DR TALPAZ: With ruxolitinib therapy the disease becomes resistant in almost every case. We have observed 2 patterns of “resistance” to ruxolitinib. The first is not necessarily resistance — it can be described as a mixture of intolerance and resistance. The patient’s disease never responds to ruxolitinib in a significant manner with regard to the spleen. This occurs in half of the patients. The second pattern can be described as true resistance, in which the disease stops responding to ruxolitinib.

The published data and our own clinical experiences tell us that all or almost all patients will have some kind of response, but the truth is that if the patient experiences a minimal response it will be fleeting. We observe the disease stop responding and the symptoms returning. The spleen starts to enlarge and the white blood cell count starts to increase. You cannot treat optimally in these situations because each time you treat, either the anemia or the thrombocytopenia gets worse, even with a tiny dose, so you stop treatment. I have patients who have experienced 4 years of response to ruxolitinib, and then their disease stopped responding.

If the patient’s symptoms are no longer being controlled and ruxolitinib therapy is discontinued, no splenic rebound occurs. The spleen doesn’t come back all the way. The symptoms typically reappear 5 to 7 days after treatment interruption. This further shows that the major effect of ruxolitinib is interference with cytokine production. The rebound is mainly in the form of the symptoms associated with cytokine production, like fever, night sweats and so forth.

Two experimental JAK1 inhibitors are being tested in myelofibrosis. One of these has a modest effect in terms of the splenomegaly and the symptoms. It’s much weaker than the JAK2 inhibitors. However, half of the patients recovered from the anemia and became transfusion independent. That’s rather a surprising effect.

The second is a JAK1/2 inhibitor, momelotinib, which is being investigated at the Mayo Clinic. Its effect on the spleen is probably slightly inferior to that of ruxolitinib, but more than half of the patients in the Phase I/II study became transfusion independent and experienced a reversal of anemia. So it’s probably more a JAK1 inhibitor than a JAK2 inhibitor, but still it’s an interesting one.

We are not sure whether other inhibitors being developed will override resistance to JAK2 inhibition. The mechanism of resistance or lack of responsiveness to JAK2 inhibition is not completely understood. Ross Levine argues that the typical JAK2 homodimers that activate the JAK-STAT pathway do not form in the persistent presence of a JAK2 inhibitor. Instead JAK2 heterodimerizes with JAK1 and TYK2, and as a consequence it can override the effect of JAK2 inhibitors and resistance is developed. Theoretically, if the treatment is stopped the original homodimer reestablishes itself and becomes sensitive to JAK2 inhibitors again. But the point is that not all JAK2 inhibitors are the same. If additional agents are approved and enter the market, they may not all have the same profile of myelosuppression, activity or toxicity.

DR VERSTOVSEK: The practical question is, what is “resistance” to ruxolitinib? Unfortunately, I see quite a few patients who come from the community who are labeled as resistant because they were administered too low a dose of ruxolitinib — let’s say 5 mg BID — with no attempt to increase the dose. Or a patient started with a good dose but then developed anemia and the doctor lowered the dose to 5 mg BID and no response occurred. At this dose, the patient is now “resistant.” The issue is mostly about managing and optimizing the dose of ruxolitinib rather than real resistance. Primary resistance to ruxolitinib at 10 mg BID or higher is rare. In the COMFORT-I study only approximately 3% of the patients did not respond at all. That’s rare.

DR LOVE: Have you observed any cases in which the disease has been managed optimally with ruxolitinib, then progresses but the patient subsequently responds to an investigational JAK inhibitor?

DR VERSTOVSEK: An investigational JAK inhibitor may be useful in patients who are losing response to ruxolitinib. Some experience with that has already been gained in other studies. Certain studies did allow enrollment of patients who were previously exposed to other JAK2 inhibitors. A study with pacritinib allowed prior exposure to JAK2 inhibitors, and we observed that people can respond to different JAK2 inhibitors.

So far about 10 different JAK2 inhibitors have been evaluated in clinical studies. They differ a little, primarily in terms of which additional targets they affect. By default, they’re all ATP binding site inhibitors for JAK2, but they are not specific to the JAK2 mutation. What differs among the agents is whether they affect other members of the JAK family, like ruxolitinib and the momelotinib compound also inhibiting JAK1. These are JAK1 and JAK2 inhibitors, which may be relevant because the inflammatory cytokines that we talked about in the pathophysiology of myelofibrosis are inhibited by dual inhibition of JAK1 and JAK2. With JAK2 inhibitors that do not inhibit JAK1, you do not see a decrease in inflammatory cytokines. Perhaps this is the advantage of these 2 compounds over others. The additional inhibition of other tyrosine kinases may affect either efficacy or the toxicity profile.

Pacritinib is a JAK2 inhibitor but it does not inhibit JAK1 and therefore it has no anti-inflammatory effect. However, it does decrease the spleen size and improve quality of life in a number of patients. Pacritinib also inhibits FLT3, which has no real relevance for myelofibrosis but perhaps explains why these compounds cause occasional problems with nausea, vomiting and diarrhea because FLT3 inhibitors as a group have these side effects. Perhaps it’s not as active as the JAK1 and JAK2 inhibitors like ruxolitinib. The benefit of this drug is observed primarily in patients with a low blood cell count.

Because ruxolitinib has the potential to decrease the platelets and red blood cell counts, some investigators wondered what its utility might be in these patients who start the therapy with particularly low counts? Pacritinib may offer a solution because no myelosuppression occurs. It was as effective in patients with low platelet counts, for example, as in patients with good platelet counts. Hopefully, this and other agents will be developed, particularly for patients who start with a low blood cell count.

The fact that pacritinib and other JAK inhibitors also inhibit FLT3 may not work in their favor because the dose-limiting toxicity has been gastrointestinal. The nausea, vomiting and diarrhea are low grade but have the potential to compromise improvements in quality of life. Most notably, in a recent ASH report on pacritinib approximately 70% of the patients stopped therapy after 10 months on average. So FLT3 inhibition has the potential to compromise the delivery of a drug on a long-term basis.

DR GOTLIB: In terms of discontinuing ruxolitinib therapy, no data compare stopping ruxolitinib abruptly to tapering the treatment, but I generally favor tapering the treatment over 7 to 10 days. This is a homegrown approach based on clinical judgment.

DR LOVE: Have you observed any cases in which the disease has been managed with a JAK inhibitor, the treatment is discontinued and then the disease subsequently responds to another JAK inhibitor?

DR GOTLIB: We’ve performed all the major trials with the leading 3 JAK inhibitors. Some patients have had to discontinue momelotinib or fedratinib, and when I started them with ruxolitinib they experienced some benefit. One should not overglorify or overestimate the amount of benefit. If the spleen is particularly large, then it may shrink again by several centimeters, or if the symptoms are breaking through, they may improve a little. This is not a dramatic transformation from one JAK inhibitor to the other. It’s a modest mitigation. Each of the JAK inhibitors shrink spleens and improve symptoms well. Momelotinib shows some improvement in anemia and the need for transfusions, which is important. That’s where its niche may be.

DR JABBOUR: For a patient on ruxolitinib for whom I am discontinuing treatment, I would taper ruxolitinib therapy unless the patient was experiencing side effects.

I have not seen a meaningful clinical response to a subsequent JAK inhibitor in disease truly resistant to ruxolitinib. I cannot state that if a patient’s disease fails to respond to one JAK1 or JAK2 inhibitor, it will not respond to another.

DR STEENSMA: For a patient with myelofibrosis who needs to discontinue treatment, I would stop ruxolitinib therapy abruptly.

DR LOVE: Have you observed any cases in which the disease has been managed with a JAK inhibitor, the treatment is discontinued and then the disease subsequently responds to another JAK inhibitor?

DR STEENSMA: I don’t know whether any research on this issue has been published, but our clinical trial experience includes cases in which one JAK2 inhibitor works well for the patient and another doesn’t. I have 1 patient whom we sent to transplant this past week who is a good example. This patient had polycythemia vera diagnosed in 1991, and 3 years ago the disease progressed to myelofibrosis. I placed him on a clinical trial we had with pacritinib (SB1518). He was faring well with that agent — his spleen shrank, his counts were good and his symptoms went away. Last year the clinical trial was discontinued.

At that point I administered ruxolitinib off study and almost immediately the patient’s condition began to worsen. I increased the dose from the initial 20 mg to 25 mg BID then to 30 mg BID and could not get the disease to respond. I had to switch therapies completely. We tried pegylated interferon alpha 2a and then cladribine, which helped him a little. Now he is undergoing a stem cell transplant. This is a case of a patient who had an excellent experience on one JAK2 inhibitor and then we couldn’t continue that benefit with another JAK2 inhibitor.

I believe this occurs in part because the profiles of these JAK2 inhibitors are distinct. They all have slightly different kinase inhibitory patterns. Some inhibit JAK1 to a greater extent than JAK2. Some have inhibitory activity also on JAK3, FLT3, TYK2 and PDGFR. They are all a little different from one another, so I definitely believe that some patients will respond to one and not to another. To date, most of the clinical trials have enrolled patients who have received other therapies only, such as hydroxyurea, androgens and thalidomide, because the JAK2 inhibitors have not been around for long. Most trials have excluded patients who’ve received prior JAK2 inhibitors. However, it has been my clinical experience and that of my colleagues that distinctions are apparent.

DR SPIVAK: In terms of discontinuing ruxolitinib, I can envision a scenario in which symptoms worsen, the spleen is progressively enlarging even with dose escalation and I become concerned about further suppressing production of blood cells. I haven’t run into that yet, and we have no standard schedule for discontinuing ruxolitinib. However, I would prefer to taper therapy, depending on the current dose.

I have not stopped ruxolitinib for anyone yet to be able to answer whether disease that is resistant to this agent will also be resistant to other JAK2 inhibitors. I have had patients for whom treatment with a different tyrosine kinase inhibitor failed who subsequently responded to ruxolitinib.

DR MESA: An article published by Ross Levine’s group speculated that a dose interruption of JAK2 inhibition followed by a rechallenge might possibly help to overcome resistance. They did not observe traditional resistance in terms of a mutation affecting binding but rather the ability of the cell’s signaling pathways to compensate for the JAK2 inhibition. In their preclinical work in the laboratory they were able to restore sensitivity to the drug. This is clearly experimental, but their paper raised the question whether, for a patient who responds and then loses response, it is possible that rechallenging with a JAK2 inhibitor after a break may have benefit.

As we have moved people from one clinical trial of a JAK2 inhibitor to another, we have in a sense replicated this scenario of having an off period between treatments with JAK2 inhibitors. We have seen disease that either didn’t respond or stopped responding to a JAK2 inhibitor such as ruxolitinib and then gained benefit from another JAK2 inhibitor administered on a new trial.

Several other JAK inhibitors look promising. Fedratinib (SAR302503) is an investigational JAK2 inhibitor that improved splenomegaly and symptoms in a randomized Phase III study comparing it to placebo. It is clearly active, but its development has been put on hold after a small number of patients developed Wernicke encephalopathy. The exact mechanism of this adverse effect is unknown, but it may be related to interference with thiamine metabolism.

Momelotinib and pacritinib are being evaluated in Phase III studies. Momelotinib is being compared to ruxolitinib in an attempt to demonstrate superiority in terms of anemia and noninferiority in terms of splenomegaly and symptoms. Pacritinib causes less thrombocytopenia and anemia, and the Phase III study is including patients with thrombocytopenia. These 2 agents are being developed with different strategies, focusing on anemia for momelotinib and thrombocytopenia for pacritinib.

The next tier of agents in development includes LY2784544, NS-018 and BMS-911543. They have all demonstrated activity in patients with splenomegaly and symptoms. The data are too limited at this point to determine any differentiation among them.