Tag 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.
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
Results from phase 1 of the MANIFEST clinical trial to evaluate the safety and tolerability of pelabresib in patients with myeloid malignancies
Eytan M. Stein, Amir T. Fathi, Wael A. Harb, Gozde Colak, Andrea Fusco & James K. Mangan
ABSTRACT
Pelabresib (CPI-0610), a BET protein inhibitor, is in clinical development for hematologic malignancies, given its ability to target NF-κB gene expression. The MANIFEST phase 1 study assessed pelabresib in patients with acute leukemia, high-risk myelodysplastic (MDS) syndrome, or MDS/myeloproliferative neoplasms (MDS/MPNs) (NCT02158858). Forty-four patients received pelabresib orally once daily (QD) at various doses (24–400 mg capsule or 225–275 mg tablet) on cycles of 14 d on and 7 d off. The most frequent drug-related adverse events were nausea, decreased appetite, and fatigue. The maximum tolerated dose (MTD) was 225 mg tablet QD. One patient with chronic myelomonocytic leukemia (CMML) showed partial remission. In total, 25.8% of acute myeloid leukemia (AML) patients and 38.5% of high-risk MDS patients had stable disease. One AML patient and one CMML patient showed peripheral hematologic response. The favorable safety profile supports the ongoing pivotal study of pelabresib in patients with myelofibrosis using the recommended phase 2 dose of 125 mg tablet QD.
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.
CTI BioPharma Announces Extension of FDA Review Period for Pacritinib in MF with Severe Thrombocytopenia
SEATTLE, Nov. 30, 2021 /PRNewswire/ — CTI BioPharma Corp. (Nasdaq: CTIC) today announced the U.S. Food and Drug Administration (FDA) has extended the review period for the New Drug Application (NDA) for pacritinib for the treatment of adult patients with intermediate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF) with a baseline platelet count of <50 × 109/L. The Prescription Drug User Fee Act (PDUFA) action date has been extended by three months to February 28, 2022.
In the second quarter of 2021, the FDA granted priority review for CTI’s NDA for patients with myelofibrosis with a PDUFA date of November 30, 2021. In the course of product labeling discussions, the FDA requested additional clinical data, which was submitted to the agency on November 24, 2021. Earlier today, the FDA informed the Company that it considers the data submission to constitute a “major amendment” to the NDA and therefore the PDUFA date has been extended by three months to provide additional time for a full review of the submission. At the current time, CTI is not aware of any major deficiencies in the application.
“CTI is continuing to engage collaboratively and constructively with the FDA during review of our NDA,” said Adam R. Craig, M.D., Ph.D., President and Chief Executive Officer of CTI Biopharma. “We are committed to providing patients suffering from cytopenic myelofibrosis with a new treatment option as soon as possible and are confident in pacritinib’s potential to establish a new standard of care.”
Pacritinib is a novel oral kinase inhibitor with specificity for JAK2, IRAK1 and CSF1R, without inhibiting JAK1. The NDA was accepted based on the data from the Phase 3 PERSIST-2 and PERSIST-1 and the Phase 2 PAC203 clinical trials, with a focus on the severely thrombocytopenic (platelet counts less than 50 x 109/L) patients enrolled in these studies who received pacritinib 200 mg twice a day, including both frontline treatment-naive patients and patients with prior exposure to JAK2 inhibitors. In the PERSIST-2 study, in patients with severe thrombocytopenia who were treated with pacritinib 200 mg twice a day, 29% of patients had a reduction in spleen volume of at least 35%, compared to 3% of patients receiving the best available therapy, which included ruxolitinib; 23% of patients had a reduction in total symptom scores of at least 50%, compared to 13% of patients receiving the best available therapy. In the same population of patients treated with pacritinib, adverse events were generally low grade, manageable with supportive care, and rarely led to discontinuation. Platelet counts and hemoglobin levels were also stabilized.
Selecting Therapy to Treat MF
OncLive
Pankit Vachhani, MD: Fedratinib is a JAK2 inhibitor that was recently FDA approved for treatment of patients with myelofibrosis, intermediate-2 and high risk. We consider using this drug either in the frontline space or in a setting where ruxolitinib has previously been used and failed the patient in giving them a long-term benefit.
When a patient is newly diagnosed with myelofibrosis, if their platelet count is higher than 50 x 109 per liter and they happen to be intermediate-2 or high risk in terms of their risk stratification, one could either use ruxolitinib or fedratinib in that setting. A key thing to consider here is the need for an assessment for stem cell transplant. Should a patient progress after using the first JAK2 inhibitor, they could use the alternative JAK2 inhibitor, or consider clinical trials at that point as well.
If, on the other hand, a patient has lower-risk myelofibrosis, the key thing to identify is whether they are symptomatic. For patients who are symptomatic, one could use ruxolitinib to alleviate the patient’s symptoms despite the disease being lower risk in nature. If one should need to use alternative agents, these would include drugs like hydroxyurea or interferon. In the event that the patients have lower-risk myelofibrosis and are asymptomatic, one may choose to monitor the patients every few months to assess their symptomatology, spleen volume or length, and assess their platelet counts.