Evaluation of RESPONSE Trials Guides Use of Ruxolitinib in Polycythemia Vera

December 13, 2020
Targeted Oncology Staff

Case-Based Peer Perspectives Spotlight Live, October 2 CBPP Spotlight,

During a Targeted Oncology Case Based Peer Perspectives event, Andrew Kuykendall, MD, assistant member, Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, discussed the use of ruxolitinib as treatment of 67-year-old patients with polycythemia vera.

During a Targeted Oncology Case Based Peer Perspectives event, Andrew Kuykendall, MD, assistant member, Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, discussed the use of ruxolitinib as treatment of 67-year-old patients with polycythemia vera.

Targeted Oncology™: Do you consider the National Comprehensive Cancer Network (NCCN) guidelines for inadequate response to cytoreductive therapy during decision-making?

KUYKENDALL: The NCCN talks about some of the reasons [why] you would consider switching off…one therapy and maybe switching to another.1 It’s largely when we don’t think we’re doing as well as we could be doing for the patients. Either they’re requiring a lot of phlebotomies, they’re having a lot of symptoms, or they had a thrombosis; these are reasons why you might say that another agent may be better.

The algorithm for polycythemia vera [in NCCN shows] high-risk characteristics as being 60 years or older and/or having a history of thrombosis. Once these patients are considered high risk, then you’re going to do a couple of things. One is asking for a phlebotomy, as is recommended for everyone; for cytoreductive therapy in the first line, we usually pick hydroxyurea or pegylated interferon. [Others are] managing cardiovascular risk factors— stopping smoking is a big [thing to] advise with some of these patients—and then monitoring for any thrombosis.

Later on, once you have them on therapy, you’re getting a sense of whether they’re doing well or if another agent would be reasonable. And this is what I was referring to. Potential indications for changing therapy would be intolerance, resistance to hydroxyurea…if our main goal is preventing thrombosis, and someone has thrombosis while on a certain cytoreductive therapy, perhaps a change would be indicated.

Frequent phlebotomies are challenging [because] patients [have] to come in once or twice a month to get blood taken. And sometimes, with [fewer] places doing phlebotomies, it’s a challenge to figure out a place that will do it in any sort of efficient manner. Signs of splenomegaly, thrombocytosis, and leukocytosis are other lab [results] that may indicate that another agent might be reasonable. Other options [are] ruxolitinib [Jakafi] as a second-line therapy, and then hydroxyurea if interferon was used previously or vice versa. In some older patients, busulfan can be considered as a way to control the counts, even though this is probably less frequently used [now] than it has been historically.

How would you manage a patient who has had JAK2-positive polycythemia vera for the past 5 years but whose hemoglobin levels are normal, who hasn’t needed phlebotomies in multiple years, and who selfdiscontinued hydroxyurea?

Whenever I have a patient with polycythemia vera that all of a sudden doesn’t need phlebotomies anymore, I frequently will do a bone marrow biopsy to see if they have some fibrosis, if we’re seeing this change from polycythemia vera to post–polycythemia vera myelofibrosis. Other reasons for this development [can be] nutritional deficits like iron deficiency.

The [essence] of masked polycythemia vera is [when] a patient’s bone marrow biopsies look like polycythemia vera but they’re iron deficient and can’t achieve the hematocrit or hemoglobin [levels] necessary for that. I believe that [for] someone that has cardiovascular risk factors over the age of 60 or [has] had a prior thrombosis—even if they don’t need to have a cytoreduction—if their counts aren’t high enough, hydroxyurea probably has a benefit. We know that hydroxyurea impacts epithelial cells, it allows [the] release of nitric oxide, which relaxes these cells. I typically would favor a high-risk patient being on hydroxyurea even if they’re not requiring phlebotomies, and even if their numbers aren’t super high.

In that case, I typically would use the lowest dose [of hydroxyurea]. I use 500 mg daily, and if the patient can tolerate that well, then I’ll continue that and there’s some protection there. When we look back, a lot of the data for hydroxyurea and its thrombotic risk reduction is, in essential thrombocythemia, not polycythemia vera. Investigators have looked retrospectively at large cohorts of patients with polycythemia vera and shown that giving hydroxyurea in high-risk patients reduces the risk. Presumably, these are patients who are also getting phlebotomies, and are on aspirin or [whose condition is] otherwise well managed. We know that phlebotomy alone isn’t enough for high-risk patients, but in high-risk patients who aren’t requiring phlebotomy, I still think hydroxyurea probably has some benefit.

What findings have investigators observed with ruxolitinib in this setting?

Looking at some of the ruxolitinib data, [the agent was used as] second-line [therapy] in the RESPONSE study [NCT01243944]. There are 2 polycythemia vera trials evaluating ruxolitinib, RESPONSE and then RESPONSE-2 [NCT02038036]. The RESPONSE study enrolled patients with polycythemia vera requiring phlebotomies who hadn’t had a JAK inhibitor, [and were] on hydroxyurea or [were] intolerant or had inadequate response, and had splenomegaly. They were randomized to either ruxolitinib or standard therapy.2

The primary end point was a composite end point between hematocrit control and spleen response, and 21% of patients met that primary end point compared with 0.9% on standard therapy. If you separate them out, 38.2%—which is remarkably close to what we see with myelofibrosis—had a 35% reduction in their spleen volume, and 60% had hematocrit control. So, either one in isolation appears to be better with ruxolitinib as opposed to standard therapy, and for what it’s worth, standard therapy largely meant continuing hydroxyurea at different doses.

When you look at symptom reduction, ruxolitinib is good at controlling symptoms. The study looked at the Myeloproliferative Neoplasm Symptom Assessment Form that included 14 symptoms, and these were separated into symptoms that were related to splenomegaly, hyperviscosity, and cytokines. Across the board, ruxolitinib seemed to help with all of those, especially these cytokine symptoms, which does a good job of decreasing JAK [activation], which is closely related to cytokine overproduction.

In myelofibrosis, we talk about ruxolitinib and we know that patients progress and there’s a survival benefit, but patients can progress to acute myeloid leukemia, and the disease can get worse. About 50% of patients come off…ruxolitinib within 3 years if they have [myelofibrosis]. That’s not necessarily what we see with ruxolitinib in polycythemia vera. Patients have durable, long-term responses that seem to go on for some time.

How have the data evolved for this trial?

[RESPONSE has] 5 years of data.3 The chance of maintaining this spleen volume reduction and hematocrit control at 224 weeks, starting at week 32, is 73% and 72%, [respectively]. These are patients who are benefiting in terms of their spleen and their hematocrit control, and this benefit is lasting 5 years when [these] data cut off.

The long-term RESPONSE study results [show] the complete hematological response going out [to] 246 weeks. There was a 55% chance of maintaining complete hematologic control at this [point]. RESPONSE-2 enrolled patients who had a big spleen and who did not have splenomegaly.4 They were able to achieve similar levels of hematocrit control, complete hematologic response, [and] improvement in symptoms, [but] did not have the reduction in spleen volume because they didn’t have big spleens. So, it’s not just a spleen drug, it does a good job with polycythemia vera in controlling hematocrWhat is the toxicity profile of ruxolitinib?

Anemia and thrombocytopenia are much less common when you’re treating polycythemia vera because these patients are starting with high hematocrit [levels] and high platelet counts to begin with, for the most part. But [regarding] infections, now [that] we’re thinking about these patients being on this for 5 or more years, shingles reactivations and other low-grade infections [such as] nasopharyngitis mand bronchitis are more common in patients treated with ruxolitinib as opposed to best available therapy. Patients should be counseled on this; this should be monitored. We recommend that patients get the new shingles vaccine as well it as well.

Looking specifically at thromboembolic events—our focus of treatment in polycythemia vera is reducing the incidence of this— the incidents [are] low in patients who are treated with ruxolitinib and possibly less [than we are aware of]. Even though this was not a primary end point of the study, it does look [as though], at least nominally, these are less frequent in patients who are treated with ruxolitinib as opposed to those who were on best available therapy.

Other safety concerns [include] second malignancies. This is something we need to consider. In the ruxolitinib environment, it looked a bit more common to have second malignancies as opposed to best available therapy. Also, something for those of us in Florida [to consider], we always need to counsel our patients on nonmelanoma skin cancers. Most everyone in Florida should be seeing a dermatologist if they’re not already, but this is more common, to see nonmelanoma skin cancers in patients on ruxolitinib. I’ve had some remarkable cases with patients who have had occasional squamous or basal cell cancers, and then they go on ruxolitinib and [are] required to come off the [other] medications. Rarely, but it’s happened a few times. This is something to make sure you counsel your patients on, seeing their dermatologist while they are on the medication.

What are your thoughts on this poll?

It looks like most people are saying, ‘I’ve used it frequently as second line therapy.’ We’ve got a [few] saying that they don’t use it too much, but when [it is] used it’s as second-line therapy. We’ve got a vote for “never used it,” and a vote for using it in the first- and second-line settings. I think that this is by the book. This is approved for patients post hydroxyurea, but I think [for] patients that present with a lot of itching and a big spleen, there is a temptation to use this in the frontline setting. At least I’ve had that temptation.

I think that the interesting thing about ruxolitinib and polycythemia vera is that a risk factor for a suboptimal response to ruxolitinib is additional mutation. With polycythemia vera, we don’t often see this. These are largely patients that have just a JAK2 mutation, and frequently at a high allele burden. That’s another predictor for good ruxolitinib response a high allele burden of JAK2, greater than 60%.

My experience has been largely positive in that setting; patients can get remarkable improvements because you’re dealing with a less complex disease. It’s probably the same reason we see good responses in patients with myelofibrosis [whom we are] treating early, because you have a less complex disease that has less mutation, [fewer] genetic insults, and less molecular complexity that’s easier to control. [ruxolitinib’s] approved in the second-line setting and hydroxyurea does a good job controlling blood counts and reducing the need for phlebotomy in most patients. Not every patient with polycythemia vera is highly symptomatic, even though I think in those that are, especially with pruritus, ruxolitinib seems to do a fantastic job of controlling some of those symptoms.

How has coronavirus disease 2019 (COVID-19) affected the use of ruxolitinib?

I haven’t had any patients that I’m aware of on ruxolitinib with COVID-19. I’ve had several other patients who were not on ruxolitinib, but I’ve heard from various people across the state that have had an experience where they’ve had patients that were on ruxolitinib, and they’ve tried to titrate it off; some of the symptoms got worse, [so they] titrate it back up and some of the symptoms got better. That’s anecdotal, and there’s a potential for cytocidal release with ruxolitinib discontinuation, so it’s not to say that those are COVID-19 symptoms coming up, but these are patients who are COVID positive.

JAK inhibitors are being used to study at least severe COVID-19 infections, not ruxolitinib but other JAK inhibitors. I think it’s a challenge [and] a case-by-case basis. I’d be nervous taking patients of it if the patients are doing relatively well. But at the same time, you could argue that ruxolitinib causes some sort of immune dysfunction and impacts T cells, and respiratory infections are more common, so I think it’s a challenge to know what to do. The respiratory infections that were seen on the COMFORT studies [NCT00952289, NCT00934544] and on the RESPONSE trials are usually minor. It may be that [ruxolitinib] allows it to be easier for you to get a respiratory infection, but I don’t know that once you have COVID-19, or once you have a respiratory infection, that there’s any benefit in stopping at that point.


1. NCCN. Clinical Practice Guidelines in Oncology. Myeloproliferative neoplasms, version 1.2020. Accessed October 2, 2020. https://bit.ly/3gYt5at

2. Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015;372(5):426-435. doi:10.1056/NEJMoa1409002

3. Kiladjian JJ, Zachee P, Hino M, et al. Long-term efficacy and safety of ruxolitinib versus best available therapy in polycythaemia vera (RESPONSE): 5-year follow up of a phase 3 study. Lancet Haematol. 2020;7(3):e226-e237. doi:10.1016/S2352-3026(19)30207-8

4. Passamonti F, Griesshammer M, Palandri F, et al. Ruxolitinib for the treatment of inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): a randomised, open-label, phase 3b study. Lancet Oncol. 2017;18(1):88-99. doi:10.1016/S1470-2045(16)30558-7