 Following a patient with polycythemia vera [PV], we dually are trying to be sure that we’re preventing thrombosis and bleeding, controlling symptoms, but we always have an eye on the issues of disease progression. Polycythemia vera can progress in 1 of 2 ways. One, it can progress into myelofibrosis. That progression typically is accompanied by enlargement of the spleen. It’s accompanied typically by a change in the symptom profile, the development of fatigue, that is different from what had existed before. Spleen-related symptoms, catabolic symptoms, such as inadvertent weight loss. Indeed, in our society nobody—yours truly included—loses weight without trying. Sometimes even when you try, you don’t lose weight. When a patient comes in and he tells me they’ve lost 20 pounds and didn’t try, sadly I know that means something has changed profoundly in terms of their metabolism to have that happen. That too can be a strong indicator that something has taken a change for them.

Additionally, there is a change in the profile of the counts where one begins with erythrocytosis. Perhaps they become iron deficient and have still a robust hemoglobin, but over time they might develop anemia, even if the iron deficiency has been corrected. That’s a major red flag of the disease changing.

There can tend to be a progressive leukocytosis. There can be leukoerythroblastosis, where we begin to see changes in the differential, myelocytes, metamyelocytes, other earlier myeloid cells being released in the circulation earlier than normal because of the fibrosis process occurring in the bone marrow. Additionally, there can be enlargement of the spleen sometimes to a significant degree.

We then confirm that there has been a change with repeating the bone marrow aspirate and biopsy showing a change with increase in reticulin fibrosis, rarely increases in collagen fibrosis, not uncommonly, the development of additional karyotypic abnormalities or other NGS [next-generation sequencing] mutations that can arise for these individuals.

The NCCN [National Comprehensive Cancer Network] Guidelines are helpful for the management of MPNs [myeloproliferative neoplasms], and I’m honored that Dr [Srdan] Verstovsek and I were involved with the inaugural development of these guidelines. Guidelines help to provide the guardrails of therapy. What should we be considering and what are decision points? In a patient with P [polycythemia] vera who is already on management—whether that’s with a current cytoreductive therapy or they’ve not begun cytoreductive therapy—if they have a thrombotic event, that clearly is something we are trying to avoid. We must circle back and say should that trigger a change in therapy. If they were not on cytoreductive therapy, it likely means that we should begin cytoreductive therapy. If they were on cytoreductive therapy, it raises the question if it has failed. I look to see if the counts were adequately controlled. Was the therapy achieving what we needed to. Was that patient being compliant in terms of the therapy? If the goal was to have their counts controlled with Hydrea but they weren’t taking it, then they haven’t necessarily failed Hydrea. If we can get them back on Hydrea, great, but if they were on fully therapeutic Hydrea and the counts were controlled and they still had an event, that would certainly trigger the thought of thinking of them as being hydroxyurea resistant, and we might switch them to ruxolitinib or an alternative second-line therapy.

Indeed, it is key whenever we’re employing 1 of these approaches, and we decide whether they’ve been beneficial or whether we need to change gears. What is the target? Let’s say that with hydroxyurea, the target is to get the platelet count under 400,000 per mm3, the white count under 10 per mm3, the hematocrit under 45% without needed phlebotomy. Are they able to achieve that in a way that is tolerated? You give them the medication, but it takes a dose that leads to excess of toxicity. That’s another reason for failing hydroxyurea. If with the dose that they’re on they’re not achieving that, we need to push the dose to achieve that goal. Either we achieve that goal or we decide they’re not tolerating the medicine sufficiently, they’re resistant, then we’ll consider switching. That is crucial both for the NCCN Guidelines as well as the European LeukemiaNet guidelines: Are they having benefit or are they not?

If not, if they fail hydroxyurea, then we have indicated ruxolitinib, the JAK inhibitor, that both can help in terms of that thrombosis and phlebotomy-free survival for the patient with PV. But that also can be beneficial in terms of evidence of progression with either splenomegaly, difficult symptom control and those challenges in terms of progression.

Videos

Ruben A. Mesa, MD, highlights signs of disease progression and the utilization of guideline recommendations in the occurrence of a thrombotic event when treating polycythemia vera. 

PV Progression and Guideline-Directed Management

 When we begin with the concept of disease burden for a patient with P [polycythemia] vera, 1 has a discussion. I had that discussion with a patient today. Our goals with P vera are to keep the disease as invisible in the life of the afflicted patient as possible. That begins with trying to diminish the risk of thrombosis or bleeding. We know that key factors are control of the hematocrit—typically in low-risk patients with phlebotomy, to keep a strict hematocrit of under 45%. Recent trials show that keeping individuals under 45% is beneficial and has a differential effect in decreasing the risk of thrombosis or bleeding. There are individuals that sometimes need a more targeted approach based on their symptoms or other disease-related features, but 45% should be the ceiling.

Additionally, we use low-dose aspirin assuming there is not an aspirin allergy or other contraindication. This can help with symptoms but also help decrease that risk.

Another goal with low-risk PV is making sure that the therapies we’re using are adequately addressing the difficulties a patient has. There are low-risk patients who are symptomatic or don’t tolerate phlebotomy to the degree that we wish they could. In those circumstances, that might be an indication to consider a change in therapy or the addition of cytoreductive therapy. Indeed, our group presented an analysis at ASH [American Society of Hematology Annual Meeting] looking at low-risk patients and showed that there are many individuals, perhaps up to half, who have had cytoreductive therapy at some point during the course of their disease for some of these gaps that can exist with management, using solely phlebotomy and aspirin.

NCCN [National Comprehensive Cancer Network] Guidelines utilize a simple way of dividing patients into low risk for thrombosis and high risk for thrombosis when we talk about PV [polycythemia vera]. High risk is defined by age over 60 or a history of blood clotting. Roughly, two-thirds of the patients are such.

What do we do about this? We start the phlebotomy, like in other patients. That would decrease the hematocrit, and the goal is below 45%. We give patients baby aspirin. That’s to decrease the stickiness between the cells. In high-risk patients, we also start hydroxyurea or the guidelines would say pegylated interferon. These are 2 alternatives as a cytoreductive therapy. We want to decrease the numbers. We want to maintain constantly hematocrit below 45%, normalize the white blood cells and platelets if we can, and control the quality of life. The symptoms and the symptomatic splenomegaly should be controlled if possible.

The hydroxyurea is a pill. You take it daily, and it works in many patients. But it may not work optimally, meaning controlling these factors in everybody. Retrospective chart reviews identified that about 40% of the patients are managed, 40% suboptimally, and 20% not optimally at all. They are resistant, refractory, or intolerant. That comes from retrospective chart reviews, because there was never a formal study of hydroxyurea to assess the benefits through these parameters. It’s just that historically we have been using it for 50 years.

Occasionally there are adverse effects, ulcers or skin sores down on the legs, low-grade fevers, loss of hair, indigestion. Maybe 10% of the patients may have them. We monitor for myelosuppression as well, not just for these nonhematologic parameters. We want to make sure it’s not suppressing the counts too much. Of course, we then want to optimize the therapy. We want to make sure it’s controlling the blood cell count symptoms in the spleen. If it does not, you still need phlebotomies. White blood cell counts and platelets are still high, the spleen is symptomatic, patients have a lot of systemic systems—any of these would identify patients that are not optimally managed. Maybe they’re even resistant or refractory. In that case, you would perhaps choose something else, like a second-line therapy.

Every patient with high-risk disease should be given cytoreduction. But if the patient is younger, let’s say a 25-year-old has PV and blood clot, we would not give hydroxyurea to that patient. Pegylated interferon is the norm, because that’s a biological agent. It’s given as an injection under the skin once a week at the beginning, perhaps less often later. Particularly in younger people, because of the durability or a need for durable cytoreduction control, we stay away from chemotherapy. Hydroxyurea is a chemotherapy. We use interferon, pegylated interferons, that are long lasting or long acting can be given to older folks as well. They’re much safer. NCCN Guidelines would identify hydrea or interferon—hydrea in most patients, but interferon has a role and maybe even more than we would like to accept, much more in the older patients as well, particularly because it’s a biological agent and can potentially change the bone marrow environment, affect the malignant clone. These are potentials of this therapy that are to be explored.

Key opinion leaders discuss treatment goals, considerations, and guideline recommendations for patients with low- or high-risk polycythemia vera.

Therapeutic Considerations in Polycythemia Vera

 The diagnostic criteria for polycythemia vera that we follow are based on the World Health Organization [WHO] 2016 Guidelines, and fundamentally they begin with the presumption that you are suspicious if you have P [polycythemia] vera. Why might you be suspicious if someone has P vera? Clearly unexplained erythrocytosis, an unexplained vascular event, sometimes unexplained leukocytosis, thrombocytosis, or others, particularly if they might have erythrocytosis that is masked because they’ve had iron deficiency or for some other reason.

Fundamentally, it starts with a clinical suspicion with secondary things you’re trying to exclude in your differential diagnosis: smoking or other chronic hypoxic states, sleep apnea, use of androgens is a common cause of secondary erythrocytosis, EPO [erythropoietin]–producing tumor. The diagnosis fundamentally is around unexplained erythrocytosis and the presence of a mutation explaining that. Namely, the 

The WHO criteria, once you prove erythrocytosis, want you to establish a diagnostic molecular marker such as the JAK2, and look at the bone marrow for the typical histological features as it relates to erythroid precursors, hypercellularity, and others consistent with P vera.

Additionally, there are minor criteria that can be considered, such as a suboptimal EPO level, if an individual lacks either of the 2 

 mutations. There are individuals who have 

-negative P vera, but this is not common in a diagnosis of an exclusion and typically need a solid case that bone marrow, low EPO, and others help establish.

Assessing risk for a patient with polycythemia vera is multifaceted. I like to think of both assessing the disease burden and the risk. The disease burden for a patient with P vera includes risk of thrombosis, risk of bleeding, potential P vera–related symptoms such as pruritis, night sweats, and difficulties concentrating, and a variety of catabolic symptoms. Additionally, sometimes they can have splenomegaly. All of that is part of burden.

Risk is 2-fold. One, there are historical criteria for risk of thrombotic or vascular events, including age over 60 or having a prior unexplained thrombotic or vascular event. Over time we have developed additional prognostic factors, which can include leukocytosis, age, prior events, and other higher-risk molecular features, such as ASXL1 or others. I find that the disease burden concept is the most relevant in terms of trying to make an impact for the patients. The prognosis piece is helpful, but prognosis is probably the most relevant concept for individuals with myelofibrosis that have typically a more aggressive disease.

Polycythemia vera is the disease of the bone marrow that makes too many red blood cells. In many patients, white blood cells and platelets as well. But red blood cells are present in all, and there is a good correlation between having a blood clot and too many red blood cells.Therefore, to decrease the thrombotic risk that is paramount in assessing patients with polycythemia vera, we would like to control the red blood cell count. We talk about hematocrit as a goal of therapy, to control hematocrit.

Hematocrit is the percentage of blood that is made up of the red blood cells, so it comes as a percentage. We want to have strict control of hematocrit in terms of having it below 45%. That’s the No. 1 goal in patients with polycythemia vera. We want to that in patients who are at a high risk for thrombosis, and maybe two-thirds of the polycythemia vera patients are such. These are defined by age over 60 or history of a blood clot. These are the 2 factors we use, history of blood clot or older than 60. These are patients at a high risk for blood clot.

In these patients, in addition to worrying about the hematocrit, we worry about the white blood cells and platelets. In these patients, we would like to control all 3 lines. If the spleen is enlarged, as it may be in some patients, and if they have a bad quality of life, we want to control them as well.

The usual goal of therapy is, No. 1, control the hematocrit, and we check the blood count maybe weekly at the beginning, phlebotomize if necessary, and then as phlebotomy kicks in and eliminates the red blood cells a lot and people become iron deficient, maybe you don’t need to follow the patients too often anymore—maybe every 2 weeks, then every month, then every 3 months. That would be a good standard practice after a while when phlebotomy is eliminated. But with the cytoreduction therapy, there would be medications that are given to high-risk patients.

Cytoreductive therapy would be controlling hematocrit, white cells, and platelets. In that case, we’re talking about complete hematologic response. The follow-up is similar in a low- or high-risk patient. The goals are well defined and built in to our NCCN [National Comprehensive Cancer Network] Guidelines.

Evaluating treatment, diagnostic criteria, and risk-assessment tools in polycythemia vera.

Diagnosis and Evaluation in Polycythemia Vera

: Classic myeloproliferative neoplasms are polycythemia vera [PV], myelofibrosis, and essential thrombocythemia [ET]. Essential thrombocythemia is the easiest to understand; the bone marrow makes too many platelets. That’s where the name comes from. It is driven by the underlying biological problem, which is not only related to the essential thrombocythemia, but it’s also related to polycythemia vera and myelofibrosis. This is uncontrolled growth of the cells due to hyperactivity of the intracellular signaling of the JAK-STAT pathway.

In this regard, essential thrombocythemia is relatively benign, unlike myelofibrosis and polycythemia vera, which tells us that some other contributors exist that would explain aggressiveness of myelofibrosis, for example. But in ET, too many platelets predispose patients to blood clotting and does not affect their survival. The goal of therapy, therefore, is to decrease the risk of blood clotting by controlling that thrombotic number and to make sure that patients have good quality of life.

Polycythemia vera, as the name implies, is a disease of all the cells. Polycythemia means all the cells grow in the blood. Again, this is a disease of the bone marrow with the same biological problem as essential thrombocythemia but presenting differently. Too many red blood cells, that’s No. 1; 60% of patients have high white cells, and 60% have high platelets. Some may have a big spleen, or systemic symptoms from circulatory problems. Life expectancy is close to normal. And like in ET, thrombotic events are the main problem. We need to control the thrombotic risk, because the risk of dying is related to too many blood cells in circulation, and thrombosis can, unnecessarily I should say, shorten the life expectancy. Assessment of thrombotic risk, the same as in ET, is paramount.

In myelofibrosis, we are talking about something else. There is a growth of fibers in the bone marrow. We believe it’s possibly a reaction to the presence of malignancy. Some patients present early with the disease with not too much fiber, maybe no fibers at all; this is so-called prefibrotic myelofibrosis. These patients present like patients with essential thrombocythemia, with too many platelets, and we treat them as we do patients with ET, decreasing thrombotic risk. But the bulk of patients with myelofibrosis are the ones who come with fibers in the bone marrow that limit the growth of the cells. This results in anemia, thrombocytopenia, low white cell count, particularly anemia, very big spleen, big liver, bad quality of life, night sweating, low-grade fevers, itching, and a shorter life expectancy of 5 to 7 years.

You can say that ET and PV are relatively benign; thrombosis is a problem. Myelofibrosis has multiple other problems: low blood cell count, big organs, bad quality of life, and short life expectancy.

Srdan Verstovsek, MD, PhD, provides an overview of the similarities and differences between myeloproliferative neoplasms, including polycythemia vera, myelofibrosis, and essential thrombocythemia.

An Overview of Myeloproliferative Neoplasms

Polycythemia Vera: An Update on Clinical Trials

Real-World Use of Ruxolitinib in Polycythemia Vera

Emerging Therapeutic Options in Polycythemia Vera  

Goals in Treating Low-Risk Primary Myelofibrosis

Risk, Prognosis, and Nontransplant Options in Primary Myelofibrosis

A Look at Fedratinib and the JAKARTA Trials

COMFORT Data and  Ruxolitinib in Myelofibrosis

Experts discuss the role of transplant and evaluating options in patients with myelofibrosis. 

A Review of Pacritinib and PACIFICA Data

Experts provide insight on therapeutic approaches of myeloproliferative neoplasms, highlighting clinical trial data and disease characteristics of polycythemia vera, primary myelofibrosis, and essential thrombocythemia.

Individualizing Treatment Approaches in MPN 

 I truly appreciate this discussion. Before we conclude, I’d like to get final thoughts from each of you. I’m going to start with Dr. Krisstina Gowin. Krisstina?

Over recent decades, we’ve made great progress in the treatment of myeloproliferative neoplasms [MPN], in their diagnosis and their prognostic characterization. Looking at the molecular characteristics is so important.

We’ve now developed wonderful therapies that are effective for spleen reduction, for symptom reduction, and we have more emerging data to be thinking about transplantation earlier in the course of disease, as well as thinking about early transplant referral. We have upcoming therapies that are exciting, so it’s a hopeful and optimistic time for both patients and their treating physicians, and the treatment of MPNs.

I would add that I’m incredibly excited, having been in this field for many years, along with my colleagues on the panel.

We’ve evolved from an era where we had almost no therapies that were being specifically developed for MPNs to now having multiple FDA-approved therapies that have been approved on the basis of large, well-done Phase 3 studies, and many more in the pipeline, going along with further understanding of the biological underpinnings of the disease. It’s a time of tremendous hope for our MPN patients: better options and better ability to control their disease, a bright future ahead.

 Thank you, Ruben. Dr. Jamile Shammo. Jamile?

I’d like us to think of the MPNs as malignancies and treat them as such. We all need to obtain better baselines for our patients and consider evaluations at periodic times so that we can employ all the available therapies for patients who we take care of appropriately.

I want to thank everybody for allowing me to participate today; it was a wonderful discussion. I second everything that has been mentioned in the closing remarks, but I almost feel like it is the beginning. There is always more to learn or more to do; anything that we address opens another chapter to address it better or in a different way forward.

It is an exciting time. It has been discussed very well where we are now from 10 or 20 years ago; it’s incredible, but there is so much to do. We are all together in the fight for our patients, so I cherish the next tasks, and hopefully we’re going to get together again for a longer discussion about the new developments next year again.

 Thank you again, to our viewing audience. I also want to thank 

® for asking me to moderate this session. They are incredibly valuable to me, I’ve learned so much from my colleagues around the country, around the world, in just this hour and a half on the management of patients with various hematologic malignancies. We hope you found this 

® discussion to be useful and informative to you as well.

Advances in the Management of MPNs

 Krisstina, we know that there are some patients with ET [essential thrombocytopenia], especially young women, who can present with a high platelet count and be completely asymptomatic. However, is there a platelet count at which you need to intervene? You’ve focused on thrombotic risk; how about bleeding risk?

At the higher levels of thrombocytosis, you certainly get a potential risk of acquired von Willebrand factor and a risk of hemorrhagic complications. No, the answer is that there is not a magic platelet number. In those patients, you can safely monitor the platelet count and think about if there are thrombotic events. In those who are high risk, you think about cytoreduction with high platelet counts before initiating aspirin.

 High-risk does include a platelet count over 1.5 million mm3, doesn’t it? Or does it? To say that they should get cytoreductive therapy, Jamile, what do you think about that?

Platelet count was considered in the high-risk population, but after finding out about the molecular mutations, patients who have CALR, for example, can present with a high platelet count. Those are the people, by the way, who end up bleeding because even though they know this disease, everybody thinks, “Maybe aspirin,” but that would not be advisable.

In patients who have CALR, even if they have low-risk disease, they have no reason to be on aspirin, especially if they have no prior thrombotic complications. We need to keep that in mind. What I would like to do is get a von Willebrand factor panel making sure that we’re not dealing with a von Willebrand before I start my aspirin. If the patient has prior thrombotic events, and you feel like you have to initiate cytoreduction, then this would be the way to go. Hydroxyurea is a go-to drug in this instance. If you have a low-risk disease patient with cardiovascular events and a JAK2, in this instance, then the consideration of aspirin is certainly reasonable because those people tend to have higher thrombotic events.

Granted, when you’re talking about patients who have ET since their leukemic progression, myelofibrotic transformation is the lowest. Assuming we’re identifying ET, not prefibrotic MF [myelofibrosis], then you need to be careful about inducing complications with the treatment. We like to prevent problems, and that would be 1 way to make sure you know what the molecular lesions are, and then treat high-risk patients with cytoreduction plus aspirin, assuming no prior von Willebrand disease.

 The PT-1 study suggested that hydroxyurea was superior to anagrelide?

 There are some conflicting data on that. Frankly, I have patients who have been on anagrelide with reasonable control of their platelet count. Most people need to realize that anemia can be a consequence of this, cardiac complications could be a consequence, and there are difficulties in obtaining the drug from the manufacturer. If you can get it, there’s probably a small subset of patients who may benefit from it, but I tend to gravitate toward hydroxyurea. I don’t know how other people feel about this.

 Interferon is another option for these patients. Ruben, do you want to say something about that?

It is certainly included in our NCCN [National Comprehensive Cancer Network] Guidelines for ET as a consideration. However, it’s not FDA approved. There is now a pegylatedinterferon study for patients with ET who have failed Hydrea [hydroxyurea]. The study is being led by Srdan and I with many colleagues around the world, randomizing patients between that and anagrelide.

We want people to consider that trial as an option as both a way to obtain interferon but also to be able to definitively answer that question and hopefully get to the status of an FDA-approved therapy for these individuals. Having used a lot of pegylated interferon alpha 2a off-label over the years, it certainly is efficacious, and we showed a nice second-line study through the MPN [myeloproliferative neoplasm] Research Consortium with Ron Hoffman, John Mascarenhas, Abdulraheem Yacoub, and others of that group showing the benefit of that agent.

Essential Thrombocythemia: Treatment Optimization

 I’d like to spend 5 minutes on essential thrombocytopenia [ET] before we get to concluding remarks. Jamile, how do we diagnose ET?

There are diagnostic criteria that were set forth by the WHO [World Health Organization]. Essentially, you have to demonstrate clonality of the myeloproliferation, ruling out secondary thrombocytosis and other entities as well. It could be mass PV [polycythemia vera], it could be early myelofibrosis, it could be MPNs [myeloproliferative neoplasms], MDS [myelodysplastic syndrome], ring sideroblasts with thrombocytosis.

It’s important to meet all 4 points—according to the WHO, with platelet counts over 450,000 per mm3—finding bone marrow proliferation of megakaryocytes in clusters that are mildly atypical, finding no or minimal fibrosis, ruling out other entities, and demonstrating clonality in the presence of driver mutation. If there are no driver mutations, then demonstrating other clonal populations by performing a next-generation sequencing panel, which could be done on the bone marrow or the peripheral blood. That’s how ET should be done.

You have to realize that about 10% of the patients with ET may not have driver mutation, in which case it’s important to look at the bone marrow biopsy. I realize it can be really difficult in those instances. I’m sure I have a bunch of patients who have thrombocytosis that is reactive, but I cannot prove the clonal nature of it, yet there is no other reason for it, hence they are stuck with that characterization.

 Krisstina, how do we risk stratify in ET?

Risk stratification within ET is based on age: 60 years or older is high risk, and younger is lower risk. Additionally, very similarly to polycythemia vera, we’re looking at the risk of prior thrombotic events. What is unique, and this is within the NCCN [National Comprehensive Cancer Network] Guidelines, is that we’re now incorporating the 

 V617F mutation as part of the risk stratification.

Those who are low risk are less than 60 years old, have no thrombotic events, and are 

 negative. Intermediate patients are greater than 60 years old, have no thrombotic events, and have no thrombosis. Higher-risk patients have a history of thrombosis at any age and are 

 positive. This helps to tailor how we treat these patients for low-risk disease.

We focus on managing their vasomotor symptoms, and monitoring for new thrombotic events, or new symptom evolution. With the high-risk disease, we’re focusing more on cytoreduction with hydroxyurea or interferons.

Classifying Patients With Essential Thrombocythemia

 Moving along from there, Srdan, we may soon have a third JAK inhibitor: pacritinib. Can you tell us about the data supporting that and how it would impact treatment options?

You are correct. There are other JAK inhibitors; there have been many JAK inhibitors in testing. Pacritinib is the 1 that is less myelosuppressive, and it can possibly be beneficial to patients who have lower platelets.

The thing with treating patients with lower platelets, and particularly platelets below 50,000 per mm3, for which fedratinib or ruxolitinib are not suggested, is that it is a hot topic: 10% to 20% of patients may have or develop low platelets over time, and there is nothing to do. The low platelet number is a bad prognostic factor.

In this setting, pacritinib is being tested at the moment in a randomized study, which is the 1 you mentioned, the PACIFICA study, specifically focusing on this group of people. It is an area of unmet need where the therapy with this drug may improve the symptoms and signs, and it may provide some durability of a good quality of life for unfortunate people like that. We are embracing that study very much. There is absolutely nothing else that can be done; there are no other studies in this setting at all.

 Thank you. Ruben, how about a high-level view of what might be exciting at ASCO 2020 [American Society of Clinical Oncology Annual Meeting] or EHA [European Hematology Association Congress] in myelofibrosis [MF], not in PV [polycythemia vera].

Sure, there are a couple of things. First, pivoting off the pacritinib study, which I’m very excited about as a coinvestigator, I would highlight the momelotinib phase 3 study. Momelotinib is another JAK1/2 inhibitor with potential differentiation around anemia.

The MOMENTUM study is now going to be opening looking at patients who have difficult to control MF, who have failed ruxolitinib and have anemia. It’s a randomized study of momelotinib versus danazol. We’re going to be sharing at EHA some further updates regarding the mechanism of action of that agent, looking at suppressing hepcidin, which could be a mechanism in terms of improving anemia.

At this year’s ASCO, there was an interesting potential new therapeutic target that was mentioned regarding the use of CD47. It was a study that came out of the United Kingdom looking at CD47 on the cell surface as a potential target that might be applicable in both MPN [myeloproliferative neoplasm] patients and MDS [myelodysplastic syndrome] patients.

At EHA, we’ll also hear further updates in terms of important studies, in terms of both information from fedratinib as well as further updates from the BET inhibitor from Constellation Pharmaceuticals, Inc, that’s being looked at alone or in combination for more difficult MF, as well as other exciting updates from some of our ongoing studies.

 Some of the most interesting biology that I’ve read about in the last couple of years is how the truncated calreticulin [CALR] protein is excreted from cells and acts as an agonist for the MPL receptor. I hope I didn’t tune out for a second there, but did you talk about targeting that CALR protein?

That is certainly held as an area of opportunity, and there are studies in development looking at both vaccine approaches and other cellular surface antibodies and such. None of those have reported any data yet, but it has been felt that calreticulin may be 1 of the more accessible targets in terms of the driver mutations because you can get to the cell surface.

That is certainly a hope: that we will be able to have that selectivity against the mutant-driving cells in those patients with MPNs. That would probably start with calreticulin-mutated patients with myelofibrosis who have more difficult disease.

Primary Myelofibrosis: Trials of Interest

 Srdan, how do you choose in first-line setting between ruxolitinib and fedratinib? Fedratinib is a pure JAK2 inhibitor, so is it effective at controlling symptoms like ruxolitinib?

On the results from the JAKARTA study, the results appear to be similar, although we did not compare 1 to the other in a randomized way. The results appear to be similar in terms of controlling the spleen and the symptoms between the ruxolitinib and the fedratinib.

There are some differences, as we just explained, in the toxicity profile, but the most attractive part for fedratinib for me is what Ruben has said. The results of JAKARTA2 study, this is the second-line study, certainly indicate its potential role in the setting where we don’t have options at all.

The reanalysis of that study, which was an open-label phase 2 study published 3 months ago, showed that about 50% of the patients will officially achieve the response, which is 35% volumetric reduction. Regardless of that percentage, it is valuable in many patients for whom we need to control the symptoms and signs after ruxolitinib. That is where I see a major role; it has a minor role in the frontline setting and a major role in the second-line setting.

JAK2 Inhibitor Selection for Primary Myelofibrosis

 We now have a second FDA-approved drug, fedratinib, in myelofibrosis. I’m going to turn to Ruben to discuss the clinical trial data, and then I’m going to ask Srdan to talk about, since they’re both indicated in the first-line setting, how you choose between these 2. Let’s start with Ruben.

There are 2 main studies. First, the pivotal study, which was the JAKARTA study that looked at 2 different doses of fedratinib: 400 mg and 500 mg versus placebo. It showed without question vast superiority in terms of control of spleen and symptoms. To remind folks again, this was several years ago, so this was concurrent during the approval time of ruxolitinib. This is a different study from what might have been done if it was much more recent.

It clearly showed benefit, without question. Adverse effects included some GI

adverse effects, potential for cytopenias, and in a small number of individuals, a neurological adverse effect that was potentially related to Wernicke encephalopathy.

A close look at that still puts that somewhat in question, but the agent is approved with a black box warning to monitor and replace thiamin before patients begin on the therapy and monitor for Wernicke encephalopathy. It functionally should not be a large issue in that this was a rare adverse effect and should be prophylaxed with thiamin. That is the basis of that frontline approval. The delay in approval was in resolving this whole issue of thiamin, Wernicke encephalopathy, as well as the drug development pipeline and delay.

There is also second-line data with a second-line trial led by Dr Harrison from the United Kingdom, myself, and many of our colleagues who we’ve recently updated at ASH and EHA, and it was recently published. That found a good 30% to 35% response rate for spleen and symptoms in the second-line setting for individuals who had failed ruxolitinib by relatively rigorous criteria in terms of resistance or intolerance. It was clearly active in the second-line setting for people who had failed ruxolitinib.

We’re pleased to see the commercial availability of a second agent, and it’s certainly something people should be considering for their patients who have failed ruxolitinib, for whom you do not have a good alternative clinical trial to consider. Fedratinib is approved and is an option for these individuals.

I will make 1 comment on dose as well. In the pivotal study, there was both the 400-mg and 500-mg dose. The 400-mg dose was felt to optimize efficacy, and there was more toxicity in the 500-mg arm, so 400 mg is the dose.

 Krisstina, the other toxicity is GI toxicity with diarrhea. Is there anything special you do or tell your patients?

Absolutely. Setting the stage for the potential adverse effect of diarrhea as a toxicity so they’re anticipating it is extremely important. Then do coadministration with some of our great antiemetics, which we now have available.

There is subduraconin, which is oral, which I have been using particularly for patients who have a history of being sensitive to medications and are potentially at high risk for significant nausea, but diarrhea is a problem as well. Managing the symptomatic diarrhea with Imodium, Lomotil, I have even gotten some GI input for patients who potentially may need more advanced therapies for managing the diarrhea.

Fedratinib for Primary Myelofibrosis

 Jamile, for the sake of time, I want to ask a few directed questions about practical management of patients on ruxolitinib. I often get asked, “What do you do with the drug prior to a surgical intervention?” Or “How about if the patient is admitted for some other inflammatory disorder: pneumonia, infection? How do you manage ruxolitinib during that time? Do you abruptly stop it? Do you taper it? How do we do this?”

I try to avoid abrupt stoppage of the drug as much as possible, but if someone is having surgery, and they’re going to be unable to take PO medications, then you can hold the drug for a few days. I try not to extend this over a week if I can help it. I try to avoid dose interruption as much as possible.

 Sometimes when a patient gets admitted and they’re sick or they’re intubated, I cannot continue ruxolitinib. And you can’t taper it, so I’ll give them a low dose of prednisone. Does anyone else do that? Is there any science behind it?

There’s no question that prednisone, in certain circumstances, can provide a bit of additional relief, but there can be low-grade rheumatologic conditions and other things they might have that might benefit from that as well. Prednisone certainly has some impact, without question, with all the limitations that exist in terms of chronic use of corticosteroids.

Ruxolitinib and Surgical Interventions

 Let’s move on now. I want to discuss the clinical trial data that has led to first the approval of ruxolitinib: the COMFORT-1 and COMFORT-II trials. On our panel is Srdan, who has clearly played a major role among other faculty members here in the development of ruxolitinib for myelofibrosis. Srdan, tell us about the data.

The studies that we are talking about were done a long time ago. These are the COMFORT-1 and COMFORT-II studies that led to ruxolitinib approval.

As time goes on, we learn a lot about the overall outcome of patients, and that has led us to not only realize that the drug is very good for control of the large spleen, symptomatic splenomegaly, and for improving the quality of life, but also to be able to extend life of the patients by virtue of changing the metabolism in the body: the albumin goes up, cholesterol goes up, performance status goes up, the ability to walk improves, and improvement in the kidney function has been reported last year.

Organ function and metabolism improves, and you control the disease signs and symptoms, which translates into prolongation of life for a few years. It’s also recognized by regulatory bodies, and it’s on the label for its use, but that’s not the reason to use it, right? The reason to use it is to intervene for immediate benefit: controlling the signs and symptoms, and with that, hope that life will be prolonged.

It’s evident in other studies that came along later, for example the JUMP study that was published recently in a final form, suggesting that early intervention matters and that we should not wait for the patients to be in a dying mode with high risk, a very big spleen, bad blood cell counts, and bad quality of life.

Early intervention is leading us to be able to provide optimal dosing, meaning the highest dose in a safe way, which will then decrease the spleen the most because it seems that the decrease of the ultimate size of the spleen that you can achieve on therapy dictates the durability of the benefit, and in many studies, it has been associated with life extension.

We learned that earlier intervention gives you the opportunity to provide a better dose; you have less myelosuppression, which is a toxicity related to the ruxolitinib in particular, and that will translate in the overall outcome that is beneficial, so the patient is not only feeling well but also living longer. This is where the major issue is: How do you initiate? You should follow the guidelines on how to initiate best in those cases regarding when to initiate: earlier on, don’t wait for patients to be advanced.

You then optimize the dose to get the maximum safe dose in the early few months to get that response to the maximum. That is the tricky part because anemia happens in about 50% of the patients. Patients may already be anemic; by early intervention, perhaps you have less of a problem with that.

Many worry about providing a high dose, and as you know, last year, there was a very interesting report with the European Hematology Association of a study suggesting that you should start with a lower dose of ruxolitinib, 10 mg twice a day, and then increase. Every month, you would go from 10 mg twice a day, to 15 mg, to 20 mg, to 25 mg. In that way, you avoid unnecessary myelosuppression, yet you can optimize the dose to the maximum safe dose. The results were similar to results reported in COMFORT-1 and COMFORT-II trials 10 years ago.

If there is a point to learn from most recent data—which is not published in papers; it was the poster last year—it is that we learn as we go. We can get to the same benefits on the spleen symptoms and life prolongation by alternative dosing regimens. Go from low to high, but don’t stay low. Go from low to high in a few months.

 That’s an important point. Without that data that you just mentioned from Europe, for years I’ve been starting at a lower dose and increasing, and quite frankly, it’s to enhance patient compliance. If you scare them away with complications in the first month, it might be hard to keep them on it. There might be some market data to suggest that many patients got 1 month and then didn’t get any more therapy.

Starting at a lower dose makes sense from a patient compliance standpoint, and they often feel better right away, even at the lower dose. The point you make is critical, both in PV and in MF, but this drug is not 1 dose fits all. You need to optimize the dose to maximize benefit. Thank you for that.

The other thing that’s interesting about the data is this: We’ve all seen that the survival curves from COMFORT-1 and COMFORT-II are superimposable early on and cross over, suggesting that the benefit in long-term outcome may be in controlling symptoms sooner rather than later. Those patients in the COMFORT-1 study, as I remember as 1 of the many investigators, were sick patients; they didn’t have anything else. They had big spleens and constitutional symptoms.

You’ll remember that 66%, two-thirds, of the patients in these studies were high-risk, and one-third were intermediate-2. There are more modern studies, even from analysis of general practice in Europe, that suggests that early intervention makes it easier for us to manage the patients, and the survival benefit is also enhanced because you can maintain patients much longer on the therapy.

It’s all a circle that we are trying to put together; the data that would help us achieve most of the benefit for our patients: early intervention, better dose and spleen as the target, in addition to quality of life. That is the way we are learning over the last 10 years about how to optimally use JAK inhibitors in the community settings.

 Correct me if I’m wrong, but I don’t know of any data with ruxolitinib, fedratinib, or interferon that says intervention with those agents decreases the risk of leukemic transformation. If that’s the case, it suggests that it’s symptom control, improvement in quality of life, nutritional status, muscle mass, and all those things that may be most important with the treatment.

You’re absolutely correct. There is no evidence for improvement in the risk of a transformation for progression to acute myeloid leukemia, which is an important point, not only to emphasize the benefit but also to say the disease is still there, and it can transform. Early intervention with a transplant, as we talked about transplant quite a bit, is encouraged.

I encourage my patients, even though they may have excellent response to ruxolitinib, to look at transplant as an option and potentially do the transplant if they have a donor when they feel the best. There is now evidence that it means that there’s possibly a better outcome with the transplant itself. As Ruben described, these 2 issues—the medical management and the transplant—go hand in hand. There is no comparison between the 2; they should be combined.

Ruxolitinib for Primary Myelofibrosis

 Jamie, let’s come back to that question about intervention for intermediate and high-risk patients versus low-risk or asymptomatic patients. We all know we see the 66-year-old with 2% blasts 1 day, and right then, that would make that patient intermediate-2: a candidate for ruxolitinib or fedratinib, the 2 FDA-approved agents. However, they’re completely asymptomatic, or at least they tell you so. We can ask Ruben to comment on whether that’s true if they’re completely asymptomatic.

Let’s say you have somebody who is happy with their quality of life, and they’re 66 years old, and they have 2% blasts 1 day or they have a sweat every 3 months. They’ve made it to the intermediate-risk group. Do you rush to put all those patients on therapy? What kind of conversation do you have with patients about that?

It’s a question, Harry, because it’s a commitment when you start a patient with myelofibrosis on ruxolitinib. There is a lot of blood testing that you have to do, there is follow-up, and there is a lot more that they need to do. They have to be convinced that they are in need of added treatment.

Your point about making sure that we have totally validated their symptoms in some kind of measure, as opposed to just, “Yeah, I’m feeling fine,” is extremely important. What about their spleens? Have they grown larger over time? Those questions are all important. There are a couple of studies, even though the initial COMFORT studies, which I know Srdan will talk about, looked at intermediate-2 and high-risk disease.

There are some data to support the use of ruxolitinib in some intermediate-1 patients that have splenomegaly or symptomatology. We have to be flexible in understanding each patient and think of other symptoms they are dealing with: Do they justify the initiation of treatment that will require frequent monitoring? Once they start, they’re set to continue, right? It’s a conversation we need to have with the patient.

 Yeah, and sometimes I don’t convince my patients. I clearly have intermediate-risk patients, and after talking with them and looking at their family, I say “This patient is symptomatic,” and the patient says, “I don’t want to start a chronic medication yet.” It’s the fun part about being a doctor.

Ruben, let’s come back to NCCN Guidelines. What is recommended for the intermediate- and high-risk patients? How do you choose between these? We’ll then get into the clinical data.

 Excellent. The guidelines are certainly based on the most broadly used risk score. We talk about intermediate and high risk by which criteria? Those have still been based off the DIPSS, which are the most broadly available and used criteria, but it does bring up some other more granular issues in prognosis that Jamile had brought up.

For intermedaite-1-risk patients, they have a heterogenous prognosis because we realize that some of those might be young individuals with anemia and a high-risk molecular mutation that by MIPSS70 might be much more high risk. But by DIPSS, they might still be intermediate-1.

The full gamut exists under the NCCN Guidelines from JAK inhibition for splenomegaly and symptoms to allogeneic transplant for people who might be higher risk, to even just observation if they were intermediate-1 solely on the basis of age. That was probably the most mixed group. If your patient falls in the intermediate-1, I strongly advise physicians—particularly of patients of transplantable age—to get an NGS panel to further clarify their prognosis.

For intermediate-2 and high-risk patients, that is your most standard group. That is the largest group of patients with MF. That initial decision is this: Do you consider transplant in the near term? Building on that discussion you had with Krisstina regarding who the candidates are, anyone who says that it’s an easy decision is not the person facing the transplant.

Comparing a transplant with medical therapy is comparing 2 different animals altogether. It’s different both philosophically and in terms of scope. The frontline medical therapy includes ruxolitinib, which has been the frontline therapy for many years, but it now also fedratinib under the NCCN Guidelines since September 2019.

JAK inhibition is used with the goal of improving spleen, symptoms, and aspects of the disease. Importantly, we then have to monitor for efficacy and decide on whether frontline therapy has had sufficient efficacy. Or one considers perhaps switching from 1 of those agents to another or alternative approaches.

Treating Intermediate/High-Risk Primary Myelofibrosis

 I want to come back and take us away from the brink of mortality and with advancing risk to circle back to the low-risk patient. We’ll talk about the Cervantes criteria. A very small percentage of patients, about 10% in that analysis, had low-risk disease. Krisstina, do you see these patients? Would you ever consider therapy for a low-risk patient, symptomatic or asymptomatic?

Patients definitely present with low-risk myelofibrosis. In those patients, this is where we’re assessing whether they are associated with a symptom burden. In those patients who have low-risk disease by the DIPSS [dynamic international prognostic scoring system] or the MIPSS70 [mutation-enhanced international prognostic scoring system]—the more sophisticated prognostication tools—still have a significant symptom burden. Those are patients for whom we can consider intervening.

I recently worked with the CIBMTR [Center for International Blood and Marrow Transplant Research] and a group of academic centers looking at the role of stem cell transplantation. Interestingly, there was even a group within that analysis with low-risk disease who proceeded to stem cell transplantation. Some physicians would say that, for the treatment of myelofibrosis, the only true curative measure is allogeneic stem cell transplantation, and in patients who are wishing for a more aggressive and disease-modifying approach even in low-risk disease, some physicians are proceeding with that.

There’s not significant evidence to support that approach, and the best evidence is in the intermediate-2 and higher, and more recently considering intermediate-1a disease. We look at the patient’s goals, their risk status, and their symptom burden.

In general, though, for low-risk disease, we monitor these patients’ counts to see if they are transitioning to a higher-risk phenotype, a higher DIPSS. Are they having molecular evolution? Are there more high-risk mutations recurring over time? We’re taking all these pieces of the puzzle to decide when to initiate therapy and how aggressive to initiate therapy.

 Thank you for that, Krisstina. You prompted a question I was going to ask you later because you are the 1 member of our panel who is a believer in stem cell transplant. You are a transplant physician, and I also think it’s because you’re probably the youngest, and it is a young person’s job to take care of these patients.

I’m going to come to a question for you: Our challenge in picking patients for the curative option of transplant is the data are intermediate-2 and high risk, but those are often the patients who are cachectic, have huge spleens, and have other issues that may preclude them from being an ideal transplant candidate. On the other hand, you have low-risk patients who may be healthy and able to undergo stem cell transplant, even with its risk.

My question for you is this: Is there anything you use in that low-risk patient to talk with them more aggressively about transplant, like mutation analysis or cytogenetics? Does that influence your opinion?

Absolutely. That’s a great question. At the University of Arizona Cancer Center are using these molecular characteristics to help guide us. We know that there are particularly high-risk phenotypes within myelofibrosis, particularly the triple-negative patients, the 

. These are extremely high-risk phenotypes: genotypes that can certainly have a higher risk of transformation to acute myeloid leukemia down the line.

The idea of intervening when patients are a bit younger, a bit more robust with higher performance status, fewer comorbidities, less splenomegaly, and fewer cytopenias is certainly attractive for a conversation with the patient. There are certain approaches, so for patients who are developing more splenomegaly, we can certainly use ruxolitinib as a bridge to control the splenomegaly symptoms before we take them to allogeneic stem cell transplant.

This is such an institutional approach, so every institution and every academic center for transplant will have a different approach and a different discussion. As a community, we’re moving toward an earlier discussion. For community physicians, I would like to impart the importance of early academic referral.

Often, we see that these patients are referred to academic centers when they’re already symptomatic from their disease. They have intermediate-2 or high-risk disease, and they’re saying, “Now it’s time to transplant.” No. It could have been a lot smoother. The donor selection takes time. All these things take time, so if it’s early within the disease course it can be better for the patient.

 I agree. I’m going to remind our viewers that you opened the transplant door, so I’m jumping ahead in our agenda, and I’m going to keep you on the spot as our local expert. Let’s say you have a myelofibrosis patient. I’ve heard that if you don’t do a myeloablative preparative regimen, you might as well not do it in a patient with myelofibrosis. It’s not going to work. Any truth to that? How do you select the regimen?

I’d like to clarify, I’m not an allogeneic stem cell transplanter.

I have done some research in this area. In general, this is a polarizing issue within the transplant community, and there are not significant data that would sway one to myeloablative versus reduced intensity conditioning.

This is an institutional preference. This needs to be looked at in the literature. It’s a challenge because myelofibrosis is a rare disease, and to do prospective analysis in this is very difficult. I don’t know if we’ll ever achieve that, so continued retrospective analysis will help move the ball forward. To answer your question: It’s polarizing, and it’s controversial.

Management of Low-Risk Primary Myelofibrosis

We can continue to talk about polycythemia vera for quite some time, which is different from 10 years ago, or maybe 20 years ago, even before the 

However, it’s time to move on, and I’m going to ask Jamile to start with a discussion of patient classification and risk stratification in myelofibrosis. For the sake of time, we will not spend a lot of time on the diagnostic criteria, which are well-published by the WHO and will move on to risk stratification and how that affects management of patients. Jamile?

There are multiple prognostic scoring schema that have been developed over the years. The first was published in 2009 by Cervantes, and it’s called the IPSS [International Prognostic Scoring System], which was a tool utilized at the time of diagnosis to risk stratify patients relative to their survival. There were 5 variables that were utilized: age over 65, white blood cell count over 25,000 per mm3, peripheral blast count over 1%, presence of constitutional symptoms, and hemoglobin below 10 g/dL.

That gave you 4 risk groups with median overall survival ranging from 130-some months down to 27 months, so you can see a tremendous variation of variability. In general, people think low-risk to INT-1 [intermediate-1 risk] is lumped together as 1 entity and then INT-2 and high-risk disease as another.

Mostly, stem cell transplant patients were offered to intermediate- and high-risk disease, but it then became clear that, as people went on to live with this disorder, they acquired other features that may also correlate with worse outcomes, namely the development of anemia transfusion and transfusion dependence. This is why the Dynamic International Prognostic Scoring System [DIPSS] was created to account for the development of anemia in patients who may not have been at the outset.

That was the next advance, and later, the DIPSS plus also accounted for a few other variables, including the platelet count below 100,000 per mm3, the presence of adverse cytogenetic abnormalities, and the development of transfusion dependency. The bottom line is that, whichever score you utilize, remember that the IPSS is good for the time of diagnosis, and the dynamic scores are good throughout the disease scores.

When the mutations became available with 

, people started to look at the impact of those mutations on the outcome of patients who had myelofibrosis. There was a trend to think to include those mutations into the scoring schema, so there’s something called mutation-enhanced international prognostic scoring system [MIPSS70], which encompasses the presence of certain mutations that are labeled as high risk. That evolved into the MIPSS70-plus, which includes cytogenetic abnormalities.

All that culminated in the genetically inspired prognostic scoring system, and that includes both molecular and cytogenetic abnormalities. I know this is a lot of information, and all the little bullets that you have in there to construct a scoring schema are interesting, and it may help in selecting people who may be candidates for stem cell transplant patients. I will stop there.

 Thanks, Jamile. That was an excellent summary, because it has evolved and now includes the mutational and cytogenetic data, which are prognostically important.

Primary Myelofibrosis: Risk Stratification

 I completely agree with those comments about symptom control outside phlebotomy control, hematopoietic control, and splenic volume reduction. We now have more tools for treating patients, and we alluded to 1 earlier: pegylated form of interferon, and Ruben alluded to the updated EHA. Srdan, do you want to tell us about the PROUD-PV study?

We are talking about the major development in the polycythemia vera arena in terms of new therapeutic options. Perhaps many colleagues in the United States do not know that a year ago, there was approval of ropeginterferon, what I call a super long-acting interferon, in Europe for polycythemia vera patients. It’s given under the skin every 2 weeks, and after a year, you can even switch to once a month. It was approved to be given to patients with polycythemia vera for control of the blood cell counts.

The goal is complete hematopoietic response, not in patients with a big spleen, because it’s perhaps not applicable when given to patients with big spleens. In that setting, the drug has been superior, after about 3 or 4 years of therapy, to hydroxyurea. That was the PROUD-PV study that you mentioned: the randomized study between hydroxyurea and ropeginterferon in patients who were either newly diagnosed, not previously treated with cytoreductive therapy, or already on hydroxyurea for some time but not optimally managed.

They were not refractory and not resistant, but there was room for improvement. In that randomized study, the analysis showed that, after 1 year, there was no superiority of interferon, but we know that interferons take time to work. After several years, 3 or 4 years, superiority was seen.

Regardless of the comparison to hydroxyurea, the label allows its use for polycythemia vera, and it doesn’t talk about first- or second-line, or about it being superior or inferior to hydroxyurea, which is in accordance with the European leukemia guidance and the NCCN Guidelines as well. Ruben described this well: The guidelines would say cytoreductive therapy and hydroxyurea or interferon.

At least in Europe, and hopefully soon in the United States, we’ll have a ropeginterferon to offer to our patients. It is much less toxic, it has better efficacy when you have less toxicity, and I’m looking forward to embracing these in our own patients here at The University of Texas MD Anderson Cancer Center.

 Before we move on, any other comments about what’s coming or what’s new in PV? That was the major highlight coming out of EHA. One final question about the use of interferon: It’s been touted as something that is more of a disease-modifying agent because some earlier studies show decreases in, for example, the 

 allelic burden. Has that been shown? Can you tell us about that from the PROUD-PV or other randomized trials, Srdan?

This particular information is quite interesting because this is the only therapy that may, in some patients, give an eliminated 

 clone by virtue of not being detected by our sensitive testing. That has been noted in the past with commercially available long-acting interferon Pegasys [peginterferon alfa-2a] in clinical studies.

This is offline use of that medication, but in ropeginterferon studies at the last ASH, there was a similar report of about 10% to 15% of the patients achieving the molecular response, not detectable 

We hope that means a lot for these people, but perhaps it’s not a cure. We don’t associate this with a cure, but if you have no detectable 

 mutation, that would mean that there may be no or minimal malignancy there anymore. That would perhaps cancel it in the long-term benefit for these patients in the future. It is something to follow; it’s not the goal of the therapy, but it’s an interesting correlative study that is evidence of the biological ability of these medications to alter, possibly, the natural course of the disease.

Ruben A. Mesa, MD, FACP, UT Health San Antonio MD Anderson Cancer Center

Articles