CHA2DS2-VASC Predicted Thrombotic Risk in Patients With MPNs and Atrial Fibrillation

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November 16, 2023

Andrea S. Blevins Primeau, PhD, MBA

Although CHA2DS2-VASC does not account for myeloproliferative neoplasms (MPNs), it accurately predicted thrombotic risk in this patient population with atrial fibrillation (AF). However, HAS-BLED did not predict bleeding risk, according to the results of a retrospective study.

“Further investigation is needed to refine risk scores in MPN,” the authors wrote in their report. The study, which was published in the Journal of Thrombosis and Thrombolysis, analyzed data from 1617 patients with and 24,185 matched patients without MPNs from the National Readmission Database. All patients had AF. The primary outcomes were in-hospital or 30-day readmission for bleeding or thrombosis.

Characteristics were balanced between the cohorts. Overall, 29% of patients were on long-term anticoagulation, 25% were on long-term antiplatelet therapy. Comorbidities were common, with 76% of patients with hypertension, 42% with congestive heart failure, 35% with anemia, 33% with coronary artery disease, 24% with chronic lung disease, and 22% with diabetes.

However, patients with MPN were not at an increased risk of bleeding, with 2.60% experiencing a bleed compared with 2.98% of patients without MPNs (OR, 0.87; 95% CI, 0.63-1.19). Risk of bleeding was not accurately predicted by HAS-BLED, with a c-statistic of 0.55 (95% CI, 0.46-0.64) among patients with MPNs. For patients without MPN, the HAS-BLED was moderately predictive (c-statistic, 0.56; 95% CI, 0.54-0.58).

Patients with MPN were more likely to experience bleeding if their MPN type was essential thrombocythemia (P =.009), if they had anemia (P <.001), peripheral vascular disease (P =.024), or chronic kidney disease (P =.047). However, after multivariate analysis only ET remained independently associated with bleeding (adjusted OR, 3.08; 95% CI, 1.04-9.16).

Any hospital readmission within 30 days occurred among 18.6% of patients with MPN compared with 11.9% of patients without MPNs (P <.001). Within 90 days, 26.4% and 20.4% of patients with and without MPNs had a hospital readmission (P <.001).

Cardiovascular (CV)-related hospital readmission, which included arterial thrombosis, heart failure, and arrythmia, was also more common among patients with MPNs, occurring among 6.2% compared with 5.0% without MPN within 30 days (P =.046). However, there was no significant difference in CV readmission rates during the 90-day period.

Reference
Leiva O, How J, Grevet J, et al. In-hospital and readmission outcomes of patients with myeloproliferative neoplasms and atrial fibrillation: insights from the National Readmissions Database. J Thromb Thrombolysis. Published online October 15, 2023. doi: 10.1007/s11239-023-02900-z

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Allogeneic HCT Provides OS Benefit Independent of TP53 Allelic Status in MDS

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November 18, 2023

By Kyle Doherty

Patients with myelodysplastic syndrome (MDS) harboring a TP53 mutation experienced a survival benefit with allogeneic hematopoietic cell transplantation (HCT) compared with non-HCT treatment regardless of TP53 allelic status, according to findings from an analysis of the phase 2 Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1102 study (NCT02016781) published in the Journal of Clinical Oncology.1

Findings from a univariate analysis showed that, irrespective of treatment strategy, patients with a TP53 mutation (n = 87) experienced a 3-year overall survival (OS) rate of 21% (standard error [SE] ± 5%) compared with 52% (SE ± 4%) among patients who were TP53 wild-type (n = 222; HR, 2.55; 95% CI, 1.86-3.50; P < .001). Additionally, the 3-year OS rate among patients with a single TP53 mutation (n = 39) was comparable with that of patients with a TP53 multi-hit mutation (n = 48), at 22% (SE ± 8%) vs 20% (SE ± 6%), respectively (HR, 1.29; 95% CI, 0.79-2.11; P = .31).

When HCT was used as a time-dependent covariate, patients with a TP53 mutation who received HCT (n = 48) experienced a 3-year OS rate of 23% (SE ± 7%) vs 11% (SE ± 7%) in patients who were treated with non-HCT therapy (n = 32; HR, 1.76; 95% CI, 1.02-3.06; P = .04). Moreover, the 3-year OS rate among patients with very high-risk MDS per the Molecular International Prognostic Scoring System per molecular International Prostate Symptom Score (IPSS-M) without a TP53 mutation who received HCT (n = 22) was significantly improved compared with those with the same risk profile and mutational status who received non-HCT therapy (n = 8), at 68% (SE ± 10%) vs 0% (SE ± 12%), respectively (P = .001).

“The absence of a non-HCT control group in [other] retrospective analyses has called into question whether the long-term survival observed in these studies was reasonably attributable to the transplantation intervention,” investigators wrote. “In this study, we directly addressed this question and now conclude definitively that reduced intensity transplantation mediates long-term survival for patients with TP53-mutated MDS compared with non-HCT treatment. Moreover, we show that the benefit of HCT over non-HCT treatment was independent of TP53 allelic state and not restricted to specific subgroups of TP53-mutated MDS.”

Previously published findings from the primary analysis of BMT CTN 1102 showed that patients who received reduced intensity conditioning HCT (n = 260) achieved a 3-year OS rate of 47.9% (95% CI, 41.3%-54.1%) compared with 26.6% (95% CI, 18.4%-35.6%) among those who were treated with non-HCT therapy or best supportive care (n = 124), for an absolute difference of 21.3% (95% CI, 10.2%-31.8%; P = .0001). The 3-year leukemia-free survival rates were 35.8% (95% CI, 29.8%-41.8%) vs 20.6% (95% CI, 13.3%-29.1%), respectively (absolute difference, 15.2%; 95% CI, 13.3%-29.1%; P = .003).2

BMT CTN 1102 was a multicenter prospective trial that evaluated the efficacy of reduced intensity conditioning HCT (donor arm) vs that of hypomethylating therapy or best supportive care (no donor arm) in patients with IPSS intermediate-2 or high-risk de novo MDS who were 50 to 75 years old. To perform their genetic analysis of BMT CTN 1102, study authors performed targeted DNA sequencing on frozen whole blood samples collected at the time of enrollment, which were available for 229 patients in the donor arm and 80 patients in the no donor arm. Baseline patient characteristics did not differ significantly between those in the donor and no donor arms.1

Patients included in the genetic analysis (n = 309) had a median age of 66.9 years (range, 50.1-75.3), with most patients being over 65 years old (61.8%). Most patients were female (62.1%), had IPSS intermediate-2 disease (66.7%), and complex karyotype (65.0%). At baseline, the median hemoglobin was 9.3 g/dL (range, 8.1-10.7) and the median platelet count was 70 x 109/L (range, 34-132).

In addition to a univariate analysis, investigators constructed 2 multivariable models adjusted for age at enrollment, performance status, IPSS risk status, MDS disease duration, and clinical and genetic variables. One model was based on random assignment on the basis of donor availability and the other compared HCT vs non-HCT treatment with HCT representing a time-dependent covariate.

Additional findings from the univariate analysis showed that, outside of TP53 mutations, the presence of KMT2Apartial tandem duplications was associated with a decrease in 3-year OS rate compared with those who did not have these duplications (HR, 2.21; 95% CI, 1.22-3.99; P = .009). However, patients with a germline DDX41 mutation (HR, 0.39; 95% CI, 0.17-0.87; P = .022) and somatic mutations in STAG2 (HR, 0.57; 95% CI, 0.34-0.96; P = .034) displayed superior OS compared with those who did not have these mutations.

Results from the donor vs no donor analysis revealed that patients in the donor arm experienced an OS improvement compared with those assigned to the no donor arm (HR, 1.60; 95% CI, 1.10-2.32; P = .013). Among patients with a TP53 mutation, assignment to the donor arm did not significantly improve OS compared with the no donor arm (HR, 1.76; 95% CI, 0.95-3.26; P = .073).

In the model that compared HCT with non-HCT treatment, patients who received HCT (n = 197) experienced a significantly lower risk of death compared with those treated with non-HCT therapies (n = 78; HR, 2.31; 95% CI, 1.53-3.49; P < .001). Findings from this model showed that patients with a TP53 mutation had a much greater risk of dying if they did not receive HCT vs those who did (HR, 3.89; 95% CI, 1.87-8.12; P < .001), which study authors noted could signify that, “…HCT might improve long-term survival in patients with mutated TP53, independent of other risk factors.” Investigators also found molecular clearance of TP53 mutation before HCT not to be predictive of long-term survival.

“Together, these data indicate that no patient with TP53-mutated MDS should be excluded from consideration for HCT a priori on the basis of TP53 status alone. Despite the relative benefit of HCT over non-HCT treatment, however, the absolute survival benefit remains modest, meriting value-based discussions between physicians and patients on the appropriateness of transplantation,” study authors concluded.

Reference

  1. Versluis J, Saber W, Tsai HK, et al. Allogeneic hematopoietic cell transplantation improves outcome in myelodysplastic syndrome across high-risk genetic subgroups: genetic analysis of the blood and marrow transplant clinical trials network 1102 study. J Clin Oncol. 2023;41(28):4497-4510. doi:10.1200/JCO.23.00866
  2. Nakamura R, Saber W, Martens MJ, et al. Biologic assignment trial of reduced-intensity hematopoietic cell transplantation based on donor availability in patients 50-75 years of age with advanced myelodysplastic syndrome. J Clin Oncol. 2021;39(30):3328-3339. doi:10.1200/JCO.20.03380

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Increased Understanding of the Mechanisms of Myelofibrosis Helps Usher in New Treatments and Novel Agents

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November 16, 2023

By Ryan Scott

Research providing a growing understanding of the molecular mechanisms of myelofibrosis has helped facilitate the development of new treatments for this patient population, and novel agents are poised to continue emerging in this space, according to Gaby Hobbs, MD.

In February 2022, the FDA approved pacritinib (Vonjo)for the treatment of patients with intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 109/L.1 Additionally, the regulatory agency approved momelotinib (Ojjaara) for the treatment of patients with intermediate- or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis, and anemia in September 2023.2 Both agents inhibit ACVR1, and their approvals are examples of how the growing understanding of the biology of myelofibrosis is informing drug development.

“We have a better understanding of several mechanisms that are involved in the development and the pathophysiology of myelofibrosis,” Hobbs said in an interview with OncLive® following a State of the Science Summit™ (SOSS) on hematology, which she chaired.

In the interview, Hobbs discussed how further research into the biology of myelofibrosis has propelled the development of novel therapies for this patient population, expanded on ongoing and upcoming investigations of various agents, and highlighted the role that biomarkers play in the diagnosis, prognosis, and treatment response evaluation for these patients. Hobbs is a hematology-oncology physician, the clinical director of Leukemia Service, and an assistant in medicine at the Massachusetts General Hospital in Boston.

OncLive: Your presentations at the SOSS centered around the evolving treatment landscape of myelofibrosis and current standards of care. What were the key points you aimed to highlight during these discussions?

Hobbs: There have been a lot of changes in the therapies available for [patients with myelofibrosis] over the last couple of years. The first presentation focused on providing a brief overview of the current standard of care and new therapies that are available for [treating patients with] myelofibrosis.

The second talk [focused] an area where there’s still a lot of unmet need, which is anemia, [and I wanted to] give the audience an idea or approach on how to manage anemia for these patients, especially [after] the approval momelotinib.

What is the current understanding of the molecular mechanisms of myelofibrosis? How has this influenced the development of personalized treatment strategies for this patient population?

[The increased understanding of the mechanisms of myelofibrosis] has helped with some of the new drug approvals, including pacritinib and momelotinib. We were [previously] focused mostly on the JAK/STAT signaling pathway; now we appreciate that there are other signaling pathways that may also be involved in the pathophysiology of this disease.

For example, momelotinib and pacritinib also inhibit the ACVR1 pathway, which leads to an improvement in anemia. That’s a very clear way in which we’ve had improvement in therapies based on better understanding of the biology of [myelofibrosis].

Beyond momelotinib and pacritinib, are there any other agents currently under investigation in myelofibrosis that are intriguing?

There are many different agents that are currently being studied. The one that is most likely closest to being available to patients is luspatercept-aamt [Reblozyl], as that is already approved for patients with myelodysplastic syndrome, and that specifically will help patients with anemia. With regards to other novel therapeutics, there are many agents that are currently under development, including drugs like the telomerase inhibitor imetelstat, the BCL-2/BCL-XL inhibitor navitoclax, the BET inhibitor pelabresib [CPI-0610], the MDM2 inhibitor navtemadlin [formerly KRT-232], and the XPO1 inhibitor selinexor [Xpovio].

There are many agents under development now that [could] change the field of myelofibrosis from just having single-agent JAK inhibitors to having combination therapies that could hopefully help our patients live with less symptoms and also live longer.

What role do biomarkers play in the diagnosis, prognosis, and treatment response evaluation for patients with myelofibrosis?

When you say biomarkers in myelofibrosis, we rely significantly on genetic mutations and a variety of different risk scores to prognosticate for our patients. We know that patients with JAK2 mutations have different outcomes than those with CALR mutations. More specifically, we know that having additional mutations outside of JAK/STAT mutations also contribute to a negative prognosis, and those include mutations such as ASXL1, IDH, SRSF2, and EZH1. Those genetic mutations help us to understand prognosis with these patients, when taken into conjunction with other clinical variables that are included in [risk] scores.

References

  1. CTI BioPharma announces FDA accelerated approval of VONJO™ (pacritinib) for the treatment of adult patients with myelofibrosis and thrombocytopenia. CTI BioPharma Corp. News release. February 28, 2022. Accessed November 8, 2023. https://www.prnewswire.com/news-releases/cti-biopharma-announces-fda-accelerated-approval-of-vonjo-pacritinib-for-the-treatment-of-adult-patients-with-myelofibrosis-and-thrombocytopenia
  2. Ojaara (momelotinib) approved in the US as the first and only treatment indicated for myelofibrosis patients with anaemia. News release. GlaxoSmithKline. September 15, 2023. Accessed November 8, 2023. https://www.gsk.com/en-gb/media/press-releases/ojjaara-momelotinib-approved-in-the-us-as-the-first-and-only-treatment-indicated-for-myelofibrosis-patients-with-anaemia

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Dr. Lucia Masarova Discusses Indirect Comparison of Pacritinib and Momelotinib in Myelofibrosis

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November 16, 2023

By Patrick Daly

Dr. Masarova of The University of Texas MD Anderson Cancer Center in Houston, spoke with HemeToday on findings from a matched indirect treatment comparison of pacritinib and momelotinib in patients with mild myelofibrosis.

“I think it’s fantastic that we have a fourth inhibitor. It’s really good that [momelotinib] has a very broad indication for patients with myelofibrosis and anemia, where we haven’t had actually any drug,” Dr. Masarova said.

She detailed the mechanism of action of momelotinib and highlighted the relative benefits in safety and anemia response compared with pacritinib.

“The anemia responses that we have seen all seem to be little higher than those we’ve seen before although the mechanism of these agents is reported to be very similar. So that’s something that we’ll have to learn in clinical practice how to best sequence these patients and these agents in terms of patients responses,” Dr. Masarova said.

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$72 Million Funds Neoantigen-based Cancer Vaccine Candidates

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November 14, 2023

(Precision Vaccinations News)

Nouscom recently announced the completion of its Series C equity financing, raising $72 million that will be used to continue advancing and expanding Nouscom’s wholly-owned clinical pipeline to achieve multiple clinical value catalysts.

As of November 13, 2023, the funding proceeds will support the following initiatives:

Readout from Nouscom’s ongoing randomized Phase 2 clinical trial for NOUS-209, an off-the-shelf vaccine targeting 209 shared neoantigens, in combination with pembrolizumab for the treatment of Mismatch Repair/Microsatellite Instable Metastatic Colorectal Cancer.

Final readout from the ongoing Phase 1b study and advancement of NOUS-209 monotherapy in Lynch Syndrome carriers investigating the potential to intercept, prevent, or delay cancer before it occurs. LS carriers have a genetic predisposition to and, consequently, a higher risk of developing certain cancers. Promising initial results from this study were reported on October 31, 2023.

Completion of a Phase 1b study evaluating NOUS-PEV, a personalized cancer immunotherapy, in combination with a checkpoint inhibitor in patients with advanced melanoma and entry into randomized Phase 2 trials in indications with high unmet medical needs.

Nouscom has also exclusively out-licensed VAC-85135, an off-the-shelf immunotherapy developed under a multi-project agreement, which is currently under evaluation in a Phase 1 clinical trial for the treatment of Myeloproliferative Neoplasms sponsored by Janssen Research & Development and Bristol Myers Squibb.

Dr. Marina Udier, Chief Executive Officer of Nouscom, commented in a press release, “…. This financing will allow us to further accelerate development across our wholly-owned clinical portfolio reporting multiple clinical trial readouts, including from our ongoing randomized Phase 2 clinical trial with NOUS-209.”

“These Phase 2 data, if positive, have the potential to position Nouscom’s neoantigen-based cancer vaccines amongst the most thrilling developments in the field.”

According to a Review Article published by the journal Frontiers in Immunology in February 2023, Neoantigen vaccines are based on epitopes of antigenic parts of mutant proteins expressed in cancer cells. These highly immunogenic antigens may trigger the immune system to combat cancer cells.

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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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