From MPN Forum: An open letter on Interferon

March 2014

An Open Letter to the MPN Community in the United States (Originally published at MPNForum)

By Hans Hasselbalch, Roskilde Hospital, Professor, Department of Hematology,University of Copenhagen

Dear Friends, Colleagues and Patients…

About 25 years ago recombinant interferon (IFN) was used successfully for the first time in the treatment of essential thrombocythemia and a few years later in the treatment of polycythemia vera and hyperproliferative myelofibrosis. Since then many studies have confirmed that IFN benefits a large number of MPN patients. (Throughout this letter IFN stands for rIFNα, or recombinant interferon-alpha.)

In this context I am worried  by the reported claims by Dr. Ayalew Tefferi that IFN is no better than HU and busulphan in the MPNs. If Tefferi has said so, it is problematic that a colleague, who may be aware of his great impact on the “scientific community ” and MPN-patients’ care, stands up and not tells the truth.

Dr. Richard Silver and I and others have during the years delivered a large number of papers – studies and reviews – documenting that interferon is not ” an experimental drug” to be used only in selected cases. Interferon is an old horse in the circus which – for unknown reasons – has been neglected, dismissed and thrown away.

In some of his papers – even educational papers in Am J Hematol – Tefferi has mentioned IFN as an inferior agent to hydroxyurea and not to be used in ET, PV or  myelofibrosis. I cannot dissect or understand the reasons for his anti-IFN attitude. When Tefferi now and then in the reference list cites IFN it is often a citation of his own “Letter to The Editor in Blood” reporting on 11 patients with advanced myelofibrosis achieving no benefit of IFN and not tolerating IFN very well due to too high a dosage. From this data Tefferi obviously has concluded that IFN is not a drug of choice for MPN patients while he totally neglects all the data on IFN in the literature, showing that it is working very well and is benefical for the large proportion of patients with MPNs, including  patients with hyperproliferative myelofibrosis as well – shown in studies by Silver and Kiladjian.

Thus, true opinion leaders on the use of IFNs in MPNs are relatively few in the world  and can independently tell quite another story on IFN in MPNs – Richard Silver as the very first, Heinz Gisslinger from Austria and Jean-Jacques Kiladjian from Paris and – of course – not to forget – my colleagues in Sweden and Norway. These colleagues have a huge experience – as do I – in the use of IFNs in MPNs – at least 20 years and we have treated hundreds of patients with IFN during these years.

Accordingly, we have been thus privileged to have experienced:

  • Low dose IFN normalizes peripheral blood counts within a few months in the large majority of patients with ET, PV and hyperproliferative MF.
  • Low dose IFN decreases the need for phlebotomies in the large majority of PV patients within the first 6-12 months but still some patients need phlebotomies in the second ( and third) year.
  • Low dose IFN is well tolerated by the large majority of patients (10-20 % do not tolerate IFN very well – a challenge and a research project why it is so. Soon a study will be launched in Denmark offering IFN-intolerant patients combination therapy with Jakafi .  The rationales for this combination therapy  are described in my most recent paper in Expert Reviews Hematol 2014.
  • Low dose IFN is able to induce regression of myelofibrosis in a subset of patients with hyperproliferative myelofibrosis ( Silver RT et al Blood, June, 2011 ; Kiladjians group in Br J Haematol 2013 ).
  • Low dose IFN induces deep molecular remissions as assessed by the JAK2V617F alelle burden and normalisation of the bone marrow – being sustained even after discontinuation of IFN for up to 5 years (published by the Danish MPN-group  in Ann Hematol and in Hematology ).
  • Low dose IFN – according to the above findings – is the only agent having the potential to induce “minimal residual disease ” / ” operational cure ” in MPNs.
  • Low dose IFN has been shown also to reduce the hard end points – thrombosis and hemorrhage – as compared to historical controls.
  • Low dose IFN is : Pegasys 45 ug x 1 subcutaneously (sc)  per week equivalent to PegIntron 30 ug x 1 sc /week.

Conclusions:

  • In 2014  IFN is not an experimental drug in MPNs.
  • In 2014 we have about 25 years experience with the use of IFN in the treatment of MPNs
  • In 2014 we have only one agent – interferon – which has the capability to revert disease progression by inducing minimal residual disease with normalization of the bone marrow in a subset of patients with PV – even being sustained for years without treatment and –  in addition – having the potential to revert bone marrow fibrosis
  • In 2014 we  put great efforts in combatting advanced myelofibrosis, which is characterized by multiple genomic alterations being built up during clonal evolution from the early stages of this cancer – ET and PV. Most lately, telomerase inhibition with Imetelstat has been shown to revert myelofibrosis, but not without significant side effects and the sustained beneficial impact has to be  confirmed in larger series of patients. Our concern about this drug has been reinforced by the FDA halt in clinical trials due to toxicity.
  • In 2014 MPN authorities do not recommend treatment of MPNs at the earliest cancer stage – ET and PV , despite a huge amount of data showing that these early cancers – as all other cancers – will steadily evolve with increasing genomic instability, subclone formation , resistance to treatment and ultimately leukemic transformation in some patients.
  • In 2014 MPN authorities do not recommend to treat MPNs with IFN at their earliest cancer stage – ET and PV – despite a huge amount of data showing that only this agent with no alternatives has the potential to revert the disease process as evidenced by induction of deep molecular remissions and – in a subset of PV patients – normalisation of the bone marrow which is even sustained after cessation of treatment for up to 5 years. 
  • In 2014 we have to discuss and consider if it is still ethical not to offer MPN patients the best available therapy – IFN – at the earliest cancer  stage where the chance of a successful outcome is likely the very best at any time. In this regard MPNs are not different from any other cancer.
  • In 2014 we know that the beneficial IFN effects include among others immune enhancing effects with “restoration of defective tumor immune surveillance ” – of “defective radar surveillance”  and – in addition – telomerase inhibition, which has been shown to revert the advanced myelofibrosis stage but not without side effects and without the long term experience which we have with IFN in MPNs.
  • In 2014 IFN should accordingly be considered as upfront treatment in all newly diagnosed patients with ET, PV and hyperproliferative myelofibrosis, the aim being to treat a cancer from the very beginning to prohibit cancer progression from early cancer stage (ET/PV ) to the advanced cancer stage – myelofibrosis – when immature cells -including stem cells ( CD34+ cells ) egress from the burning hell ( the bone marrow niches – “the chicks flying prematurely from their the nests” – ) to the circulation to seed ( metastasis ) in the spleen, the liver and elsewhere .

In 2014 the world is divided in two – the one having access to IFN and the one not having access to IFN.

  • In 2014 in the world having access to IFN  most patients have the advantage of being treated with IFN with the likely outcome that their counts steadily decline within weeks or months and in the JAK2V617F positive patients with a decline in the JAK2-allele burden as well.

This is fortunate, since the JAK2V617F allele is a thrombosis promoter per se and – according to some epidemiological studies – a tumor promoter as well. Furthermore, the JAK2V617F allele burden induces increasing genomic instability predisposing to additional mutations , subclone formation , resistance to treatment and utimately leukemic and myelofibrotic transformation. To this end the JAK2V617F allele has most recently been shown to induce the generation of reactive oxygen species (ROS) ( Marty et al Leukemia 2013 ), which also induces genomic instability etc. The latter finding is certainly supportive of the viewpoint that the MPNs are “A Human Inflammation Model for Cancer Development,” as most recently described in Leukemia Research .

  • In 2014 in the other world – not having access to IFN – you follow a risk stratification system, allowing patients with low risk MPN -< 60 years , no prior thrombosis, platelets < 1500 units  – to be followed without any cytoreductive therapy but only being treated with aspirin and in PV phlebotomies as well. When are these patients then candidates for cytoreductive therapy ?  They are so, when they succumb to the catastrophe – the thrombosis event or the major hemorrhage, potentially debilitating the patient the rest of his/her life. Then , in most non-IFN-access centers – these patients are treated with hydroxyurea – a potentially leukemogenic agent when being used for long periods – 10 % risk of acute myeloid leukemia (AML) /myelodysplasia (MDS) after about 10 years, 15 % after about 15 years and 20 % after about 20 years.

In 2014 –  for all these reasons – we should treat our MPN cancer patients when the cancer is diagnosed and not adhere to “The Wait and Watch Strategy ” but instead follow “The Early Intervention Concept with Interferon” to combat MPN cancer as early as possible and prohibit cancer progression. This concept is also increasingly prevailing in Central Europe where some authorities also abandon hydroxyurea and even believe based on supporting data that hydroxyurea may not only elicit AML /MDS but solid tumors as well. This makes sense when realising that hydroxyurea impairs DNA repair mechanisms and tumor suppressor function (p53) as well.

In 2014 it is very exhausting and distressing for MPN-patients that the “Hematological Scientific Community” will not uniformly take notice of the vast amount of convincing data showing that IFN is a highly potent agent which has changed the lives of hundreds of MPN-patients worlwide – even inducing minimal residual disease .

In this perspective – what are we waiting for ? – In my opinion far too many patients have been put on the waiting list according to “Wait and Watch Strategy” and suffer the catastrophe before being treated for their cancer.

We have to rethink the academic approach that we should search the highest level of evidence – the results from a randomised trial comparing hydroxyurea to interferon in high risk patients (The MPN-Consortium Study). In the meantime, our MPN patients will suffer. I think that the time is ripe to reconsider /rethink if the approach – “Wait and Watch ” – is indeed ethical when we know for sure that a substantial proportion of our MPN patients during the course of the disease will suffer thrombotic /hemorrhagic events. Without IFN treatment we know, that the cancer – as all other cancers –  will steadily  evolve along the inevitable path from early cancer stage (ET/PV) to the advanced cancer stage – myelofibrosis – when there is no way back for most patients.

Instead, we should all put our efforts together to break down the barriers between the two worlds – to fuse our concepts on IFN as the cornerstone in today and tomorrow’s treatment of MPNs – likely in the future in combination with statins and JAK2-inhibitors or other targeting agents displaying a synergism with IFN.

Obviously, this pathway is much more fruitful and will undoubtedly open new horizons for our patients instead of being locked as victims by stringent and opposing opinions between MPN authorities.This pathway – the fusion of the two worlds and without barriers between them –  will benefit our patients and – I am convinced – will greatly enlighten the horizon, improve their quality of life and hopefully, also for a large proportion of patients, revert disease progression to a minimal residual disease state.

To  finish – my viewpoint on IFN and on the randomised MPN Consortium Trial

For those of us confident in interferon and having decades of experience with interferon,  I need to cite a lovely US patient who visited me a few months ago in Roskilde for my advice on IFN. “This interferon is really working for me! You saved my life I think. I am very grateful and we now just need to convince the rest of the world of the need for early treatment. I am out there singing from our hymn sheet but it is amazing to me how often the world is skeptical of the obvious. As you said to me once, I remember it well, “I do not need to throw a coin on the ground 100 times to prove that will not bounce off the ground and back into my hand”

Best wishes and good night from Copenhagen

Hans

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