A Grand Time in Grand Rapids

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MPN Advocacy & Education International held an in-person patient/caregiver event in Grand Rapids, Michigan on April 25th. The room buzzed with excitement and camaraderie as patients and caregivers had the opportunity to engage with each other and MPN experts on a wide range of topics. 

Dr. Anas Al-Janadi gave an overview of the history of MPNs and defined where we are in our current understanding of the disease and what the future may hold. While exciting discoveries were made that supported the development of drug therapies for MPN patients; such as the JAK2 mutation in 2005 and later the MPL and CALR mutations, the MPN community is still working to better understand the reasons for disease progression and ways to reduce symptom burden.

Dr. Kristin Pettit, on the heels of her wedding (Congrats, Dr. Pettit), discussed the challenges MPN patients have flying, having elective or emergency surgeries, symptom management, and some critical women’s issues. Each topic had the following take-aways: check with your doctor and practice good self-care. Dr. Pettit emphasized hydration, healthy eating, exercise and reducing stress.

Dr. Aaron Gerds shared a play-by-play of diagnosing and treating MPNs. He began by situating ET, PV, and MF on the greater spectrum of Myeloid Neoplasms. Dr. Gerds, along with the other experts that presented, stressed the importance of a good clinical examination including a thorough history and a hands-on physical examination. Gerds went on to describe the testing required to make a proper MPN diagnosis, such as; blood counts, chemistries, infectious disease, bone marrow biopsy, and molecular testing. Afterwards, he walked us through the process of navigating individual risk and treatment options using the National Comprehensive Cancer Network (NCCN) Guidelines for Myelofibrosis. 

Justin Grinell, owner and head trainer of State of Fitness, reminded us that our health is not our fault, but it is our responsibility. He shared some ways to move toward a healthy lifestyle by incorporating an 11 min movement break in our day. To take just 11 minutes each day doing something active at your own Zone 2 (when your heart rate is 180 minus your age) can have an accumulative positive effect on not just your body but on your brain as well. Be sure to look for Justin this summer during our Healthy Summer Series webinars where you can join Justin for a quick lunch-time workout. 

Finally, Dr. Craig Kessler implored patients to ask questions. Ask your doctor questions about the treatment plan they create for you. Ask what component of MPN symptoms they are focusing on, and how the treatment they recommend will address that component (anemia, blood counts, spleen reduction, etc.). He stressed getting your COVID-19 vaccine and boosters. He also made clear that your questions matter and not to be afraid to ask.

We want to thank the specialists for sharing their valuable information and spending their time away from their respective institutions. We also want to thank our patients and their family members and friends for joining us and asking such thought-provoking questions. We hope that you will have a chance to join us at our next MPN Advocacy and Education International in-person event in Asheville, NC on Thursday August 22nd. To learn more, please visit www.mpnadvocacy.com/events-list.

Dr Sekeres on the Rationale for the FDA Approval of Momelotinib in Myelofibrosis

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Mikkael A. Sekeres, MD, MS

Mikkael A. Sekeres, MD, MS, professor, medicine, chief, Division of Hematology, Leukemia Section, the University of Miami Health System, Sylvester Comprehensive Cancer Center, discusses the background on the FDA approval of momelotinib (Ojjaara) for the treatment of patients with anemic myelofibrosis.

At a recent OncLive® State of the Science Summit™ on hematologic malignancies, Sekeres and colleagues provided updates in the realm of myelodysplastic syndromes. Notably, one of these updates includes the FDA approval of momelotinib for the treatment of adult patients with intermediate or high-risk myelofibrosis with anemia. Originally, the phase 3 SIMPLIFY-1 (NCT01969838) and SIMPLIFY-2 (NCT02101268) trials investigated momelotinib compared with ruxolitinib (Jakafi) and momelotinib compared with best available therapy, respectively, Sekeres begins. In SIMPLIFY-2, although patients receiving momelotinib didn’t show a significant improvement in spleen response, they experienced a notable enhancement in symptom score, a benefit that is crucial for patients with myelofibrosis, he reports.

Subsequently, the phase 3 MOMENTUM trial (NCT04173494) was initiated, randomly assigning symptomatic patients with myelofibrosis in a 2:1 ratio to receive either momelotinib or danazol. Notably, significant improvement in symptom scores was observed with momelotinib, Sekeres states, saying that furthermore, substantial improvement in spleen size reduction was noted, forming the basis for momelotinib’s FDA approval. Additionally, there was a trend toward enhanced red blood cell transfusion independence rates among patients, Sekeres adds.

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Masarova on the Latest Updates Across Myeloproliferative Neoplasms

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Lucia Masarova, MD

Lucia Masarova, MD, PhD, assistant professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses some of the latest updates across myeloproliferative neoplasms (MPNs).

She discusses some significant studies, including the TRANSFORM-1 and MANIFEST-2 studies (NCT04472598; NCT04603495), and emerging therapeutic approaches, like combining ruxolitinib (Jakafi) with other agents, such as pelabresib (CPI-0610) and navitoclax.

Transcription:

0:09 | We are waiting for the top-line results of the phase 3 studies of the frontline ruxolitinib and the navitoclax vs ruxolitinib and placebo, as well as the top-line results of the other combo of ruxolitinib and pelabresib vs ruxolitinib and placebo. Both of those, the TRANSFORM-1 and MANIFEST-2 study studies, are highly expected results. They are coming to see whether we can move from the monotherapy of a JAK inhibitor to the combination of arms of both of the agents. That will expand the field, hopefully, and we will see where it is going to go. [There are] excellent results for spleen control that are exciting, the symptoms will need to be worked out, so we will see where it goes.

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Connecting Spleen Volume Reduction to Survival Outcomes in MF

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Targeted Oncology Staff

CASE SUMMARY

A 68-year-old woman presented to her physician with symptoms of mild fatigue. Her spleen was palpable 6-7 cm below the left costal margin​, but she had no known comorbidities. Next-generation sequencing revealed a JAK2 V617F mutation​, and her karyotype was46XX.​ A bone marrow biopsy showed megakaryocyte proliferation and atypia with evidence of reticulin fibrosis​, and a blood smear was positive for leukoerythroblastosis​.

Her laboratory values also led to a diagnosis of primary myelofibrosis (MF). Risk stratification based on the dynamic international prognostic scoring system gave her a score of intermediate-1, and based on the mutation-enhanced international prognostic score system for transplantation-age she was also determined to be at intermediate risk​.

DISCUSSION QUESTIONS

  • Did the overall survival data from the COMFORT-I trial (NCT00952289) and COMFORT-II trial (NCT00934544) impact the way you manage patients with MF?​
  • How do you monitor and manage anemia in patients with primary MF prior to starting Janus kinase (JAK) inhibitor therapy?​

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How the PERSIST-2 Results Show The Benefit of Pacritinib in MF

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Targeted Oncology Staff

Targeted Oncology: What was the make-up of the PERSIST-2 trial (NCT02055781) looking at pacritinib (Vonjo) in patients with myelofibrosis (MF)?

JOHN MASCARENHAS, MD: This was the more interesting of the 2 PERSIST studies. PERSIST-2 looked at patients with platelets of 100,000/µL or less.1 So, the cytopenic patient with MF could have been given a Janus kinase [JAK] inhibitor before being enrolled, and half did in this study…but these are patients that were hard to treat, which was opposite to the set-up of the COMFORT-1 [NCT00952289] and COMFORT-2 [NCT00934544] studies.2 [Patients in PERSIST-2 study] were given either 400 mg daily or 200 mg of twice daily pacritinib vs patients on best available therapy [BAT], which could also include ruxolitinib [Jakafi], with a coprimary end point of spleen volume reduction of 35% or more and reduction of the total symptom score at week 24.1

What stood out among patients enrolled in either arm of the study?

I think what’s important to appreciate is when asking the investigator what they would give to patients who were randomly assigned to the BAT arm is that there is a lack of options available. In the BAT arm, 45% of patients got low-dose ruxolitinib, 19% had no options, while some patients were getting hydroxyurea [19%], steroids [13%], and even interferons [2%], which I would argue don’t work in this setting.1 These were patients who had higher-risk disease, and half of them had hemoglobin counts less than 10 g/dL, and the median platelet count was somewhere around 50,000/µL [in a majority of patients in both arms].

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New Data Challenge Traditional Treatment Paradigm in MPNs, Says Dr Raajit Rampal

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Laura Joszt, MA

New data challenge the traditional thinking that low-risk patients with myeloproliferative neoplasms are largely just treated with phlebotomy and aspirin and have shown the benefits of medication, such as ropeginterferon, said Raajit Rampal, MD, PhD, hematologic oncologist, associate attending physician, Memorial Sloan Kettering Cancer Center.

Transcript

Interferons have been around for decades, but what unanswered questions remain about their use?

I think it really is about: when to start, who starts, and for how long should they be treated? Those, to me, are kind of key questions. There’s relatively recent data that looked at treating patients with polycythemia vera, who are low risk with ropeginterferon vs what we traditionally do, which is to use things like phlebotomy and aspirin. There at least seems to be some signal to suggest that those patients may derive a benefit. Our traditional thinking is we leave the patients alone except for phlebotomy and aspirin, and if they have a blood clot or symptoms or something, maybe we put them on medication. If not, we only treat them if they’re high risk. But this data was actually provocative in the sense that it said, “Well, if you take these low-risk patients, there may be some clinical benefits to them by starting early.”

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Carotid Plaque Burden and Neutrophil-Lymphocyte Ratio in Patients with Philadelphia Negative Myeloproliferative Neoplasms and Their Relation to JAK2 V617F Mutation

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Mahmoud Gaber, Mohamed Ezeldin, Mustafa Adel Younis, Moamen Abdelfadil Ismail, and Asmaa Ahmed Abdel-baset

 

Abstract

Background: Philadelphia negative myeloproliferative neoplasms are characterized by clonal myeloid cell proliferation. The JAK2V617F mutation may influence inflammation and atherosclerosis. Neutrophil-Lymphocyte Ratio and carotid plaque burden are markers associated with inflammation and cardiovascular risk, respectively.

This study aimed to investigate the relationship between NLR, carotid plaque burden, and JAK2V617F mutation in PN-MPN patients.

Patients and Methods: A retrospective case-control study included 90 PN-MPN patients and 60 controls. Data on demographics, comorbidities, thrombosis, laboratory parameters, carotid plaque burden, and JAK2V617F mutation status were collected.

Results: Age, gender distribution, smoking status, and comorbidities did not significantly differ between PN-MPN patients and controls. Thrombosis incidence in PN-MPN patients did not significantly differ from controls. Carotid plaque burden and NLR were significantly higher in PN-MPN patients compared to controls (p=0.024 and p<0.001, respectively). Majority of PN-MPN patients (78.9%) had positive JAK2V617F mutation status. NLR was significantly higher in PN-MPN patients with positive JAK2V617F mutation compared to negative (p=0.001). There was a significant difference in thrombosis incidence between patients with positive and negative JAK2V617F mutation status.

Conclusion: The study identified a significant link between higher N/L ratios and the JAK2V617F mutation in patients with PN-MPNs, proposing the N/L ratio as a potential marker for disease activity or mutation status. Despite observing a higher incidence of thrombosis in MPN patients and increased carotid plaque in PN-MPN patients compared to controls, no significant correlation was found between these cardiovascular risk markers and the JAK2V617F mutation status, suggesting other factors influence thrombosis risk in these patients.

Parsaclisib Added to Ruxolitinib Decreases Spleen Volume and Improves Symptom Scores in Myelofibrosis

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Kyle Doherty

The PI3Kδ inhibitor parsaclisib added to a stable dose of ruxolitinib (Jakafi) reduced spleen volume and improved symptom scores for patients with myelofibrosis who experienced a suboptimal response to ruxolitinib, according to findings from a phase 2 study (NCT02718300) published in Blood Adv.

Final results of the study revealed that patients who received daily-to-weekly dosing of parsaclisib (n = 32) and those who received all-daily dosing of parsaclisib (n = 42) achieved a decrease in spleen volume of at least 10% at 12 weeks at rates of 28.0% and 59.5%, respectively. Moreover, patients achieved a 50% decrease or more at week 12 in Myelofibrosis Symptom Assessment Form symptom scores at rates of 14% and 28%, respectively; the rates of at least a 50% decrease at week 12 in Myeloproliferative Neoplasms Symptom Assessment Form symptom scores were 18% and 32%, respectively.

“Ruxolitinib reduces spleen volume, improves symptoms, and increases survival in patients with intermediate- or high-risk myelofibrosis. However, suboptimal response may occur, potentially because of signaling via the PI3K/protein kinase B pathway,” Abdulraheem Yacoub, MD, professor of Hematologic Malignancies and Cellular Therapeutics at KU Medical Center in Kansas City, Kansas, and coauthors wrote. “The addition of parsaclisib to stable-dose ruxolitinib can reduce splenomegaly and improve symptoms, with manageable toxicity in patients with myelofibrosis with suboptimal response to ruxolitinib.”

The study authors added that parsaclisib was designed with a different molecular structure than earlier-generation PI3K inhibitors—the orally bioavailable, potent, and highly selective next-generation inhibitor may in turn be able to limit both on- and off-target toxicities that were previously seen.

Additional findings from the study demonstrated that in the overall population evaluable for the primary end point (n = 65), the median change in spleen volume was −163.6 cm3 (range, −735.6 to 10173 cm3), with a median percentage change of −11% (range, −47% to 444%). At week 24, these figures were −192.0 cm3 (range, −2040 to 761.4 cm3) and −10% (range, −89% to 34%) among 49 evaluable patients. The median percentage change was greater among patients who received all-daily dosing compared with those who received daily-to-weekly dosing both at 12 weeks (−15.0% vs −2.0%) and 24 weeks (−19.0% vs −2.5%, respectively).

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Utilization of Momelotinib for Myelofibrosis With Anemia Can Result in Small Savings

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Laura Joszt, MA

Although momelotinib to treat myelofibrosis (MF) with anemia has a higher acquisition cost, it is partially offset by savings when transfusion-related costs are reduced, according to a poster being presented at the AMCP Annual Conference, held April 15-18, 2024, in New Orleans, Louisiana.1

MF is a rare cancer in the bone marrow that disrupts the production of blood cells.2 MF causes anemia because of the extensive scarring to bone marrow. This extensive scarring also causes patients to have a low number of platelets, increasing their risk of bleeding. Patients may also have an enlarged spleen.

Momelotinib inhibits Janus kinase (JAK) 1, JAK2, and activin A receptor type 1. In September 2023, the FDA approved momelotinib to treat patients with intermediate- or high-risk MF with anemia.3

The approval of momelotinib was based on data from the phase 3 MOMENTUM trial, which found clinically significant improvements for patients treated with momelotinib vs danazol.4 A quarter of patients treated with momelotinib had a 50% or greater reduction in total symptom score compared with only 16% of patients on danazol.

Since the approval, the National Comprehensive Cancer Network (NCCN) has added momelotinib5 to its Clinical Practice Guidelines in Oncology for Myeloproliferative Neoplasms. Momelotinib was added as a category 2A treatment for patients with high-risk MF. It was also added as a 2B category treatment for patients with lower-risk MF.

Patients with MF who have anemia and are dependent on transfusions have increased medical costs and poor prognosis, the authors of the AMCP poster noted. JAK inhibitors may provide improvements in symptoms and spleen size, but they could worsen or induce anemia. However, momelotinib has been shown to reduce spleen size.4

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Predictors of clinical outcome in myeloproliferative neoplasm, unclassifiable: A Bone Marrow Pathology Group study

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Genevieve M Crane, MD, PhD; Julia T Geyer, MD; Beenu Thakral, MD; Sa A Wang, MD, Geoffrey D Wool, MD, PhD; Ke David Li, MD; Adam R Davis, MD; Leonardo Boiocchi, MD; David Bosler, MD; Carlos E Bueso-Ramos, MD, PhD

April 10, 2024

Abstract

Objectives

Myeloproliferative neoplasm, unclassifiable (MPN-U, revised to MPN, not otherwise specified in the fifth edition of the World Health Organization classification) is a heterogeneous category of primary marrow disorders with clinical, morphologic, and/or molecular features that preclude classification as a more specific MPN subtype due to stage at diagnosis, overlapping features between MPN subtypes, or the presence of coexisting disorders. Compared with other MPN subtypes, the contribution of the mutational landscape in MPN-U in conjunction with other clinical and morphologic biomarkers to prognosis has been less well investigated.

Methods

We performed a multicenter, retrospective study of MPN-U (94 cases) to better define the clinicopathologic features, genetic landscape, and clinical outcomes, including subgroups of early-stage, advanced-stage, and coexisting disorders. The Dynamic International Prognostic Scoring System (DIPSS) plus scoring system was applied to assess its relevance to MPN-U prognosis.

Results

Multivariate analysis demonstrated bone marrow blast count and DIPSS plus score as statistically significant in predicting overall survival. Univariate analysis identified additional potential poor prognostic markers, including abnormal karyotype and absence of JAK2 mutation. Secondary mutations were frequent in the subset analyzed by next-generation sequencing (26/37 cases, 70.3%) with a borderline association between high molecular risk mutations and overall survival.

Conclusions

This study, as one of the largest of MPN-U studies incorporating both clinicopathologic and molecular data, moves toward identification of biomarkers that better predict prognosis in this heterogeneous category.

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