Category Archives: Myelofibrosis

Momelotinib Could Represent Pivotal New Treatment Option in Myelofibrosis

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Ryan Scott
Aaron T. Gerds, MD, PhD, expands on the potential role of momelotinib in the treatment of patients with myelofibrosis who present with anemia, details the data from MOMENTUM, and explains what FDA approval of momelotinib could mean for the treatment of this patient population.

The benefits in symptom burden, spleen size, and transfusion dependence demonstrated by treatment momelotinib in patients with myelofibrosis represent a potential key advance for this treatment paradigm, according to Aaron T. Gerds, MD, PhD.

A new drug application (NDA) seeking the approval of momelotinib as a potential therapeutic option in patients with myelofibrosis is currently under review by the FDA, and the review period was extended to a target action date of September 16, 2023.1

The NDA is supported by data from the phase 3 MOMENTUM trial (NCT04173494), which evaluated the agent in patients with symptomatic and anemic myelofibrosis who received a prior JAK inhibitor. Data showed that 25% of patients treated with momelotinib (n = 130) experienced a reduction in tumor symptom score of at least 50% at week 24 compared with 9% of patients treated with danazol (n = 65; proportion difference, 16%; 95% CI, 6%-26%; P = .0095).2

Additionally, 39% of patients in the momelotinib arm achieved a spleen volume reduction of at least 25% from baseline to week 24 vs 6% in the danazol arm (P < .0001); moreover, 22% and 3% of patients, respectively, experienced a reduction of 35% or more (P = .0011). At week 24, the rates of transfusion independence were 30% (95% CI, 22%-39%) for momelotinib and 20% (95% CI, 11%-32%) for danazol (noninferiority difference, 14%; 95% CI, 2%-25%; 1-sided P = .0016).

“The potential approval of momelotinib is incredibly important for patients. Having additional agents to treat myelofibrosis would be welcomed. As little as a couple of years ago, we only had 1 approved therapy to treat myelofibrosis,” Gerds said in an interview with OncLive®. Gerds is an assistant professor in the Department of Medicine, a member of the Developmental Therapeutics Program, and medical director of the Case Comprehensive Cancer Center in Cleveland, Ohio.

In the interview, Gerds expanded on the potential role of momelotinib in the treatment of patients with myelofibrosis who present with anemia, detailed the data from MOMENTUM, and explained what FDA approval of momelotinib could mean for the treatment of this patient population. Gerds also serves as an associate professor of Medicine in the Department of Hematology and Medical Oncology at the Cleveland Clinic Taussig Cancer Institute.

OncLive: How could the potential approval of momelotinib affect current and future practice patterns for patients with myelofibrosis?

Gerds: The [potential] approval of momelotinib could be another pivotal moment in the care of patients with myelofibrosis. I would argue that the first pivotal moment was the discovery of recurrent JAK2 mutations, followed several years later by the approval of ruxolitinib [Jakafi], the first JAK inhibitor.

Momelotinib provides an extra opportunity for patients, specifically patients who have anemia along with enlarged spleens and significant symptom burden. This drug promises to try to hit all 3 of those key elements of care in patients with myelofibrosis with a single pill.

What unmet needs exist for patients with myelofibrosis and anemia?

Anemia itself in these patients is a key unmet need. Roughly 40% of patients will be anemic at the time of diagnosis. It is common diagnostic and prognostic criteria that is used to predict who may have aggressive disease. Anemia will also develop in patients within the first year after diagnosis, and at some point, every patient will develop anemia as the [bone] marrow begins to fail. Therefore, anemia is something that is incredibly common and difficult to treat.

We can give red blood cell transfusions to combat anemia, but that comes with adverse effects, such as iron overload, transfusion reactions, and the development of alloantibodies. Moreover, blood is a valuable and somewhat scarce resource. The Red Cross is constantly trying to get us to donate more blood because it is a scarce commodity, and it is also expensive to do red blood cell transfusions. In general, it’s one of the biggest costs in delivering health care for patients with hematologic malignancies. For all these reasons, treating anemia is incredibly important.

Treatments for anemia are somewhat limited. I mentioned transfusions already, and there are also erythropoiesis stimulating agents [ESAs] that can be given. Another drug, luspatercept-aamt [Reblozyl], is already approved to treat anemia in patients with myelodysplastic syndrome and beta thalassemia. It is used off-label to treat anemia in patients with myelofibrosis. danazol is also commonly used.

We already have these 3 agents; however, none of them are perfect or work 100% of the time, and there are still many patients who suffer from anemia who have [myelofibrosis]. Any new agent that is coming along that can potentially treat anemia in a different mechanism of action is always welcome.

What is the mechanism of action of momelotinib, and what prompted this agent’s examination in patients with myelofibrosis?

Momelotinib, in terms of treating anemia, works very differently than ESAs, luspatercept, and danazol. It works by inhibiting ACVR1, also known as ALK2, which is a regulator of hepcidin. Hepcidin is a key piece in what we think about in hematology in iron regulation and red blood cell production. It is a hot topic in myeloproliferative neoplasms right now, and it has been in the world of hematology for some time.

Hepcidin is a master iron regulator that helps regulate the shuttling of iron out of the iron stores, making it available for the body to use, for example, to make red blood cells. In patients with myelofibrosis, they have anemia or an inflammatory block, meaning that hepcidin levels are very high and can shut a lot of those iron stores. By lowering the levels of hepcidin by blocking ACVR1, we can restore effective erythropoiesis by dropping that anemia or inflammatory block. That component of a patient’s anemia can be reversed, potentially by this medication.

What were some of the key efficacy data from MOMENTUM?

The MOMENTUM study pitted momelotinib vs danazol, looking at a couple of key end points. The first was symptom burden reduction, and we also looked at spleen volume reduction—traditional end points for measuring response with JAK inhibitors in patients with myelofibrosis. Another key end point was transfusion independence, and that was the proportion of patients who were transfusion independent at weeks 24 and 48.

We saw that momelotinib outperformed danazol in terms of spleen volume reduction, as well as symptom burden reduction. Momelotinib was also statistically not inferior—this was a non-inferiority analysis—for transfusion independence at week 24 compared with danazol.

What does the safety profile look like for momelotinib in this population?

With respect to safety, one of the early concerns during the development of momelotinib was an increased risk of peripheral neuropathy. This was seen in some earlier studies. However, in subsequent investigations, such as the SIMPLIFY trials [NCT01969838; NCT02101268] and the MOMENTUM study, we did not see excess neuropathy in patients treated on momelotinib compared with best available therapy or danazol, respectively. The rates of peripheral neuropathy were similar in the 2 groups. That was a key take-home point in terms of safety data from the MOMENTUM study.

Certainly, some patients did develop cytopenias while on momelotinib, as well as danazol. There weren’t excess gastrointestinal toxicities, as we see with some of the other JAK inhibitors. There was no signal toward increased risk of non-melanoma skin cancers or bile reactivations. However, we certainly watch for those things whenever we’re treating a patient with a JAK inhibitor.

If it is approved, where do you see momelotinib fitting into the current treatment paradigm for this population?

With the potential approval of momelotinib, we will see what the uptake looks like in everyday practice. That will be a big part of what happens with this medication: how organically it is picked up by different oncologists and hematologists out there in the community. Clearly, it has efficacy in patients with anemia, so it would be right at home in the treatment of a patient who has myelofibrosis who needs spleen volume reduction and symptom control, and has anemia.

If we look closely at the MOMENTUM inclusion criteria, those patients did have prior exposure to a JAK inhibitor for at least one month, and they all had hemoglobin [levels] less than 10g/dL; that is where this drug tends to shine. However, the amount of JAK inhibition given to those patients prior to going on MOMENTUM was limited. We also do have up-front data in patients previously untreated [with a JAK inhibitor] from the SIMPLIFY trials. You could say that if a patient with myelofibrosis and is borderline anemic, they could also benefit from momelotinib, not just in the second line, but potentially in the frontline setting as well.

References

  1. Verstovsek S, Gerds AT, Vannuchi AM, et al. Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study. Lancet. 2023;401(10373):269-280. doi:10.1016/S0140-6736(22)02036-0
  2. GSK announces extension of FDA review period of momelotinib. News release. GlaxoSmithKline. June 16, 2023. Accessed August 31, 2023. https://www.gsk.com/en-gb/media/press-releases/gsk-announces-extension-of-fda-review-period-for-momelotinib/

Goals of Managing Cytopenic Myelofibrosis in Younger Patients

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Targeted Oncology Staff

During a Targeted Oncology™ Case-Based Roundtable™ event, Naveen Pemmaraju, MD, and participants discussed the role of JAK inhibitors in managing myelofibrosis particularly in younger patients who may receive allogeneic stem cell transplant. This is the first of 2 articles based on this event.

CASE SUMMARY

A 62-year-old man presented to his primary care physician (PCP) with symptoms of fatigue, night sweats, and increased bruising​. He had a history of type 2 diabetes, hypercholesteremia, and hypertension​. The PCP noticed lower hemoglobin concentration (11 to 9.5 g/dL) and platelet count (350 × 109/L to 195 × 109/L) from a previous annual physical examination. ​He was referred to a hematologist/oncologist for consultation and evaluation​. ​

Two months post-PCP visit, he went to a hematologic oncologist. Exam findings included a spleen 5 cm below left costal margin, fatigue and night sweats worsening​, bone pain​, hemoglobin of 8.7 g/dL, and platelet count of 135 × 109/L ​. He was diagnosed with primary myelofibrosis (MF); ​bone marrow fibrosis of grade 2, with 35% bone marrow blasts. He had a history of squamous cell carcinoma of the skin​.

Molecular analysis showed a JAK2 V617F mutation and normal cytogenetics​. Blood smear reveals leukoerythroblastosis: 1% blasts by manual count/flow cytometry​. His ECOG performance status (PS) was 2. ​

DISCUSSION QUESTIONS

  • In your practice:​
    • When do you initiate therapy for a patient with MF? ​
    • What is the importance of symptom control? ​
    • How important is it to initiate therapy early? ​
    • When do you start JAK inhibitor therapy?​
    • Do you choose your initial JAK inhibitor based on patient symptoms? ​

DAI CHU LUU, MD: My standpoint is that a 62-year-old is still young. I have transplant physician within 5 miles of my practice. I would definitely send to a transplant physician…see what they have to say, and then follow up on the recommendations. Usually they’ll give recommendations and then I’ll act on them. Whenever things get tough, I’ll send it to them to establish care.

NAVEEN PEMMARAJU, MD: That’s great. What do you think about JAK [Janus kinase] inhibitor therapy? [Would you use] monotherapy as standard of care up until the transplant?

LUU: Yes.

PEMMARAJU: If the platelets are below 50 × 109/L, what we’ve been doing [in the past] is either giving ruxolitinib [Jakafi] or low-dose ruxolitinib. Maybe you’re doing something different. Has anyone yet prescribed the new agent, pacritinib [Vonjo], which is approved in this lower than 50 × 109/L setting?

SRIKAR MALIREDDY, MD: I have prescribed pacritinib. I had a patient on ruxolitinib for the longest time and then eventually the disease progressed and I could not do any more administration of ruxolitinib. He’s been on [pacritinib] for at least 7 to 8 months.

PEMMARAJU: [Was there] any diarrhea or bleeding events? Or has it been well tolerated?

MALIREDDY: There were no [tolerability issues]. I was very careful with starting with a low dose, and then ramping up. We also watched the platelet counts, and so far…[he has] 30 × 109/L to 40 × 109/L platelets.

PEMMARAJU: What dose did you start? Did you start at 100 mg? Because the approved dose is 200 mg twice daily.1

MALIREDDY: Yes, I started at 100 mg. [Since] he was tolerating it, he is at the maximum dose right now. He’s at 200 mg.

PEMMARAJU: That’s a great story. Did you have any difficulty getting it through insurance or through your specialty pharmacy?

MALIREDDY: This was one of the patients…who initially got azacitidine [Onureg] in combination with ruxolitinib. He was on a clinical trial for that.

PEMMARAJU: For the ruxolitinib/azacitidine trial [NCT01787487]?

MALIREDDY: Yes, exactly. He had some severe cytopenias, myelosuppression, and all that [on the clinical trial]. Eventually, the cytopenias progressed, then [he started on pacritinib]. I didn’t have any issues with getting approval.

PEMMARAJU: That’s great. The combined answer from both of you is the cutting-edge state of the art, which is offering a JAK inhibitor [while] trying to get to [allogeneic stem cell] transplant. We all assume—and it ends up being correct a lot of the time in our patients with myeloproliferative neoplasms as opposed to leukemia or some of the other [disease] states— what happens is [patients have an] ECOG PS of 2 to 3, but they have PS of 0 to 1 after the initiation of JAK inhibitor. With ruxolitinib, it’s usually about 3 months that you see it. After 1 week to 1 month, you start feeling great; by month 2 and 3 is the plateau.

DISCUSSION QUESTIONS

  • What are the therapeutic goals of therapy for a patient with aggressive disease? ​
  • When do you consider clinical trial enrollment?

PEMMARAJU: All of us in the field are thinking about the significance of cytopenic MF. It helped lead to the drug approval for this JAK inhibitor [pacritinib], which is great because I have had several similar situations in prescribing it. It’s a very well tolerated drug. But…how frequent is this? Most people in our field think that the cytopenias are treatment related or they happened later on. That is common. But thrombocytopenia and anemia can occur in a quarter or more of our patients at baseline. Some of these patients present…with fairly advanced disease. How often do you encounter a baseline platelet count of less than 50 × 109/L at any point in the myelofibrosis trajectory? And before pacritinib…what were you giving these patients if you had to treat them?

JAGATHI CHALLAGALLA, MD: [I would give] low-dose ruxolitinib, or if they’re transfusion independent, just observation.

PEMMARAJU: Yes, exactly, [or] sometimes we would…give danazol or steroids. Now we know that delivering suboptimal doses is leading to suboptimal outcomes.2 If you’re not reducing the spleen, not improving the symptoms, patients won’t do as well. The benefit of pacritinib…is you can give the full dose of the drug. We heard 1 story of being very cautious, but you can prescribe it as the 200 mg dosing even in the thrombocytopenic setting.1 Just watch out for diarrhea, usually resolved in the first 4 to 6 weeks. It’s usually well managed, but you and the patient need to know about it. There was some concern about cardiac bleeding events…particularly for patients on anticoagulants, but it is a fairly well-tolerated drug.

Say the patient is 82 years old, and transplant is off the table. [For] low platelet count, you’re giving a low dose of ruxolitinib, [or] you’re giving pacritinib…or fedratinib [Inrebic]. What is the goal of therapy in a patient who’s a non-transplant candidate for whom you’re giving a JAK inhibitor?

ANANTH ARJUNAN, MD: For the patient, the symptom improvement is critical. Along with that getting the spleen [size] down is important, not just for survival benefit, but for the patient to feel better. In terms of discussing treatment options, we go through the different JAK inhibitors, typically based off comorbidities, and then their [blood cell] counts. I haven’t found a reason to use fedratinib. It’s usually a question of ruxolitinib or pacritinib. For clinical trial enrollment, any time is appropriate, although we might wait until they become JAK inhibitor resistant, although you have some options recently with momelotinib.

References:

1. Vonjo. Prescribing information. CTI BioPharma Corp; 2022. Accessed August 29, 2023. https://tinyurl.com/yxjnn7yu

2. Maffioli M, Mora B, Ball S, et al. A prognostic model to predict survival after 6 months of ruxolitinib in patients with myelofibrosis. Blood Adv. 2022;6(6):1855-1864. doi:10.1182/bloodadvances.2021006889

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CWP-291 by JW Pharmaceutical for Thrombocythemia Myelofibrosis: Likelihood of Approval

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August 30, 2023

CWP-291 is under clinical development by JW Pharmaceutical and currently in Phase I for Thrombocythemia Myelofibrosis. According to GlobalData, Phase I drugs for Thrombocythemia Myelofibrosis have a 90% phase transition success rate (PTSR) indication benchmark for progressing into Phase II. GlobalData’s report assesses how CWP-291’s drug-specific PTSR and Likelihood of Approval (LoA) scores compare to the indication benchmarks.

GlobalData tracks drug-specific phase transition and likelihood of approval scores, in addition to indication benchmarks based off 18 years of historical drug development data. Attributes of the drug, company and its clinical trials play a fundamental role in drug-specific PTSR and likelihood of approval.

CWP-291 overview

CWP-291 (CWP-232291) is under development for the treatment of hematological tumors including relapsed or refractory acute myeloid leukemia (AML), chronic myelomonocytic leukemia-2, relapsed and refractory multiple myeloma, gastric cancer, myelofibrosis (PMF), post-polycythemia vera (PPMF), castration-resistant prostate cancer (CRPC) and post-essential thrombocythemia (PTMF). The drug candidate is administered intravenously. It acts as Sam68 inhibitor. It was also under development for the treatment solid tumors such as breast cancer, liver, lung cancer and myelodysplastic syndrome.

JW Pharmaceutical overview

JW Pharmaceutical, a subsidiary of JW Holdings Corp, is a provider of generic drugs. The company develops and markets analgesics, antipyretics and cold remedies, antidote agents, antimicrobials, anticancer agents, and others. It offers multivitamins and antianemia agents, contact lens care and ophthalmic agents, antifungal agents, cardiovascular agents, and gastrointestinal agents. JW Pharmaceutical also offers topicals, amino acid solutions, flexible IV containers, IV solutions, respiratory agents, nephrology agents, CNS, urology agents and diabetic agents. The company offers products for cardiovascular, gastrointestinal, nephrology and antianemia, anticancer and neuropsychiatry. It operates through its production and manufacturing facilities in South Korea. JW Pharmaceutical is headquartered in Seoul, South Korea.

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Dr Halpern on the Investigation of Upfront Ruxolitinib and Navitoclax in Myelofibrosis

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Anna B. Halpern, MD

Anna B. Halpern, MD, physician, assistant professor, Clinical Research Division, Fred Hutch; assistant professor, hematology, University of Washington School of Medicine, discusses investigational efforts being developed to expand on the use of ruxolitinib and navitoclax in earlier treatment lines for patients with myelofibrosis.

In cohort 3 of the phase 2 REFINE trial (NCT03222609), the combination of ruxolitinib and navitoclax was evaluated in the upfront setting for patients (n=32) who had not been previously exposed to a JAK inhibitor. The study’s primary end point was spleen volume reduction of 35% or greater from baseline at week 24.

An exploratory analysis of this cohort was presented at the 2022 ASH Annual Meeting and Exposition, Halpern begins. Findings showed that navitoclax plus ruxolitinib produced a spleen volume reduction of at least 35% at week 24 across specific patient subsets, she details. These subsets consisted of patients 75 years of age or older, those with a high Dynamic International Prognostic Scoring System score, and those with HMR mutations. The percentage of patients who experienced optimal spleen volume reduction in these subgroups are 50%, 33%, and 47%, respectively.

Notably, changes in bone marrow fibrosis and reductions in the variant allele frequency (VAF) of the driver gene mutation were seen with the combination regimen in many patients, Halpern continues. Half of patients achieved a greater than 20% reduction in VAF from baseline at week 12 or 24, while a greater than 50% VAF reduction from baseline occurred in 18% of patients. When comparing those with or without HMR mutations, no differences in greater than 20% VAF reduction from baseline to week 12 or 24 were observed between populations.

These results indicate the potential disease-modifying ability of ruxolitinib and navitoclax, suggesting that reductions in bone marrow fibrosis and VAF may serve as biomarkers for disease modification, Halpern states. Notably, long-term outcomes cannot be definitively assessed as correlates for leukemia, progression, and survival, she adds. The viability of these 2 biomarker candidates should be assessed more short term, and in larger study populations, Halpern concludes.

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Selinexor by Karyopharm Therapeutics for Chronic Idiopathic Myelofibrosis (Primary Myelofibrosis): Likelihood of Approval

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August 28, 2023

elinexor is under clinical development by Karyopharm Therapeutics and currently in Phase II for Chronic Idiopathic Myelofibrosis (Primary Myelofibrosis). According to GlobalData, Phase II drugs for Chronic Idiopathic Myelofibrosis (Primary Myelofibrosis) does not have sufficient historical data to build an indication benchmark PTSR for Phase II. GlobalData uses proprietary data and analytics to create drugs-specific PTSR and LoA in the Selinexor LoA Report. 

GlobalData tracks drug-specific phase transition and likelihood of approval scores, in addition to indication benchmarks based off 18 years of historical drug development data. Attributes of the drug, company and its clinical trials play a fundamental role in drug-specific PTSR and likelihood of approval.

Selinexor overview

Selinexor (Xpovio, Nexpovio) is an antineoplastic agent. It is formulated as film coated tablets for oral route of administration. Xpovio in combination with dexamethasone is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM) who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody. Xpovio is indicated for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least 2 lines of systemic therapy. Xpovio in combination with bortezomib and dexamethasone is indicated for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. It is also under development for the treatment of soft tissue sarcoma, osteosarcoma, leiomyosarcoma, pleomorphic liposarcoma, synovial sarcoma, epithelial ovarian cancer.

Selinexor (KPT-330) is under development for the treatment of light chain amyloidosis, anaplastic astrocytoma, diffuse intrinsic pontine glioma (DIPG), high-grade glioma (HGG), newly diagnosed advanced hepatocellular carcinoma, metastatic urothelial carcinoma, relapsed or refractory peripheral T cell lymphoma and natural killer T cell lymphomas,  relapsed/refractory indolent non-Hodgkin lymphoma (R/R iHNL), malignant peripheral nerve sheath tumor (MPNST), leiomyosarcoma, endometrial stromal sarcoma, ovarian carcinoma, endometrial carcinoma, fallopian tube cancer, metastatic triple negative breast cancer, thymoma, non-small cell lung cancer, cervical carcinoma, non-Hodgkin lymphoma, melanoma, colon cancer, gastroenteropancreatic tumors, prolymphocytic leukemia, small lymphocytic lymphoma, recurrent glioblastoma, follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia (CLL), relapsed/refractory multiple myeloma (MM), relapsed and refractory acute myelogenous leukemia (AML), diffuse large B-cell lymphoma, chondrosarcoma, synovial sarcoma, liposarcoma, leiomyosarcoma, blast-crisis chronic myelogenous leukemia (bc-CML), relapsed and refractory acute lymphoblastic leukemia, rectal cancer, lung cancer, gynecological cancer, Penta-refractory multiple myeloma, recurrent/refractory high-grade gliomas, myelofibrosis, primary myelofibrosis, Post-Polycythemia Vera Myelofibrosis, Post-Essential Thrombocythemia Myelofibrosis (Post-ET MF), Ewing sarcoma and myelodysplastic syndrome, gastrointestinal stromal tumor (GIST), non-small cell lung cancer and recurrent glioma. The drug candidate is administered orally as a tablet and topically as a gel. It is a SINE compound that acts by targeting CRM1 (chromosome region maintenance 1 protein, exportin 1 or XPO1). It is being developed based on Selective Inhibitor of Nuclear Export (SINE) compound technology.

It was also under development for the treatment of coronavirus disease 2019 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), refractory or relapsed Richter’s transformation, metastatic castrate-resistant prostate cancer, advanced squamous cell carcinoma of head and neck, lung cancer and esophageal cancer, relapsed/refractory cutaneous T cell lymphoma, relapsed small cell lung cancer, rectal adenocarcinoma, gastric cancer, metastatic colorectal cancer and diabetic foot ulcers.

It was also under development for the treatment of recurrent glioblastoma multiforme.

Karyopharm Therapeutics overview

Karyopharm Therapeutics (Karyopharm) discovers and develops novel drugs for the treatment of cancer and other diseases. The company’s core technology harnesses the inhibition of nuclear export as a mechanism to treat patients suffering from cancer. Karyopharm’s lead product, Xpovio, is being developed for the treatment of multiple myeloma, and relapsed or refractory diffuse large B-cell lymphoma. Its pipeline drug candidates include selinexor, eltanexor, verdinexor, and KPT-9274. Karyopharm’s drug candidates are indicated for the treatment of various hematological and solid tumor malignancies including multiple myeloma, diffuse large B-cell lymphoma, liposarcoma, glioblastoma and endometrial cancer. The company has operations in the US, Israel and Germany. Karyopharm is headquartered in Newton, Massachusetts, the US.

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Hobbs Examines Frontline JAK Inhibition for Intermediate-Risk Myelofibrosis

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Targeted Oncology Staff

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 an unexplained 12-lb weight loss.
  • Her spleen was palpable 8 cm below the left costal margin.
  • Karyotype: 46XX
  • Bone marrow biopsy results: megakaryocyte proliferation and atypia with evidence of reticulin fibrosis
  • Genetic testing results: JAK2 V617F mutation; CALR negative
  • A blood smear revealed leukoerythroblastosis.
  • Laboratory values:
    • Red blood cell count: 3.40 × 1012/L
    • Hemoglobin level: 13.2 g/dL
    • Hematocrit: 36%
    • Mean corpuscular volume: 94 fL
    • White blood cell count: 23.0 × 109/L
    • Platelet count: 450 × 109/L
    • Peripheral blood blasts: 1%
  • Diagnosis: primary myelofibrosis
  • Risk:
    • International Prognostic Scoring System: intermediate-2
    • Mutation and Karyotype-Enhanced International Prognostic Scoring System for Primary Myelofibrosis in adults 70 and younger: intermediate

TARGETED ONCOLOGY: How do the 3 Janus kinase ( JAK) inhibitors that are approved in this setting compare with each other?

HOBBS: Ruxolitinib [Jakafi] was the first JAK inhibitor [to be approved].1 I think they got lucky that it got approved way before fedratinib [Inrebic]2 and pacritinib [Vonjo],3 even though I think it’s worth noting [that] fedratinib and pacritinib… started their process of clinical trials a long time ago. Unfortunately, they ended up getting held up during their trials.

The indications of these 3 drugs are fairly similar: intermediate- or high-risk myelofibrosis (for pacritinib, specifically for patients with platelet counts of less than 50 × 109/L).4-6 For ruxolitinib, the [starting dose] is based on platelet count, not on hemoglobin level.4

In practice, probably a lot of physicians don’t adhere strictly to the platelet criteria, and in a patient who is a little frail or cytopenic or who has anemia, you could maybe start at a lower dose and then escalate, depending on how they tolerate the treatment. Fedratinib is given as a [once-daily] dose of 400 mg, and it was studied in patients with a platelet count of at least 50 × 109/L.5 The dose of pacritinib is 200 mg twice daily.6 So ruxolitinib is the only one where you really [adjust] the dose a lot.

CASE UPDATE

The patient is not interested in transplant; a decision was made to initiate ruxolitinib.

What clinical trial data supported the use of ruxolitinib?

It’s amazing that these data are 11 years old. The studies were published in The New England Journal of Medicine. These data came from phase 3 randomized studies that compared ruxolitinib with placebo in COMFORT-I [NCT00952289] and ruxolitinib with best available therapy in COMFORT-II [NCT00934544].

The COMFORT-I and COMFORT-II studies demonstrated very similar things, [with ruxolitinib leading] to a significantly improved decrease in spleen volume [the percentage of patients with at least a 35% reduction; reductions of 41.9% and 28% were seen in the experimental arms of COMFORT-I and COMFORT-II, respectively]. Most patients on ruxolitinib had some improvement in splenomegaly, even if they didn’t meet the arbitrary 35% spleen volume reduction [cutoff].7,8

Similarly, patients on ruxolitinib compared with both placebo and best available therapy had a significant improvement in symptoms.7,8 In my experience, for patients who have lots of symptoms like itching and so on, there’s really nothing that can make those symptoms go away [as well as] the JAK inhibitors do.

The COMFORT studies used the Myeloproliferative Neoplasm Symptom Assessment Form plus other measures. These studies demonstrated that there was an improvement in symptoms like fatigue and appetite issues, and there was also overall improvement in global health status and functional status.7,8

The long-term data from the COMFORT studies have shown a survival benefit in the patients who were treated with ruxolitinib [median overall survival (pooled data from both studies), 5.3 years vs 3.8 years for the experimental and control arms, respectively].7,9

I think it’s interesting to think about why that was. Was it because of less transformation to leukemia, or was it because of an improved functional status and the ability to eat, drink, and be more functional and have a decreased inflammatory state? I think that is still unclear.

What was the relationship between spleen response and survival among patients treated with ruxolitinib?

Even though we don’t know the mechanism that’s driving the survival benefit, we do know that spleen response did correlate with outcomes [in a multicenter study of ruxolitinib]. Patients who had a spleen response seemed to do better than those who didn’t.10 And I think that’s intuitive. Patients who have more resistant disease obviously aren’t going to do as well.

What was the relationship between ruxolitinib dose and response (spleen volume or total symptom score) in the COMFORT-I trial?

An important point is that if you give a low dose of a JAK inhibitor, it’s not going to be that effective. That was definitely true for the spleen. Ruxolitinib was more effective at higher doses for spleen volume reduction. Interestingly, for symptom improvement, some patients had a good response with respect to some of their symptoms with a lower dose, but to get the maximal spleen response, you needed a higher dose. The responses didn’t always track exactly together.11

How was ruxolitinib tolerated in these studies?

It was, in general, well tolerated. But not surprisingly, ruxolitinib was associated with higher rates of anemia, thrombocytopenia, and neutropenia compared with placebo [and best available therapy].7,8

What data inform the use of ruxolitinib in patients with a platelet count in the range of 50 × 109/L to 100 × 109/L?

We know how to use ruxolitinib, [but] we use it on-label, [so when a patient’s platelet count is] below 100 × 109/L, we [don’t know] what to do. Do we give 5 mg? We know that a lower dose of ruxolitinib is not that effective. There was a study called EXPAND [NCT01317875], a phase 1b dose-finding study that evaluated different starting doses of ruxolitinib in patients with low platelet counts.

The patients were divided into a group of patients with platelet counts of 75 × 109/L to 99 × 109/L and another group of patients with platelet counts of 50 × 109/L to 74 × 109/L. They demonstrated that 10 mg twice daily was the maximal safe dose for both groups and showed that patients were able to stay on that dose.12,13

Similar to the COMFORT studies, the results of the EXPAND study showed that even if patients had low platelets, if they were treated with a slightly higher dose of ruxolitinib, they ended up having a pretty good response in terms of symptoms as well as in terms of spleen volume [Table].12,13 These data highlight that it’s probably safe to give ruxolitinib at lower platelet counts and also demonstrate that the higher dose, more than 5 mg, is associated with a greater improvement in spleen [volume reduction] in particular.

What data inform the use of ruxolitinib in patients with anemia of grade 3 or 4?

[Nearly half of the] patients on the COMFORT-I study had anemia at baseline.7,8 Importantly, efficacy was maintained despite anemia, and although some patients had to adjust their dose or receive a transfusion, [less than 1% of patients] had to discontinue ruxolitinib because of anemia.7 I would imagine that in the real world that would probably be different.

Some ruxolitinib studies have shown that if a patient develops anemia while on ruxolitinib, it’s not as bad as if they have anemia de novo, especially if that happens early in treatment.14 Of course, if a patient has been on ruxolitinib for a year or 2 and all of a sudden [develops] anemia, that’s different and probably related to disease progression.

It’s important to note that if you put a patient on ruxolitinib, they [can] become a little bit anemic. Some of them will [be anemic] the first month and then find their new baseline, which isn’t always exactly where they were before but is a little higher than the nadir. But that decrease at the beginning of treatment is not as concerning as that anemia that we see in patients who present up front with anemia.

How does a patient’s baseline hemoglobin level influence your decision of whether to give ruxolitinib?

I feel comfortable giving the drug. I would probably not give the on-label dose on the basis of their platelet count because especially those patients who are in the 7 [g/dL hemoglobin] range, I’m going to make them transfusion dependent.

But it’s something that warrants a conversation. It depends on how symptomatic that patient is. If a patient has horrible night sweats and is bothered by their spleen, they may not be as bothered by their anemia. But I do struggle with that, so if the patient is not that symptomatic, maybe I won’t push that JAK inhibitor as much or the dose as much.

It depends on the situation. Many times, I’ll do the JAK inhibitor alongside an erythropoiesis-stimulating agent [ESA] or something like that. I don’t love the recommendation to just give the [on-label] dose and give transfusions. I would prefer not to have to give transfusions.

Q:If the erythropoietin level is less than 500 mU/mL, do you give ruxolitinib? Do you add other agents?

I’ll try danazol or an ESA. Personally, I haven’t had that much success with ESAs in myelofibrosis. I’ve used luspatercept-aamt [Reblozyl] off-label, both with ruxolitinib and by itself, but…some of the insurances require that I try the ESA first.

Q:Would you consider using lenalidomide (Revlimid)?

I rarely end up using it. It is a little better tolerated than thalidomide [Thalomid]. It’s definitely an option, especially for those patients with thrombocytopenia [because] you don’t have much else to do. But I don’t find [these drugs] to be the most well tolerated. But that is definitely a recommendation. You can use [lenalidomide] to try to help with anemia.

REFERENCES

1. Deisseroth A, Kaminskas E, Grillo J, et al. U.S. Food and Drug Administration approval: ruxolitinib for the treatment of patients with intermediate and high-risk myelofibrosis. Clin Cancer Res. 2012;18(12):3212-3217. doi:10.1158/1078-0432.CCR-12-0653

2. FDA approves fedratinib for myelofibrosis. FDA. Updated August 16, 2019. Accessed May 16, 2023. https://tinyurl.com/5ej7s4tx

3. FDA approves drug for adults with rare form of bone marrow disorder. News release. FDA. March 1, 2022. Accessed May 16, 2023. https://tinyurl.com/4jcus8km

4. Jakafi. Prescribing information. Incyte Corporation; 2023. Accessed May 16, 2023. https://tinyurl.com/ua3rzhwr

5. Inrebic. Prescribing information. Bristol Myers Squibb; 2023. Accessed May 16, 2023. https://tinyurl.com/ms6emc6k

6. Vonjo. Prescribing information. CTI BioPharma Corp; 2022. Accessed May 16, 2023. https://tinyurl.com/5bpdwhku

7. 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

8. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787-798. doi:10.1056/NEJMoa1110556

9. 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

10. 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

11. Verstovsek S, Gotlib J, Gupta V, et al. Management of cytopenias in patients with myelofibrosis treated with ruxolitinib and effect of dose modifications on efficacy outcomes. Onco Targets Ther. 2013;7:13-21. doi:10.2147/OTT.S53348

12. 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

13. Gugleilmelli P, Kiladijan JJ, Vannucchi A, 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. Poster presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; virtual. Accessed May 16, 2023. https://tinyurl.com/bdzymsst

14. Gupta V, Harrison C, Hexner EO, et al. The impact of anemia on overall survival in patients with myelofibrosis treated with ruxolitinib in the COMFORT studies. Haematologica. 2016;101(12):e482-e484. doi:10.3324/haematol.2016.151449

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Dr Halpern on the MANIFEST Trial of Pelabresib and Ruxolitinib in Myelofibrosis

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Anna B. Halpern, MD

Anna B. Halpern, MD, physician, assistant professor, Clinical Research Division, Fred Hutch, assistant professor, hematology, University of Washington School of Medicine, discusses key efficacy data from the phase 1/2 MANIFEST trial (NCT02158858) investigating the BET inhibitor pelabresib (CPI-0610) plus ruxolitinib (Jakafi), and highlights the agents clinical significance in patients with myelofibrosis.

The global, open-label, nonrandomized, multicohort study evaluated the efficacy of the JAK inhibitor combination therapy vs pelabresib alone for treatment-naive or pretreated patient populations, Halpern begins. The trial involved 4 separate cohorts. These cohorts included the use of pelabresib in patients with JAK inhibitorpretreated myelofibrosis, pelabresib plus ruxolitinib in patients with ruxolitinib-pretreated myelofibrosis, pelabresib plus ruxolitinib in patients with JAK inhibitor–naïve myelofibrosis, and pelabresib alone in patients with essential thrombocythemia.

Halpern reports that results from the JAK inhibitor–naïve cohort showed that pelebresib plus ruxolitinib reduced spleen volume by at least 35% in 68% of patients, emphasizeing that total symptom score decreased by at least 50% in 56% of patients at 24 weeks. The data cutoff date for these findings was July 29, 2022.

Moreover, exploratory analysis revealed that 28% of patients had a grade 1 or greater improvement in fibrosis, while 29.5% experienced a greater than 25% reduction in JAK2 V617F VAF by week 24, Halpern details. These outcomes are of particular interest because they may indicate the disease-modifying ability of this combination, Halpern explains.

Based on these findings, the ongoing randomized, double-blind, phase 3 MANIFEST-2 trial (NCT04603495) is evaluating upfront pelabresib plus ruxolitinib vs ruxolitinib alone in a larger cohort of patients with JAK inhibitor–naïve myelofibrosis, Halpern concludes. Enrollment to this study was completed in May 2023, and topline findings are anticipated to report out in late 2023.

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FDA Grants Fast Track Designation to Myelofibrosis, Nasopharyngeal Cancer Therapies

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July 21, 2023

By Matthew Shinkle

The FDA granted fast track designation to two oncology therapies.

Selinexor (Karyopharm Therapeutics) — a selective inhibitor of nuclear export — received the designation for treatment of myelofibrosis, including primary myelofibrosis, post-essential thrombocythemia myelofibrosis and post-polycythemia vera myelofibrosis.

“Selinexor’s unique mechanism of action, XPO1 inhibition, is a novel and potentially fundamental mechanism in myelofibrosis,” Reshma Rangwala, MD, PhD, chief medical officer of Karyopharm, said in a company-issued press release.

The company initiated a pivotal phase 3 trial to assess the efficacy and safety of once-weekly selinexor in combination with ruxolitinib (Jakafi, Incyte) for JAK-naive patients with myelofibrosis. Initial data are expected in 2025.

BRG01 (Biosyngen) — an adoptive immune cell therapy — received the designation for treatment of certain patients with relapsed or metastatic nasopharyngeal carcinoma. The designation applies to use of the agent by patients with Epstein-Barr virus-positive disease.

FDA granted orphan drug designation to BRG01 earlier this year.

  • Karyopharm receives FDA fast track designation for selinexor for the treatment of myelofibrosis (press release). Available at: https://investors.karyopharm.com/2023-07-17-Karyopharm-Receives-FDA-Fast-Track-Designation-for-Selinexor-for-the-Treatment-of-Myelofibrosis. Published July 17, 2023. Accessed July 19, 2023.
  • Biosyngen’s first-in-class cell therapy BRG01 receives FDA fast track designation (press release). Available at: https://www.biosyngen.com/index.php?m=home&c=View&a=index&aid=107. Published July 10, 2023. Accessed July 19, 2023.

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BMS-986158–Based Combos May Provide Another Viable Treatment Approach in Myelofibrosis

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August 4, 2023

Courtney Flaherty

Haifa Kathrin Al-Ali, MD, provides background on the phase 1/2 study of BMS-986158, presents initial efficacy and safety data from the study, and discusses her hope that novel combination regimens like these could achieve the challenging goal of disease modification in myelofibrosis in the future.

The investigational, oral BET inhibitor BMS-986158 administered with either first-line ruxolitinib (Rituxan) or second-line fedratinib (Inrebic) showcased early efficacy and tolerability in patients with intermediate- or high-risk myelofibrosis. These data suggest that strategies combining BET and JAK inhibition can not only address myelofibrosis-related symptoms but may show potential for disease modification, according to Haifa Kathrin Al-Ali, MD.

Findings from the dose-escalation portion of the phase 1/2 CA011-023 trial (NCT04817007) were reported at the 2023 EHA Congress, and showed that both regimens had manageable toxicity profiles. In part 1A of the study, 82% of patients given BMS-986158 plus ruxolitinib experienced an any-grade treatment-related adverse effect (TRAE); this percentage was 75% in part 1B, which evaluated BMS-986158 plus fedratinib. Dose-limiting toxicities (DLTs) occurred in 2 patients in part 1A and 3 patients in part 1B.

Early efficacy data demonstrated that first-line BMS-986158 plus ruxolitinib led to spleen volume reduction (SVR) that became particularly robust by week 24. By week 48, 80% of patients (95% CI, 28%-100%) given the first-line ruxolitinib combination (n = 5) and 50% of those given the second-line fedratinib regimen experienced an SVR of at least 35%. In the ruxolitinib arm, the mean spleen volume change was –46.7% at week 12, –59.9% at week 24, and –56.3% at week 48; in the fedratinib arm, these percentages were –29.1%, -30.8%, and -33.0%, respectively.

“There is still a way to go, but these preliminary data are quite encouraging,” said Al-Ali, a professor of Translational Oncology and head of the Krukenberg Cancer Center at the University Hospital of Halle (Saale) in Germany.

In an interview with OncLive®, Al-Ali provided background on the phase 1/2 study of BMS-986158, presented initial efficacy and safety data from the study, and discussed her hope that novel combination regimens like these could achieve the challenging goal of disease modification in myelofibrosis in the future.

OncLive: What was the rationale for investigating the use of BET inhibitors as monotherapy or in combination with JAK inhibitors in myelofibrosis?

Al-Ali: We know that in patients [with myelofibrosis] there is a NF-κB–mediated pro-inflammatory cytokine profile. [This] leads to a dysregulated bone marrow microenvironment and osteoblastic differentiation, which contributes to the bone marrow fibrosis. It’s rational to use BET inhibitors because they have been shown to reduce or inhibit the expression of BET-targeted oncogenes like c-MYC and MYC.

Please describe the design of this study. Which patients were included this analysis, and what were the key objectives of the research?

This is an open-label, phase 1b/2 study. It mainly included patients with myelofibrosis who had splenomegaly and [had] either intermediate-1 [disease] plus symptoms, intermediate-2 [disease], or high-risk [disease, according to the Dynamic International Prognostic Scoring System]. The trial consisted of a dose-escalation phase followed by a dose-expansion phase. In the dose-escalation phase, there were also 2 parts. Part 1A [involved] first-line treatment with the BET inhibitor plus ruxolitinib in patients who had no previous exposure to ruxolitinib. [Part 1B consisted of] the second-line combination, [where] the BET inhibitor was combined with 400 mg of fedratinib and [was administered] once daily [to] patients with either intolerance or resistance to ruxolitinib.

This was a phase 1 study. [At the 2023 EHA Congress,] we presented the data from the dose-escalation phase, so the primary objective is always safety. The secondary objective was efficacy in terms of SVR. There were some exploratory analyses on JAK2 allele burden as well as bone marrow fibrosis.

According to data presented at the congress, what should be known about the safety of BMS-986158?

Regarding safety, [we] found that both the first-line combination with ruxolitinib or the second-line combination with fedratinib were feasible, tolerable, and the safety profiles were manageable. The main AE was thrombocytopenia, which is a class effect; it’s manageable and transient with dose modification or dose holding. The second major AEs were gastrointestinal [toxicities, including] diarrhea and nausea. Generally, these [effects] were mild, never led to the discontinuation of patients from the trial and were quite manageable.

What were the efficacy findings reported with these combinations?

Regarding efficacy, there are very promising results [showing] SVR of at least 35% from baseline by MRI. In the first-line cohort, there was a rapid and relevant reduction from baseline spleen volume [of at least 35%] in [73%] of patients [at week 12]. This seemed to be sustainable. Looking at SVR at week 24, 100% of patients [experienced] SVR. This is a phase 1 [study], and we should be careful, but these are encouraging results.

[Similar results were seen] with the second-line treatment, although the [duration of] follow-up was shorter. At week 12, at least [38%] of the patients [experienced] more than a 35% reduction in spleen volume. These are also encouraging results.

Finally, evidence for disease modification might be seen regarding JAK2 allele burden reduction. [This was] seen quite early, starting by cycle 6 in all the patients [with] JAK2-mutated [disease]. Additionally, in patients with follow-up bone marrow biopsies that could be evaluated, there seems to be a significant reduction in at least 1 grade of fibrosis by week 12 or week 24. [The study includes a] small number of patients, and these are preliminary, encouraging data. This bone marrow fibrosis regression seems to be associated with a hematological, [specifically] anemic, response.

You mentioned that potential evidence for disease modification may have been observed with this in the form of JAK2 allele burden reduction. In myelofibrosis, what efforts are currently underway to develop disease-modifying therapies that go beyond standard approaches focused on symptom management?

One of the major challenges [in myelofibrosis] is to see [clear evidence of successful] disease modification. All the biomarkers you can measure, like bone marrow fibrosis or a reduction in allele mutational burden, should have a clinical outcome correlation. This is a big challenge.

In the future, it is crucial to move away from only SVR and symptom improvement. We have great drugs that could do that. We have to wait for data from phase 3 randomized trials, and we need time to learn and [understand] the benefit of these combination treatments. My wish is to [achieve] sustainable, durable, clinical responses for patients with these combinations, but this is still an area with a lot of unanswered questions.

Are any next steps planned for the investigation of BMS-986158 in this disease?

The next step [for this research] is going further with the trial. The expansion phase has started for the first-line combination treatment in patients who are ruxolitinib naïve. The same will hopefully be happening for the second-line treatment. If these all [show] positive signals, we will move to a phase 3 clinical trial.

What is your main takeaway message for colleagues regarding this presentation?

The takeaway message is that it is feasible to have these combinations. We have learned how to dose [them] and how to manage AEs, which is the first step [for] every treatment. We have [also] shown encouraging preliminary clinical data regarding SVR, [as well as] some encouraging translational aspects like reduction in JAK allele burden or improvement in bone marrow fibrosis.

Overall, what was most exciting about this year’s EHA Congress?

[This year’s EHA Congress has] been particularly exciting. It is almost [solely] a myeloproliferative neoplasm congress because [there are] so many new, exciting datasets [being presented]—not only for a myelofibrosis, but also for polycythemia vera and essential thrombocythemia. At the end of the day, the most important winners will be the patients.

Reference

Ayala R, Lopez N, Abulafia AS, et al. BMS-986158, a potent BET inhibitor, as monotherapy and in combination with ruxolitinib or fedratinib in intermediate- or high-risk myelofibrosis (MF): results from a phase 1/2 study. Presented at the 2023 EHA Congress; June 8-11, 2023; Frankfurt, Germany. Abstract S213.

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Momelotinib Outperforms Danocrine in Myelofibrosis Symptom Mangament

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August 3, 2023

Brielle Benyon

Patients with previously treated myelofibrosis (a type of myeloproliferative neoplasm) tended to benefit more regarding symptom, spleen and anemia outcomes when administered a regimen of momelotinib compared with those given Danocrine (danazol), according to updated findings of the recently completed phase 3 MOMENTUM trial.

“Momelotinib was associated with durable symptom, spleen, and anemia benefits, late responses after week 24 and favorable safety through week 48. These results highlight the potential benefits of treatment with momelotinib in patients with myelofibrosis, particularly those with anemia,” the researchers wrote in their findings, which were published in the journal The Lancet Hematology.

The study involved 195 adults with post-polycythemia vera or post-essential thrombocythemia myelofibrosis that were previously treated with a JAK inhibitor for 90 days or more. Two-thirds of participants (130 patients) were randomly assigned to receive momelotinib, while the other third (65 patients) were randomly assigned to receive Danocrine.

After 24 weeks, all patients were eligible to receive momelotinib, and 93 (72%) and 41 (63%) in the momelotinib and Danocrine groups, respectively, entered the momelotinib open-label extension period.

Among the patients who continued on momelotinib treatment and were evaluable based on total symptom score criteria, 30 (45%) patients in the original momelotinib group and 15 (50%) in the Danocrine groups responded to treatment, meaning that their disease shrank or disappeared from the therapy.

A total of 45 patients (34.62%) in the momelotinib group died of any cause compared with 26 (40%) in the Danocrine group.

Momelotinib works by inhibiting JAK2 signaling pathway. Of note, JAK2 is a genetic mutation that is commonly found in patients with myeloproliferative neoplasms and leads to scarring in the bone marrow. This scarring inhibits the marrow’s ability to produce healthy blood cells — a condition known as myelofibrosis.

Long-term follow-up revealed no new side effects from momelotinib, with the most common non-blood-related side effects from the drug being diarrhea (45 patients [26%] in the momelotinib group) and weakness or lack of energy (28 [16%]). The most common moderate to severe (grade 3 or 4) side effects were thrombocytopenia (33 [19%]) and anemia (30 [18%]). A total of 79 patients (46%) given momelotinib experienced at least one serious side effect, and 30 patients (18%) died from a treatment-emergent side effect, with two fatal treatment-emergent side effects considered to be potentially linked to momelotinib.

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