Abbas Looks at the Use of Ruxolitinib and Fedratinib in Myelofibrosis

CASE SUMMARY

A 68-year-old woman presented to her physician with symptoms of mild fatigue, moderate night sweats and abdominal pain/fullness lasting 4 months; she also reported increased bruising and unexplained weight loss​. Her spleen was palpable 8 cm below the left costal margin. Genetic testing showed she was negative for a JAK2 V617F or CALR mutation. Her karyotype was 46XX​ and a bone marrow biopsy showed megakaryocyte proliferation and atypia with evidence of reticulin fibrosis.

A blood smear revealed leukoerythroblastosis and she was diagnosed with primary myelofibrosis​ with a risk score of Dynamic International Prognostic Scoring System intermediate-2 and was also considered intermediate risk on the MIPSS70 score. However, the patient is not interested in transplant and a decision was made to initiate ruxolitinib (Jakafi).

DISCUSSION QUESTION

What data demonstrates the efficacy of ruxolitinib for a patient like this?

JONATHAN ABBAS, MD: [In the final analysis of the phase 1b EXPAND dose finding study (NCT01317875)], in patients who started with a lower dose of ruxolitinib, there was some thrombocytopenia [at 40%], but platelets were pretty much OK with only 25% of patients with decreasing platelets and then anemia was acceptable [at 25% as well].¹ So you can still have efficacy with some acceptable cytopenias is the take home if you put the effort into the ruxolitinib dosing.

In looking at spleen response [of these patients] at lower doses because of the thrombocytopenia, we are still seeing patients have tremendous clinical improvement, and spleen response. In their total symptom scores [TSS], looking at response, you can definitely see improvement [there as well].

Jonathan Abbas, MD

Director, Acute Leukemia Program

Ascension St. Thomas Midtown Hospital​

Tennessee Oncology​

Nashville, TN​

In patients with profound anemia [in the COMFORT-I study (NCT00952289)], I don't know if there's a tremendous amount of conclusions there other than the ruxolitinib patients, regardless of having anemia, did very well whereas anemic patients who were on best available therapy or on placebo, not surprisingly, are the ones who [had lower efficacy].²

GREGG SHEPARD, MD: The main problem I have with a lot of my patients is anemia becoming more emergent during treatment and becoming more transfusion dependent over time. I dose reduce and they're on 10 mg once a day, or 5 mg twice a day, and we saw the data previously where efficacy is not great when the dose is that low. So, I don't know that's just a struggle [I have].

If the efficacy is not there at less than 10 mg twice a day, then do you just stop the drug completely, or give people supportive care, or look for a trial, or try to increase the dose back up to 10 or 15 mg twice a day and just give them more transfusions?

ABBAS: If you put someone on a Janus kinase [JAK] inhibitor and they're doing great and symptoms are then improving, but now you're driving anemia into a transfusion-dependent state so you dose reduce. Now you're starting to see possibly a loss of clinical response that you had to dose reduce so much, even if the anemia might be getting better. What's our next step there? Are we offering patients growth factor support when we're treating them? Is that a scenario people have run into?

IBRAHIM NAKHOUL, MD: We've frequently had to use erythropoiesis stimulating agents (ESAs), but it's not been all that successful.

JACK ERTER, MD: I'll echo that. I have tried ESA support, and things of that nature, with no benefit.

ABBAS: I'm with you. I've tried it and I can't say it's ever been terribly successful. While we're on this topic, 1 thing that's out there which might not be a too off label to try if you want, is luspatercept [Reblozyl]. Luspatercept in some early studies did have some nice effects on anemia in myeloproliferative neoplasms and is in some later-phase trials.³ So that's a drug that might be able to provide some better hematologic support for these patients, but…that's a potential file-away for later options.

DISCUSSION QUESTION

How has data from the JAKARTA trial (NCT01437787) impacted your practice?

ABBAS: The JAKARTA trial randomly assigned fedratinib [Inrebic] or placebo to patients with either primary or secondary myelofibrosis.⁴ Spleen volume reduction was excellent with a tremendous…number of people who clinically benefited [with 37% vs 1% in the placebo arm], so you can see how well the fedratinib arm did.

Now, we do see some gastrointestinal [GI] toxicities [at all adverse event (AE) grades] with fedratinib [like diarrhea (66%)]. We don't like cross-trial comparisons, but we live off it anyways, and I think there is a little more GI signaling in fedratinib [than ruxolitinib]. Then we saw degrees of anemia [74%] and thrombocytopenia [47%] comparable with what we've seen with ruxolitinib.

The rare AEs with fedratinib included 1 case of Wernicke encephalopathy on treatment, 1 case with an unknown origin, and 2 cases after data lock. This did lead to a black box warning for this, so you do want to make sure the thiamine deficiency isn't something you want to worry about in a fedratinib patient. Have any of you used fedratinib?

MICHAEL BYRNE, DO: I've used it. My experience with it was not positive. I thought it was toxic and not effective, so I've not been in a rush to use it.

ABBAS: In my clinical experience…it was the exact same experience as you.

SHEPARD: I have a patient currently on it who's in the waiting period to get an allogeneic transplant because they failed ruxolitinib and they were off all therapy for a while, just on supportive care. We put her on fedratinib in hope that it would get better…but I have not seen any improvement so far. The patient's still anemic and transfusion dependent, tolerating it fine, just no better.

ABBAS: What was the ruxolitinib failure? Was it a non-response, was it due to non-tolerability, or both?

SHEPARD: It was interesting. It was a patient who was put on it because they had post- polycythemia vera myelofibrosis and primarily symptomatic with anemia, but never had symptomatic splenomegaly at all. They were put on ruxolitinib, and it did not help their anemia get any better, so [they were] taken off it. It was the same thing with fedratinib. So, now we’re waiting for a possible allogeneic transplant for them.

ABBAS: That’s great. How do we monitor the patient from our case...do people do serial imaging?

ERTER: In this specific disease, yes, I think the splenomegaly is so obvious that I don't think there's a huge advantage to getting ultrasounds or CT scans compared with a lot of other diseases we treat.

^References

^{1. 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}

^{2. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012 Mar 1;366(9):799-807. doi:10.1056/NEJMoa1110557}

^{3. Kubasch AS, Fenaux P, Platzbecker U. Development of luspatercept to treat ineffective erythropoiesis. Blood Adv. 2021;5(5):1565-1575. doi:10.1182/bloodadvances.2020002177}

^{4. Pardanani A, Tefferi A, Masszi T, et al. Updated results of the placebo-controlled, phase III JAKARTA trial of fedratinib in patients with intermediate-2 or high-risk myelofibrosis. Br J Haematol. 2021;195(2):244-248. doi:10.1111/bjh.17727}