Patients without the JAK2 V617F mutation benefit equally from JI therapy as those with the mutation


Patients without the JAK2 V617F mutation benefit equally from JI therapy as those with the mutation

Elias Jabbour, MD

DR JABBOUR: I frequently hear physicians say, “Oh, the patient doesn’t have a JAK2 mutation, so he won’t respond to ruxolitinib.” It’s important to understand that dysregulation of the JAK2 pathway may or may not be driven by a mutation, and the JAK inhibitor we have available to us blocks this dysregulation. Whether the JAK2 is mutated or not, treatment efficacy with ruxolitinib is similar. We should not view the response rate as mutation dependent.

DR LOVE: Do you generally believe that ruxolitinib is slowing down the progression of the disease or that it is addressing the secondary consequences and clinical symptomatology?

DR JABBOUR: Most of the JAK2 or JAK inhibitors available today do not have activity or have minimal activity in the bone marrow. Most of their effect is peripheral through the blockade of interleukin/cytokine flare rather than directly in the bone marrow. Therefore, I believe for the future we have to move toward combination therapy. It’s a first step to target the symptoms of the disease without targeting much of the bone marrow. We have to combine this kind of therapy in order to target the bone marrow and the spleen or the peripheral symptoms of the disease.

John O Mascarenhas, MD

DR MASCARENHAS: It was initially thought that only patients with JAK mutations would benefit from JAK inhibitors. That has turned out not to be the case. All patients with myelofibrosis have heightened activity of the JAK-STAT signaling pathway in their hematopoietic system. The JAK2 V617F mutation is only 1 factor that can lead to upregulation of this pathway. It’s because of the heightened activity of this pathway that the JAK1/2 inhibitor ruxolitinib in particular has been successful in the treatment of myelofibrosis, irrespective of V617F mutational status.

DR LOVE: When you consider the downstream consequences of inhibiting JAK2, do you specifically think of cytokines?

DR MASCARENHAS: This is an emerging area that I find fascinating — how cytokine levels may correlate with the clinical features of the patient and how modulating those levels may correlate with symptom improvement. Early ruxolitinib Phase I/II studies have shown that inhibiting the JAK1/JAK2 pathways leads to the marked downregulation of upregulated inflammatory cytokines that’s associated with improvement in many of the symptoms, including pruritus, bone pain and fevers.

A number of papers have been published by Dr Ayalew Tefferi and other groups on correlations between specific cytokine expression and disease phenotype. A lot more work will be done in the future on how that can be used in the clinical context, but I believe the data are immature at this point.

DR LOVE: Do you generally believe that ruxolitinib is slowing down the progression of the disease or that it is addressing the secondary consequences and clinical symptomatology?

DR MASCARENHAS: I haven’t yet seen evidence that convinces me that ruxolitinib is slowing, halting or reversing the progression of disease. I definitely believe that it provides a tremendous palliative benefit in terms of symptoms and the spleen. A survival benefit has been shown in 2 randomized studies, but the survival benefit is likely due to an improvement in performance status and sense of wellbeing rather than necessarily a biologic effect at the level of the bone marrow.

Moshe Talpaz, MD

DR TALPAZ: Nobody knows for certain that JAK2 is the major driver in this disease. If it is, then why is the mutation also present in polycythemia vera, a different disease from myelofibrosis? You have to assume that other events occur. Otherwise why are 2 diseases distinct in their behavior sharing the same driver? Something doesn’t make sense here.

Let’s assume, though, that JAK2 is an important component. The mutation in JAK activates the JAK-STAT pathway, which is a proliferative metabolic pathway in the cell. It’s an interesting mutation that removes a repressor that inhibits JAK kinase functioning. However, you don’t need a mutation in JAK2 to activate the JAK-STAT pathway. You can activate the pathway through any of a multitude of signals, such as extracellular cytokines.

It’s apparent that in myelofibrosis other molecules play a role, such as NF-kappa-B, which is linked to some extent to JAK, and interleukin-6, which requires active JAK2 to function. Interleukin-6 and its whole cascade of signaling can be equally active in JAK2 mutation-positive and negative disease. Perhaps it is the inhibition of other signaling pathways in which JAK2 plays a role that is responsible for the benefit observed with JAK2 inhibitors.

Little relationship exists between benefit from ruxolitinib and the presence of a JAK2 mutation. I would say the responses among patients with JAK2 mutation-positive disease are slightly more frequent than responses in patients who don’t have the mutation. This disease has now been well characterized in terms of mutations. Incidentally, with next-generation sequencing the average number of mutations in myelofibrosis is about 6. So we are not talking about solid tumors with hundreds of mutations. We are talking about a small number of mutations.

The interesting point is the following: About 50% or maybe even fewer patients with myelofibrosis have JAK2 mutations. What about the remaining patients? At the ASH 2013 meeting a new mutation was characterized and described by an Austrian group and another from the UK, who demonstrated a mutation in a gene called calreticulin, which is present in the vast majority of patients with JAK2 mutation-negative disease. So we have 2 mutually exclusive dominant mutations in this disease that account for almost all of the patients.

But another group of mutations exist that are not exclusive. They coexist with JAK2 and can coexist with calreticulin. A group of epigenetic regulators, ASXL1, EZH2, SRSF2 and IDH1/2, have been studied by a European group, and those genes are associated with worse prognosis. The presence of these genes indicates a high molecular-risk group.

Jason Gotlib, MD, MS

DR GOTLIB: Ruxolitinib inhibits both JAK1 and JAK2. Inhibition of JAK2, albeit nonselective, probably has an effect on the clone of abnormal cells harboring the JAK2 mutation. Fifty to 60% of patients with myelofibrosis have a JAK2 V617F mutation. In that regard, the portion of the drug that inhibits JAK2 likely has an effect on malignant cells. We know that JAK1 is important for inflammatory signaling pathways, and inhibition of JAK1 may mediate the inflammation or symptoms related to myelofibrosis. Ruxolitinib may therefore be useful in addressing the symptomatology of the disease. If you can decrease the clonal burden of the malignant cell and somehow mitigate inflammation, those are at least 2 basic reasons why these drugs may work. Many of the other explanations are not proven.

No correlation exists between JAK2 mutation and benefit from ruxolitinib. The JAK2 mutation burden does not decrease in patients receiving ruxolitinib. If physicians believe that those without the mutation will not respond to ruxolitinib, then 40% of patients will not derive benefit from this treatment.

DR LOVE: So would you agree or disagree with this statement, that regardless of JAK mutation status, the JAK pathway is generally activated in patients with myelofibrosis and that is related to why these patients benefit from ruxolitinib or other JAK inhibitors?

DR GOTLIB: Ross Levine has done gene expression analysis, studying which genes are activated in patients who have primary or post-polycythemia vera or post-essential thrombocythemia myelofibrosis, and regardless of whether JAK2 is mutated, there’s a clear indication that JAK-STAT activation is a common theme among these disorders. This may relate to the fact that other interdigitating pathways feed into JAK-STAT. Other proteins activate JAK-STAT, so the route to activating the JAK-STAT pathway doesn’t only go through JAK2.

Francisco Cervantes, MD, PhD

DR CERVANTES: We don’t know exactly why patients without JAK2 mutations respond to JAK2 inhibitors. Some of the JAK inhibitors target JAK2 and JAK1, while others are purely JAK2 inhibitors. JAK1 is important in the regulation of some cytokines that have a role in the symptoms of myelofibrosis and, apparently, also in the splenomegaly that occurs with the disease. But it is also important to note that some pure JAK2 inhibitors reduce the splenomegaly and abolish the constitutional symptoms without decreasing the cytokine levels. So we need to perform additional studies to understand.

Hagop M Kantarjian, MD

DR KANTARJIAN: The JAK2 mutation is not the target of the JAK2 inhibitors. JAK2 inhibitors can work in patients with myelofibrosis who have the JAK2 mutations or in those who don’t. The JAK2 mutations put the JAK2 pathway in overdrive, but the JAK2 pathway is activated anyway in many patients, including those who don’t have the JAK2 mutation. The JAK2 inhibitors have a nonspecific effect in suppressing the JAK2 pathway, and along the way they might have some effect at higher doses in producing anemia and thrombocytopenia.

The reasons why we do not have a good understanding of the JAK2 inhibitors in myelofibrosis are, first and simply, that it’s a new field. Second, at the beginning opinions of the myelofibrosis experts differed about how effective and how beneficial the agents were. Now we have more mature data from the Phase III randomized trials COMFORT-I and COMFORT-II. They continue to show a beneficial effect, and both studies are showing an effect on survival.

I believe it becomes part of our mission to try to get the information to the community oncologists so they can use these drugs for patients with myelofibrosis when the indication exists that ruxolitinib or JAK2 inhibitors might be beneficial. We still have some way to go in terms of our knowledge about the pathophysiology of myelofibrosis and the benefits of ruxolitinib and JAK2 inhibitors alone or in combination in these patients.

DR LOVE: At one point I heard some discussion about studying allele burden in relationship to benefit from JAK inhibition. Has that been evaluated?

DR KANTARJIAN: That is being studied, but one has to remember that so far with ruxolitinib and perhaps with other JAK2 inhibitors, we are not able to suppress the burden of the JAK2 mutation. It could be that with new and improved JAK2 inhibitors this might happen. Interestingly, we have seen an improvement in the JAK2 burden with other agents, such as lenalidomide in combination with steroids, which we have not seen with the JAK2 inhibitors.

Alessandro M Vannucchi, MD

PROF VANNUCCHI: Several studies have failed to show any prognostic relevance of the JAK2 mutation. In terms of quantifying the JAK2 mutation, we and others have reported that, considering the entire population of patients treated, ruxolitinib produces little, if any, change in terms of reducing the JAK2 allele burden. Our group has reported, however, that a category of patients exists who experience more than 20% reduction in the JAK2 allele burden. This reduction is associated with a greater chance of achieving a reduction in the spleen size.

Srdan Verstovsek, MD, PhD

DR VERSTOVSEK: The basic problem with all patients with myeloproliferative disease is hyperactivity of the JAK-STAT pathway, an intracellular pathway that leads to cell growth. In about half of the patients with myelofibrosis, we believe this pathway is active because of a mutation in a JAK2 gene that makes the JAK2 enzyme active all the time. In the remaining portion of patients the hyperactivity might be due to 1 of the many other mutations that may be present in patients with myeloproliferative diseases. It is a more complicated genetic disease than we originally thought, and multiple mutations may be present in the same patient.

But all patients have hyperactivity of the JAK-STAT pathway. Ruxolitinib and other JAK inhibitors are not JAK2 mutation-specific. They inhibit the native JAK2. Because JAK2 is active in all the patients, with or without JAK2 mutation, JAK2 inhibitors work in everybody.

Jerry L Spivak, MD

DR SPIVAK: When we are using a JAK2 inhibitor it doesn’t matter whether we can detect the mutation JAK2 V617F. About half of the patients with primary myelofibrosis do not have a known mutation in JAK2. The remaining patients have the JAK2 V617F mutation, and a small proportion of patients have mutations in the thrombopoietic receptor. Stem cells do not need JAK2 to survive, but all committed progenitor cells — red blood cells, white blood cells, platelets or the cells that will become them — need JAK2 to survive and multiply. Where the JAK2 inhibitors fit in is that they reduce the production of the later cells. The JAK2 inhibitors get rid of the abnormal red blood cells, and this leads to the initial anemia observed in patients, and then the normal clones come back. So you actually improve bone marrow function that is important to the patient in terms of having enough platelets, enough red blood cells and not too many white blood cells.

JAK2 becomes important in the stem cell because although the stem cell doesn’t need it, if JAK2 becomes overactive because of, let’s say, a mutation, it will lead to an increase in reactive oxygen species in the cell, which is harmful to the structure of the DNA and causes double-strand breaks. So overactive JAK2 can be toxic to the stem cell. A JAK2 inhibitor does not signal a stem cell to “die,” but it improves the milieu in the stem cell because it prevents an overactive kinase from causing genetic damage. In my view, if you use a JAK2 inhibitor you will improve stem cell function and you will decrease the number of the malignant clones that abound. JAK2 inhibitors allow a normal clone to surface.