Science & Medicine

Jakafi — MPN Event of the Year

The Year of Jakafi

By Zhenya Senyak

And the debate goes on…

Even before the Editorial Board of MPNforum determined Jakafi was the story of our MPN Year, there were rumbling clouds over the horizon.

Dr. Ayalew Tefferi,  Professor of Hematology and Medicine at Rochester’s Mayo Clinic,  followed up his letter to the New England Journal of Medicine with a more detailed Report. And as a mark of his concerm over patient safety issues he produced another study, “1000 Patients with Primary Myelofibrosis…” with his Mayo Associate, Dr. Animesh  Pardanani, accompanied by a YouTube video.

Clearly the doctor was taking his case directly to MPN patients and their caregivers.

No issue could be more important to us as MPN patients.

 Myelofibrosis, along with leukemias, are the acute forms of our chronic MPNs.  All of us – without exception – either have myelofibrosis, are progressing toward myelofibrosis, or are concerned about myelofibrosis.

 Until Ruxolitinib , a JAK inhibitor, seemed likely to clear its scientifically valid, double blind, Phase III trials, we were stranded with limited conventional therapies. There was no relief from the murderous symptoms of MF – organ swelling, loss of appetite and wasting, bone pain, thrombosis, pleural effusion —  on to an early and painful death.

With COMFORT (Controlled MyeloFibrosis study with Oral JAK inhibitor Treatment) studies wrapping up internationally and domestically,  principal investigators Srdan Verstovsek (M.D. Anderson),  Ruben Mesa (Mayo Clinic, Scottsdale),  Claire Harrison ( Guy’s and St. Thomas, London) and others published their findings in the New England Journal of Medicine,  presented charts and statistics at  the big  ASCO Conference in Chicago,  first week of June, 2011 and appeared at conventions and professional meetings over the next six months  to share their findings with MPN patients, physicians and hematologists.

In the MPN community, the relief and euphoria were overwhelming.

No, we had no cure but we had a pill that could reverse the worst of symptoms and hold MF at bay until a cure could be found.  MPNforum published a special report  Ruxolitinib on Trial with expanded coverage.

Tefferi published his letter in the NEJM a month before the November CR&T meeting in NYC.  Although Verstovsek and Mesa were at the meeting —  along with Drs. Jerry Spivak, Richard Silver,  Barbui, Ron Hoffman MPN Research Foundation chief Bob Rosen and Barbara Van Husen —  and others no one raised the issue publicly.

No public mention of the Tefferi letter was made even though Jakafi – the trade name that would be adopted for Ruxolitinib by its developer, Incyte, in the event of anticipated FDA approval  —  was featured in the CR&T presentations, workshops and patient exchanges.  It was the elephant in the room.

In part, this silence was a mark of respect for the eminence, reputation, and lifelong work of Dr. Tefferi.  In part it was ignorance of the basis of his concerns.  And in part, it was simply premature.  Ruxolitinib had not yet become Jakafi so no one was at risk.

That has all changed. The FDA approval came within weeks!  In a few short months, some of us are now taking Jakafi and many others are in the queue or considering it.  Now it’s no longer an academic problem or a problem among high rankjing hematologists but a down to earth life and death matter for us, the MPN patients.

Sources: To help determine whether or not Jakafai therapy is a risky option,  we reviewed Dr. Tefferi’s concerns with him, went through his publications and videotape closely, revisited the Clinical Trial slides and data supporting Ruxolitinib submitted to the FDA, and listened to an Incyte webcast investor meeting at which both securities analysts and media subjected Drs. Verstovsek and Harrison to focused questions.

    It was in response to one of those questions that we found personal resolution of the conflicting views.  Dr. Claire Harrison is a level-headed, conservative hematologist who was principal investigator of the European (COMFORT II) arm that studied Ruxolitinib.

When pushed by an investment analyst on the issue of safety she said she would prescribe Jakafi to ““80% of my patients who have bothersome splenomegaly and or troubling symptoms” and she found “toxicity in COMFORT II was equivalent to standard therapies in Europe….  The only ones I wouldn’t treat (with Jakafi)are anaemic or thrombocytopenic patients.”

 In the end concluded the MPN patient’s best interests would be served by presenting a summary of positions and data links to source material.

The most significant document we found was not the 1000 MF Patient study published this month with the video but Dr. Tefferi’s October 27 Brief Report  in Mayo Clinical Proceedings entitled “Serious Adverse Events During Ruxolitijnib Treatment Discontinuaiton in Patients with Myelofibrosis.”   The 1000 MF patient study, an important and historic document, essentially elevates the importance. Of the new DIPPS Plus risk assessment tool . His remarks on Ruxolitinib are limited to concluding comments on the applicability of the drug to perhaps 20% of intermediate risk patients, about the same level as SCT.   His preference for SCT in young patients with intermediate-2 risk is based in his assessment that there is no proven survival advantage with Ruxolitinib.

In the Brief Report, however, Tefferi advances more serious claims at some greater length and warns of the need to advise patients of “potentially catastrophic adverse events during drug discontinuation.:” From all sources, Tefferi’s concern seem to resolve to four issues presented here along with summarized conclusions of the data (available in full through the links)

>>NOTE>>    These are public domain  patient data submitted to the FDA and presented at  ASH and/or ASCO along with documents freely available for review  from the  The Mayo Clinic.  The list was submitted to Dr. Tefferi who said he would respond within one week after publication of the new COMFORT II studies.  These are now in peer review and will be available soon.

The Four Core Issues


1. Tefferi believes the benefits of Ruxolitinib are modest and possibly not durable.

COMFORT investigators conclude   “While the study was not powered to show a survival benefit, analysis of data however shows that people live longer on Ruxolitinib.”

“Ruxolitinib has clearly demonstrated rapid, significant and durable response in relieving the symptoms of MF.”


Tefferi:   Patients need to be warned of potentially catastrophic adverse events during drug discontinuation.  He speculates  this may be caused by rapid change in inflammatory cytokine activity.

COMFORT Investigator:  “If you need to discontinue, symptoms will come to baseline.  Ruxolitinib will not harm anybody.”


Tefferi:   Patients withdrew from the clinical trial – or were with drawn – because of toxicity or progress of disease.

COMFORT data:  “11% patients withdrew from the trial due to side effects, the same percent as withdrew from the placebo arm due to side effects.”

COMFORT investigator:  “It’s amazing to have a drug to offer that makes a difference with no toxicity. I have 200 MF patients.  The only ones I wouldn’t treat with ruxolitinib are asymptomatic with no splenomegaly burden. ”


Tefferi : Ruxolitinib can cause anemia and/or thrombocytopenia.

COMFORT investigators: Both severe anemia and too low a platelet count are
grounds to discontinue therapy.  Both conditions can be managed with combinatorial drugs.

 Why should different groups of concerned, experienced hematologists come up with different conclusions from the same data?

 As opposed to the Phase III Clinical Trials where recruited cohorts and their controls — — those who get the drug and those who don’t – are carefully matched, Phase I/II clinical trials are designed to measure dosage and drug toxicity.  Centers have different control groups and patients recruited of varying age and condition with no attempt to match cohorts.

While minimal and maxium tolerated doses of Ruxolitinib were common to the trials at different sites, the attending physician has great latitude in protecting the well-being of patients on the trial. Accordingly both dosages and withdrawal rates, particularly physician initiated discontinuation, varied greatly

The balance of the ASH COMFORT I presentation slide set can be seen here.

Take me back to the Contents

© Zhenya Senyak and, 2011. Unauthorized use and/or duplication of this material without express and written permission from this blog’s author and/or owner is strictly prohibited. Excerpts and links may be used, provided that full and clear credit is given to Zhenya Senyak and with appropriate and specific direction to the original content.


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