Expert Discusses Latest Developments in MPNs


Rami Komrokji, MD, shares his insight on the various types of MPNs, how these diseases can be diagnosed and managed, and the next steps needed to improve patient outcomes.

Rami S. Komrokji, MD

Diagnostic and treatment advances have advanced the field of myeloproliferative neoplasms (MPNs) over the past several years, says Rami Komrokji, MD, who discussed MPNs at the 2017 OncLive® State of the Science Summit™.

Komrokji notes, however, that further refinement is needed with molecular testing, risk stratification, and the development of novel therapies.

OncLive: Please provide an overview of your talk on MPNs.

In an interview with OncLive, Komrokji, vice chair of malignant hematology and section head for leukemia and MDS at Moffitt Cancer Center, shared his insight on the various types of MPNs, how these diseases can be diagnosed and managed, and the next steps needed to improve patient outcomes.Komrokji: The field had evolved in the last few years with all of the discoveries in biology, the integration of somatic gene mutations in diagnosis, and risk certification for those patients. I gave a bit of an overview of the biology of the disease, the difference between the disease initiating, and mutations versus the phenotype driving mutations. I went into a little bit more detail about those mutations like JAK2 V617F, the calreticulan mutation, or MPL mutations— what we call phenotype-driving mutations.

We also discussed the risk models used for every disease—how we risk-stratify the patient—and we briefly went through an algorithm of how we managed those patients. In PV, we discussed the need for phlebotomies and cytoreduction therapy in patients who are considered high risk. We discussed how to manage patients with myelofibrosis based on the risk. If they have a higher risk, we consider them for transplant. If patients have constitutional systems, JAK2 inhibitors are becoming the standard of care for them. If they are predominately cytopenic or anemic, then there are different options, including immunomodulatory agents.

MPNs can be pretty tricky to diagnose. Do you foresee any advancements or improvements with diagnostic tools in the next couple of years?

Finally, I tried to update on what was presented at past ASH Annual Meetings. There are a couple of trials looking at newer formations of interferon, which had been a treatment commonly used in MPNs, but those are of a new format. They are the first 2 trials that look at a head-to-head comparison with hydroxyurea.The second part is that there is always some overlap between those myeloid diseases. There are MDS and MDS/MPN diseases. There is always that kind of continuum of those myeloid diseases, and sometimes the line is not that distinct between those categories.

Advancement recently had been integrating some of the molecular data into the diagnostic criteria. If a patient has a JAK2 V617F mutation or calreticulan mutation, in a way that obviously excludes secondary or reactive. If a patient is having an infection, they will not have a clonal marker for the disease. In MPNs, we are a little bit ahead of MDS in integrating molecular data. Those are helpful in that setting.

There are certain mutations that obviously will be more unique for a subtype. Now, the JAK2 does not distinguish a myeloproliferative myelofibrosis from ET or PV, because they're the same mutation. It can be seen in MDS/MPN, but it's not going to be seen in patients with MDS alone.

Molecular testing definitely makes the diagnosis easier. The best example is probably PV. In the past, the main struggle was trying to distinguish it primarily from secondary polycythemia. We know that almost 98% of patients with PV would have a clonal marker. If it doesn’t, then we start to work out for less common hereditary causes of PV.

JAK2 is an important target now in MPNs. Are there any other emerging molecular abnormalities that can be targeted with potential therapies?

The good thing is that those tests are now very widely available now that they can be checked on peripheral blood that doesn’t even need a bone marrow test to be done. That’s how the progress was done, and the new criteria actually reflect that.Even in the JAK/STAT pathway, I don’t think we completely unfolded the story there. As mentioned during my talk, the JAK/STAT pathway is the whole mark of the disease’s activation of that pathway. We’ve had 1 drug approved, but there had been other drugs where their development has not been as successful. There are opportunities to target the pathway itself by better JAK2 inhibitors and, in a way, second- or third-generation JAK2 inhibitors—medications that can target the downstream effect of the JAK2.

Some of the efforts also recently had been trying to combine things with ruxolitinib (Jakafi) or JAK2 inhibitors. Ruxolitinib is the one approved commercially and is now available to patients. There are studies looking at Pim kinase, which seems to be an important pathway in patients with MPNs.

There are trials looking at combining JAK2 inhibitors with Pim kinase, for example. There are studies that are going to be looking at JAK1 inhibitors also in MPNs. Also, the TGF-beta pathway is important in anemia in MPNs—particularly in myelofibrosis. Targeting the TGF-beta pathway is also entrusting to handle the unmet need of cytopenia or anemia in patients with myelofibrosis.

Do you foresee transplant always having a role in MPNs?

There had been some ongoing studies with telomerase inhibitors like imetelstat. We will soon hear about the results of those studies. In addition to phenotypic-driving mutations, we may have patients who have an IDH2 mutation that we now have targeted therapy for. That's a very small subset in MPNs, but as we delve into those targeted therapies, we will also start having a very individualized or selective population where we go after in clinical studies.The decision of transplants in MPNs, as well as myelodysplastic syndrome, is always a benefit-risk analysis. The reality as of today is that it's the only curative option for those diseases. Short of that, there is no cure for those diseases.

The cure rates are variable. We are probably talking about the 40% to 50% cure rate without a genetic stem cell transplant for different types of MPNs. Obviously, there are a lot of different things that determine that: how advanced is the disease, the risk of the disease, the cytogenetics, and the patient comorbidities status. We can say we can cure roughly 40% to 50% of patients without a genetic stem cell transplant.

The counterpart for that is the risk of the procedure. There is always around 20% to 30% of what we call transplant-related mortality within the first year of transplant. Transplant is an intense procedure where patients have to stay in the hospital for 1 month and an apartment across the hospital for 2 months.

We are always weighing the benefits and the risks of that procedure. We look at the patient. We can transplant older patients as long as they are functional. We look at the comorbidities, but we also look at the disease—that's why we look at all those risk models. We are trying to get an estimate of how risky or how bad is the disease. If I have a patient with PV where the expected survival is 30 years, or even myelofibrosis that comes as a low risk where the expected survival is 12 years, we cannot justify the 20% transplant-related mortality. If a patient comes as a high-risk myelofibrosis where the estimated survival is 1 to 2 years, we would consider a transplant.

That’s what we are doing all the time. We are trying to weigh benefit and the risk of the procedure. Where we see the risk of the disease exceeds the risk of the procedure, obviously, we’re thinking of transplant. In general, we think of it for patients who have intermediate- or high-risk disease, for example, in myelofibrosis. There is no doubt that we have been doing more transplants for those patients in the past few years.

What do you hope community oncologists took away from your talk and the State of the Science Summit™ as a whole?

Also, the introduction of the JAK2 inhibitors allows us to a little bit more patients to transplant because many times in the past, the patients were sick because of the disease. They had so many constitution symptoms like cachexia. With JAK2 inhibitors, they get better, they feel better, their performance improves to a point that we can take them to transplant. From my talk, it's the need for getting the accurate diagnosis on those patients in myeloproliferative diseases, getting the right molecular testing at the beginning, and, if in doubt, having somebody who's experienced. I gave a couple of examples labeled as myelofibrosis that they really have much more treatable diseases like hairy cell leukemia or marginal zone lymphoma. That's always the first step. It's also essential to spend some time on risk stratification to get an idea of where the patient risk is and then manage it.

In general, the field is evolving. There were so many different talks about integration of molecular status and molecular profile for patients. In myeloma, we heard about so many new drugs, how best to sequence them, and how to use them. What we have here is a good model of the collaboration between us and the community of practices. We've built this very good relationship where patients are referred to us and where each of us is very specialized in one disease. We outline the management, we get all those information about the patients, and then we return the patients to their community oncologists, who are very experienced skillful clinicians and treat the patients closer to home. We are getting at a point that is very specialized. At 1 point, the patients will benefit from a consult with a tertiary academic center or somebody who is very specialized in this disease.

Even in the context of hematological malignancies, you can tell the exponential expansion in knowledge in those diseases. What's promising is we've learned so much about those diseases in the last 5 years, which is equivalent to many years, and the hope in the coming few years that we are going to translate that to all better treatment options available for our patients.