Health Canada Slated to Review New Drug Submission for Momelotinib in Myelofibrosis

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Kristi Rosa

Health Canada has accepted for review the new drug submission seeking the approval of momelotinib in patients with myelofibrosis, according to a recent announcement from GlaxoSmithKline.1 The submission is based on findings from the phase 3 SIMPLIFY-1 (NCT01969838) and MOMENTUM (NCT04173494) trials.

Specifically, SIMPLIFY-1 data showed that of the 86 patients who received momelotinib, 31.4% (95% CI, 21.8%-42.3%) experienced a spleen volume response (SVR) reduction of 35% or higher vs 32.6% (95% CI, 23.4%-43.0%) of the 95 patients who received danazol.2

Moreover, findings from MOMENTUM indicated that a tumor symptom score (TSS) of at least 50% was observed in 25% of the 130 patients given momelotinib per the Myelofibrosis Symptom Assessment Form (MFSAF v4.0), representing a treatment difference of 16% (95% CI, 6%-26%; P < .01).2,3 The MFSAF v4.0 TSS change from baseline in the momelotinib and danazol arms were -9.4 and -3.1, respectively, equating to a difference of -6.2 (95% CI, -10 to -2.4; P = .001).

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Abstract WP249: Risk for Ischemic and Hemorrhagic Stroke is Increased in Veterans Exposed to Agent Orange and Those With Myeloproliferative Neoplasms

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Natasha Mathur, Andrew Tiu, Zoe McKinnell, Puneet Gill, Martha Antonio, Shanshan Liu, Guoqing Diao, Ramesh Subrahmanyam, Craig M Kessler and Maneesh R Jain

Abstract

Agent Orange (AO) is a dioxin containing defoliant and carcinogen used in the Korean and Vietnam War. There is limited evidence of the association between AO exposure among Veterans and stroke. Stroke is not yet part of the list of presumptive conditions according to the Promise to Address Comprehensive Toxics (PACT) Act which provides Veterans and their survivors disability compensation for conditions arising from exposure to AO. Myeloproliferative Neoplasms (MPN) are uncommon etiologies of stroke but whether AO exposure increases incidence of stroke in MPN has not been described.

Utilizing the Veterans Affairs Informatics and Computing Infrastructure (VINCI) database, a case-control study was performed from 1/1/2006 – 1/26/2023 on the Veterans from Illinois, the state most representative of the US population. ICD-9 and -10 codes identified Veterans with stroke and MPN. AO exposure was verified on the Veterans’ service duration and location. Qualitative data were compared by chi-square tests.

Among 586,555 Veterans from Illinois, there were 15,455 ischemic stroke (IS), 1,593 hemorrhagic stroke (HS), 2,752 MPN, and 59,393 with AO exposure. Among MPNs, there were 237 IS (41 with AO) and 26 HS (3 with AO). IS and HS were associated with AO exposure, OR 1.34 95% CI 1.28-1.41, p<0.0001, and OR 1.20 95% CI 1.03-1.39, p=0.02, respectively. MPN is associated with IS and HS, OR 3.52, 95% CI 3.08-4.03, and OR 3.54, 95% CI 2.4-5.23, both p<0.0001, respectively. There is no significant association with AO exposure among Veterans with MPN with stroke. Among non-MPN Veterans with AO exposure, there was an earlier median age of IS and HS, 67 vs. 70 and 67 vs. 71, both p<0.0001. There was no difference in median age of stroke among MPN Veterans with or without AO exposure. There were no differences with rates of hypertension, hyperlipidemia, diabetes, smoking, heart failure, and pulmonary hypertension among MPN Veterans with stroke with and without AO exposure.

In conclusion, there is an association of AO exposure with IS and HS with an earlier onset among those exposed. There is a strong association between MPN and stroke independent of AO exposure. The biologic plausibility of endothelial dysfunction and accelerated atherosclerosis from AO exposure warrants further investigation.

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Ambitious £4 million project to develop clinical platform for blood cancer prevention

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4th Feb 2024 – Edward Pinches

Professor George Vassiliou from the Wellcome-MRC Cambridge Stem Cell Institute (CSCI), University of Cambridge will spearhead the project, which focuses on myeloid blood cancers, a group of blood cancers that accounts for more than 11,000 deaths each year in the UK.

The blood cancers, which affect both the bone marrow and blood, include acute myeloid leukaemia (AML), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and rarer cancers like chronic myelomonocytic leukaemia (CMML).

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Truong on the Rationale for Investigating ERK2 Substrate Binding Modalities in MPNs

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Billy Truong, PhD candidate, Fox Chase Cancer Center, discusses the rationale for investigating the functions of ERK2 substrate binding modalities in myeloproliferative neoplasms (MPNs).

Truong and colleagues are conducting research investigating cell signaling programs that are altered in MPNs. Specifically, treatment resistance often arises from the activation of the MAPK pathway, Truong says. Approximately 85% of cancers have genetic modifications in proteins, especially in the RAS protein, which ultimately drive uncontrolled tumor cell proliferation, Truong explains.

Downstream of the MAPK pathway is the ERK2 protein, which is a common target of cancer therapies, Truong notes. However, drugs that target the kinase function of ERK2 are traditionally designed to be nonspecific and are therefore toxic to healthy cells expressing ERK2, Truong emphasizes. Accordingly, drug specificity remains an unmet need for patients with MPNs.

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A Patient Story: Labor of Love

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I have been living with an MPN for thirty-four years and sometimes that’s hard to believe!

When I was a young thirty years old, I was diagnosed with Essential Thrombocythemia.  After several years of adjusting to that diagnosis, my life became very routine.  I was working part-time as a teacher, raising two kids, and my husband and I were foster parents.  And six years after my diagnosis we adopted our third child.

Time moved along and in 2016 I was diagnosed with Myelofibrosis. Although I always knew that myelofibrosis was a possibility, I must admit the diagnosis shocked me.  Treatment started and we met with a transplant doctor to search for a donor. Much to our surprise we discovered that I had no donors in the registry.  I was also told that I would have less than a 1% chance of finding a matched donor due to having not one, but two rare HLA markers.

That disappointment was the motivation I needed to start helping myself and others.  My community helped me host donor drives and raise money for BeTheMatch.  We added over one thousand donors to the registry in three donor drives! I joined Facebook groups specifically for myelofibrosis and from these groups, I learned that patients consider the date they receive their new stem cells as their new birthday.

Even though a transplant was not going to be in my near future, I wanted to spread joy to those having a stem cell transplant.  I started making personalized “Happy Birthday” pillowcases and looked for patients in the Facebook groups posting about their upcoming transplants. The pillowcases are made from fabric printed with Happy Birthday, and I add a colorful border that has their name embroidered on it. Before I ship the pillowcases, I take a picture and post it to the Facebook page which allows me to get the word out that I gift pillowcases and for other group members to post well wishes. Now about 40% of the pillowcases I ship are based on requests and that makes me very happy!

Since I started making the pillowcases in the Fall of 2016, I have shipped two hundred ninety-two pillowcases to forty-one states and to seven countries!

I have found different kinds of happy birthday fabric so the patient never knows what design they will receive.  My pillowcases are made with prayers for the patient’s peace, patience, and perseverance as they recover.

I’ve come to realize that my diagnosis with not one, but two MPNs has become a real blessing to me.  We would not have adopted our youngest child without this diagnosis, I would not have had so many friends and family tell me how much I mean to them without this diagnosis, and I would not have been able to spread so much joy through the gift of the pillowcases without this diagnosis.

I feel that my life is like a book. It is up to me to decide how I am going to fill those pages. I have been blessed by a God who loves me fiercely and has given me an attitude of gratitude. So, I will fill those pages with goodness and work on blessing others.

Tremblay’s Approach to Cytoreduction Across MPNs

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Douglas Tremblay, MD

Douglas Tremblay, MD, assistant professor of medicine at the Icahn School of Medicine at Mount Sinai, discusses the factors which influence the decision to recommend cytoreduction for patients with essential thrombocytopenia (ET) and polycythemia vera (PV).

According to Tremblay, deciding when to start cytoreductive therapy in patients with chronic myeloproliferative neoplasms (MPN) patients like those with PV and ET hinges on accurate risk assessment. While risk stratification tools like the European LeukemiaNet (ELN) classification or the IPSET-Thrombosis score are valuable, Tremblay cautions against oversimplifying things.

He also emphasizes that different factors can indicate which patients are high-risk, including biological age and individual cardiovascular risk factors. Overall, utilizing a personalized approach to risk assessment is key when deciding on cytoreductive therapy for patients with MPN patients. Age should be considered within the context of their overall health and potential for vascular complications. With a personalized approach, experts can ensure that cytoreductive therapy is reserved for those who truly stand to benefit and avoids unnecessary treatment for others.

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Hobbs Highlights Key Research in Hematologic Malignancies at the 2023 ASH Annual Meeting

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Courtney Flaherty

Ruxolitinib (Jakafi)-based combinations continue to demonstrate promising ability to address splenomegaly and a signal toward improvement of tumor-related symptoms in myelofibrosis. As novel targets for development are unearthed and considered for evaluation in combination with standard JAK inhibition, the assessment of other meaningful end points is necessary to confirm the true benefit of such agents alone or in combination across myeloproliferative neoplasms (MPNs), according to Gabriela Hobbs, MD.

Results from the phase 3 TRANSFORM-1 study (NCT04472598)were presented at the 2023 ASH Annual Meeting and demonstrated that up-front navitoclax and ruxolitinib (Jakafi) significantly reduced spleen volume by 35% or more at week 24 vs ruxolitinib plus placebo in patients with myelofibrosis.1 Despite this, no significant difference in total symptom score (TSS) was observed between the arms.

Additionally, data from the phase 3 MANIFEST-2 trial (NCT04603495) showed that pelabresib (CPI-0610) plus ruxolitinib reduced spleen volume by 35% or more in 65.9% of patients with JAK inhibitor–naive myelofibrosis vs 35.2% in those who received placebo/ruxolitinib (95% CI, 21.6-39.3; P < .001). The agent also trended toward improving TSS reduction by 50% (TSS50) at 24 weeks.2

“One of the things we must answer as a field is: What is the benefit of using combination therapy for this disease?” Hobbs, who is clinical director of the Leukemia Service at Massachusetts General Cancer Center, and an assistant in medicine at Massachusetts General Hospital in Boston, Massachusetts, stressed in an interview with OncLive®News Network: On Location during the 2023 ASH Annual Meeting. “We need to have end points that are meaningful, [as well as] therapies that are well tolerated and affordable for patients.”

In the interview, Hobbs discussed the significance of key data from the TRANSFORM-1 and MANIFEST-2 trials for patients with myelofibrosis, expanded on the ongoing or future development of novel targets and potential combination regimens across MPNs, and spotlighted the phase 1/2 SAVE study (NCT05360160) and other key research efforts being made in leukemia.

OncLive: What key data on novel ruxolitinib-based combination regimens were reported at the 2023 ASH Annual Meeting?

Hobbs: I primarily treat MPN, and this is probably the first ASH Meeting where 2 different phase 3 studies [in this space] were presented at the same time. The navitoclax data are impressive, specifically when it comes to the improvement that we see with the combination of navitoclax and ruxolitinib for improving spleen volume response [SVR]. That can be very meaningful for patients—especially those with myelofibrosis who have very large spleens. We saw a very similar SVR with the combination of pelabresib and ruxolitinib as up-front therapy in patients who had not received a JAK inhibitor before.

How do you distinguish between these 2 agents in clinical practice?

In addition to showing an impressive improvement in SVR, neither study showed a dramatic improvement in symptoms [with the combinations] compared with ruxolitinib alone. That’s something that we need to consider. Pelabresib probably did a better job at improving symptoms than navitoclax. However, we need to start thinking about whether there are more meaningful end points other than expecting agents to improve SVR and symptoms. For example, could they potentially delay progression to leukemia, improve overall survival, or improve treatment outcomes in general or after transplant? Those are difficult end points to demonstrate, so they weren’t the primary objectives of the studies.

What other emerging agents of interest were discussed during the meeting?

There were lots of interesting novel agents presented at the meeting. There is a single-agent study [examining] a selective PIM kinase inhibitor and [we saw] some updated results in approximately 30 patients who have received the agent. [The agent appears to be] incredibly well tolerated, with very little impact on blood counts in a group of heavily pretreated patients. We’re also seeing a variety of other agents that are being developed. We’re seeing results from [the phase 2 VALENTINE-PTCL01 (NCT04703192)] study with the LSD1 inhibitor valemetostat tosylate [DS-3201b], an agent that also helps to prevent the development of fibrosis.

Are any of these agents viable options for further investigation as part of combination regimens?

That is the question to answer in [the] MPN [field]. Many studies have focused on combining a novel agent with a JAK inhibitor, primarily with ruxolitinib since it’s the one that has been around for the longest. I wouldn’t be surprised if the future of myelofibrosis [will be] to utilize combinations. [However,] we must remember that there’s a difference between treating patients in clinical trials vs treating patients in real life.

At this year’s meeting, findings from the phase 1/2 SAVE study of revumenib (SNDX-5613) plus decitabine/cedazuridine, (ASTX727) and venetoclax (Venclexta) were also presented. How did the results live up to expectations surrounding the use of menin inhibitors, and what are the next steps for the regimen?

That was an exciting study [done in] a group of patients with heavily pretreated AML. Some of these patients had undergone allogeneic stem cell transplantation and had received several lines of [prior] therapy. Patients who have refractory AML must go to clinic very frequently. Being able to offer them a regimen that’s all oral is very meaningful because [they do not] have to come to clinic as frequently to receive an IV hypomethylating agent. Most patients had at least some response [to the combination], and many had impressive responses. [Notably,] many patients had been previously treated with venetoclax. Menin inhibitors have been practice-changing in AML, and we’ve seen some responses [with this approach] in patients who have previously not responded to anything else. I look forward to seeing [more about] this combination, and hopefully [we can] bring it into earlier lines of therapy.

What were the biggest updates in chronic myeloid leukemia (CML) according to data presented at the meeting?

CML is very interesting. We all think that CML is a disease that we’ve conquered. We [see] great outcomes and almost normal life expectancy in most patients who are responding to therapy. [However], there is still a lot of development in the field. Several studies are investigating asciminib [Scemblix] in several different ways. The first study that we see is the [phase 3] ASCEMBL study [NCT03106779] comparing asciminib with bosutinib [Bosulif]. Updated [data presented at this year’s meeting] showed that asciminib is still outperforming bosutinib in terms of molecular remissions. [Investigators are] also studying asciminib in different, more creative ways in CML. They’re combining asciminib with other TKIs either in the up-front setting or in a later-line setting because of its slightly different mechanism of action. We’re also seeing the development of other TKIs that are either similar to asciminib or similar to ponatinib [Iclusig] in their mechanisms of action. There is still a lot of drug development in a disease where we thankfully have [achieved] a lot of great outcomes.

[It will be interesting to see how this next generation of agents impact current practice,] especially if they improve tolerability. For a disease where [a patient has] to be on life-long therapy, it’s important to have agents that are well tolerated.

Editor’s note: This interview was conducted prior to the conclusion of the 2023 ASCO Annual Meeting.

References

  1. Pemmaraju N, Mead AJ, Somervaille T, et al. Transform-1: a randomized, double-blind, placebo-controlled, multicenter, international phase 3 study of navitoclax in combination with ruxolitinib versus ruxolitinib plus placebo in patients with untreated myelofibrosis. Blood. 2023;142(suppl 1):620. doi:10.1182/blood-2023-173509
  2. Rampal R, Grosicki S, Chraniuk D, et al. Pelabresib in combination with ruxolitinib for Janus Kinase Inhibitor treatment-naïve patients with myelofibrosis: results of the MANIFEST-2 randomized, double-blind, phase 3 study. Blood. 2023;142(suppl 1):628. doi:10.1182/blood-2023-179141

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Exploring the Molecular Aspects of Myeloproliferative Neoplasms Associated with Unusual Site Vein Thrombosis: Review of the Literature and Latest Insights

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by Erika Morsia1,2,*, Elena Torre1, Francesco Martini 2,3, Sonia Morè 1,2, Antonella Poloni 1,2, Attilio Olivieri 1,2 and Serena Rupoli 1

Abstract

Myeloproliferative neoplasms (MPNs) are the leading causes of unusual site thrombosis, affecting nearly 40% of individuals with conditions like Budd–Chiari syndrome or portal vein thrombosis. Diagnosing MPNs in these cases is challenging because common indicators, such as spleen enlargement and elevated blood cell counts, can be obscured by portal hypertension or bleeding issues. Recent advancements in diagnostic tools have enhanced the accuracy of MPN diagnosis and classification. While bone marrow biopsies remain significant diagnostic criteria, molecular markers now play a pivotal role in both diagnosis and prognosis assessment. Hence, it is essential to initiate the diagnostic process for splanchnic vein thrombosis with a JAK2 V617F mutation screening, but a comprehensive approach is necessary. A multidisciplinary strategy is vital to accurately determine the specific subtype of MPNs, recommend additional tests, and propose the most effective treatment plan. Establishing specialized care pathways for patients with splanchnic vein thrombosis and underlying MPNs is crucial to tailor management approaches that reduce the risk of hematological outcomes and hepatic complications.

Molecular Genetic Profile of Myelofibrosis: Implications in the Diagnosis, Prognosis, and Treatment Advancements

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by Tanvi Verma 1, Nikolaos Papadantonakis2, Deniz Peker Barclift1 and Linsheng Zhang

Simple Summary

Myelofibrosis refers to fibrosis in the bone marrow associated with certain bone marrow cancers. It is a characteristic of primary myelofibrosis and may develop later in other bone marrow cancers with overproduction of blood cells, such as polycythemia vera and essential thrombocythemia. It has been confirmed that mutations in three key genes, Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia oncogene (MPL), can increase the activity of blood-producing cells, make them grow more actively, and are associated with the development of myelofibrosis. Approximately 80% of myelofibrosis cases carry additional mutations that often involve proteins that control how genes are turned on and off. The presence of mutations provides evidence of a cancerous process. The order in which these mutations occur can influence how the disease manifests. Studies have shown that fibrosis is secondary to the cancerous process and is closely linked to abnormal cell growth driven by mutations. Sophisticated scoring systems have been developed to guide treatment decisions. Specific mutations and genetic changes significantly affect the scores and survival of individual patients. Currently, common treatment involves JAK inhibitors, which can help improve clinical symptoms; however, only a small number of patients show significant alleviation in the biology of the malignant process. New treatments being explored in clinical trials include drugs that target the regulation of genes and substances that modulate the immune system or inflammatory processes. Combining these with JAK inhibitors shows promising results, especially in patients with complex genetic profiles. In the future, by studying more genes, it is expected that researchers will uncover the reasons behind cases where mutations are not found in the three key genes and understand how genetic changes are connected to variable disease presentations, ultimately guiding personalized treatment plans for better outcomes with a chance for cures.

Abstract

Myelofibrosis (MF) is an essential element of primary myelofibrosis, whereas secondary MF may develop in the advanced stages of other myeloid neoplasms, especially polycythemia vera and essential thrombocythemia. Over the last two decades, advances in molecular diagnostic techniques, particularly the integration of next-generation sequencing in clinical laboratories, have revolutionized the diagnosis, classification, and clinical decision making of myelofibrosis. Driver mutations involving JAK2, CALR, and MPL induce hyperactivity in the JAK-STAT signaling pathway, which plays a central role in cell survival and proliferation. Approximately 80% of myelofibrosis cases harbor additional mutations, frequently in the genes responsible for epigenetic regulation and RNA splicing. Detecting these mutations is crucial for diagnosing myeloproliferative neoplasms (MPNs), especially in cases where no mutations are present in the three driver genes (triple-negative MPNs). While fibrosis in the bone marrow results from the disturbance of inflammatory cytokines, it is fundamentally associated with mutation-driven hematopoiesis. The mutation profile and order of acquiring diverse mutations influence the MPN phenotype. Mutation profiling reveals clonal diversity in MF, offering insights into the clonal evolution of neoplastic progression. Prognostic prediction plays a pivotal role in guiding the treatment of myelofibrosis. Mutation profiles and cytogenetic abnormalities have been integrated into advanced prognostic scoring systems and personalized risk stratification for MF. Presently, JAK inhibitors are part of the standard of care for MF, with newer generations developed for enhanced efficacy and reduced adverse effects. However, only a minority of patients have achieved a significant molecular-level response. Clinical trials exploring innovative approaches, such as combining hypomethylation agents that target epigenetic regulators, drugs proven effective in myelodysplastic syndrome, or immune and inflammatory modulators with JAK inhibitors, have demonstrated promising results. These combinations may be more effective in patients with high-risk mutations and complex mutation profiles. Expanding mutation profiling studies with more sensitive and specific molecular methods, as well as sequencing a broader spectrum of genes in clinical patients, may reveal molecular mechanisms in cases currently lacking detectable driver mutations, provide a better understanding of the association between genetic alterations and clinical phenotypes, and offer valuable information to advance personalized treatment protocols to improve long-term survival and eradicate mutant clones with the hope of curing MF.

European Commission Approves Momelotinib for Myelofibrosis/Anemia

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Ariana Pelosci

The European Commission granted marketing authorization to momelotinib (Omjjara) for patients with primary myelofibrosis who have disease-related splenomegaly or moderate to severe anemia, according to a press release from GSK.1

This indication also covers patients with post polycythemia vera myelofibrosis or post essential thrombocythemia myelofibrosis who are JAK inhibitor naïve or received previous treatment with ruxolitinib (Jakafi). The authorization is based on results from the phase 3 MOMENTUM trial (NCT04173494), which analyzed the use of momelotinib and danazol in patients with symptomatic and anemic myelofibrosis.2

“The challenges of living with myelofibrosis can be burdensome, and symptomatic patients can experience spleen enlargement, fatigue, night sweats, and bone pain. Until now, there have been no options specifically indicated to treat these symptoms in patients who also experience anemia. The authorization of [momelotinib] brings a new treatment option with a differentiated mechanism of action to these patients in the European Union,” Nina Mojas, senior vice president of Oncology Global Product Strategy at GSK, said in the press release.

In the trial, the total symptom score response at week 24 was 24.6% (95% CI, 17.49%-32.94%) for patients receiving momelotinib vs 9.2% (95% CI, 3.46%-19.02%) in the danazol arm (P = .0095). Additionally, a reduction of splenic volume by 25% occurred in 40.0% (95% CI, 31.51%-48.95%) of patients in the momelotinib arm vs 6.2% (95% CI, 1.70%-15.01%; P <.0001) in the danazol arm. A 35% reduction in spleen volume was also observed in 23.1% (95% CI, 16.14%-31.28%) in the momelotinib arm and 3.1% (95% CI, 0.37%-10.68%; P = .0006) in the danazol arm.

In September 2023, the FDA approved momelotinib for patients with intermediate- or high-risk myelofibrosis, including primary and secondary myelofibrosis, who are experiencing anemia.3 In November 2023, the European Medicine’s Agency’s Committee for Medicinal Products for Human Use expressed a positive opinion for momelotinib.4 The positive opinion was one of the final steps leading to the approval of the drug in the European Union.

“I think [momelotinib] will make an immediate impact. There clearly are individuals now who are on JAK inhibitors like ruxolitinib or fedratinib [Inrebic] who have significant anemia who will immediately be potential candidates,” Ruben A. Mesa, MD, FACP, said in an interview with CancerNetwork® prior to the FDA approval. Mesa is the president of the Enterprise Cancer Service Line and senior vice president at Atrium Health; executive director of the National Cancer Institute-designated Atrium Health Wake Forest Baptist Comprehensive Cancer Center; and vice dean for Cancer Programs at Wake Forest University School of Medicine.

References

  1. European Commission authorises GSK’s Omjjara (momelotinib). News release. GSK. January 29, 2024. Accessed January 29, 2024. https://shorturl.at/ntuvy
  2. Mesa RA, Gerds AT, Vannucchi A, et al. MPN-478 MOMENTUM: phase 3 randomized study of momelotinib (MMB) versus danazol (DAN) in symptomatic and anemic myelofibrosis (MF) patients previously treated with a JAK inhibitor. J Clin Oncol. 2022;40(suppl 16):7002. doi:10.1200/JCO.2022.40.16_suppl.7002
  3. Ojjaara (momelotinib) approved in the US as the first and only treatment indicated for myelofibrosis patients with anaemia, News release. GSK. September 15, 2023. Accessed January 29, 2024. https://shorturl.at/jnNQY
  4. GSK receives positive CHMP opinion recommending momelotinib for myelofibrosis patients with anaemia. News release. GSK. November 13, 2023. Accessed January 29, 2024. https://bit.ly/3MEYpOl

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