September 17, 2012
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Studies offer hope that JAK inhibitors may be reasonable therapy for myeloproliferative neoplasms

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In late 2011, the FDA approved the JAK inhibitor ruxolitinib for the treatment of myelofibrosis.

Ruxolitinib (Jakafi, Incyte) became the first FDA-approved drug for symptom alleviation in myelofibrosis, and several more experimental drugs are in development.

Myelofibrosis, a progressive and frequently debilitating bone marrow disease, is considered a type of chronic leukemia. The condition disrupts the body’s production of blood cells, leading to the formation of scar tissue in the bone marrow and forcing blood cells to produce in the spleen and liver. This can lead to a severely enlarged spleen and liver, as well as anemia.

Harry S. Jacob, MD, FRCPath(Hon), HemOnc Today’s Chief Medical Editor, led a round table discussion during the HemOnc Today section editor’s retreat about JAK1 and JAK2 inhibitors and their possible role in alleviating the symptoms in myeloproliferative neoplasms, specifically myelofibrosis.

The round table discussion follows.

Roundtable Participants

  • Harry S. Jacob, MD, FRCPath(Hon)
  • Moderator

  • Harry S. Jacob
  • HemOnc Today chief medical editor
  • Edward Gordon-Smith, MD, MSc, FRCPath
  • Edward Gordon-Smith, MD, MSc, FRCPath
  • St. George’s Hospital Medical School
  • A. Koneti Rao, MD
  • A. Koneti Rao, MD
  • Temple University School of Medicine
  • Morton Coleman, MD
  • Morton Coleman, MD
  • Weill Cornell Medical College
  • Munir Ghesani, MD
  • Munir Ghesani, MD
  • St. Luke’s-Roosevelt Hospital Center and Beth Israel Medical Center
  • Joseph Aisner, MD
  • Joseph Aisner, MD
  • UMDNJ-Robert Wood Johnson Medical School
        Jacob:

        It’s been shown that about 50% of patients with myelofibrosis, de novo myelofibrosis that has not been preceded by polycythemia vera or central thrombocythemia, have a mutation in the JAK2 protein tyrosine kinase.

        The hope was — in analogy to the tyrosine kinase inhibition story in chronic myelogenous leukemia — that one might have, in fact, a specific cure from myeloproliferative syndromes and, particularly, myelofibrosis.

        Close to 100% of traditional polycythemia vera have a JAK2 mutation, so that was an even more exciting possibility, that one might have an actual cure for that relatively more benign situation.

        Harry S. Jacob, MD, FRCPath(Hon), Chief Medical Editor of HemOnc Today, said JAK inhibitors such as ruxolitinib have markedly increased quality of life for some patients with myeloproliferative neoplasms.

        Harry S. Jacob, MD, FRCPath(Hon), Chief Medical Editor of HemOnc Today, said JAK inhibitors such as ruxolitinib have markedly increased quality of life for some patients with myeloproliferative neoplasms.

        Photo courtesy of Harry S. Jacob, MD, FRCPath(Hon), reprinted with permission.

        Multiple papers at the 2011 American Society of Hematology Annual Meeting and the European Hematology Association (EHA) meeting in London hyped the role of JAK inhibitors. The hype was that we might have a reasonable therapy for these conditions. Now it appears these inhibitors are useful in terms of ridding patients of some of the ancillary problems of myelofibrosis, but not the hematologic problems.

        They are useful in diminishing spleen size. That’s not trivial. Many of these patients have rather enormous spleens and have serious symptoms associated with early satiety, with portal venous hypertension and occlusion because of the massive increase in blood supply and infarctions of the spleen.

        Associated with this, and possibly truly related in a mechanistic way, is that most of these patients with very large spleens also have what appear to be major cytokine release phenomena, with fatigue, sweatiness, weight loss, cachexia and ascites.

        The JAK2 inhibitors have markedly increased quality of life of those patients who had these ancillary cytokine-like effects. They have markedly increased some of the signs and symptoms of splenomegaly. But they have not dealt in any substantive way with the hematopoietic insufficiency that these patients generally have, perhaps with a slight exception of some degrees of anemia and/or thrombocytopenia. Some of these patients have been mildly ameliorated, but certainly not the patients who are having difficulty because of poor marrow production of hematopoietic cells.

        Ayalew Tefferi, MD, a professor of medicine at Mayo Clinic in Rochester, Minn., and a HemOnc Today section editor, has written a large tome about the downside of these inhibitors, at least as viewed by the Mayo Clinic experience. The downside seems to be side effects that, in fact, become intolerable to as much as 50% to 70% of the patients they have had on the drugs at Mayo Clinic.

        Those side effects include increasing anemia, increasing thrombocytopenia, gastrointestinal problems and diarrhea. Some of the patients have developed polyneuropathies, which have curbed the enthusiasm some people — including Tefferi and his group — have for these drugs.

        There is now one FDA-approved drug for the use in myelofibrosis. That drug is called ruxolitinib (Jakafi, Incyte). There are at least seven or eight other experimental drugs that are being talked about that also have specificity for JAK2, but not complete specificity in most cases.

        With that introduction, I would invite Ted Gordon-Smith to comment about some of the studies he heard about that came out of the European meeting, and some of the side effects that may have been talked about at that meeting.

        ‘A substantial step forward’

        Edward Gordon-Smith, MD, MSc, FRCPath: Myelofibrosis is an unpleasant disorder and is linked to two rather benign conditions, polycythemia vera and essential thrombocythemia (ET).

        Dr. Tefferi seems to say that the side effects aren’t acceptable for polycythemia vera and ET, as well as for myelofibrosis. It’s important to distinguish myelofibrosis — primary or secondary — from polycythemia vera and ET.

        Quite rightly, Dr. Tefferi says, these drugs — which have side effects — should not be used in polycythemia and ET, but who would want to do that anyway? Physicians wouldn’t want to use hefty cytotoxic drugs to suppress the immune system in benign rheumatoid arthritis or some such.

        So we have to be clear about what these drugs are being used for. It’s important that we stick to symptomatic myelofibrosis with spleens 5 cm or more below the left costal margin and poor quality of life, which were the criteria included in the only two phase studies that are being carried out on these inhibitors, one conducted with placebo and one with best available treatment.

        Dr. Tefferi says they should be compared with best available treatment. COMFORT-II was such a trial and the results were not as dramatic as if you compared the JAK2 inhibitor with placebo, but they were still substantial and quality of life was improved. So this produced a certain amount of hope, not hype. Hope is what we should have. Having seen patients with tedious, awful symptoms, to relieve the symptoms is not trivial. It’s important.

        Now, it is not surprising that the targeted tyrosine kinase inhibitors other than imatinib (Gleevec, Novartis) and so on do not produce the sort of cure that you would see in CML because you’re not dealing with a neo-product, which causes the hematopoietic changes.

        But it doesn’t matter that you haven’t cured a condition that has a reasonable life span if you get rid of the problems of quality of life and big spleen and misery of the condition. The fact that there are other drugs coming on is also of great interest.

        The dose of the drugs is determined by what was used in the COMFORT-I and COMFORT-II trials, which were 15 mg and 20 mg. Of course, side effects occur. We all know that when you have an FDA approval, the dosage that was used for that trial is the one that’s licensed. It may be possible to improve things by dose reduction, so I don’t think it should be dismissed or written off just because there are side effects.

        Of course, it’s the question of long-term follow-up. The hematologic problems are not a great problem, to be honest, because that’s what people suffer from with myelofibrosis anyway. The gastrointestinal problems will need careful investigation.

        It’s not a cure, but it’s a substantial step forward to have a family of drugs that do inhibit the pathways, the things that are thought be important in the progression of the disease. It is exciting to have something that would help these patients other than radiation and some of the other rather ineffective therapies that are used for enlarged spleens. But Dr. Tefferi is right: You shouldn’t think of using it in asymptomatic patients or patients who don’t have myelofibrosis.

        Ideal patients, ideal indications

        Jacob: I would have no problem using these inhibitors for serious conditions that I’ve seen a bit of — patients with marked splenomegaly from myelofibrosis, patients who suffer with severe ascites, which seems to be associated with marked blood flow to the massive spleen, and therefore venous return and therefore portal hypertension, and associated also with this are patients who develop esophageal varices from these great big spleens and the big venous flow and bleeding.

        Forget quality of life for a moment. These are two acute catastrophic kinds of conditions. In these cases, I would jump in in a second with these inhibitors because they do work on splenomegaly.

        Now, I have no idea from the papers I’ve read whether anybody has specifically talked about whether varices are decompressed and/or ascites are improved, but I look forward to hearing about that either from others at this table or from future studies.

        A. Koneti Rao, MD: There are many things that we still don’t know. These drugs are not specific for JAK1 or JAK2. They’re not specific for the mutant JAK2 vs. the wild-type JAK2. Thirdly, it has not been shown — at least in the one study that I’m aware of — that the mutant allele burden actually goes down on treatment. We need a better understanding of the basic abnormality in myeloproliferative neoplasms and myelofibrosis.

        This same JAK2 abnormality occurs in two other entities that are relatively more benign, polycythemia vera and ET. So there must be something more that’s going on, and that’s what we may need to know before we’ll have a more definitive therapy.

        I’m not saying that the COMFORT trials didn’t show efficacy. They certainly did. It was impressive, and what they showed in spleen size and so on is certainly convincing enough to use it in the right patient with the right indication.

        Gordon-Smith: That’s clearly true. We need to know more about myelofibrosis. But it doesn’t detract from the fact that these systems, at the moment, relieve some of the symptoms.

        The fact that one is ignorant about why something works doesn’t mean you necessarily have to throw out what works because you’re a bit ignorant. It would be a mistake to dismiss the treatment because we don’t know exactly how it works.

        And it is specific. These drugs are specific for the pathway. They don’t work on other tyrosine kinases, but they do inhibit phosphorylation of the STAT pathway and the JAK2 itself in vitro, and they prevent proliferation of cells that have that mutation. So there’s enough evidence to carry on, but it’s not a panacea, and it would be wrong to present that it is.

        Rao: I’m not disagreeing with you.  This is a drug that is going to advance what we have in these patients. My point was that we need …

        Gordon-Smith:  Something to compare others with anyway.

        Rao: Exactly. The comparison to CML and imatinib may not be correct in this particular instance.

        Gordon-Smith: Those of us who have used splenic embolization to reduce the spleen size would be pleased to have anything that comes along.

        Role of interferon, particle therapies

        Morton Coleman, MD: The most important point is that it’s proof that our better understanding of the cellular signaling mechanisms has resulted in our having a new drug to use, although certainly imperfect. What I wonder is, how come no one has made a big deal about interferon, especially with [pegylated interferon alfa-2b (PegIntron, Schering-Plough)], which is easy to give and to take.

        Gordon-Smith: Rueben Mesa, MD, actually gave a paper at EHA on pegylated interferon. It’s not free of side effects, of course, but again it gives us a standard, or at least a comparator, to work against.

        Munir Ghesani, MD: In the past, we used to see the referrals in a preselected patient population where we would give particle therapies to these patients. It seems to have been phased out. I don’t see any more referrals for phosphorus-32 or any of the therapies in these patients.

        Jacob: That has been phased out. Hydroxyurea works well in polycythemia vera, as it does in ET. We have another drug, anagrelide (Agrylin, Shire). The increased leukemogenesis that was found with [phosphorus-32] led people to say, “Why use it if we have other drugs that work just as well?”

        That dots the i’s and crosses the t’s of what Ted Gordon-Smith was talking about. We have good ways of dealing with benign conditions. The average median survival in polycythemia vera is probably around 20 years or more, so we’re not dealing with a situation that you have to possibly produce a lethal leukemia, and so we don’t use [phosphorus-32 ] anymore.

        Developments of JAK mutations

        Joseph Aisner, MD: Do we know anything about the nature of the mutations? Are they activating?

        Jacob: The JAK2 is thought to be an activating mutation and it can’t be inhibited.

        Aisner: Single mutation or double mutation?

        Jacob: The major one has been a single mutation. There may be a couple of others, but probably well more than 90% have been a single mutation. But it’s also been pointed out these drugs work regardless of whether the patient has a mutation or not, so that was another indication that we’re not dealing with a specific problem that’s causing the disease that we’re able to inhibit. If a patient has got wild cytokine-like quality-of-life problems, it makes sense to give them something that will help that, even though we’re not specifically dealing with a causative mutation and we don’t know what the cause of myelofibrosis is. My guess is it probably is going to be several causes. In fact, there have been several other mutations found in 10% or 15% of patients. It reminds one of the muddy thinking that goes on in the myelodysplastic syndrome. It’s not a syndrome. It’s multiple causes and multiple diseases, and we get clogged up thinking about a cure for any one of them. The same thing is going to happen here. These agents seem to work well with the cytokine problems that these patients have and have nothing whatsoever to do with the underlying hematopoietic abnormality and/or the secondary fibrosis that occurs. 

        Gordon-Smith: With regard to the other mutations that occur in a relatively small proportion of myelofibrosis, they’re all on the JAK-STAT hematopoietic pathway. They’re not different genes. That’s why it has something to do with, or an important part to play in, myelofibrosis. But obviously, it’s not the only part.  If you turn off the JAK2-STAT pathway, you improve at least temporally the problems associated with myelofibrosis. 

        Coleman: Whatever happened to platelet-derived growth factor?

        Gordon-Smith: It’s lurking about, but it’s further down the pathway as the cause of fibrosis. And that’s interesting because, of course, the response in immune thrombocytopenia to patients who do not have inhibition of megakaryocytopoiesis but have what we expect, the proliferation, are they the ones that get more of the fibrosis? That’s what you would expect, but I’m not sure that it’s been studied.

        References:
        • Gowin K. Haematologica. 2012;doi:10.3324/haematol.2011.061390.
        • Tefferi A. N Engl J Med. 2011;365:1455-1457.
        • Verstovsek S. Abstracts #278, #793 and #3851. Presented at: 53rd ASH Annual Meeting and Exposition; Dec. 10-13, 2011; San Diego.
        Disclosures:
        • Drs. Jacob, Gordon-Smith, Rao, Coleman, Ghesani and Aisner report no relevant financial disclosures.