Expert Details Developments in MPN Paradigm

David S. Snyder, MD, associate professor of oncology and urology at Johns Hopkins Medicine

David S. Snyder, MD

Ruxolitinib (Jakafi), the sole FDA-approved agent for the treatment of patients with myelofibrosis, though effective in reducing splenomegaly and mitigating constitutional symptoms, does not significantly or reliably reduce the molecular burden or prevent progression to acute leukemia, noted David S. Snyder, MD.

Ongoing research is aiming to address the gap in efficacy as improved understanding of molecular markers comes to the forefront. “It looks like the more secondary mutations you have, the more aggressive the disease tends to be,” explained Snyder. “Those are things we're learning in terms of prognosis [and will hopefully] lead to specific targeted therapies of value.”

OncLive: Please provide an overview of your presentation.

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Multiple Myeloma and Myeloproliferative Neoplasms, Snyder, associate chair and professor, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, detailed these mutations and discussed investigational treatments within the field of myeloproliferative neoplasms (MPNs).Snyder: The field of MPNs is hitting its stride with new molecular markers that are being defined. We know about the important driver mutations including, JAK2, CALR, and NPL. Now, we are learning more about the prognostic importance of secondary mutations. The hope is that some of these findings will lead to targeted therapies. That’s what led to ruxolitinib, the only FDA-approved drug [that was developed for myelofibrosis]. There are other JAK2 inhibitors in clinical trials, one of which is pacritinib.

There are non-JAK2 inhibitors that are being studied, as well; imetelstat is an example of that. It's a telomerase inhibitor, which is a totally different kind of molecule. There are still a lot of unmet needs in this area. Ruxolitinib is the leader right now; it has very good properties that enable shrinking spleens and curbing constitutional symptoms, but there is a lot that it doesn't do. It doesn't significantly or reliably reduce the molecular burden. It doesn't seem to prevent progression to acute leukemia, and it's not a cure.

[Cure is] something we would all [like] to be able to reach for. In the meantime, there's allogeneic stem cell transplantation, which is the only curative option for [patients with] myelofibrosis. We presented some of our work from City of Hope at the 2017 Annual ASH Meeting. [Stem cell transplant] is not a perfect answer either. There are a lot of toxicities associated with it, including morbidity and mortality; however, for the right patient, it's the only curative option.

How have you seen ruxolitinib impact the landscape since its approval?

For polycythemia vera (PV), I spoke about the current state-of-the-art regimen, hydroxyurea, which remains to be the frontline drug of choice when cytoreduction is needed. Before that, low-dose aspirin and phlebotomy has been and still is the mainstay treatment. For those who need something further, hydroxyurea is [indicated in the] first-line [setting]. There are other options. Ruxolitinib is now FDA approved as a second-line therapy for patients with PV who are resistant or intolerant to hydroxyurea. Interferon is [also] making a resurgence. There are these newer formulations of interferon—pegylated interferon—that are longer lasting and may be less toxic than the standard interferon.It's very good at what it does: shrinking spleen size and controlling constitutional symptoms, which are very important sources of clinical problems for our patients. It is part of the reason why patients lose weight, have decreased muscle mass, and poor performance status. If physicians can significantly reduce the spleen size and improve their patient's ability to eat, that can help performance status.

Reducing some of the constitutional symptoms also improves a patient’s quality of life. The use of ruxolitinib does, however, lower platelet count. Physicians must be careful about that and adjust the dose appropriately. It may worsen anemia, at least initially, which is a problem that most patients are dealing with already. For most patients, if their hemoglobin drops, it will recover to baseline after a few months. That effect does not seem to impair or impact the ultimate benefits of the drug.

What are some other identified mutations and their corresponding treatments?

It can still be used for patients with anemia. There is a subset of patients who may get prolonged survival by virtue of taking ruxolitinib. The original studies, COMFORT-I and COMFORT-II, weren't specifically designed to show survival benefit, but further analyses revealed that some patients do get that benefit. There are some patients—not a majority, but some—who we may see a reduction in the JAK2 burden and/or some reduction in the circulating blasts. However, it's not reliable of an effect, and it doesn't seem to prevent that ultimate transformation to acute leukemia, if it's going to come. Besides JAK2, CALR is the next most common driver mutation. There are 2 subtypes of CALR; type 1, which is a deletion and type 2, which is an insertion. It turns out that the way mutated CALR works is that it ultimately feeds through the JAK2-STAT pathway, just like the JAK2 mutation. A drug like ruxolitinib or another JAK2 inhibitor is known or likely to be as effective in patients with CALR mutations as are those with a JAK2 mutation, though it’s a different mechanism. Mutated CALR seems to bind externally to the MPL or EPO receptor. It lends itself to potentially being a target for immune reactivity because it has the unique antigen structure at the mutated site and is extracellular. There is ongoing work looking at the immunogenicity of CALR mutations and potentially leading the way to developing a CAR T-cell strategy.

For MPL, the mutation is in the receptor that activates the JAK2-STAT pathway; it too is amenable to JAK2 inhibition. Some of the secondary mutations are ASXL1, TET2, and IDH1/2. There are some specific drugs available already, and more coming, that target some of those mutations like IDH1/2. There are [also] oral inhibitors; I don't know that they've been studied in the context of MPNs, but it certainly would be something worth looking at for those patients who have those added mutations.

For now, the presence of those mutations is [a] helpful prognostic [indicator], and that's important to give patients an idea of what to expect. It also helps potential transplant candidates decide when it might be an appropriate time to move in that direction. There is a new prognostic scoring system called the MIPSS70 and the MIPSS70-plus, which incorporates some of the same factors that the DIPSS does, but they add in some of these molecular markers. The presence of the CALR type 1 mutation is a very positive finding; it adds a certain benefit to your overall prognosis. In contrast, the absence of that mutation confers more of a negative prognosis.

Personalized medicine and targeted therapies are emerging. Not all patients with myelofibrosis are the same. The presence of these different markers helps to define subtypes of patients. It may be that some of the drugs that are being developed may work better with 1 profile compared with another. Ruxolitinib seems to [work] in patients with JAK2 mutations or patients with CALR or NPL.

Are there ongoing trials looking at other JAK2 inhibitors?

Early studies of imetelstat show that 7 patients had either complete remissions or partial remissions, which is unheard of in other studies. If you look at the profile for those patients, all of them had JAK2 mutations with a V617F mutation without an ASXL1 mutation. That may define a subset of patients who may be more likely to get a good response to imetelstat. In contrast, patients who have other profiles may not [benefit] from that drug. I say that with caution because it was based on a small number of patients. There's an ongoing phase II trial of imetelstat, which will hopefully add to the database and either confirm [or deny] that initial observation.Pacritinib is one; that's a JAK2 inhibitor that doesn't inhibit JAK1 like ruxolitinib does. There have already been a couple of phase III trials with that drug. It has similar outcomes and benefits as ruxolitinib in terms of reducing splenomegaly and controlling constitutional symptoms. It seems to be easier on the platelet issue compared with ruxolitinib. Patients with low platelet counts may still be able to tolerate pacritinib at good therapeutic doses, whereas those patients either cannot receive ruxolitinib or have to have markedly reduced doses of the drug, [which] will be less effective. That's [a potential] advantage of pacritinib.

For a while, the FDA put a temporary hold on the trials because there were concerns about hemorrhagic events, specifically intracerebral and also episodes of congestive heart failure. After further analysis and a little bit of restructuring of the protocol, the FDA put it back on study. The current trial incorporates a dose reduction. A randomized trial between 3 doses of pacritinib, including a lower dose than what was previously used, was done to ask whether that lower dose might be safer and still effective. That remains to be seen.

Another drug, fedratinib, was around for a while and then was taken off the table by the FDA because there were some concerns about neurologic toxicity, specifically Wernicke’s encephalopathy. After further analyzing patients, it's not so clear that the drug itself was the culprit. It may be issues with the patient population, [in terms of vitamin and other] deficiencies. In any case, the drug is now back in active studies. We'll see how that comes out.

Is there anything else you would like to emphasize with regard to patients with MPNs?

There are other drugs that are not necessarily JAK2 inhibitors; imetelstat is one. Antifibrotic agents like PRM-151 are being studied. There are combination trials using ruxolitinib as a starting point and then adding a partner to it, whether it is interferon or drugs that target different pathways. [These include] hedgehog inhibitors to see if you can synergize 2 drugs with totally different mechanisms of action.It's important for physicians to refer their patients to centers that see a lot of these kinds of patients. They are rare diseases, so no one practitioner is going to have very many patients in their practice. All patients with these diseases should be given the opportunity to potentially participate in a clinical trial, or be considered for an allogeneic stem cell transplant.

At the age of diagnosis, how old are patients?

They should be given the opportunity to meet with a transplant center who can review the comorbidities for the patient, review the logistics of transplant, potential outcomes and risks involved, and help a patient decide if that's an option for them. Transplantation may have a bad reputation because it is an intense and somewhat toxic regimen. The stakes are high because the goal of therapy is to cure the disease. For our patients who get through it and do well, they're hopefully restored to a full life.For myelofibrosis, it's an older age group; 65 or so is the median age. Not too long ago, we would only consider people who were up to about age 50 or 55 as candidates. Now, with what's called “reduced-intensity conditioning regimens,” we can lessen the immediate toxicity of the regimen and open it to patients who are significantly older.

There's really no absolute age limit currently; it goes well into the 70s. I'm sure somebody, somewhere has transplanted a patient who is 80 years old, but we've definitely offered transplant to patients into their 70s. They have to be in otherwise fairly good health as far as their major organ function. Since most of the patients with these diseases are in that age group, the [more expansive age group] is potentially very beneficial for them.

For PV, it's a younger onset, typically in the 40s. There is a period of 10 to 15 years or so of fairly stable disease. Eventually, most patients with PV will transform to secondary myelofibrosis with enough time.