JAK Inhibitor Therapy in the Myeloproliferative Neoplasm Population

Part 2: Maximizing Efficacy and Survival With Ruxolitinib for Myelofibrosis

During a live virtual event, Ruben Mesa, MD, discussed the clinical trials and challenges of using ruxolitinib for patients with myelofibrosis.

Targeted OncologyTM: What were the results of the COMFORT I (NCT00952289) and COMFORT II (NCT00934544) studies of ruxolitinib (Jakafi)?

RUBEN MESA, MD: The COMFORT studies are a decade old in data, but they compared ruxolitinib with placebo or best alternative therapy.

[Ruxolitinib was] unequivocally effective for helping to improve splenomegaly and symptoms in in the majority of the patients.1 There’s about half that met the formal response criteria, but it’s pretty much a continuous variable. Almost all patients’ spleens shrink to some degree. We found over time, if that’s over 10%, they probably have both symptomatic benefit and a survival benefit.

And there was the [COMFORT II study of] ruxolitinib compared with best alternative therapy. So, it was much better than hydroxyurea or other options that physicians could use.2

Symptomatically, patients felt quite a bit better.1,2 Having had been involved with 20 to 30 trials before ruxolitinib, it was striking to see what the difference was. Patients felt much better in a much shorter amount of time, and it helped not only 1 symptom but multiple types of symptoms.

There was a difference compared with best alternative therapy [including hydroxyurea].2

What are the overall survival (OS) outcomes for patients who received ruxolitinib for myelofibrosis?

One of the things we’ve found over time is that patients live longer.3 The study was not a survival study; it would have been impractical to do so. But, caring for many of these patients, there’s no question that they’re living longer. It’s not a cure, and there’s no plateau on the [Kaplan-Meier] OS curve, although there are some long-term survivors. I’ve had some patients that have been on [ruxolitinib] since 2007, and these are individuals that we would have expected an OS of just 2 to 3 years. That’s the exception, but there are some extremely long-term survivors.

Now, why did they live longer? It’s probably a range of [factors]. It may be less risk of progression, less inflammation in the bone marrow that’s conducive to additional mutations developing, and less debilitation.

How is spleen response related to survival outcomes?

We have found that survival is probably tied to some degree with the quality of their response, and that having a spleen response matters.4 And dose intensity probably matters.5,6 I don’t think that this is telling us that just because the spleen shrinks, patients live longer. I think that this is kind of a biomarker, if you would, of a response to a Janus kinase (JAK) inhibitor. If they respond, then they’re likely to live longer, and that corresponds to a smaller spleen, but I don’t think that they live longer solely because of the improvement in the spleen.

We have learned over time that dose matters, and that lower doses of ruxolitinib help a bit with symptoms, but are probably inadequate for giving this improvement in survival phenomenon.

What does the phase 1b EXPAND study (NCT01317875) show about patients with low platelet counts?

Over time, we have learned that if patients have lower platelet counts, it can be overcome by starting at a low dose and then increasing the dose. I see sometimes in the patients that I see, is that patients went down to a low dose, or started on a low dose because their platelets were low, but the dose has not been subsequently increased. So, they started on 5 mg twice a day, they feel a little bit better, the spleen’s a little bit smaller, and they remain on that dose. This study helped to show that you can increase the dose, and by increasing the dose it may make an impact in terms of their outcome.7

Were serious adverse events observed in the EXPAND study?

With low platelet counts—again, the rate of AEs was not problematic. If platelets counts are low, they’re going to drop a little bit further, but what we don’t see really are risks, any significant risk of hemorrhage or things that really would be a true outcome in terms of the lower counts.8

Do you recommend increasing the dose if the patient’s platelet count is under 50,000/μL?

Yes, but after time. So, I find that if they’ve been on the dose for about 8 weeks or so, and the counts are holding OK, if you increase the dose further their platelets won’t typically [continue] to go down. The phenomenon is that they tend to drop at first, but then afterwards they don’t continue to drop in a dose-dependent fashion.

So, I’ve had some patients with an aggressive disease, where I have them on ruxolitinib and azacitidine [Vidaza] for acute leukemia and myelofibrosis. I may try to push the dose in terms of how they’re doing, and quality of life, and sometimes I can push that if their platelets are [30,000/μL to 35,000/μL], and the platelets won’t necessarily continue to go down. What they were able to see is that the response rates, even in these lower platelet groups, were pretty good by being able to push the dose.7


1. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799-807. doi:10.1056/ NEJMoa1110557

2. Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787-98. doi:10.1056/NEJMoa1110556

3. Verstovsek S, Gotlib J, Mesa RA, et al. Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses. J Hematol Oncol. 2017;10(1):156. doi:10.1186/s13045-017-0527-7

4. Palandri F, Palumbo GA, Bonifacio M, et al. Durability of spleen response affects the outcome of ruxolitinib-treated patients with myelofibrosis: Results from a multicentre study on 284 patients. Leuk Res. 2018;74:86-88. doi:10.1016/j.leukres.2018.10.001

5. Palandri F, Palumbo GA, Bonifacio M, et al. Baseline factors associated with response to ruxolitinib: an independent study on 408 patients with myelofibrosis. Oncotarget. 2017;8(45):79073-79086. Published 2017 Jun 27. doi:10.18632/oncotarget.18674

6. Menghrajani K, Boonstra PS, Mercer JA, et al. Predictive models for splenic response to JAK-inhibitor therapy in patients with myelofibrosis. Leuk Lymphoma. 2019;60(4):1036-1042. doi:10.1080/10428194.2018.1509315

7. Vannucchi AM, Te Boekhorst PAW, Harrison CN, et al. EXPAND, a dose-finding study of ruxolitinib in patients with myelofibrosis and low platelet counts: 48-week follow-up analysis. Haematologica. 2019;104(5):947-954. doi:10.3324/haematol.2018.204602

8. Guglielmelli P, Kiladjian J, Vannucchi AM, et al. The final analysis of EXPAND: a phase 1b, open-label, dose-finding study of ruxolitinib (RUX) in patients (pts) with myelofibrosis (MF) and low platelet (plt) count (50 × 109/L to < 100 × 109/L) at baseline. Blood. 2020;136(suppl 1):4-5. doi:10.1182/blood-2020-137742