Category Archives: Myelofibrosis
Addition of Parsaclisib to Ruxolitinib Decreases Spleen Volume and Improves Symptom Scores Among Patients With Myelofibrosis
The addition of parsaclisib to stable-dose ruxolitinib treatment decreased spleen volume, improved symptom scores, and yielded acceptable safety among patients with primary or secondary myelofibrosis (MF), according to findings from a phase 2 trial published in Blood Advances.
Abdulraheem Yacoub, MD, The University of Kansas Cancer Center, Kansas City, Kansas, and coauthors explained that although ruxolitinib has demonstrated beneficial results among patients with intermediate- or high-risk myelofibrosis, “suboptimal response may occur, potentially because of signaling via the phosphoinositide 3-kinase (PI3K)/protein kinase B pathway.”
In this phase 2 trial, the study authors aimed to measure the potential benefit of adding PI3Kδ inhibitor parsaclisib to ruxolitinib treatment among patients with primary or secondary myelofibrosis who did not have optimal responses to ruxolitinib alone. The primary end points were dosing, efficacy, and safety of this treatment combination.
All patients included in this study stayed on a stable dose of ruxolitinib. Among these patients, 32 were administered parsaclisib at 10 or 20 mg once daily for 8 weeks, then once weekly afterward (daily-to-weekly dosing). Additionally, 42 patients were administered parsaclisib at 5 or 20 mg once daily for 8 weeks, and then 5 mg once daily afterward (all-daily dosing).
JAK-STAT Pathway–Targeting Approaches in Myelofibrosis Are Evolving
During a Targeted Oncology™ Case-Based Roundtable™ event, Raajit K. Rampal, MD, gave an overview of the classification, risk assessment, and current therapy options for patients with myelofibrosis.
RAAJIT K. RAMPAL, MD, PHD: Nothing has changed in terms of the 2022 [World Health Organization] classification, unlike what has happened with myelodysplastic syndrome.1 JAK-STAT signaling is a hallmark of MPN pathogenesis, and all of the mutations that we’re aware of at the moment—JAK2, CALR [calreticulin], and MPL—function in the JAK-STAT pathway. MPL is the thrombopoietin receptor which complexes with JAK [Janus kinase].
CALR is interesting, because CALR was discovered in 2013 but we think at the moment CALR complexes with MPL and results in the aberrant activation of MPL, but CALR does traffic to the cell surface.2,3 That makes it a target for immunotherapy. That is the target of a couple of clinical trials; one is open [LIMBER (NCT06034002)] and the other is about to open, which is really interesting [and] could change everything in MPNs.
All that being said, there are still at least 8% to 15% of myelofibrosis cases that are “triple negative.”2,3 If you look at those cases by gene expression profiling, they have the JAK-STAT signature. The issue with those cases is that we haven’t identified the particular lesion that occurs there, but it is a JAK-STAT–activated lesion, regardless of what the actual driver is. Those are the important things to think about with regards to how the disease is driven.
Study Reveals Real-World Characteristics of Patients With Secondary Myelofibrosis
February 6, 2024
Jonathan Goodman, MPhil
A study published in the Annals of Hematology has highlighted the characteristics of patients with post-essential thrombocythemia or post-polycythemia vera myelofibrosis (PET-MF and PPV-MF, respectively) treated during the ruxolitinib era.
Although the characteristics of patients with primary MF are well-established, less research has evaluated real-world data from patients with PET-MF or PPV-MF. Given that primary and secondary forms of the disease may have different prognoses, a greater understanding of the clinical and patient characteristics in the latter group is important. For this prospective study, researchers in Japan aimed to determine the real-world characteristics and prognoses among patients with PET-MF or PPV-MF.
Overall, data from 314 patients were evaluated, among whom 197 had PET-MF while 117 had PPV-MF. At the time of diagnosis, in the PET-MF and PPV-MF groups, the median ages were 70 and 70 years, respectively, 49.7% and 53.8% of patients were male, and the periods from ET or PV diagnosis to MF progression were 9.64 and 10.38 years. The majority of patients in both groups received ruxolitinib treatment (74.6% in the PET-MF group and 83.8% in the PPV-MF group).
Health Canada Slated to Review New Drug Submission for Momelotinib in Myelofibrosis
Health Canada has accepted for review the new drug submission seeking the approval of momelotinib in patients with myelofibrosis, according to a recent announcement from GlaxoSmithKline.1 The submission is based on findings from the phase 3 SIMPLIFY-1 (NCT01969838) and MOMENTUM (NCT04173494) trials.
Specifically, SIMPLIFY-1 data showed that of the 86 patients who received momelotinib, 31.4% (95% CI, 21.8%-42.3%) experienced a spleen volume response (SVR) reduction of 35% or higher vs 32.6% (95% CI, 23.4%-43.0%) of the 95 patients who received danazol.2
Moreover, findings from MOMENTUM indicated that a tumor symptom score (TSS) of at least 50% was observed in 25% of the 130 patients given momelotinib per the Myelofibrosis Symptom Assessment Form (MFSAF v4.0), representing a treatment difference of 16% (95% CI, 6%-26%; P < .01).2,3 The MFSAF v4.0 TSS change from baseline in the momelotinib and danazol arms were -9.4 and -3.1, respectively, equating to a difference of -6.2 (95% CI, -10 to -2.4; P = .001).
Molecular Genetic Profile of Myelofibrosis: Implications in the Diagnosis, Prognosis, and Treatment Advancements
by Tanvi Verma 1, Nikolaos Papadantonakis2, Deniz Peker Barclift1 and Linsheng Zhang
Simple Summary
Abstract
European Commission Approves Momelotinib for Myelofibrosis/Anemia
The European Commission granted marketing authorization to momelotinib (Omjjara) for patients with primary myelofibrosis who have disease-related splenomegaly or moderate to severe anemia, according to a press release from GSK.1
This indication also covers patients with post polycythemia vera myelofibrosis or post essential thrombocythemia myelofibrosis who are JAK inhibitor naïve or received previous treatment with ruxolitinib (Jakafi). The authorization is based on results from the phase 3 MOMENTUM trial (NCT04173494), which analyzed the use of momelotinib and danazol in patients with symptomatic and anemic myelofibrosis.2
“The challenges of living with myelofibrosis can be burdensome, and symptomatic patients can experience spleen enlargement, fatigue, night sweats, and bone pain. Until now, there have been no options specifically indicated to treat these symptoms in patients who also experience anemia. The authorization of [momelotinib] brings a new treatment option with a differentiated mechanism of action to these patients in the European Union,” Nina Mojas, senior vice president of Oncology Global Product Strategy at GSK, said in the press release.
In the trial, the total symptom score response at week 24 was 24.6% (95% CI, 17.49%-32.94%) for patients receiving momelotinib vs 9.2% (95% CI, 3.46%-19.02%) in the danazol arm (P = .0095). Additionally, a reduction of splenic volume by 25% occurred in 40.0% (95% CI, 31.51%-48.95%) of patients in the momelotinib arm vs 6.2% (95% CI, 1.70%-15.01%; P <.0001) in the danazol arm. A 35% reduction in spleen volume was also observed in 23.1% (95% CI, 16.14%-31.28%) in the momelotinib arm and 3.1% (95% CI, 0.37%-10.68%; P = .0006) in the danazol arm.
In September 2023, the FDA approved momelotinib for patients with intermediate- or high-risk myelofibrosis, including primary and secondary myelofibrosis, who are experiencing anemia.3 In November 2023, the European Medicine’s Agency’s Committee for Medicinal Products for Human Use expressed a positive opinion for momelotinib.4 The positive opinion was one of the final steps leading to the approval of the drug in the European Union.
“I think [momelotinib] will make an immediate impact. There clearly are individuals now who are on JAK inhibitors like ruxolitinib or fedratinib [Inrebic] who have significant anemia who will immediately be potential candidates,” Ruben A. Mesa, MD, FACP, said in an interview with CancerNetwork® prior to the FDA approval. Mesa is the president of the Enterprise Cancer Service Line and senior vice president at Atrium Health; executive director of the National Cancer Institute-designated Atrium Health Wake Forest Baptist Comprehensive Cancer Center; and vice dean for Cancer Programs at Wake Forest University School of Medicine.
References
- European Commission authorises GSK’s Omjjara (momelotinib). News release. GSK. January 29, 2024. Accessed January 29, 2024. https://shorturl.at/ntuvy
- 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
- Ojjaara (momelotinib) approved in the US as the first and only treatment indicated for myelofibrosis patients with anaemia, News release. GSK. September 15, 2023. Accessed January 29, 2024. https://shorturl.at/jnNQY
- GSK receives positive CHMP opinion recommending momelotinib for myelofibrosis patients with anaemia. News release. GSK. November 13, 2023. Accessed January 29, 2024. https://bit.ly/3MEYpOl
SOHO State of the Art Updates and Next Questions | Diagnosis, Outcomes, and Management of Prefibrotic Myelofibrosis
Pankit Vacchani, Sanam Lohgavi, Prithviraj Bose
Abstract
Prefibrotic primary myelofibrosis (prefibrotic PMF) is a myeloproliferative neoplasm with distinct characteristics comprising histopathological and clinico-biological parameters. It is classified as a subtype of primary myelofibrosis. In clinical practice, it is essential to correctly distinguish prefibrotic PMF from essential thrombocythemia especially but also overt PMF besides other myeloid neoplasms. Risk stratification and survival outcomes for prefibrotic PMF are worse than that of ET but better than that of overt PMF. Rates of progression to overt PMF and blast phase disease are also higher for prefibrotic PMF than ET. In this review we first discuss the historical context to the evolution of prefibrotic PMF as an entity, its presenting features and diagnostic criteria. We emphasize the differences between prefibrotic PMF, ET, and overt PMF with regards to presenting features and disease outcomes including thrombohemorrhagic events and progression to fibrotic and blast phase disease. Next, we discuss the risk stratification models and contextualize these in the setting of clinical management. We share our view of personalizing treatment to address unique patient needs in the context of currently available management options. Lastly, we discuss areas of critical need in clinical research and speculate on the possibility of future disease course modifying therapies in prefibrotic PMF.
Dr Vincelette on MYC Expression in Myelofibrosis
Nicole D. Vincelette, PhD, postdoctoral fellow, Moffitt Cancer Center, discusses findings from a study investigating the role of MYC expression and S100A9-mediated inflammation in a subgroup of triple-negative myeloproliferative neoplasms (MPNs).
To determine how MYC expression drives MPNs, such as polycythemia vera, essential thrombocythemia, and primary myelofibrosis, Vincelette and colleagues conducted a study in which they generated a mouse model that overexpresses MYC in the stem cell compartment. This analysis demonstrated that MYC overexpression was associated with the mice developing a myelofibrosis-like phenotype, which included anemia, atypical megakaryocytes, splenomegaly, bone marrow fibrosis, liver fibrosis, spleen fibrosis. The mice also experienced adverse clinical outcomes, such as reduced overall survival (OS), compared with wild-type mice, Vincelette says.
Since the MYC-overexpressed mice developed myelofibrosis, the next step of this research was to investigate how MYC drives myelofibrosis, Vincelette explains. Investigators performed single-cell RNA sequencing to compare the bone marrow cells from MYC-overexpressed and wild-type mice. MYC overexpression correlated with upregulation of the S100A9 protein, which contributes to inflammation and innate immunity, according to Vincelette. Therefore, MYC drives the development of myelofibrosis through S100A9-mediated chronic inflammation. To validate the role of S100A9 downstream of MYC in myelofibrosis, investigators created a mouse model with S100A9 knockout in the presence of MYC overexpression, Vincelette notes. The S100A9 knockout protected against the development of myelofibrosis phenotype in that mouse model, Vincelette emphasizes.
By generating a mouse model that overexpresses S100A9, investigators also determined that S100A9 overexpression alone contributes to the development of myelofibrosis phenotypes, Vincelette says. When investigators treated the MYC-overexpressing mice with the S100A9 inhibitor tasquinimod (ABR-215050), the agent only partially abrogated the myelofibrosis phenotype, meaning the mice had reduced atypical megakaryocytes and splenomegaly. Additionally, the mice developed anemia and no OS difference occurred between tasquinimod and vehicle treatment, potentially because of off-target drug effects, Vincelette concludes.
Fedratinib Improves Myelofibrosis Management Compared With Ruxolitinib
By Patrick Daly – Last Updated: January 17, 2024
Treatment with fedratinib, a Janus kinase inhibitor (JAKi), induced superior spleen volume reduction (SVR) and symptom response rates compared with best available therapy in patients with myelofibrosis (MF) who previously received ruxolitinib, according to data from the open-label phase III FREEDOM2 study, presented at the 65th American Society of Hematology Annual Meeting & Exposition.
“Most patients on best available therapy received ruxolitinib, highlighting a need for an alternative JAKi,” stated lead author of the study, Claire Harrison, MD, FRCP, from Guy’s and St. Thomas’ NHS Foundation Trust in London, England.
The FREEDOM2 trial enrolled patients aged 18 years or older with primary, post-polycythemia vera, or post-essential thrombocythemia MF with splenomegaly who were intolerant or refractory to, or relapsed after ruxolitinib. The primary endpoint was SVR ≥35% (SVR35) at the end of the sixth 28-day cycle.
Fedratinib for Myelofibrosis Treatment Superior to Ruxolitinib
In total, 201 patients were randomized to fedratinib (n=134) or best available therapy (n=67). The cohort had a median age of 70 (interquartile range, 64-74), 52.2% were male, 54.7% had primary MF, and 76.1% had a Dynamic International Prognostic Scoring System risk score of intermediate-2.
Overall, 70.1% of patients in the best available therapy arm received ruxolitinib, 10.4% received hydroxyurea, and 7.5% received ruxolitinib plus hydroxyurea. Additionally, 46 (68.7%) patients in the best available therapy arm crossed over to fedratinib after either disease progression or the sixth cycle response assessment.
With a median follow-up of 15 months at the data cutoff, researchers reported the fedratinib group had a significantly higher SVR35 rate of 35.8% at the end of cycle six compared with best available therapy at 6.0% (P<.0001). Fedratinib also yielded superior SVR ≥25% at the cycle six assessment and superior SVR35 at any point during treatment. The rate of symptom response at the end of cycle six was 34.1% with fedratinib versus 16.9% with best available therapy (P=.0033).
In short, “fedratinib demonstrated superior SVR and symptom response rates compared with [best available therapy]” in patients with MF and prior ruxolitinib treatment, concluded Dr. Harrison and colleagues.
Reference
Harrison CN, Mesa RA, Talpaz M, et al. Efficacy and safety of fedratinib in patients with myelofibrosis previously treated with ruxolitinib: results from the phase 3 randomized FREEDOM2 study. Abstract #3204. Presented at the 65th ASH Annual Meeting & Exposition; December 9-12, 2023; San Diego, California.