RESPONSE and RESPONSE-2 are 2 phase 3 studies, long-term studies that evaluated the role of ruxolitinib, a JAK inhibitor, in patients with polycythemia vera [PV] who were resistant, refractory, or intolerant to hydroxyurea. Hydroxyurea is the first-line choice in a great majority of the patients with PV. But about 20% to 25% of patients do not really do well. They are resistant or refractory and intolerant. They still need phlebotomy. In the RESPONSE study, for participation in that study, they needed to have a big spleen. In the RESPONSE-2 study, they did not have to have a big spleen. That was an additional factor to evaluate.

The goals of the therapies were in the second-line setting to compare ruxolitinib with best-available therapy, whatever the doctor wants to do, in achieving the control of the hematocrit, and then after that, also control of the spleen in the RESPONSE study, and control of the white blood cells and the platelets and the symptoms in all these studies. This is a challenge, because usually you need to have some time to assess these benefits. These are studies that took about a year to have a first glimpse in the response. The first study, the RESPONSE study, led to approval of ruxolitinib. The RESPONSE-2 study followed, of course, and now we have a 5-year follow-up to talk about from these 2 studies.

I would start ruxolitinib in patients who are suboptimally managed with hydroxyurea that have no good control of the red blood cell count, are still on phlebotomies, or have uncontrolled white cells or platelets, uncontrolled symptomatic splenomegaly, or general systemic symptoms. These are the factors we utilize to judge the benefit of any therapy in PV, particularly red blood cells, but other factors are important as well. If that is not achieved, or if patients have toxicities from hydroxyurea, then ruxolitinib is full-fledged choice for a second-line therapy.

We start with 10 mg twice a day, unlike in myelofibrosis, for which ruxolitinib is also approved. Here, everybody starts with 10 mg twice a day. We expect that two-thirds of the patients need more, from 10 mg twice a day; in a month or 2, you go to 15 mg, and then to 20 or 25 mg twice a day. Only 5% need less than 10 mg twice a day. For some reason, even that low dose is too much for them. But the expectation is to start ow and then go to higher. With that, you have excellent response.

In the first study, the RESPONSE study, about 60% of the patients had elimination of phlebotomy during the observation period, and the same happened in the RESPONSE-2 study. The spleen was very well controlled in patients with a big spleen on the RESPONSE study. Other benefits, controlling of white blood cells and platelets and the symptoms, were seen in most patients over a long period of time. After 5 years, we know that of those who responded, many of them are still responding. And there are no real major adverse effects. Remember, ruxolitinib in myelofibrosis, which was the first indication, was associated with anemia and thrombocytopenia as an adverse effect. These are benefits in PV. We don’t have major problems here. Occasional shortness of breath or diarrhea or a rash, which are low grade and go away on their own without need for dose adjustments. It’s effective over the long term without major adverse effects.

 At ASH [American Society of Hematology Annual Meeting] there was a very nice international observation, real-world-evidence study from our colleagues in Europe looking at the use of ruxolitinib in patients with P [polycythemia] vera who had been resistant or intolerant to hydroxyurea. What they reported, in this ongoing observational phase 4 study in 352 patients with P vera, is that their experience was very similar to what has been reported in the RESPONSE-2 study. Namely, the therapy was very effective in decreasing the number of phlebotomies the patients needed or making the phlebotomy independent with better control of hematocrit. Overall they had a mean daily dose of around 21 mg of ruxolitinib, very consistent with that 10 mg twice-a-day dosing, and many individuals were able to remain subtly on that dose.

Adverse events that they had reported were modest but could include low-grade infections, some low-grade bleeding events, and a low rate of secondary neoplasms, the majority of which were cutaneous, which has been identified as 1 of the potential toxicities of JAK inhibition.

Presented at ASH as well, by my colleague Dr Brady Stein, were data with a trial that I’ve been 1 of the investigators on. The REVEAL study was a prospective observational study for patients with polycythemia vera on mortality and causes of death.

There have been over 2500 patients enrolled into this ongoing observational study. What they identified in terms of causes of death was a little surprising. For the causes of death, 72% had a known cause of death, and overall numbers of death is less than 10% of that overall cohort but still a significant number—250 or so individuals have passed away. A third of these individuals from thrombotic complications, broadly worded; 12% in solid tumors; bleeding in 6.3%; and 15.4% from a hematologic malignancy, assuming many of those potentially associated with P vera.

Looking at these data, they suggest that P vera–related causes of death are a higher percentage than one might expect overall, and that the 4-year mortality was greater than 10%, even though the mean age of enrollment was only 66 years of age. This helps reinforce the thinking that polycythemia vera is purely a benign disease for many individuals, which is probably inaccurate in that having an accurate diagnosis and effective therapy is important when we’re thinking about patients with polycythemia vera and look forward as more of these data from REVEAL to help guide us further in terms of refining our treatment algorithms.

Videos

Experts discuss clinical trial updates in polycythemia vera, including data from RESPONSE, RESPONSE-2, an international observational study of ruxolitinib, and REVEAL. 

Polycythemia Vera: An Update on Clinical Trials

 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.

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

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.

Srdan Verstovsek, MD, PhD, MD Anderson Cancer Center

Articles

Polycythemia Vera: An Update on Clinical Trials

PV Progression and Guideline-Directed Management

Therapeutic Considerations in Polycythemia Vera

Diagnosis and Evaluation in Polycythemia Vera

An Overview of Myeloproliferative Neoplasms

Individualizing Treatment Approaches in MPN

Rapid Readouts: Momelotinib's Spleen, Symptom, and Anemia Efficacy

Rapid Readouts: Long-Term Results from SIMPLIFY-1 and SIMPLIFY-2