compared to ruxolitinib but, paradoxically, thrombocytopenic bleeding was not averted and, of course, the drug is still on hold by the FDA because of intracranial hemorrhage and cardiac toxicity. In this regard, it is my opinion (contrary to the FDA, which does not treat MPN patients) that if a thrombocytopenic PMF patient needs treatment for symptomatic splenomegaly, ruxolitinib should be given since platelets can always be administered if necessary and because the patient is not going to improve without therapy. Importantly, with ruxolitinib therapy, the platelet count may actually increase, unlike treatment with HU. Low dose thalidomide is also especially useful in this situation and can be given with ruxolitinib.

The promise of Momelotinib was that it would improve anemia or reduce transfusion requirements but the drug does have neurologic side effects like some other JAK2 inhibitors and to date no new data was presented to suggest that it is superior to ruxolitinib.

JAK inhibitors vs, BAT
Going forward, I think it time to acknowledge that comparing JAK2 inhibitors or pegylated interferon to so-called “best available therapy” is irrational because there no excuse for the routine use of chemotherapy, HU or otherwise, in PV, ET or PMF. We now have two effective, nonmyelotoxic targeted therapies, one directed at the involved hematopoietic stem cells and one at the mutation-addicted hematopoietic progenitor cells, both of which can do what chemotherapy cannot do.

Precision medicine
What we really need to learn is why some MPN patients do not respond to these agents or fail to achieve a durable response. Clearly, PMF differs in its clinical behavior from MF arising from ET or PV, while many PV and ET patients do not require drug therapy. Truly, therefore, the time for precision therapy in the MPN is now and clinical trials should be directed at learning how to maximize the benefits of ruxolitinib and pegylated interferon, alone or together, leaving chemotherapy in the 20th century where it belongs.

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John Crispino, PhD, Northwestern

One of the most devastating complications of the MPNs is progression to AML. Not only do we lack effective therapies, we also know little about the basis for transformation, and have only one genetic model that can be leveraged for drug development.

At this ASH meeting, there were several presentations related to the biology of AML progression. In all cases, the investigators set out to combine Jak2V617F expression with a genetic perturbation that is associated with secondary AML with the intent of modeling progression. Examples included the introduction of deficiencies in DNMT3A, PTPN1, or JARID2 into Jak2V617F mutated cells in vivo.

Although none of the animal models developed AML,deletion of each gene led to a striking enhancement in disease, with decreased survival and increased severity in every respect, including fibrosis.

Despite not modeling AML progression, these studies are significant in several respects. First, they inform us that leukemic progression likely requires multiple genetic defects rather than a single secondary change beyond the JAK2 mutation. Second, the mice provide a platform for testing the effect of tertiary mutations on disease. Third, the animal models are another resource for pre-clinical studies of novel agents in a model of advanced disease.

In the end, although we do not know the causes of evolution to AML, we are getting closer to understanding the genetic basis of disease progression.

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ruben mesa at ASH

Ruben Mesa, MD, Mayo Clinic, Scottsdale


Two large phase 3 trials had information regarding the use of long-acting       interferons. Pegylated interferon alpha 2b (Ropeginterferon) a trial done in Austria and Europe called the PROUD PV Study. The second, the MPD Research Consortium Trial of Hydroxyurea vs. Interferon (pegylated interferon alpha 2a Pegasus MPD RC 112).The PROUD PV Study was in patients with high risk polycythemia vera     comparing Ropeginterferon vs. hydroxyurea. At a high level, what could be said is that the interferon and hydroxyurea were fairly similar through a year of follow-up in terms of control of blood counts, decreasing risk of blood clot or bleeding events and tolerability. Longer term follow-up on this study, which was presented suggested increasing number of molecular responses in the Ropeginterferon treated patients after a year.

The MPD RC 112 Study was pegylated interferon alpha 2a (Pegasus) in high risk PV and ET and was an interim analysis. Through a year in the patients in which we have information similar to PROUD PV, interferon was not inferior to hydroxyurea regarding controlling counts, decreasing risk of blood clots, bleeding events and bone marrow features.

I presented in parallel the symptom assessment between these two groups and found that in the first six months pegylated interferon alpha 2a probably worked more rapidly in improving P-vera related symptoms. However, side-effects from Pegasus are not irrelevant and did negate some of these benefits with longer follow-up. In aggregate, these studies are ongoing and these confirm that interferon clearly is not inferior to hydroxyurea in any way for controlling counts and decreasing the risk of blood clots or bleeding. Likely it will take much longer term data to be able to prove whether or not long acting interferons are able to slow down progression of the disease.

New JAK Inhibitors

The Pacritinib trial Persist 2 was presented at the meeting and demonstrated in patients with a platelet count of less 100,000 with Pacritinib, in particular the dose of 200mg twice daily was better than Pacritinib 400mg a day or best alternative therapy (largely including ruxolitinib modified doses for patients with myelofibrosis and a platelet count of lest 100,000). Concerns of side-effects  including bleeding or cardiovascular side-effects seem to be by far the least in those patients treated with Pacritinib 200mg twice a day and overall was viewed as favorable data. These data along with the data from Persist 1 are currently being analyzed by the regulatory bodies that evaluate whether Pacritinib will come off a clinical hold and whether it will be approved as a therapy in the future for patients with myelofibrosis with marked thrombocytopenia.

Two large phase 3 trials of Momelotinib have recently been concluded; Simplify 1 and Simplify 2. No data was presented at ASH regarding these phase 3 trials; however a press release was made public in November by the manufacturer, Gilead, which showed that Momelotinib seemed to be non-inferior to Ruxolitinib or controlling splenomegaly, was slightly inferior to for controlling symptoms,  but was superior for improving anemia. All of these results will likely be made public in the near future in detail for assessing what is the next step for Momelotinib.

Ruxolitinib Combinations

Further beneficial information regarding Ruxolitinib pre-allogeneic stem cell transplant, Ruxolitinib with hypomethylating therapy for patients with advanced disease (Azacitidine or Decitabine) were presented all with favorable results in consideration in particular in those individuals with advanced disease it may increasingly become part of clinical practice.

Anagrelide at Intermediate Risk ET

A trial done in Europe suggesting the importance potentially of cytoreduction; in this study, Anagrelide better than placebo for patients with intermediate risk ET, those with an age of 40-60 that had not had prior thrombotic events.

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John Mascarenhas, MD, Mount Sinai Medical Center

This year at ASH we saw a lot of prospective data on IFN-alpha for ET and PV specifically with the agents Pegasys and ropeginterferon.

These are clearly active agents and the results presented by myself and Heinz Gisslinger add to the experience of the larger community of researchers. The data from the MPD-RC 112 is still early (interim analysis) and provides blinded analysis demonstrating equivalent complete hematologic response rates for both agents at a year. This speaks to the fact that pegasys in particular needs to be provided over an extended period of time and the deeper responses are likely to be better appreciated after a year, we will see when the final results are provided at the end of 2017.

Also shows HU is capable of inducing bone marrow pathologic responses and even molecular responses and this was somewhat surprising to many investigators. Longer term follow up will be essential to better distinguish true differences in tolerability and efficacy. The PROUD-PV study showed that ropeginterferon is active and can induce clinical responses and may be better tolerated than Pegasys with less frequent dosing.

The pharmacokinetics of this agent  are different than Pegasys due to the novel pegylation technology used to make the drug. This may in fact explain why the drug can be dosed less frequently and perhaps have better tolerability. Dr Gisslinger also presented data in which patients could effectively be transitioned from other forms of IFN to ropeginterfon safely and effectively in early PMF. So this looks like a potentially viable agent in MPNs and the MPD-RC is planning a trial called RESCUE which would allow patient that were receiving Pegasys on the MPD-RC 111 and 112 trials to transition onto ropeginterferon. This investigator initiated multi-center trial will hopefully open 2nd Q of 2017.

We also saw that Pacritinib was both effective and safe in MF patients with low platelets and particularly <50K from the results of the PERSIST-2 trial. This drug has been on full clinical hold but we are hopeful that the data from the final results presented at the late breaking abstract session will reassure the FDA and allow for this drug to move forward and be available for low platelet patients suffering from debilitating symptoms and spleen.

Lastly we saw that mutational profiling continues to play an increasing role in understanding the pathobiological mechanisms of MF and ET/PV and is being incorporated into risk stratification systems for prognostication and very soon will be used inform therapeutic decision making and targeted treatments.

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Dr. Robyn Scherber

Robyn Scherber, MD, OHSU

1) The field is moving more towards JAK2 inhibitor use earlier in the disease course.
2) We have lots of genetic data that was highly (almost over) emphasized– but there are unmet needs in how to use the large volumes of genetic data. Specifically, we need to figure out the role of these genetic mutations in risk scoring algorithms, early disease management, and transplant setting.
3) Ruxolitinib had is day in the limelight, but there are some new up-and-coming drugs that may be set to steal the show in the near future

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Srdan Verstovsek, MD, PhD, MD Anderson

The takeaway review conversation  with Dr, Verstovsek covered much the same territory visited by our other MPN specialists. A year is too early to draw conclusions on the interferon trials and some discussion of discoveries of new mutations and the fate of last year’s contenders, imetelstat and PRM-151. He thought we should not yet count out PRM-151 — this is Promedior’s drug to help reduce fibrosis in the marrow —  as he believes they were reviewing data in preparation for a new trial. (Since Janssen dropped the low dose Imetelstat arm for lack of efficacy much of the excitement powering this telomerase inhibitor seems to have disappeared.  High dose imetelstat was implicated in severe adverse effects leading the FDA to place a hold on an earlier trial.)

Verstovsek talked a bit about Sotateret (ACE-011) a potential emerging drug to ameliorate anemia associated with myelofibrois. Unlike erythropoiesis- stimulating agents which often carry unacceptable risk and minimal efficacy, Sotateret  binds to  Transforming Growth Factor (TGF) Beta releasing its restriction of normal red blood cell production.   Initial results from a clinical trial,  open to transfusion dependent MF patients, sponsored by Celgene, have been very encouraging. The trial is currently enrolling [NCT01712308].

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Richard Silver MD

Richard T. Silver, MD, Weill-Cornell

Dr. Silver thought the results of the two HU and IFN trials were of interest but somewhat premature for an oral presentation at ASH.  He wasn’t surprised, not even at the molecular responses secured by HU. He had published on all that years earlier. He was only surprised that results were published at all after only one year. And with so small a sample. As the world’s pre-eminent interferon expert and evangelist, his response was understandable, even predictable.  What was surprising was his presentation of a a study he, Nick Cross et al, had presented at ASH 2016.

The question: Could low dose interferon could impact the progress of myelofibrosis in patients with high risk mutations?   Here in three slides is the unqualified answer.  With his permission we will see if we can publish the full study and slide set in the MPN Quarterly Journal.





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Brady Stein, MD, Northwestern

Given my special interest in MPNs, of course my focus was on attending the MPN education session, along with the oral and poster abstract sessions.
The educational session was high quality and practical, as is always the case.

The new WHO 2016 MPN criteria

Leaders in the field helped the audience navigate the revised WHO 2016 criteria, which place special emphasis on determining the precise MPN subtype.  The biggest change occurs for PV, as the hemoglobin threshold has been lowered, so as to avoid missing “masked PV” or labeling inappropriately as ET.  Strong emphasis was made regarding distinction of ET, from early or prefibrotic MF, given the prognostic impact.

Driver mutations

A second educational session reviewed what is known, and unknown about the impact of driver mutations, as well as non-driver mutations, such as those that are considered “high risk.”  In ET, the driver mutational profile impacts thrombosis risk, as those with CALR have a lower risk for thrombosis than those with JAK2 mutations.  In MF, the driving mutations confer an independent impact on prognosis—again, the prognosis appears more favorable for those with CALR mutations.  A window into the biological contributions was provided as well, as well as new discoveries in “triple-negative ET.”  This is actually a heterogeneous group, as some have MPL mutations outside regions we typically test for, and others have hereditary/germ-line MPL and JAK2 mutations.  Some have no clear clonal marker, suggesting that some with “triple-negative” ET may not actually have ET!  The non-driving mutations clearly impact prognosis in MF.  Data are relatively consistent here.  How we act on this information is still the challenge.  Perhaps the impact from similar mutations on ET/PV prognosis will also be elucidated, but I suspect even less actionable than MF. The last session took us through the challenge of decision-making when selecting transplant candidates for MF.

HU v. peg-IFN

Prior to the oral sessions, I was most eager to learn of results comparing HU and peg-IFN.  There were two such studies.  As you know, the first came from the MPD-RC.  Unfortunately, peg-IFN failed to outperform HU with regard to efficacy and safety.  Further, as presented, there was a surprising degree of bone marrow and molecular changes in the HU group.  Perhaps we should not yet be discouraged; only half the cohort was presented, and the impressive results from peg-IFN have a time-dependence.  In the second randomized study, ropeginterferon, administered each 2 weeks, proved non-inferior to HU with regard  to efficacy.  Personally, I was hoping for superiority.  A similar caution was provided—best to wait until the data mature.  However, if with longer follow-up, results still prove disappointing, the importance of phase 3/controlled studies is validated.  Uncontrolled studies provide intrigue and speculation, but randomization and control/comparison are needed prior to a widespread adoption.

Pacritinib, momelotinib, etc.

With regard to JAK-inhibition, results from the PERSIST-2 study were presented.  This agent would fill a niche for those with thrombocytopenia, who have an unmet need.  The data suggested that pacritinib out-performed best therapy (I am not sure what best therapy would be here) with regard to spleen reduction, but not symptom improvement.  GI side effects are the unique toxicity. We are all waiting on the status of the FDA hold.  The phase 3 studies of momelotonib were not presented, but as you know, a press release is out and I would expect a presentation at EHA or ASCO.  NS-018 remains a viable JAK-inhibitor, given that the agents ahead of it have faced challenges.  This agent demonstrated a modest response rate, even among those with prior JAK-inhibitor use.

A unique combination was presented, involving ruxolitinib with a PI3KD inhibitor.  This was a phase 1 study, determined to find to the proper dose for further development.  We cannot comment on efficacy, but it is a unique combination to follow.

In terms of non-JAK inhibitor options, sotatercept was presented for MF-anemia.  This is an aspect of MF care without yet a satisfying therapy.  Five of 14 pts responded; the next development will include a pairing with ruxolitinib.

As a hematologist who focuses on MPN’s, I remain hopeful given an unprecedented number of clinical trials.  Am I still quite envious of the situation in CML?  Absolutely.  More work needs to be done, for certain.  Am I willing to accept HU as the best option for ET and PV?  Not just yet.

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Professor Claire Harrison Guy's & St. Thomas'

Claire Harrison, MD, Guys’ and St. Thomas’ NHS
My take home messages from ASH this year are varied.

Grouping them by disease in ET we saw data from the extended release anagrelide preparation “Areta trial”. This was a study for patients with at-risk ET aged 40-60, platelets <1000 and and a risk factor for thrombotic complications. End points included increase in platelet count or thrombotic event. Platelet counts increased for placebo treated patients 15 vs 2 and there were 17 thrombosis/bleeding events for placebo vs 11 on extended release anagrelide.

This trial is difficult to interpret in my view it shows that patients who are aged between 40-60 with ET who have a cardiovascular risk factor should consider treatment though most clinicians in the UK would already be treating these patients. However I note that patients still had events (11 on treatment) so this calls into question what treatment.

Then the data with IFN in PV and ET from MPD RC112 and for PV in PROUD PV. Two different studies, different patient populations.  Patients can enter PROUD PV for example if they had not responded to HU. This means there is potential for a bias in comparative results. However effectively these studies show equivalence of HU and IFN.

Interestingly the MPD RC study reports some molecular and bone marrow responses for HU – an interesting and sometimes forgotten finding. What should patients take from these studies.. no one treatment has absolute superiority over another and perhaps the best one for you is the one you feel the best when taking?

Some interesting data for endothelial cells and JAK activation and neutrophils forming TRAPS that are inhibited by JAKi but not by HU though this data is further from the clinic.

For MF more data on predictors of response to ruxolitinib from Francesca Palandri,  an amazing database they have in her unit. Focus again on the High Molecular Risk mutations. I didn’t think there was anything too new there. I didn’t see too much for momelotinib.  There was data from the Mayo clinic but this is single centre multiply pre-treated patients. I would prefer to look at the phase 3 studies when they are available.

 I find the data with azacytidine, decitabine plus rux interesting and in line with our own experience and UK studies. Sotatercept I think is potentially very interesting for anaemia with rux and one to watch. Finally for combo studies I for one am keeping my eye on panPIM LEE011 and the PI3K inhibitors..

A busy congress… lots of food for thought.


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