Pacritinib Is One Option for Patients with Myelofibrosis and Anemia

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The Janus kinase (JAK) 1 and 2 inhibitor ruxolitinib and the JAK2 inhibitor fedratinib, both approved by the U.S. Food and Drug Administration (FDA), are effective at reducing constitutional symptoms and spleen size in patients with myelofibrosis (MF) but often worsen anemia and increase transfusion needs. A study published in Blood Advances highlights a potential role for pacritinib among patients with MF and anemia.1

Aaron Gerds, MD, MS, associate professor at Cleveland Clinic Taussig Cancer Institute, editor-in-chief of ASH Clinical News, and a coauthor of the recent paper, pointed out that the myeloproliferative neoplasm community has become increasingly interested in the hepcidin pathway in the treatment of anemia. Anemia in MF is multifactorial but seems to be partially driven by inflammatory cytokines and disease-related inflammation. This leads to increased production of the acute phase reactant hepcidin, which reduces iron transport out of cells and decreases serum iron levels, impairing erythropoiesis.

Momelotinib is a JAK1/JAK2 inhibitor that also inhibits activin A receptor, type 1 (ACVR1), which works upstream of the hepcidin gene. On September 15, the FDA approved momelotinib for the treatment of intermediate- or high-risk MF with anemia, regardless of prior therapy, making it the first therapy specifically for MF with anemia.

Researchers wanted to explore the potential role of pacritinib in patients with MF and anemia. Pacritinib is a JAK1 sparing inhibitor of JAK2 and IRAK1 (part of the toll-like receptor signaling pathway), as well as ACVR1; it is currently FDA-approved for patients with intermediate- or high-risk MF with a platelet count below 50,000/mcL. “Pacritinib works in a very similar manner to treat anemia as momelotinib, a drug specifically developed to ameliorate anemia in MF,” Dr. Gerds said.

In the phase III PERSIST-2 study of more than 300 patients with MF and thrombocytopenia, pacritinib demonstrated benefits for anemia. Patients on pacritinib experienced higher rates of clinical improvement in hemoglobin at week 24 compared to those treated with current best available therapy (which included ruxolitinib in some patients).2

The recent study retrospectively analyzed additional data from the PERSIST-2 trial. The researchers found that of patients who still required transfusion at baseline, a significantly greater proportion of those who received pacritinib (200 mg BID) became transfusion independent compared to those on best available therapy (37% vs. 7%, respectively; p=0.001). Moreover, significantly more patients on pacritinib had a greater than 50% reduction in transfusion burden (49% vs. 9%, respectively; p<0.0001).1

The authors also performed additional in vitro data to assess the ACVR1 pathway and compare potency of other JAK2 inhibitors. They found the half-maximal inhibitory concentration (IC50) using serial dilutions and used the maximum plasma concentration at the clinically recommended dose (Cmax) to calculate inhibitory potency (Cmax:IC50). Pacritinib displayed the greater potency compared to momelotinib, fedratinib, or ruxolitinib (12.7 vs. 3.2, 1, and <0.01, respectively). Moreover, they demonstrated in further assays that pacritinib and momelotinib most potently reduced the expression of hepcidin in liver culture cells.1

Partly based on these data, the most recent National Comprehensive Cancer Network guideline recommends pacritinib as a frontline agent for patients below 100,000 platelets/mcL and as a second-line agent regardless of platelet count.3

Dr. Gerds said the retrospective nature of the study is a key limitation. He also noted that differences between baseline characteristics of patients in this and other trials with JAK inhibitors make it difficult to compare agents, and in an ideal world, a prospective trial could assess the best approach to anemia in patients with MF.

“Pacritinib led to significant numbers of patients having improvement in their hemoglobin levels in a manner that’s like the way momelotinib works,” Dr. Gerds said. “To me, the take-home point is that in patients who have MF and anemia, you want to think about pacritinib as a possible treatment for their anemia.”

Any conflicts of interest declared by the authors can be found in the original article.

References

  1. Oh ST, Mesa RA, Harrison CN, et al. Pacritinib is a potent ACVR1 inhibitor with significant anemia benefit in patients with myelofibrosis. Blood Adv. 2023;7(19):5835-5842.
  2. Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs best available therapy, including ruxolitinib, in patients with myelofibrosis: a randomized clinical trial. JAMA Oncol. 2018;4(5):652-659.
  3. Gerds AT, Gotlib J, Abdelmessieh P, et al. Myeloproliferative neoplasms. Version 2.2023. NCCN Clinical Practice Guidelines in Oncology. https://www.nccn.org/guidelines/recently-published-guidelines.

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MPN Linked to Lower Death and Cardiac Arrest, Higher Bleeding in Patients Hospitalized With AMI

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Among patients hospitalized with acute myocardial infarction (AMI), those with myeloproliferative neoplasms (MPN) have an increased risk of in-hospital bleeding but a decreased risk of in-hospital death or cardiac arrest compared with patients without MPNs. This is according to a study published in JACC: CardioOncology.

“MPN poses a clinical conundrum. They are a heterogenous group of clonal hematopoietic neoplasms that portend a prognosis measured in years in some cases,” said Orly Leiva, MD, of the New York University Grossman School of Medicine. “The association between MPN and thrombosis has been well described. However, outcomes among patients with MPN who have had AMI have not been well studied.

“There are no current guidelines on specific treatment of AMI among patients with MPN. As such, current treatment of patients with MPN, including revascularization strategy and choice and duration of antithrombotic therapies, is usually made per current guidelines of the general population and on an individual basis based on the patient’s perceived thrombotic and bleeding risks,” Dr. Leiva said. “Our study aimed to shed some light on describing the characteristics of patients with MPN admitted for AMI and outcomes compared to the general population and to encourage further study that may lead to a more refined and personalized approach to the management of AMI among patients with MPN.”

Between January 2006 and December 2018, 1,644,304 patients (mean age = 67.2 years; 61.1% male) admitted for AMI were identified using the National Inpatient Sample, which captures around 20% of hospitalizations in the U.S. Among the 5,374 patients (0.3%) with MPN, 48.8% had polycythemia vera (PV), 47.8% had essential thrombocythemia (ET), and 5.8% had primary myelofibrosis (MF). The procedures captured included left heart catheterization, percutaneous coronary intervention (PCI), mechanical circulatory support (MCS), and coronary artery bypass grafting (CABG). The researchers compared the in-hospital outcomes between patients with and without MPN. The primary outcome was in-hospital death or cardiac arrest, and the secondary outcome was major bleeding.

Baseline patient characteristics were adequately balanced between patients with and without MPN after propensity score weighting. Compared with patients without MPN, those with MPN had a lower risk of in-hospital death or cardiac arrest (odds ratio [OR] = 0.83; 95% CI 0.82-0.84) but a higher risk of major bleeding (OR=1.29; 95% CI 1.28-1.30). Patients without MPN had a decreasing temporal rate of in-hospital death or cardiac arrest and bleeding (ptrend<0.001 for both). However, patients with MPN had an increasing temporal rate of in-hospital death or cardiac arrest (ptrend<0.001) and a stable rate of major bleeding (ptrend=0.48). This was despite a similar reduction in ST-segment elevation myocardial infarction (STEMI) presentations between patients with and without MPN over time (ptrend for both < 0.001). The risk factors associated with an increased likelihood of death, cardiac arrest, or bleeding included peripheral vascular disease, anemia, STEMI presentation, and an ET and primary MF MPN phenotype.

Invasive management (left heart catheterization, PCI, or CABG) was lower, although not significantly so, in patients with MPN than in those without (68.8% vs. 71.6%; SMD = 0.06). Patients with MPN were less likely than those without MPN to undergo PCI (38.3% vs. 43.2%; standardized mean difference [SMD] = 0.10) but not CABG (8.9% vs. 8.8%; SMD = 0.002). For patients with and without MPN, use of MCS (5.5% vs. 5.0%; SMD = 0.018) and prevalence of cardiogenic shock (3.6% vs. 3.9%; SMD = 0.02) were similar.

“Our study suggested no increase in in-hospital mortality among patients with MPN compared with the general population. However, patients with MPN had increased rates of bleeding events, including gastrointestinal and procedure-related bleeding,” said Dr. Leiva. “Additionally, patients with MPN were less likely to be treated with PCI.”

Limitations to the study include its retrospective design. Further, the data in the National Inpatient Sample are abstracted from billing codes, which are prone to errors. Data on the treatment of MPN, blood counts, disease duration, and genetic testing (JAK2 mutation) are not reported and may affect cardiovascular outcomes.

“My hope is that our study spurs further research on the management of AMI among patients with MPN and other cancers to better understand bleeding and thrombotic risk and to develop therapeutic paradigms that better balance these competing risks,” Dr. Leiva said.

Any conflicts of interest declared by the authors can be found in the original article.

Reference

Leiva O, Xia Y, Siddiqui E, et al. Outcomes of patients with myeloproliferative neoplasms admitted with myocardial infarction: insights from National Inpatient Sample. JACC CardioOncol. 2023;5(4):457-468.

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CHMP Shares Positive Opinion of Momelotinib for Myelofibrosis/Anemia

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November 13, 2023

Hayley Virgil

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has expressed a positive opinion on momelotinib (Ojjaara) as a treatment for patients with moderate to severe anemia with primary myelofibrosis, post–polycythemia vera myelofibrosis, or post-essential thrombocythemia, as well as disease-related splenomegaly according to a press release from GSK.1

Patients who are JAK inhibitor naïve or have previous treatment with ruxolitinib (Jakafi) can also receive treatment with momelotinib.

The positive opinion marks one of the final steps leading to the agent’s potential approval. If approved, momelotinib would be the only agent in Europe available for treating moderate to severe anemia in newly diagnosed and previously treated myelofibrosis, as well as potentially resolving splenomegaly and other symptoms.

“Momelotinib has a differentiated mechanism of action that may address the significant medical needs of [patients with] myelofibrosis, especially those with moderate to severe anemia,” Nina Mojas, senior vice president of Oncology Global Product Strategy at GSK, said in the press release. “The vast majority of [patients with] myelofibrosis will develop anemia, causing them to require transfusions and leading a notable proportion to discontinue treatment. This positive CHMP opinion is a significant step in bringing momelotinib to patients in the EU with this difficult-to-treat blood cancer.”

The positive opinion was supported by several clinical trials, including the phase 3 MOMENTEUM study (NCT04173494) and a patient subgroup from the phase 3 SIMPLIFY-1 study (NCT02101268) with moderate to severe anemia.2,3

Findings from the MOMENTEUM trial, which included 195 patients, showed a 24-week total symptom score response rate of 24.6% (95% CI, 17.49%-32.94%) among those treated with momelotinib compared with 9.2% (95% CI, 3.46%-19.02%) in those treated with danazol (P =

.0095). Additionally, a splenic volume reduction of 25% was observed in 40.0% (95% CI, 31.51%-48.95%) vs 6.2% (95% CI, 1.70%-15.01%), respectively, as well as a 35% reduction in 23.1% (95% CI, 16.14%-31.28%) vs 3.1% (95% CI, 0.37%-10.68%; P = .0006).

Additionally, in the SIMPLIFY-1 study, which included 432 patients, investigators reported a reduction in total symptom score of 50% or more in 28.4% of patients treated with momelotinib and 42.2% in those treated with ruxolitinib (P = .98).

Common adverse effects across both studies included diarrhea, thrombocytopenia, nausea, headache, dizziness, fatigue, asthenia, abdominal pain, and cough.

The FDA approved momelotinib for patients with myelofibrosis and anemia in September 2023.4

References

  1. GSK receives positive CHMP opinion recommending momelotinib for myelofibrosis patients with anaemia. News release. GSK. November 13, 2023. Accessed November 13, 2023. https://bit.ly/3MEYpOl
  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. Mesa RA, Kiladjian JJ, Catalano JV, et al. SIMPLIFY-1: a phase III randomized trial of momelotinib versus ruxolitinib in janus kinase inhibitor-naïve patients with myelofibrosis. J Clin Oncol. 2017;34(suppl 34):3844-3850. doi:10.1200/JCO.2017.73.4418
  4. 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 November 13, 2023. https://bit.ly/46eFscj

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GSK and Queer Eye’s Thom Filicia Partner on Blood Cancer Awareness Initiative

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• GSK launches Mapping Myelofibrosis to help chart course for those affected by the disease.
• Myelofibrosis is a complex blood cancer that impacts nearly 25,000 people in the U.S.

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Issued: Philadelphia, PA

GSK plc (LSE/NYSE: GSK) has partnered with former Queer Eye star and interior designer Thom Filicia to launch Mapping Myelofibrosis, a new health education initiative aiming to help those impacted by myelofibrosis (MF) better navigate the disease. This year marks the 10-year anniversary of Filicia donating bone marrow to his brother, who was diagnosed with MF a few months prior to the transplant. Filicia now looks to use his voice to help raise awareness of this blood cancer, which can be difficult to diagnose and manage.1

MF impacts nearly 25,000 people in the U.S. and is part of a larger group of blood cancers that affect the bone marrow, called myeloproliferative neoplasms (MPNs).2,3 Each person experiences MF differently, presenting significant challenges in identifying symptoms and mapping out treatment paths.1

“After my brother’s diagnosis, we didn’t understand the magnitude of what he was up against,” said Filicia. “The reality of MF presents unique challenges for each individual, and as my brother overcame this disease, I realized the need to ensure more accessible information and resources. This experience led me to team up with GSK on Mapping Myelofibrosis to continue raising awareness of this complex blood cancer.”

Mapping Myelofibrosis includes the launch of a website featuring educational resources about MF, community stories, and messages from Filicia. In developing the initiative, GSK sought input from the MF community through collaborations with organizations including the MPN Research Foundation (MPNRF) and MPN Advocacy & Education International (MPN A&E).

Faris El Refaie, Head of Oncology, US of GSK said: “At GSK, we are committed to advancing the standard of care in oncology and supporting communities impacted by hematologic cancers. Recognizing an unmet need in myelofibrosis, we developed Mapping Myelofibrosis to cultivate awareness and provide a platform to foster support and education.”

Kapila Viges, CEO of MPN Research Foundation said: “This initiative by GSK represents a meaningful step forward in ensuring those living with MF and their families have access to tailored resources to help guide them through the complexities of this disease. Hearing Filicia tell his story reinforces the importance of enhancing our understanding of MF, and all MPNs.”

Ann Brazeau, CEO and Founder of MPN A&E said: “Ensuring that patients with MF and their loved ones feel seen and heard while navigating a rare disease is so important. Educational resources like GSK’s Mapping Myelofibrosis initiative are critical for patients and their families when it comes to making informed decisions around their care.”

In early stages, approximately one third of individuals with MF will not exhibit symptoms.1 However, key signs and symptoms of the disease may include, but are not limited to low blood counts (anemia), low platelet counts (thrombocytopenia) or enlarged spleen (splenomegaly).1 For those who have not been diagnosed, early detection of the disease may be beneficial. For those who have been diagnosed, understanding your symptoms is key to making informed decisions regarding treatment and care with your healthcare providers.1

Explore MappingMF.com to find resources and learn more.

About Mapping Myelofibrosis
GSK created Mapping Myelofibrosis to increase awareness of myelofibrosis, seeking to connect the community with educational tools, resources and stories to help navigate all aspects of the disease.

Explore MappingMF.com to find resources and learn more about myelofibrosis. You can also follow the initiative on Facebook.

About myelofibrosis (MF)
Myelofibrosis is a complex blood cancer affecting approximately 25,000 people in the U.S.2 MF is part of a larger group of blood cancers that affect the blood and bone marrow, known as myeloproliferative neoplasms, or MPNs.3 In people with MF, blood cells may not be produced in a typical way, causing inflammation and scarring of the bone marrow, which is called fibrosis.3 The signs and symptoms of MF may include severe low blood counts or anemia, enlarged spleen (splenomegaly), low blood platelets (thrombocytopenia), and other symptoms.1

GSK in oncology
GSK is focused on maximizing patient survival through transformational medicines. GSK’s pipeline is focused on immuno-oncology, tumor cell targeting therapies and synthetic lethality. Our goal is to achieve a sustainable flow of new treatments based on a diversified portfolio of investigational medicines utilizing modalities such as small molecules, antibodies and antibody-drug conjugates, either alone or in combination.

About GSK
GSK is a global biopharma company with a purpose to unite science, technology, and talent to get ahead of disease together. Find out more at gsk.com.

References:
1. Cleveland Clinic. Myelofibrosis. Available at: https://my.clevelandclinic.org/health/diseases/15672-myelofibrosis. Accessed October 2023
2. Data on file. Sierra Oncology. 2021.
3. MPN Research Foundation. Primary Myelofibrosis (PMF). Available at: http://www.mpnresearchfoundation.org/primary-myelofibrosis-pmf/.Accessed October 2023.

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Dr Tremblay on the Identification and Prevalence of MDS/MPN Overlap Syndromes

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Douglas A. Tremblay, MD

Douglas A. Tremblay, MD, assistant professor, medicine, Icahn School of Medicine at Mount Sinai, discusses the prevalence of myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap syndromes and the evolving treatment paradigm for these diseases, which he discussed in a presentation at the 41st Annual CFS®.

MDS/MPN overlap syndromes include a cluster of 4 related diseases: chronic myelomonocytic leukemia (CMML); atypical chronic myeloid leukemia; MDS/MPN with ring sideroblasts and thrombocytosis; and unclassifiable MDS/MPN, Tremblay says. These diseases are often difficult to manage because they share many characteristics that are indicative of both myeloproliferative diseases and MDS, Tremblay notes. Although these conditions are considered rare, they are likely more prevalent than initially hypothesized because of the overlapping nature of MPNs and MDS, Tremblay explains. However, treatment decisions for patients with these overlap syndromes are typically influenced by insights garnered from the MDS and MPN treatment paradigms, Tremblay emphasizes. In the future, the management of these overlap syndromes may become more specialized, Tremblay says. Tailored therapies are emerging, particularly in the CMML field, where JAK inhibitors have gained prominence, Tremblay explains.

Treatment decisions for patients with MDS/MPN overlap syndromes are largely based on the main issue patients experience, such as cytopenias, splenomegaly, or constitutional syndromes, Tremblay notes. Overall, patients with high-risk disease should be referred to autologous stem cell transplant because it is the only curative therapy for these syndromes, Tremblay says. Conversely, many of the treatment strategies for patients who are ineligible for transplant, such as hypomethylating agents (HMAs), are borrowed from the MDS/MPN treatment paradigms, Tremblay explains. However, HMAs have displayed limited efficacy in this population, Tremblay emphasizes. For instance, the phase 3 DACOTA trial (NCT02214407) showed no difference in event-free survival (EFS) or overall survival (OS) with decitabine vs hydroxyurea in patients with a myeloproliferative subtype of CMML.

Efforts to find effective therapies for patients with MDS/MPN overlap syndromes beyond HMAs have spurred research with JAK inhibitors in patients with CMML, according to Tremblay. The JAK-STAT signaling pathway is hypersensitive in CMML cells, and preclinical studies have shown the efficacy of halting that pathway, Tremblay says. Furthermore, a phase 1/2 trial (NCT03722407) showed the advantages of using ruxolitinib (Rituxan) to improve spleen and symptom responses in patients with CMML. Further research is investigating JAK inhibitors in combination with HMAs in patients with CMML and other MDS/MPN overlap syndromes, Tremblay concludes.

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Characteristics, Primary Treatment, And Survival of MDS/MPN with Neutrophilia: A Population-Based Study

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Saskia Klein (UMCG, Netherlands) Gerwin Huls (University Medical Center Groningen, Netherlands), Otto Visser (IKNL, Netherlands) Hanneke Kluin-Nelemans (University Medical Center Groningen, University og Groningen, Netherlands) Avinash Dinmohamed (Erasmus MC AND Amsterdam UMC, Netherlands)

Abstract
MDS/ MPN with neutrophilia, until recently called atypical chronic myeloid leukemia (aCML), being part of the myelodysplastic/myeloproliferative neoplasms is a very rare disease with poor prognosis. Although emerging data reveal its cytogenetic and molecular profile, integrated survival and treatment data remain scarce. We analyzed a cohort of 347 adult patients diagnosed with MDS/
MPN with neutrophilia, registered in the Netherlands Cancer Registry between 2001 and 2019. Our demographic baseline data align with other cohorts. We observed cytogenetic aberrations exclusively in patients aged >65 years, with trisomy 8 being the most common abnormality. We identified 16 distinct molecular mutations, with some patients (16/101) harboring up to 3 different mutations; ASXL1 being the most frequent one (22%). In a multivariable Cox regression analysis, only age, hemoglobin level and allogeneic hematopoietic stem cell transplant (alloHSCT) were associated with overall survival (>65 years of age HR 1.85, P=0.001 and alloHSCT HR 0.51, P=0.039). As no other treatment modality, seemed to impact survival and might cause toxicity, we propose that all patients eligible for alloHSCT should whenever possible receive an allogeneic transplant. It is imperative that we strive to improve outcomes for patients not eligible for alloHSCT. Tackling this challenge requires international collaborative efforts to conduct prospective intervention studies.

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Long-Acting Interferon: Pioneering Disease Modification of Myeloproliferative Neoplasms

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Seug Yun Yoon, Sung-Yong Kim

Abstract

Myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoietic stem cells. The malignant clones produce cytokines that drive self-perpetuating inflammatory responses and tend to transform into more aggressive clones, leading to disease progression. The progression of MPNs follows a biological sequence from the early phases of malignancy, polycythemia vera, and essential thrombocythemia, to advanced myelofibrosis and leukemic transformation. To date, the treatment of MPNs has focused on preventing thrombosis by decreasing blood cell counts and relieving disease-related symptoms. However, interferon (IFN) has been used to treat MPNs because of its ability to attack cancer cells directly and modulate the immune system. IFN also has the potential to modulate diseases by inhibiting JAK2 mutations, and recent studies have demonstrated clinical and molecular improvements. Long-acting IFN is administered less frequently and has fewer adverse effects than conventional IFN. The current state of research on long-acting IFN in patients with MPNs is discussed, along with future directions.

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MPN Subtypes May Predict Risk of Thromboembolic Events

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November 8, 2023

Johnathan Goodman, MPHiL

Patients with BCR-ABL-negative myeloproliferative neoplasms (MPNs) are at an increased risk of arterial and venous thromboembolic (ATE and VTE, respectively) complications, according to research published in Hamostaseologie. Patients with polycythemia vera (PV), furthermore, appeared to be at a particularly high risk for these events.
BCR-ABL-negative MPNs, which include PV, essential thrombocythemia (ET), and myelofibrosis (MF), are each associated with an increased risk of VTE and ATE. These events, moreover, are linked with an increased risk of both morbidity and mortality.

Previous research has suggested that JAK2 mutations are linked with an increased risk of thromboembolic events, while CALR mutations in the MF setting may reduce this risk. Detailed data in these populations are lacking, necessitating further study for risk stratification.

Overall, in the enrolled cohort, 39.1% of patients were male, the median age at MPN diagnosis was 50.7 years, and 31.7%, 34.1%, and 31.1% of patients had ET, PV, and MF, respectively; 3% of patients had an unclassified MPN. Genetic analysis showed that 69.8% of patients had a JAK2 mutation, while 14.4% of patients had a CALR mutation.

The median follow-up was 6.6 years, during which 180 first thromboembolic events were noted; 105 and 75 events were VTEs and ATEs, respectively. The incidence rate for first ATE or VTE was 2.43% per patient/year; the overall probability of a vascular event was 36.2%.

The most commonly noted VTE subtype was deep vein thrombosis (incidence rate, 0.59% per patient/year); the most common ATE subtype was stroke (incidence rate, 0.32% per patient/year).

Analysis showed that PV was linked with a higher risk of ATE or VTE (hazard ratio [HR], 1.66; 95% CI, 1.206-2.286). Compared with JAK2 mutations, CALR mutations were linked with a lower risk of these events (HR, 0.346; 95% CI, 0.172-0.699).

“While patients diagnosed with PV or generally JAK2 mutated MPN patients had a significantly increased risk of thromboembolic complications compared with the other MPN subtypes, this risk was significantly reduced in CALR-mutated patients,” the authors wrote in their report.

Reference

Wille K, Deventer E, Sadjadian P, et al. Arterial and venous thromboembolic complications in 832 patients with BCR-ABL-negative myeloproliferative neoplasms. Hamostaseologie. Published online October 9, 2023. doi:10.1055/a-2159-8767

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Exploring Promising New Treatments for Myeloproliferative Neoplasms

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By Catlin Nalley

With ongoing advancements, the therapeutic landscape for myeloproliferative neoplasms continues to evolve. Naveen Pemmaraju, MD, Associate Professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center, discussed where the field currently stands during his presentation, “Promising New Drugs for MPN Therapy,” at the International Congress on Myeloproliferative Neoplasms, held November 2-3, 2023, in New York.

When it comes to myeloproliferative neoplasms, “we have entered into a new golden era of research and potential that we have never seen before,” he noted. “Our field has been previously dominated by the first breakthrough—JAK inhibitor monotherapy—which was fantastic for our patients. However, as much of a revolution as this era was, by and large, it did not lead to cures of the disease. The only curative therapy as we close 2023 remains allogeneic stem cell transplant.”

In recent years, the field has seen breakthroughs with novel agents beyond the JAK/STAT pathway, according to Pemmaraju, who also highlighted the growing exploration of combination therapies in this patient population. “This is an important time in the MPN field,” he emphasized. “All of this is coming together, hopefully for the immediate good of our patients and then also establishing a new scientific era in myeloproliferative neoplasms,” he stated.

Main Takeaways

While discussing his presentation—and the MPN field as a whole—with Oncology Times, Pemmaraju highlighted a research study that explored life after ruxolitinib in myelofibrosis patients (Cancer 2020; doi: 10.1002/cncr.32664). Interestingly, he noted that the trial found that 40.8 percent of patients had stopped ruxolitinib at 3 years. Reasons for discontinuation included lack or loss of a spleen response, ruxolitinib-related adverse events, progression to blast phase, ruxolitinib-unrelated adverse events, and allogeneic transplantation during response.

The data also showed that the median survival after ruxolitinib was 13.2 months and the use of investigational agents was in fact associated with improved outcomes versus conventional agents, according to Pemmaraju, who noted this underscores the importance of ongoing investigation and advances.

In terms of combination treatments, Pemmaraju highlighted many different approaches, such as navitoclax, a BCL-XL/BCL-2 inhibitor. The potential of this agent has been explored in several studies, including the Phase II REFINE study (J Clin Oncol 2022; doi: 10.1200/JCO.21.02188). Data showed the addition of navitoclax to ruxolitinib among patients with persistent or progressive myelofibrosis led to durable spleen volume reduction, improved total symptom score, and hemoglobin response, reported Pemmaraju, an investigator on the trial.

Two phase III trials are currently underway to further explore the combination of navitoclax and ruxolitinib. The TRANSFORM-1 study is a frontline, upfront JAK inhibitor-naive study of ruxolitinib plus navitoclax versus ruxolitinib plus placebo. The other Phase III study, TRANSFORM-2, is looking at the efficacy and safety of this combination beyond the frontline setting.

Pemmaraju also highlighted several new novel agents that could have an impact on how we approach the treatment of MPNs. This includes but is not limited to agents that target the MDM2 pathway, telomerase inhibition, and cell cycle.

Additionally, he discussed another avenue targeting anemia in myelofibrosis. For instance, momelotinib was recently approved in September 2023 for intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis (post-polycythemia vera and post-essential thrombocythemia), in adults with anemia. Luspatercept is another example. This agent recently gained FDA approval for the treatment of anemia in myelodysplastic syndrome and is currently being studied in patients with myelofibrosis.

As the field evolves and advancements continue, Pemmaraju emphasized what is most important—the patient. “Everything we do is for our patients and every stakeholder has an important role to play,” he said. “Let’s continue to have awesome discoveries in the lab. Let’s pledge together to try to translate those quickly with all of our stakeholders who can help bring these findings to the clinic.

“And then, let’s make a pledge together to disseminate those findings accurately, faithfully, and rapidly through all platforms, not just academic literature, so that everyone can see these data in real time, debate, discuss, and have a say,” Pemmaraju concluded.

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Is Treatment for Cytopenic Myelofibrosis Still an Unmet Clinical Need?

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Madeline Caduc and Steffen Koschmieder

Nov 2023

Philadelphia-negative myeloproliferative neoplasms (MPN), including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are a group of clonal hematological disorders driven by mutated hematopoietic stem cells. MF, as de novo myeloid malignancy (primary MF: PMF) or secondary to an antecedent MPN (post-ET-MF or post-PV-MF), is a life-threatening condition associated with shortened survival and risk of leukemic transformation in about 20% of the patients. Clonal expansion of malignant myeloid stem- and progenitor cells and stromal changes along with increased proinflammatory cytokines production drive the remodeling of the bone marrow (BM) microenvironment and disrupt physiological hematopoiesis. Clinical manifestations of MF-associated progressive BM failure, such as cytopenia (anemia, thrombocytopenia), hepatosplenomegaly, constitutional symptoms (eg, weight loss, fever, night sweating), significantly impact patients’ quality-of-life (QoL) and correlate with poor prognosis for overall survival (OS).,

The identification of a constitutive JAK–STAT pathway activity and underlying somatic driver mutations in the janus kinase 2 (jak2), calreticulin (calr), and thrombopoietin receptor (mpl) genes has revolutionized the therapeutic landscape with the development of JAK inhibitors (JAKi).

Ruxolitinib, a dual JAK1/JAK2 inhibitor, was the first JAKi approved for treatment in patients with intermediate- or high-risk MF (U.S. Food and Drug Administration [FDA]) or MF with disease-associated splenomegaly or symptoms (European Medicines Agency [EMA]) and remains the standard of care. However, although 2 phase 3 clinical trials, COMFORT-I and –II, demonstrated that ruxolitinib induces rapid spleen volume reductions (SVR) as well as symptom improvement, treatment discontinuations are frequent (up to 60% in 3 y), because of grade of ≥3 cytopenia, and resulting in suboptimal symptom control, risk of disease relapse, and decreased survival.–

Nearly a decade later, the selective JAK2 and FMS-like tyrosine kinase 3 (FLT3) inhibitor fedratinib was approved for the treatment of intermediate and high-risk MF (FDA) or MF with disease-associated splenomegaly or symptoms (EMA). Although fedratinib was active in untreated patients but also patients with documented progression during ruxolitinib or intolerance to ruxolitinib, fedratinib induced comparable myelosuppression with anemia and thrombocytopenia as the most common causes for treatment discontinuation. Thus, although the development of JAKi has significantly improved MF treatment, cytopenic myelofibrosis still presents a significant unmet medical need.

Pacritinib, a potent JAK2 and interleukin-1 receptor associated kinase 1 (IRAK1) inhibitor, received FDA-approval for use in MF patients with platelet counts of ≤50 × 109/L, based on the results of the PERSIST-1 and PERSIST-2 studies. The efficacy and safety of pacritinib compared with physician’s choice of therapy (including ruxolitinib) is currently being further investigated in MF patients with severe thrombocytopenia in the phase 3 study PACIFICA (NCT03165734). Interestingly, a post hoc analysis of the PERSIST-2 study showed an anemia benefit in patients treated with pacritinib, which was attributed to activin A receptor type 1 (ACVR1) inhibition. However, further investigations are needed to unravel the detailed biological mechanisms involved, including the role of IRAK1 inhibition.

The pathophysiology of MF-related anemia has not been fully deciphered. In addition to progressive reticulin deposition, dysregulation of iron homeostasis has emerged as a pivotal process for disruption of normal erythropoiesis. Hepcidin, a key regulator of iron metabolism, was discovered to be elevated in MF patients, and this upregulation proved to be unresponsive to ruxolitinib treatment. Interestingly, the combined JAK1/2 inhibitor, Momelotinib (MMB), also inhibits ACVR1 and thereby decreases hepcidin, emerging as a promising therapeutic alternative for patients with MF-related anemia. MMB was assessed as treatment of intermediate- or high-risk MF patients in 2 phase 3 trials, SIMPLIFY-1 and SIMPLIFY-2. Although MMB met the primary endpoint in the SIMPLIFY-1 trial (noninferiority to ruxolitinib regarding spleen volume response), the key secondary endpoint was not met (noninferiority to ruxolitinib regarding symptom response). However, MMB activity demonstrated consistent anemia benefits including conversion to transfusion-independence (TI), SVR, and QoL improvement, when compared with baseline. The SIMPLIFY-2 trial evaluated the superiority of MMB over the best available therapy (BAT) in MF patients who had previously received ruxolitinib treatment. The defectiveness of currently available therapies for cytopenic MF was emphasized by the fact that 89% of the BAT patients continued treatment with ruxolitinib. However, the primary endpoint (superiority of MMB versus BAT regarding spleen volume reduction at week 24 [SVR24]) was not met, although the MMB group demonstrated a higher rate of conversion to TI, emphasizing its anemia-alleviating potential when compared with BAT. Of note, the lack of JAKi washout period before MMB-treatment start might have influenced the results.

Recently, MMB-induced anemia benefit was further investigated in the double-blind, (2:1) randomized clinical trial of MMB versus danazol, the MOMENTUM trial. This trial enrolled MF patients with failure to JAKi treatment, moderate-to-severe anemia (hemoglobin <10 g/dL), and a total symptom score (TSS) ≥10. The primary endpoint, a ≥50% reduction in the mean TSS at week 24, was met, as well as key secondary endpoints, including TI rate at week 24 and SVR24. Importantly, several of the symptoms were not directly correlated with anemia (eg, early satiety, abdominal discomfort, bone pain, and night sweats). Thus, inferiority of danazol might not be surprising. However, at the time of the study, danazol treatment was in alignment with the guidelines of the National Comprehensive Cancer Network and the European Society of Medical Oncology for the management of MF-associated anemia.

In the present HemaSphere issue, Mesa et al present novel data from the MOMENTUM trial, bridging the knowledge gap of how MMB impacts MF-associated symptoms. In line with the results of SIMPLIFY-1 and -2, MMB improved anemia and led to a higher proportion of patients achieving TI compared to the danazol group. Interestingly, some patients experienced fatigue relief without attaining TI. Although some anemia benefits might have not been captured by the strict TI endpoint of the study, these findings underscore the multifactorial pathogenesis of fatigue. Thus, MMB treatment–associated benefits may well extend beyond its proerythrogenic activity with the reduction of cytokines production as a possible mechanism for the reported TSS improvement. However, as pointed out by the investigators, although patient-reported fatigue was a secondary endpoint of MOMENTUM, the trial was not designed to explore the relationship between anemia and symptoms. Further investigations will be needed.

In addition to anemia and RBC transfusion–dependency, recent surveys emphasized severe thrombocytopenia (platelet count ≤50 × 109/L) as a critical negative prognostic factor, with higher rates of both hemorrhagic and thrombotic complications, as well as a higher risk for leukemic transformation. Furthermore, fatigue as a multifactorial and burdensome MF-symptom with significant repercussion on patients’ cognitive, physical, and social functioning was shown to be significantly increased in thrombocytopenic MF patients.

In a second publication in this HemaSphere issue, Kiladjian et al present data from their post hoc combined analysis of the SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM trials on the efficacy and safety of MMB in patients with thrombocytopenia. All patients with baseline platelet counts of <100 × 109/L were included and defined as the “sub-100 group.” Of note, patients with severe thrombopenia (<50 × 109/L) were not analyzed separately because of low patient numbers but were integrated within the sub-100 group. Overall, platelet counts were stable or increased in the MMB treated sub-100 group, enabling continuous adequate dosing beyond the initial 24-week-treatment period. Interestingly, this retrospective analysis of the SIMPLIFY trials indicates a reduced ruxolitinib effectiveness in patients with platelet counts below 100 × 109/L. The numerically higher TSS reduction, SVR, and conversation rate to TI in the MMB group may be because of a higher myelosuppressive activity of ruxolitinib, leading to more frequent dose reductions and treatment discontinuations. Thus, this post hoc analysis suggests that MMB may be superior to ruxolitinib, BAT, and danazol in patients with low platelet counts, without altering the safety profile. However, because of the descriptive nature of this analysis, prospective real world data will be required to confirm these results.

In summary, the new results of the SIMPLIFY-1, SIMPLIFY-2, and MOMENTUM trials underline the potential of MMB to expand our treatment options for MF patients, particularly those with symptomatic and/or RBC transfusion–dependent anemia. MMB has recently been approved by the FDA for the treatment of intermediate- or high-risk MF in adults with anemia.

In addition, several new therapeutic agents are presently under clinical investigation, either as monotherapy or as add-on therapies to JAK inhibitor. Much of their success will depend on their ability to target the underlying disease pathophysiology, to lead to clinically meaningful long-term eradication of the malignant clone and cure of the patients from MF. Thus, the unmet clinical need for the treatment of cytopenic MF is lessened, but it still exists.