Hobbs Highlights New Agents Being Investigated in Myelofibrosis

Gabriela S. Hobbs, MD

As the myeloproliferative neoplasm (MPN) associated with the most complications and the shortest life expectancy, myelofibrosis (MF) has been the focus of the majority of research and advances in the field.

Although ruxolitinib (Jakafi) still remains the only FDA-approved agent for treatment of this disease, there are several drugs in development. Clinical trials are currently ongoing to investigate other JAK2 inhibitors, similar to ruxolitinib, as well as other classes of agents such as PI3K inhibitors, MDM2 inhibitors, and BET inhibitors.

Gabriela S. Hobbs, MD, is currently leading 2 clinical trials at Massachusetts General Hospital (MGH) investigating new treatment approaches for patients with MF, including a trial evaluating PD-1 inhibition with pembrolizumab (Keytruda) in patients with MF and a trial looking at ruxolitinib pre, during-, and post-hematopoietic stem cell transplantation.

In an interview withTargeted Oncology, Hobbs, the clinical director of the Leukemia Service at MGH, discussed these ongoing trials, as well as recent advances in the treatment of MF and other MPNs.

TARGETED ONCOLOGY: What are some of the most recent advances that have been made in the treatment of MPNs?

Hobbs: When thinking about MPNs, we're really talking about 3 main diseases, although there are more. The 3 classic MPNs are essential thrombocytosis, polycythemia vera, and MF. Undoubtedly, there has been the most research and the most advances in MF, which makes sense because it's the most aggressive of the 3 diseases and the one associated with the most complications and a shortened life expectancy in comparison to the others.

The last 2 decades have seen a tremendous amount of improvement in our understanding of all 3 diseases. Initially, marked by the identification of theJAK2mutation in the majority of these, followed by the identification of the calreticulin (CALR) mutation and theMPLmutation, that basically accounts for most of the patients within MPN.

A big advance for MF was the approval of ruxolitinib for the treatment of patients with splenomegaly or symptoms related to MF. This has been a huge improvement in the way we treat our patients because it really makes them feel significantly better from a symptom perspective and decreases the size of their spleen so they are able to eat again. It also improves their function status, so if needed, they can go to transplant with a better functional status.

Ruxolitinib by itself has been a significant improvement in the way that we care for our patients with MF. I think more [importantly] than therapeutic advances for MF, our understanding of the genetics of MF has increased tremendously in the last decade. We now know that it's not just about having aJAK2mutation or not, but we know about the 3 main mutations that patients can have, which we call phenotypic driver mutations, but we've also started to understand that there are other mutations patients with MF have in addition to those 3 mutations that can inform their prognosis and how they'll do clinically. Before, we used to use a risk stratification model called DIPSS Plus, and now there are newer risk stratification models, such as the MIPSS70 score, which takes into account molecular markers as well, in addition toJAK2, which kind of help us better risk stratify our patients based on what genetic mutations they have or don't. That has been an improvement in the way we think about MF, for sure.

In addition to that, in terms of treatment, there has really been nothing new approved since ruxolitinib. Ruxolitinib was approved in 2011, but there is nothing that has been approved since. I think there are several other drugs that are in development and there are many clinical trials that are being initiated for MF. We can think about the drugs that are in development in 2 big categories: the JAK2-type drugs or other types of drugs. In terms of JAK2 inhibitors, there are several drugs that are under development—pacritinib, momelotinib, and fedratinib, and these are all JAK inhibitors that may get approved sometime soon. In particular, pacritinib. Those are all similar to ruxolitinib, but will probably end up having their own specific area or their own specific niche to be used either after ruxolitinib or for patients that can't get ruxolitinib.

In addition to the JAK inhibitors, there are several other compounds that are being investigated. There are some trials that are investigating a JAK inhibitor plus something else, and there are some trials that just include different therapies altogether. This year at the 2018 ASH Annual Meeting, we heard about imetelstat again, we heard about PRM-151 again, and those are just some of the drugs we've been hearing about. But there are other drugs that are being investigated for MF, whether or not that is with or without a JAK inhibitor. There are trials with PI3K inhibitors, MDM2 inhibitors, and BET inhibitors, so there are definitely a lot of different compounds that are being investigated for MF.

TARGETED ONCOLOGY: If these new agents were approved down the line, how would they fit into the treatment paradigm?

Hobbs:We're still trying to sort that out. Pacritinib has been studied in patients with thrombocytopenia, in particular, platelet counts around 50, so that could potentially be a niche for pacritinib because ruxolitinib is not approved in that platelet range. In addition, pacritinib seems to improve anemia in some patients, so for anemic patients or for patients with thrombocytopenia, perhaps pacritinib would be an interesting option. With momelotinib, the initial reports suggested that it may improve anemia in some patients, so again, that could be a place for momelotinib. Fedratinib is still to be determined in where it fits, if it improves blood counts or not, and the studies are still ongoing. 

TARGETED ONCOLOGY: What are some of the unmet treatment needs in MF?

Hobbs:A really big treatment need for MF is improving cytopenias, so patients that have anemia or thrombocytopenia or are neutropenic, there really are not a lot of medications that are effective in making those blood counts better. For example, for patients that have anemia, we have things like erythropoietin-stimulating agents, we have danazol, which is a testosterone-like agent, we have things like thalidomide (Thalomid) or lenalidomide (Revlimid) with or without steroids that can sometimes be effective in improving anemia, but not for many patients and not for a long time. Patients that have cytopenias really need new drugs that are targeted toward making that better.

TARGETED ONCOLOGY: Can you provide some background on the trial you are working on of PD-1 inhibition in advanced MPNs?

Hobbs:John Mascarenhas, MD, of Mount Sinai, and I are leading this study. The rationale for using pembrolizumab in MF is because we know that JAK/STAT activation, which is kind of the central problem in MF, leads to upregulation of PD-1 and when we have upregulated PD-1, our T cells kind of get turned off and then don't recognize the malignancy as much. There is similar rationale to why these drugs work in other diseases, but it was interesting to learn about how JAK/STAT can lead to upregulation of PD-1 since JAK/STAT signaling is abnormal in all MPNs, so we were interested in trying immunotherapy as a different approach to targeting MF. All the drugs like ruxolitinib are wonderful for improving symptoms, [but] they really don't modify disease biology. We were hoping that a drug like pembrolizumab could wake up the patient’s immune system and be effective in improving cytopenias or improving the disease in general. The study is ongoing. It's been open at Mount Sinai for a bit longer than here at MGH and we've enrolled a few patients.

TARGETED ONCOLOGY: Can you also discuss the trial of ruxolitinib pre-, during, and post-transplant?

Hobbs:Ruxolitinib has been an amazing improvement in the way we think about and treat our patients, but one problem we have with ruxolitinib is that once our patients get to the point where they need a transplant, we really don't know what to do with ruxolitinib. There have been a lot of studies looking at different schedules for tapering ruxolitinib for transplant, but one problem is that if patients are getting ruxolitinib and they're getting a benefit from ruxolitinib, we may be able to safely discontinue by doing a taper.

We now know that stopping ruxolitinib cold turkey is associated with quick rebound of symptoms. The problem is that the symptoms are ultimately going to come back and the spleen is ultimately going to grow back. For some patients, that can happen kind of quickly. If you think about a bone marrow transplant, it takes a couple of months for the transplant itself to become really active and to be able to attack the MF. It's what we call a graft-versus-tumor effect. In those couple of months, often times patients will have a growth of their spleen or return of their symptoms, and the transplant doctors really don't know what to do with the ruxolitinib. Oftentimes, transplant doctors are using ruxolitinib during the transplant period, so in the period of time where they're getting chemotherapy or conditioning before transplant, and then early post-transplant they're giving ruxolitinib to try to help the patients with their spleen or symptoms, but really, ruxolitinib isn't approved in that setting so it's kind of being used off-label. I thought it would be important to study ruxolitinib in this period of time to see if it's safe and efficacious.