Transfusion Independence With Momelotinib Impacts OS in Myelofibrosis

Haris Ali, MD

Associate Professor, Division of Leukemia

Department of Hematology and Hematopoietic Cell Transplantation

Section Leader, Myeloproliferative Neoplasms (MPH) Program

City of Hope

Duarte, CA

DISCUSSION QUESTION

• How do the most recent data on Janus kinase (JAK) inhibitors support/change your approach to treating patients?​

DRAUPADI TALREJA, MD: I'm all for momelotinib [Ojjaara]. I was never for ruxolitinib [Jakafi] but there was nothing else available, so I used it.

HARIS ALI, MD: Would you use momelotinib in the majority of your patients or just on certain patients with moderate or severe anemia?

TALREJA: I will use it for them because it reduces the spleen anyway; all [JAK inhibitors] reduce the spleen beautifully. Because it does not cause anemia and can make them transfusion independent, if they have symptoms, a big spleen, and anemia, I have many reasons to use momelotinib. So I'm going to go there, and I'm going to [use less] ruxolitinib.

ALI: Maybe the once-daily dose might be helpful as well.

ARATI CHAND, MD: Was the SIMPLIFY-1 study [NCT01969838] powered for superiority or noninferiority?

ALI: It was powered for noninferiority for [spleen volume reduction] and symptoms, and superiority for the transfusion independence.¹

CHAND: What about the adverse event [AE] profile?

ALI: Ruxolitinib has a bit more thrombocytopenia and anemia, and momelotinib has some more gastrointestinal [AEs] and nausea. Otherwise, they were quite comparable.¹

CHAND: It looks less toxic compared with ruxolitinib. I would probably change and start using more momelotinib now that is available. Earlier, we didn't have anything except ruxolitinib and fedratinib [Inrebic]. Pacritinib had such a restricted indication that you could only use it for those patients with very thrombocytopenic myelofibrosis. I think I would definitely start my new patients on momelotinib.

ALI: Would that be regardless of the hemoglobin and platelet count?

CHAND: I think so. It looks like it's better tolerated. Patients are different, so there may be patients who don't tolerate this. But in that case, it would make sense to switch and see if they tolerate ruxolitinib better. Efficacy is one thing, but tolerance is also important, especially for treatments that have to be given over prolonged periods of time.

GEORGE HAJJAR, MD: The dosing is also an issue. Adjusting the dose of ruxolitinib is very frequent, depending on the platelet count and hemoglobin level. It'd be interesting to know how many patients got the full dosing of ruxolitinib in that trial vs momelotinib.

ALI: The correct dosing is also important, but it usually goes by the package insert, like 20 mg [twice daily ruxolitinib] for patients with greater than 200 × 10⁹/L platelets, or [15 mg twice daily for patients with between 100 × 10⁹/L and 200 × 10⁹/L platelets].²

HAJJAR: Dose adjustments are always frequent. If we see platelet count drop, we have to tell the patient to decrease the dose, which will be a pain.

ALI: [In the COMFORT-I trial (NCT00952289)], although anemia was a big factor, discontinuation of ruxolitinib because of anemia was in less than 1% of the patients.³ Regardless, patients felt better with the improvement in the symptoms and the spleen symptoms. For whatever reason, that was not the one of the common reasons for discontinuation. I think one of the most common was thrombocytopenia; it wasn't anemia.

One thing with momelotinib is that it has a lot of drug interactions with OATP1B1/B3 inhibitors, including with statins and different drugs.⁴ It’s something to watch out for, because hepatic dysfunction was another reason for the hold and [we need to] look at it further. Drug interactions may be the one thing to look out for in a patient, as most of the patients over 65 will be on 5 or 6 different medication for different comorbidities.

CHAND: Was that interaction only for 1 statin or for all statins? Because [many patients] are on a statin now.

ALI: That's right, so dose reduction might be needed for the statins. There's a whole drug list with OATP1B1/B3 inhibitors, so you just have to watch for that, but it has more than 1 statin listed there.

DISCUSSION QUESTION

• How do the overall survival (OS) data influence your choice of therapy?​

ALI: We looked into an OS advantage with ruxolitinib.⁵ We don't have too much survival data with [momelotinib] but we do have with the transfusion independence vs non-independence.⁶ How does that affect your therapy?

TALREJA: I think OS [could be] better with momelotinib. With ruxolitinib, the only good thing is they feel good. It's their quality of life that helps them live longer. I don't think ruxolitinib does anything to the bone marrow to reduce the myelofibrosis, so I think momelotinib is a much better drug.

ALI: Would everyone say the same thing about momelotinib for OS compared with other JAK inhibitors including ruxolitinib?

CHAND: I don't know if you can say that momelotinib has superior OS [based on the trials], but it is basically dependent on transfusion burden. Regardless of what medication you are on, if you're transfusion dependent, your survival is poor, and if you're transfusion independent, you're going to do better in the long run.

ALI: You're right. Anemia is a big [factor]; if we'll look at the HR…among all the other risk factors like age or low platelet count, anemia is the biggest factor and transfusion dependence [is based on] patients who are more anemic, so there is definitely poorer survival in those patients.

SWARNA CHANDURI, MD: Is this because this drug works on the hepcidin as an inhibitor? Is that the reason why this is better tolerated and [leads to] less dependence on the transfusions?

ALI: Yes, [inhibiting] the hepcidin pathway, and further reduction to ACVR1 leads to [transfusion independence].⁷

CHANDURI: If this drug has the additional quality of [ruxolitinib] and improving it, then it is a better drug than ruxolitinib. But the main thing is that is why patients with anemia do better.

_References:

_{1. Mesa RA, Kiladjian JJ, Catalano JV, et al. SIMPLIFY-1: A Phase III randomized trial of momelotinib versus ruxolitinib in Janus kinase inhibitor-naïve patients with myelofibrosis. J Clin Oncol. 2017;35(34):3844-3850. doi:10.1200/JCO.2017.73.4418}

_{2. Jakafi. Prescribing information. Incyte; 2021. Accessed December 18, 2023. https://tinyurl.com/3t6dd8jj}

_{3. 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}

_{4. Ojjaara. Prescribing information. GlaxoSmithKline; 2023. Accessed December 18, 2023. https://tinyurl.com/4wc5dmet}

_{5. 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}

_{6. Mesa R, Harrison C, Oh ST, et al. Overall survival in the SIMPLIFY-1 and SIMPLIFY-2 phase 3 trials of momelotinib in patients with myelofibrosis. Leukemia. 2022;36(9):2261-2268. doi:10.1038/s41375-022-01637-7}

_{7. Oh ST, Talpaz M, Gerds AT, et al. ACVR1/JAK1/JAK2 inhibitor momelotinib reverses transfusion dependency and suppresses hepcidin in myelofibrosis phase 2 trial. Blood Adv. 2020;4(18):4282-4291. doi:10.1182/bloodadvances.2020002662}