Tag Archives: Hydroxyurea

Rovadicitinib Bests Hydroxyurea in Myelofibrosis

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Erin Clancy

The JAK2 inhibitor rovadicitinib proved more effective than hydroxyurea in patients with JAK inhibitor-naïve, intermediate-2 or high-risk myelofibrosis in a phase 2 trial presented at the ESMO Congress 2024.

These results “support the use of rovadicitinib as a new treatment option” for these patients, said study presenter Ling Pan, of West China Hospital, Sichuan University, in Chengdu, China.

The trial (NCT05020652) enrolled 105 patients with intermediate-2 or high-risk primary, post-polycythemia vera, or post-essential thrombocythemia myelofibrosis. All patients had received no prior JAK inhibitor treatment and had palpable splenomegaly.

Patients were randomly assigned 2:1 to receive rovadicitinib at 15 mg twice daily plus placebo (n=72) or hydroxyurea at 0.5 g twice daily plus placebo (n=35). Baseline characteristics were well balanced between the arms.

Treatment continued for 24 weeks, at which point patients who achieved a spleen volume reduction of 35% or greater (SVR35) maintained treatment as assigned. Those who had not achieved SVR35 by week 24 received open-label rovadicitinib at 15 mg twice daily until treatment termination criteria were met.

At week 24, the SVR35 rate was 58.33% in the rovadicitinib arm and 22.86% in the hydroxyurea arm (P =.0006). The best spleen response rate during the study period was 63.89% with rovadicitinib and 31.43% with hydroxyurea (P =.0017).

The proportion of patients who achieved a 50% or greater reduction in total symptom score at week 24 was 61.11% with rovadicitinib and 45.71% with hydroxyurea (P =.136). The best symptom response rate during the study period was 77.78% with rovadicitinib and 54.29% with hydroxyurea (P =.0136).

Eighteen patients who initially received hydroxyurea but switched to rovadicitinib after week 24 were included in the safety analysis, so 90 patients were evaluable in the rovadicitinib arm and 35 patients were evaluable in the hydroxyurea arm.

The rate of treatment-emergent adverse events (TEAEs) was 97.78% in the rovadicitinib arm and 100% in the hydroxyurea arm. The rate of grade 3 or higher TEAEs was 51.11% and 77.14%, respectively. The rate of serious TEAEs was 31.11% and 40.00%, respectively.

The most common grade 3 or higher hematologic TEAEs (in the rovadicitinib and hydroxyurea arms, respectively) were platelet count decrease (20.00% and 17.14%) and anemia (28.89% and 60.00%). The most common grade 3 or higher non-hematologic TEAE was hyperkalemia (6.67%) in the rovadicitinib arm and weight gain (2.86%) in the hydroxyurea arm.

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What are the future prospects for polycythemia vera pharmacotherapies for patients with hydroxyurea resistance?

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August 26, 2024

Megan Metzger & John Mascarenhas

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by erythrocytosis in the context of a somatic JAK2 mutation and a hypercellular marrow with an atypical megakaryocyte morphology. Virtually, all patients with PV harbor a point activating JAK2 mutation, including >95% with JAKV617F and the remainder with other activating JAK2 mutations, including exon 12 [Citation1]. Beyond the JAK2 driver mutation, acquired subclonal mutations have been described in PV involving epigenetic regulation (i.e. TET2 and ASXL1), splicing (i.e. SRSF2), and cellular metabolism (i.e. IDH2) [Citation2]. While clinically derived risk factors including advanced age, thrombosis history, and leukocyte count influence survival outcomes, clonal genomics have recently been integrated into prognostication with the mutation-enhanced international prognostic systems for PV (MIPSS-PV), which highlights the adverse prognostic role of non-driver mutations [Citation3].

Current management of PV is based on risk stratification, favoring cytoreductive treatment in patients with higher risk of thrombosis. The principal goal of PV management is to optimize patients in a way that improves the quality of life and decreases PV-related events, namely, thrombotic events, progression to myelofibrosis, and transformation to blast phase, which are ultimately associated with poor prognosis. While low-dose aspirin and therapeutic phlebotomy are standard management for all risk groups, patients with high-risk PV are recommended to be treated with the addition of a cytoreductive agent. Furthermore, cytoreductive therapy should be considered in certain subgroups of low-risk PV, including patients intolerant of venesection, those with progressive splenomegaly, individuals with persistent leukocytosis or thrombocytosis, or cases of high symptom burden such as intractable pruritus [Citation4]. Regardless of the risk group or treatment strategy, a target hematocrit (Hct) of <45% is required, as control of this hematologic parameter is associated with a lower rate of cardiovascular death and major thrombosis [Citation5].

First-line drugs of choice for PV currently include hydroxyurea (HU) and pegylated interferon alfa-2a (peg-IFN). HU was first introduced as cytoreductive therapy for PV in 1970 and has, therefore, accumulated a significant amount of data endorsing efficacy and tolerability. Despite a lack of randomized control trials and continued debate over potential leukemogenicity, there is general agreement on the net benefit of HU. Early non-randomized trials demonstrated a lower incidence of early thrombosis in HU-treated patients compared to phlebotomy-only historical controls [Citation6]. A recent reappraisal of over 1000 patients enrolled in the ECLAP study confirmed less frequent fatal and non-fatal cardiovascular events with HU treatment compared to phlebotomy alone [Citation7]. However, approximately 25% of PV patients are considered intolerant to HU because of emergent toxicities or are resistant to HU due to lack of effective cytoreduction.

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Special Interview: Living with an MPN in Childhood

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Diagnosed at age seven with Essential Thrombocythemia, Portia shared her story at the 2nd Annual Pediatric & Young Adult MPN Patient Program.

Portia, a young adult MPN patient, shared her story at the 2nd annual Pediatric & Young Adult Program

Do you remember experiencing any symptoms?

I had occasional nosebleeds that would last about twenty minutes or so. But over time, the time decreased to about ten minutes. I also experience fatigue, especially when I’m sick, all I do is sleep to try and regain any energy. Also, I’m very active and I play competitive squash, so I do experience fatigue more than an average person.

How do you cope with essential thrombocythemia (ET) symptoms and/or side effects from Hydroxyurea?

I’m very lucky that I don’t really experience too many symptoms, but I usually push through any pain that I have since I’m such a wimp about medication. I have not had any side effects from Hydroxyurea. For fatigue, I don’t take any other medication, I pretty much just work hard and try to be smart about how I utilize my energy. When playing squash, I work extra hard to make up for my fatigue, but if I really can’t breathe due to lack of oxygen, I will talk to my coach and ask for a small break to recuperate. Most coaches are very reasonable and will allow a break.

Has ET curtailed your involvement in school activities?  Sports?

When I was younger, elementary and middle school age, I would occasionally have to miss school for lab appointments, so I would have to make up work. One symptom of ET is fatigue, so I do have to deal with that in sports. But I also have Hemoglobin H, which I believe has a bigger impact on my fatigue in sports than ET. But overall, I still go about my life and continue to do the things I love.

How do you explain what you have to your friends?

As I’ve gotten older, I’ve done a lot more of my own research to further understand my condition, but to my friends, I explain that I have way too many platelets, which help clot your blood when you get a cut, and because of that, I bleed for longer.

What advice would you give other younger individuals with an MPN when peers say they don’t look sick or they’re faking?

I would tell them to do their best to ignore their hateful comments and try to explain their condition by telling them it’s something internal rather than external, that’s why they don’t appear sick. And most important, find friends who won’t judge you, and people who do, clearly aren’t your real friends, for real friends should accept you no matter what.

You are very energetic and positive, when you reach out to others your age who aren’t feeling well, what do you say to encourage them?

First, I would listen to their concerns and possible issues, and then I would tell them to keep their head held high and know that it does get better. This is just a phase and eventually, the negative parts will fade away. Also, it’s very important to know who your close friends are and be able to talk to them since many kids would rather talk to their friends rather than a parent or even a doctor since it can be intimidating. I would also say, take one day at a time and find joy in the little things, whether it’s going for ice cream or just taking a nice walk.

If you could wave a wand and change one thing in the world of MPNs, what would you change?

Personally, I would change the medicine. I really hate swallowing pills, so I would much prefer something fun to eat or drink as my medicine. I’m also very strange and would much rather have the medicine get injected into me, which I know is an option, but the majority of people aren’t a big fan of needles.