Science & Medicine

HU vs. INF. Round One, Title fight.


While all around the teeming halls of the San Diego Convention Center hematologists headed for presentations, meetings and poster exhibits, all MPN eyes were focused on a titanic face-off:  Hydroxyurea versus interferon.

In the smack down battle of the 21st Century for the hearts and marrow of the MPN community, an old, battle-scarred and much criticized veteran squared off against a sleek, younger and heavily favored rival.

The result was as surprising as the outcome of the recent American Presidential election…and almost as controversial.

On every judge’s scorecard hydroxyurea (HU) outscored, outpunched or fought interferon (INF) to a draw  as it convincingly drove its rival into the ropes in this opening round of a championship fight.  huint-logo-fullAlthough known for its speed, few anticipated the old warhorse would make such a convincing showing as it mounted an overpowering attack on polycythemia vera, essential thrombocythemia and myelofibrosis.

The battle is far from over. Interferon, known for its slower-acting, more inclusive therapeutic effects against MPNs is expected to overtake hydroxyurea  in the second round, the results of which will be reported in the summer of 2017.  But HU surprised in this first round by demonstrating its ability to reduce the JAK2 burden of MPNs and to produce a better reduction in enlarged spleen than INF.

For the past year, the two contenders were matched in an international arena, the results monitored in two different studies in dozens of countries. The older, bigger study was the MPD Research Consortium’s  MPD-RC 112 Phase III trial comparing hydroxyura to Pegasys (NCT01259856). Smaller but more anticipated was the closely watched European study mounted by the union of a Taiwanese company, PharmaEssentia, and Europe’s  AOP Orphan Pharmaceuticals.  The PROUD-PV trial NCT01949805  was a Phase III study to compare the efficacy and safety of the novel monopegylated interferon alpha 2b AOP2014 versus Hydroxyurea over the period of one year.  Word from Europe was this drug, also called ropeginterferon and, simply, P-1101,  requiring dosage only every two weeks (and at that with a nifty pen-like device) could be the heir apparent to Pegasys.

For MPN patients, finding a fresh source of pegylated interferon was becoming urgent. For weeks, following a short distribution breakdown this summer, MPN social media was buzzing with rumors that Genetech/Roche was planning to stop production of Pegasys.  Ever since Gilead released its $100,000 miracle hepatitis C drug, Sovaldi,  a major share of the market for Roche’s Pegasys suddenly weakened. Would Genentech  drop Pegasys altogether? After checking with home base in Basel Switzerland, a Genentech corporate spokesperson told MPNforum its parent company “Roche has no plans to stop PEGASYS production in the near future.” That may not be not the warm and fuzzy reassurance MPN Pegasys patients and their docs might want to hear, but it’s something. Meanwhile a lot of hope is riding on the ability of ropegintron (P-1101) to quickly negotiate the approval process of European Medicines and the FDA.

Two heavyweight investigators presented their findings from their separate sanctioned clinical trials

Professor Heinz Gisslinger (Medical University of Vienna,Austria) presentedheinz-gisslinger the Final Results from PROUD-PV  (Abstract 475) at ASH.

In prior  trials in PV patients presented at ASH during the 2012-2014 period, P-1101 chalked up an impressive record. Overall clinical response, reduction of blood cell lines,  was about 90% with 45-50% of patients showing complete response,  after 6 to 12 months and patients remaining “largely independent of phlebotomies.”

Gisslinger’s 2016 report at ASH/San Diego was more subdued  The Phase 3 study was spread across 48 sites in 13 European countries. AOP Orphan holds the license from PharmaEssentia, developer of P-1101, for Europe, Africa and much of the world outside of the United States.  . The primary endpoint of the PROUD-PV study was to compare disease response rates after 12 months along such specific parameters as hematocrit<45% without phlebotomy, platelets <400, leukocytes <10 and normal spleen size.  Secondary endpoints included reduction of JAK2 allelic burden.

Inexplicably no data was  released on those results.   Instead, via press release and Professor Gisslinger’s presenation and comments, AOP Orphan offered a summary of sometimes apologetic results.  For example, although HU demonstrated better overall hematologic response in the comparative trial (45.6% vs. 43.1% for ropeginterferon P-1101,  the difference was “statistically insignificant.” And as to the failure of INF to indicate greater reduction of enlarged spleens than HU, (21.3% reduction for r0peginterferon versus 27.6 % for HU) that was because participating PV patients had near normal spleens to begin with so the results “were not clinically relevant.”

Based solely on the ropeginterferon highly preliminary summary report, in this first round, P-1101 appears to be not quite as effective overall as HU but statistically not inferior.

P-1101 might have suffered a setback in this first round confrontation, but all AOP Orphan wanted to prove in its 12 month PROUD-PV trial was its drug was “not inferior “ to HU. It might seem to be the lowest common denominator of proof but it could be a low enough bar to secure approval in a space that badly needs a new med, specially one thought to have a better toxicity and long-term palliation profile. The continuation trial of those in the one year AOP Orphan group might provide the clinching data needed to get P-1101 on our pharmacy shelves by the end of 2017.

It was left to John Mascarenhas (Mt. Sinai Medical ) and the detailed MPD-RC report to deliver a more definitive assessment of first round results.

Dr. John Mascarenhas, Mount Sinai

Dr. John Mascarenhas, Mount Sinai

The two trials, the European ropeginterferon trial and the MPD-RC 112 trial report  (Abstract 4271: Impact on MPN Symptoms and Quality of Life of Front Line Pegylated Interferon Alpha-2a Vs. Hydroxyurea in High Risk Polycythemia Vera and Essential Thrombocythemia,   (NCT 012589856) have much in  common.

They both compared pegylated interferon with hydroxyurea  They both reported preliminary results based on a 12 month trial.

There are differences. PROUD-PV tested a relatively new formulation of interferon for efficacy in PV therapy as measured by time between phlebotomies, hematologic response and spleen reduction and reported few details.

The MPD-RC trial measured the impact of Pegasys and HU on symptoms of high risk PV and ET on Quality of Life, symptomatic relief as well hematologic and molecular responses as measured by the MPN Symptom Assessment Form, the TSS and and bone marrow biopsy and molecular response derived  by measurement of changes in JAK2 burden.


MPD-RC as well as AOP stressed their reports were preliminary and will be followed by a report on longer-term impacts of the two drugs in the summer, 2017.

However, the short term results raised eyebrows as data revealed the blockbuster finding that HU did indeed reduce the JAK2 allele burden in MPN patients.






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Dr. John Mascarenhas on the significance of the preliminary MPD-RC 112 phaseIII trial comparing HU to PEG.

‘This was a preplanned analysis to determine either a clear signal of efficacy or futility in either arm. At 12 months there was no difference in the primary outcome measure of complete response ,….Meaning that at 1 year the two drugs are equivalent in inducing normalization of counts, resolution of palpable splenomegaly and symptom burden.   There was really no difference in molecular response rates.

“Important take home points from this trial:

  1.  At an early time point of a year no clear difference in either drug in terms of hematalogic response rate. (It’s) too early to truly appreciate the durability of these responses….
  2. A year is early and perhaps when we analyze the mature data later next year with a full set of patients we will see a clear advantage in one or the other drug.
  3. HU can in fact induce hematologic and even bone marrow responses as well as molecular responses and this was somewhat unexpected although others have published similar results previously.

“In terms of patients reading this, it is imperative they do not jump to conclusions about the superiority of one agent over the other based on this interim analysis….But I would say that those on HU can at least take solace in the fact that the drug has shown activity that is often not considered possible with this agent.”

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A (very) brief history of hydroxyurea

The success of hydroxyurea should not come as a surprise. Even though it lies at the bottom of our medicine chest like an expired bottle of aspirin, it has a long and venerable scientific lineage.  HU, also known as hydroxycarbamide, decreases the production of single units of DNA – deoxyribonucleotides – by inhibiting an enzyme (ribonucleotide reductase)  necessary for the formation of  DNA .

Naturally occurring in small amounts, HU was first synthesized in 1869. Nearly 100 years ago animal testing of HU began on solid tumors, sarcoma, etc.  Clinical trial “demonstrated that the drug was a highly effective cytostatic agent in chronic myeloproliferative disorders rather than in solid tumors. ” It has been the standard of care and first line of MPN defense ever since.  (Robert Latagliata,et. al.Cancer 2012)

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Comparative retail prices

60 capsules of hydroxyurea 500mg  About $30 – $60

1 kit (4 syringes) of Pegasys 180mcg/0.5ml usually once per week. About $4000

1 vial of Intron A 10 million IU $250 Injection, three times per week. About $3000/mline short red red 50%

Here at the Asia Pacific MPN conference earlier this year, Dr. Gisslinger talks about the risk/benefit of drugs used to treat ET and PV, phenotypes that might have normal longevity and the increased danger of DNA damage from different treatment modalities.

Take me back to the Contents

© 2016, MPNforum. All rights reserved under Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported Licens

Comments on: "HU vs. INF. Round One, Title fight." (11)

  1. I was diagnosed with ET/MF at 51. I started taking 500mg HU 2 days 1000mg 1 day repeat.
    I have been doing this for a 2 1/2 years and my numbers are great. HU makes me sleepy so I take it at night. I’m very grateful for it.

  2. Melanie said:

    Cancer is a great muse.

  3. I was 73 when dx w/ET, platelets at 1.5M, JAK2+, asymptomatic. Other than platelets, all other numbers were perfectly normal. I was prescribed HU 1,000 mg daily. Within a few months, I was anemic and neutropenic. At 6 mos I needed a transfusion when neutrophils fell significantly. I had other deleterious side effects as well, e.g., diarrhea, tremors, chills, stomach pain and horrid gas. Despite all this, doctor insisted on staying on HU at same dose. New doctor tapered dose of HU till I was on 500 mg. Anemia persisted and got worse. I needed another transfusion 14 months after first and another 2 months after that. I began using Droxia 200 mg eod earlier this year. Platelets hover between 550 – 750, RBC finally in normal range as are WBC. However, I now have blasts in my blood and have been dx w/MF. At the outset of tx, hematologist mentioned that HU “rarely” causes a shift to AML. I am now prescribed Jakafi, 500 mg bid. I can’t express enough my concern that this drug will cause severe anemia and make me transfusion dependent. I do not believe enough attention is paid to the leukemogenic properties of HU or to the need to monitor individual responses to the drug. At no time has anyone bothered to tell me what my allele burden is – what it was to begin with and whether it was in any way relieved by HU. I will shortly be 76 and I honestly feel my system has been poisoned and I am faced with early death from MF. Where is the data *proving* that elevated platelets must be managed to the expense of patients’ overall health? I haven’t seen it.

  4. Sarah Lynch said:

    I developed bilateral PE while on 3000mg HU daily. Upon healing from that, I then developed excruciatingly painful ulcers on my ankle, which would not heal until I came off HU. Next on list was Anagralide, which nearly killed me (or so it felt). To assuage my hem I stayed on Ag for 6 weeks. Got to the point of not being able to breathe when walking and, enduring worrisome chest pain. Truly debilitating. Last resort was Peg-Interferon. This was less catastrophic feeling than the Ag, but still took so much out of me that I had no quality of life – felt like a sick zombie… a heavy burden of symptoms, if you will.
    I’m back on HU @ 1500 but hem thinks platelet count of 5.5-6.5 is okay since warfarin is on board (since the PE).
    The HU created problems and allowed clots – but together with blood thinner it seems tolerable. I could not imagine taking interferon for years – I had to stop after only 6 months.
    So, in the world of treatments – I think there is a bigger picture – how does one get by on the chosen treatment? I realize feeling good isn’t necessarily the first thing researchers want to know about – but certainly it should not be the last.

  5. I am now 62 years old and have been on a consistent 500 mg dosage of HU since age 39. I worried early on about long-term usage of HU, switched to anagrelide briefly with terrible side effects, traveled to Mayo Rochester, was advised by one doc that I’d probably do fine just taking baby aspirin. (My platelet counts were over a million untreated). Soon after I discontinued HU, I experienced some TIAs. That was scary enough that I went back to HU and just decided to live life, take my daily HU, get blood counts checked about every 6 mos. and just not fixate on it. Looks like maybe that was the best strategy after all! I do have the JAK2 mutation, so maybe the HU has kept that at bay more than anyone realized. Anyway, I rarely think about myself as being “afflicted” with an MPD. It’s happier for me that way! Glad to see this research.

  6. Wayne Stanfield said:

    This shouldn’t be this hard, EGO is standing in the way of real progress I’ve watched this ridiculous back and fourth for the last 5 years does anyone really care about the patient or is it about who is right? Gene editing is what we should pursue !

    • Not sure of your point, Wayne. I share your enthusiasm for gene editing, but if your platelets are over 1.5 million or your spleen is ballooning do you really want to wait another year for possible relief? There is legitimate debate over the best short-term therapy even if there is some consensus over the longer-term efficacy of interferon. These findings add scientific data to the mass of clinical evidence accumulated over decades.

  7. Richard Silver, MD said:

    “Those who cannot remember the past are condemned to repeat it.”
    – George Santayana

    The PVSG [Polycythemia Study Group] showed that HU controlled the HCT and platelet count in 80% of the patients in doses of 15 to 30 mg/kg and 70% were failure free at the end of one year, so the MPD RC data are no surprise.

    When discontinued there was brisk thrombocytosis and thus maintenance therapy was advised. The consequences of HU toxicity were thus demonstrated afterwards. I think this: “HU vs.INF”a in the current issue of MPNforum reported surprise at the effectiveness of HU which to my mind was never in doubt. In fact, the best results in the PVSG study were in the censored group, ie, those in the phlebotomy arm who were subsequently given HU. These patients were not systematically followed and the data were never reported.

    Unfortunately, this generation of MPN experts does not read the older literature and the data of the PVSG is second to none.

    • I agree with you that modern gen seems to ignore older findings and not always just in medicine. I have taken 500mg HU daily for 2 years with Asprin (currently 300mg/day). My platelets went dow: 1st month from 615 to 449. In 4 months they stabilised at around 260. Blood tests & review are every 3 months.

  8. Coyne Beverly said:

    You’re thinking of Henrietta Lacks. Her chemistry was unique and still lives. On HU for 12 years and now quite anemic. Doc says treating me is like “whack a mole”.

  9. I’m a little tired tonight
    so i won’t locate the exact name and data
    that go with the woman from Baltimore
    whose genetic difference
    made such a difference
    to the world of medicine.

    But, she lived and died,
    and, because she was studied,
    her physical self made quite a difference
    to science and to the world.
    she, of course, po’ as she was,
    was dead.

    different tides course over the planet now.
    the so-called global model has been challenged
    and tear-down is in the air.

    Can’t help thinking, though,
    about little old me.

    i’ve done well on interferon,
    which is not toxic and which is an antiviral agent.

    a different model
    a different kind of therapy
    involving different chemistry.

    Y’all sound like you want to call me off
    or, at least, defund me.

    …and, of course, the latest Taiwan-funded
    study (unopposed by Genentech??)
    is, this day, sacred.

    Who provides romaine lettuce
    also provides so much more.

    Until the next convo.

    My Doc and I have, on and off for
    eight years, been working on building
    and rebuilding

    Babies, please don’t throw me out
    with the bathwater.

    Cancer is doggedly complex and far from cured.

    People, the lucky ones, some of them,
    have been put in well-curated greenhouses
    and their cultivation has paid off,
    more than maybe.

    I’m one of them, Convention Goers.

    The emperor of all maladies,
    the blood part,
    has been solidly gained upon

    by me.

    Doctors, take off those styrofoam bowlers
    that the hedge funders and “numbers”
    have purchased for you.

    Stick to healing and to evidence,
    subjective evidence, too.

    Stick to diversity and to diverse solutions.

    Don’t wait ’til this fine, almost young,
    medicated specimen (me)
    dies in some metaphoric Baltimore ward.

    I won’t care much about the post-mortem.

    But, I sure do imagine that I’m
    being healed
    as I write.

    Love and peace to HU.
    Love and peace to INDIVIDUALS,
    who are being healed slowly over years
    and to the healers who bring them along.

    Love and peace to medicine and science.

    And, hey, you posers with the big pools,
    some of you.

    You’re gumming up the works.

    Get off the fucking gravy train

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