In this retrospective study, the authors identified the predictors of anemia response and its impact on outcomes in 72 patients with myelofibrosis treated with momelotinib. Nearly half of the patients with anemia responded to therapy, including those with transfusion dependence. Anemia response was more common in those with post-essential thrombocythemia myelofibrosis, lower serum ferritin levels, and a shorter time from diagnosis to momelotinib initiation. Patients with anemia response, those with type 1/like CALR mutations, and those without ASXL1/SRSF2 mutations had superior survival outcomes.
Momelotinib ameliorates anemia in nearly half of the patients with myelofibrosis and may improve survival in select responders.
– Charles Gaulin, MBBS
See also: GSK gets June 2023 FDA decision date for momelotinib
Instructor of Medicine, Hematology Division, Harvard Medical School & Brigham and Women’s Hospital, Boston, Massachusetts
Chi-Joan How, MD, is currently an Associate Physician of Hematology at Brigham and Women’s Hospital and Instructor in Medicine at Harvard Medical School. She did her fellowship in hematology/oncology at Dana Farber Cancer Institute. She has clinical and research interest in myeloproliferative neoplasms, particularly relevant issues that face essential thrombocythemia and polycythemia vera patients including thrombosis/bleeding, symptom control, pregnancy complications, and COVID-19 outcomes.
Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by bone marrow fibrosis with resultant cytopenias, splenomegaly, and extramedullary hematopoiesis. Anemia is a frequent complication in MF and is a negative prognostic indicator for survival. Treatments for anemia are limited, especially as currently approved JAK inhibitors, including ruxolitinib, will invariably worsen the anemia.
There is, therefore, an urgent need for novel treatments for MF that will address anemia and transfusion dependence. Momelotinib, a JAK1/2 and ACVR1 inhibitor, has recently demonstrated improved transfusion-independence rates compared with ruxolitinib in JAK-inhibitor–naïve patients with intermediate-2/high-risk MF. Improvements in anemia are thought to be related to ACVR1 inhibition, which leads to the downregulation of hepcidin production, with the resultant mobilization of iron stores for erythropoiesis.
Gangat et al evaluated the predictors of anemia response in 72 momelotinib-treated patients with MF and examined how anemia response impacts survival. Overall, anemia and transfusion response were more likely in patients with post–essential thrombocythemia (post-ET) MF and lower serum ferritin levels; a shorter time from diagnosis to momelotinib therapy also predicted improved transfusion dependence. Anemia response also had a favorable impact on overall survival, although, given that nearly half of all patients received subsequent therapies that could not be factored into the study’s retrospective design, only a short-term survival benefit could be suggested.
These results are important in informing how to individualize treatments for patients with MF. We are fortunate that the treatment landscape in MF has expanded such that there are incoming drugs beyond ruxolitinib, which, although can palliate splenomegaly and certain disease-related symptoms, also result in dose-limiting cytopenias. Based on this analysis, patients with post-ET and those with lower ferritin levels may have more favorable anemia responses with momelotinib. The finding that a lower ferritin level predicts better anemia responses is intriguing, given that momelotinib is thought to counter the “anemia of inflammation” through its downregulation of hepcidin. Intuitively, that would suggest that higher ferritin levels should predict improved responses to anemia, although this was not the case in this analysis. Further exploration of momelotinib’s impact on iron regulation as well as the validation of these predictive responses would be necessary. However, overall, the study provides practical information on which patients may benefit the most from momelotinib and confirms the importance of addressing anemia in MF.
We retrospectively reviewed 72 anemic patients with myelofibrosis (MF; median age 68 years), who were JAK2 inhibitor-naïve at the time of study entry to a phase-1/2 momelotinib clinical trial. Driver mutation profile included JAK2 69%, CALR 17%, MPL 8%, and triple-negative 6%; other mutations included ASXL1 39% and SRSF2 17%. Momelotinib was administered at a median dose of 300 mg daily. Anemia response was assessed by formal criteria and documented in 44% of all patients with hemoglobin levels below the sex-adjusted reference range (n = 72), 48% of those with hemoglobin 65 years, ASXL1/SRSF2 mutation, unfavorable karyotype, DIPSS-plus high risk, red cell transfusion need and higher serum ferritin. Multivariable analysis confirmed the favorable impact of anemia response on survival (p = .02; HR 0.5, 3/5/10-year survival; 69%/38%/25%). This survival advantage was also noted in transfusion-dependent patients (3.7 vs. 1.9 years; p = .01; HR 0.3) and appeared to be restricted to patients with an unfavorable genetic profile. The current study suggests a short-term survival benefit associated with anemia response in momelotinib-treated patients with MF.
Neat to have a decision date. The Jan 2023 results will decide it seems. This is the problem Mom is addressing:
"Anaemia is the main reason why people with myelofibrosis discontinue treatment, seen in around 40% of them at diagnosis with almost all going on to develop it eventually. As treatment with JAK inhibitors can make anaemia worse, they can raise the risk of complications and blood transfusions."
Does new study mean a long time away from perhaps coming into use please? Could this mean years? Apologies if this is a silly question, but I,m always keen to learn of my MF condition, which is causing anaemia with recent decision to increase Epo injections to weekly. Thanks to this wonderful group for all the support & info given x
There are no silly questions here, just the ones we haven't been able to find the answers to yet.
As to when it will be available, there's this:
GSK gets June 2023 FDA decision date for momelotinibPhil TaylorAugust 17, 2022
The clock is now ticking on the FDA’s review of GSK’s momelotinib for myelofibrosis patients with anemia – the center+piece of its $1.9 billion acquisition of Sierra Oncology which completed last month.
The US regulator is due to make a decision on momelotinib by 16 June, 2023, on the basis of phase 3 results reported in January, said GSK. The drug – which it has said could become a $1 billion-plus product – is meanwhile also scheduled for filing in Europe before the end of the year.
But, in the meantime, can I ask what else you're being treated with , besides Epo?
...and also, I posted what was probably an overwhelming amount of MF treatment information in response to Glyndale's post, in which she reported that she has joined the ranks of the MF'ers [bad pun intended as a bad joke/groaner], and you might find it helpful as well:
Finally, if you're not completely confident in your care team's knowledge and understanding of not only your disease, but its best treatment options, you should consider a 2nd opinion, as did I.
This is the site wherein I located my MPN [super] specialist:
Many thanks for your helpful response. I received blood transfusion 5 weeks ago, but was disappointed that it only helped for 5 days, therefore have had Epo increased to wkly. I take HU as well. & attend haematology every 6 weeks. Onwards & upwards!
I hate to sound like a downer, but as a patient advocate, I have to ask you to please think about looking into/asking about having at least a trial of interferon treatment- you may find it helps significantly more than HU, and it especially may help decrease your need for transfusions.
The postings I gave references for on Glyndale's post as noted above may give you food for thought.
Your response is appreciated PhysAssist, thank you. I find the lack of knowing about my MF condition overwhelming, so this group very helpful. My consultant at Glagow Royal Infirmary Haemotology left 2 months ago to take up post in Inverness, & her replacement will take over in January, so last couple of apps. (Every 6 wks.) I,m seeing registrars.Am so exhausted it,s taking over my life. Received blood transfusion a month ago which helped for 5 days, so last week my epo injection was upped to wkly. I take hu 500 & 1000 on alternate days. I,ve been going along with this plan , but next move is to up my hu. Because I know so little about what,s happening to me, I just plod on like all of you do, but I Don. . .,t feel well. White platelets running amok, red cells useless. Was diagnosed start of lockdown, so because trtmnt. Was delayed, I collapsed with pulmonary embolism, heart failure, & clot on lung. It,s wait & see. Next appt. I,.ll ask about interferon, as I now feel sort of isolated having been positive throughout.Last appt, l begged to be given some energy. I don,t usually go on like this, but hope I,m being helped. Gone from very active 72 to an exhausted lump, & hate to say it....getting afraid. Apologies for .Long & self indulgent post. This is a one off, to give a picture of how I feel.
No apologies are ever necessary- that's why we're all here to find and give support in our move from crisis to crisis.
To be honest, I sometimes find it hard to just relax and enjoy when things are going 'too' well, because I'm always waiting for the other shoe to drop.
Remember to keep taking those slow deep breaths- because at least that's one thing you can control, and on some days, it's just all you can do.
I'm glad you're thinking about making a change, especially as you're feeling so badly just now.
I'm sure all the others here will agree that you're in our thoughts and prayers, and that virtual hugs are heading your way.
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