Addressing Loss of Response to Ruxolitinib in Myelofibrosis

Robyn M. Scherber, MD, MPH

Robyn M. Scherber, MD, MPH

Ruxolitinib (Jakafi) failure in patients with myelofibrosis (MF) is commonly encountered in the clinic. As the only FDA-approved agent for this patient population, it is being used more often, leading to a major unmet need for patients who become refractory or resistant to this treatment.

Several clinical trials have aimed to get a better understanding of ruxolitinib failure, such as COMFORT-II, JAKARTA2, SIMPLIFY 2, and PAC203. However, this is still poorly defined, with only a few similar components within each trial’s definition of ruxolitinib failure.

Because ruxolitinib can impact a patient’s quality of life so positively, it is important to maximize the treatment as much as possible at the beginning of ruxolitinib failure, said Robyn M. Scherber, MD, MPH. If a patient is losing response due to anemia, for example, reducing the ruxolitinib dose or introducing a second agent for the anemia should be the first option.

For patients losing response unrelated to anemia, another option includes combining ruxolitinib with other agents. A number of clinical trials are investigating different pathways to target in MF, including SMAC and CDK4/6.

In an interview withTargeted Oncologyduring the 2018 Society of Hematologic Oncology Annual Meeting,Scherber, a physician at Mays Cancer Center, UT Health San Antonio MD Anderson Cancer Center, discussed the prevalence of ruxolitinib failure and how it can be managed in patients with MF. She also highlighted combination regimens and other treatments currently under investigation for this patient population.

TARGETED ONCOLOGY:Can you provide somebackground information on patients with MF?

Scherber:Our treatment approach with MF is kind of 2-fold. First off, we look at risk. We usually use risk scoring methods such as the dynamic international prognostic score (DIPS) or if patients are earlier on in the disease course, we will just use the international prognostic score that is usually used at the time of diagnosis. Once we determine risk, it helps us to really give a paradigm on how to treat the patient in terms of does this patient need to be considered for upfront transplantation or what sort of therapies we need to use.

The other thing that we are looking at is symptom burden. We have the MPN10, which is a 10-item assessment of symptoms scored individually 0 to 10 with a 0 to 100 scored system. When we are looking at symptoms, we now have symptom-based therapies. In our practice and in what we have validated as results, individuals with a total symptom score greater or equal to 20 out of 100 or if any of those individual symptoms are greater than 5, those are patients who may benefit from symptom-based therapy. So again, in addition to looking at prognostic scores, we do look at symptoms as well.

For patients who do have elevated symptoms, we know that ruxolitinib is available as a first-line treatment option and has data in terms of not only improving symptoms, but also improving spleen size, and there is some data that there is increased overall survival in patients on ruxolitinib and potentially some stabilization or reversal of bone marrow fibrosis.

TARGETED ONCOLOGY:How prevalent is ruxolitinib failure and what leads patients to treatment discontinuation?

Scherber:Ruxolitinib failure is something that we commonly encounter in clinical practice. Now, with patients on ruxolitinib potentially living longer than they have before, we are encountering ruxolitinib failure more and more often. We also have more and more patients going on to ruxolitinib, again, the only FDA-approved agent for MF, so it’s becoming more of an issue. Although some patients can stay on ruxolitinib and have good response for a long time, usually by 2 to 3 years patients will inevitably lose response to ruxolitinib.

Discontinuation of ruxolitinib treatment can be precipitated by many different items. In terms of what is ruxolitinib failure, this is something that comes up frequently in terms of questions, but has also been poorly defined by clinical trials to date. We have 4 large phase III clinical trials that have tried to pin down what ruxolitinib failure is and a true definition. There are a couple different components that are shared between these definitions.

Number 1 is duration of ruxolitinib use. The 4 main trials are the COMFORT-II trial, the JAKARTA2 trial, the SIMPLIFY 2 trial, and the PAC203 trial.They used a definition of ruxolitinib use for anywhere between 14 days to 28 days to 3 months before they felt that someone could be deemed to have ruxolitinib failure.

The other thing is spleen size, anywhere from not being able to achieve a 25% reduction in spleen size or an increase in spleen size from 10% of the lowest spleen response size.

Another thing is disease progression. They usually define this, if they do use this as a marker for ruxolitinib failure, as having blast count in the peripheral blood of more than 20% over 8 weeks or 20% blast in the bone marrow, which is a true definition of AML. Other things that they have used are CTA/CAE, or basically clinical trial thresholds for grade 3 or higher of anemia, thrombocytopenia, hemorrhage, or hematoma.

One of the things that we found to be very clinically relevant in terms of ruxolitinib failure is symptoms. Symptoms themselves should be monitored early in the disease course and over time, but 1 of the most sensitive markers that ruxolitinib is not working as well as it did before is that patients don’t feel as well as they used to. They’re starting to see recurrence of abdominal pain, shortness of breath, headaches, itching. When we see this, we start to think again that ruxolitinib may not be as effective as it was. We do check the spleen size to see if potentially there is not as much of a spleen response or patients are again gaining in spleen size; we check the blood counts.

In general, ruxolitinib failure is something we need to be careful to watch for and something we are addressing in terms of other options for treatment.

TARGETED ONCOLOGY:When a patient discontinues treatment, they fall into either 1 of 2 categories: refractory-resistant or relapse-progressive. Could you discuss the difference between these and how you define these patients?

Scherber:When we are looking at ruxolitinib failure, there’s really kind of 2 main paradigms. One is more of the ruxolitinib resistance, where we are starting to see patients even on the same dose of ruxolitinib or on a decreasing dose of ruxolitinib basically have recurrence of symptoms, recurrence of spleen, where ruxolitinib really isn’t having the same effectiveness as it had before.

This is compared to ruxolitinib intolerance or progressive disease, where ruxolitinib truly is not working as we hoped it would, and patients really aren’t benefitting from it. When I’m thinking about ruxolitinib failure, I’m seeing which category patients are falling into. Are they just getting more resistant to ruxolitinib or are they at an adequate dosing of ruxolitinib, where if I were to increase the dose I might be able to get a spleen response or symptom response back, versus I really need to start thinking about either adding on an additional agent or changing therapy for this patient because ruxolitinib alone is not able to cut it or they are not able to tolerate ruxolitinib in general.

TARGETED ONCOLOGY:What are the options for these patients?

Scherber:When we approach a patient that looks like they are losing response to ruxolitinib, as I mentioned, there are 2 paradigms. One of which is the patient might not be having a real robust response in terms of what dose they are on now and that we might be able to alter the dosing. [The other paradigm] is that ruxolitinib is truly not a good choice for them. The disease is progressing, and they aren’t able to tolerate ruxolitinib.

In the first scenario, we have a couple different options. Number 1 is I try to first look at why the dose of ruxolitinib is limited. Usually there are 3 different scenarios. Number 1 is that the spleen is having issues and there is lack of spleen response, so we are thinking that is why ruxolitinib is not working as well. In that case, if I think I can optimize the ruxolitinib dosing with some spleen-directed therapies, I will do that. Things like splenic radiation could be considered. Outcomes with splenectomy in this population are not so good.

The second ties in closely with the spleen, which is anemia. Even if I see a very large spleen in a patient with anemia that’s limiting ruxolitinib therapy, I may consider spleen-directed therapies just to try and help with that anemia so I can optimize the ruxolitinib dose.

Anemia itself can be targeted by specific agents that we have for anemia in general, such as the addition of erythropoietin along with ruxolitinib. One key thing to keep in mind is that ruxolitinib usually increases erythropoietin levels, but that being said, I will still screen those patients with anemia for their levels and if they are subpar, especially less than 200, I’ll consider adding an erythropoietin. Another agent with pretty decent efficacy, not awesome, but decent, is danazol. We can safely add in danazol with ruxolitinib as we have seen in clinical trials.

The third scenario is the presence of thrombocytopenia. In that instance, we have to start going to other agents because ruxolitinib itself, we don’t have a good agent to increase the platelet count while someone is on ruxolitinib. We can combine therapies, potentially a hypomethylating agent in addition to ruxolitinib. There’s also single agent lenalidomide (Revlimid). Although the efficacy is not fantastic, it is something we can use. The combination of ruxolitinib and lenalidomide is not recommended. Unfortunately, there is quite a bit of overlapping toxicities with that. The third agent would be panobinostat (Farydak). In previous trials, that has had a 30% response rate in terms of blood counts.

The final thing that is really interesting and might really help us optimize dosing is actually a ruxolitinib holiday. There is some data now that there is heterodimerization of JAK signaling molecules that can occur with JAK inhibitor use. We might be able to take patients off of JAK inhibitors for an unknown period of time, since it is still very new, but maybe by restarting ruxolitinib after that drug holiday we could actually re-induce response.

TARGETED ONCOLOGY:What clinical trials are currently being conducted with ruxolitinib or combination therapy?

Scherber:There are a lot of different clinical trial options that are either being looked at alone or in combination with ruxolitinib. It’s a bit much to list them all off at once, but I do have to say there are a lot of different targeted pathways such as targeting epigenetics, targeting fibrosis pathways,things like Smac inhibition,CDK4/6 inhibition.

More than ever, we have a breath of targeted therapies that usually, in combination with ruxolitinib or alone, can be tried. If these compounds are being tried in combination with ruxolitinib, usually in that setting we make sure there are no overlapping side effects, especially [since] we know ruxolitinib can cause some initial decreases in blood counts or thrombocytopenia. We want to make sure that when we add on that second agent that it’s not causing that same issue or a worsening or compounding of these issues.

TARGETED ONCOLOGY:Can you talk about the excitement with some of these investigational therapies?

Scherber:There are a lot of new therapies that are being developed for MF that are generating quite a bit of excitement as they can have good efficacy either alone or in combination with ruxolitinib. We have agents these days that are alternative types of JAK inhibitors, so this can include fedratinib, which is being looked at again. There were initial concerns of Wernicke’s encephalopathy, but now they are going back into investigational phase trials.

Another 1 that is out there is baricitinib (Olumiant), and [that is] also under investigation. We had momelotinib, but right now it is unfortunately off the table. Those could potentially be used as alternative JAK inhibitors if ruxolitinib is not working as well, or they may be considered in some cases in certain patient populations, such as for pacritinib, with lower platelet counts as a frontline therapy.

There’s a lot of other agents being looked at and 1 of the most encouraging of which is the anti-fibrosing agents.The idea with those is that we might be able to improve anemia in this patient population, also potentially stabilization of bone marrow fibrosis or reversal fibrosis. In this initial phase I/II trials, it looks very promising in combination with ruxolitinib.

We have a lot of other trials that are out there, as I mentioned CDK4/6 inhibition, SMAC mimetics, there’s specific epigenetic modifiers with things like intel-stat which I hear may be undergoing further trial investigation. It’s an exciting time for MF. A lot of good treatment options are on the horizon. I think that in the next couple of months we will hear even more as more data comes out, some of it at the larger meetings.

TARGETED ONCOLOGY:What would you say is the most important takeaway for physicians managing MF?

Scherber:When treating a MF patient that is becoming refractory or resistant to ruxolitinib, there are a couple of key points I want physicians to keep in mind. Number 1 is to make sure you have done what you can to make sure you maximize ruxolitinib. We do know it has spleen response, symptom response, patients tend to feel better on it, so trying to optimize dose is key. More often than not, I’ll see clinicians try to dose down ruxolitinib even at the first sign of some concerning anemia, and the idea that we can actually combine traditional therapies for anemia with ruxolitinib is key, things like erythropoietin or danazol.

The other thing to keep in mind is that even with ruxolitinib, when we think someone is losing response outside of anemia, the idea that we could actually combine agents with ruxolitinib has been tried in clinical trials with some good efficacy. The most notable of which is a hypomethylated agent with ruxolitinib. In that setting, we are actually seeing, especially in patients who are progressing toward blast phase, a response rate as high as over 70%.

Other things that are commercially available in the relapsed/refractory setting that we can consider are lenalidomide, panobinostat. When patients have progressed to blast phase disease, we can start to double dip into some of the new AML therapies that have come out, some of the more targeted therapies. The second point that I would like to make is that getting genetic sequencing, especially if you think a patient is gunning past the point of using ruxolitinib or maybe progressing, would be key to determine therapies and understand what is going on in the disease state.

We have targeted FLT3 inhibition, CD33 inhibition, and especially relevant to post-MPN AML, IDH1 and IDH2 inhibitors that are available for use.

I think it’s also really important to keep an eye on and open mind on what patient symptoms are, and quality of life is a third point. In our data, quality of life is independently predictive of overall survival in MPN patients, especially MF patients. Making sure we are tailoring treatments to optimize quality of life is key to helping patients live longer and healthier lives.