Tag Archives: mpn

Baseline Basophilia Associated With Aggressive MPN and Poor Outcomes

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Andrea S. Blevins Primeau, PhD, MBA
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A more aggressive disease phenotype and poorer clinical outcomes were associated with higher baseline basophil levels among patients with myeloproliferative neoplasms (MPNs), according to the results of a retrospective study published in the American Journal of Hematology.

In the study, researchers analyzed data from 195 patients who were diagnosed with an MPN between 2008 and 2019 at a single center. Cases of chronic myeloid leukemia, chronic eosinophilic leukemia, and chronic neutrophilic leukemia were excluded. Basophilia was defined as a relative or absolute increase in peripheral blood or bone marrow aspirate within 6 months of the patient’s first diagnostic biopsy.

Of the 195 patients, 40.5% had essential thrombocythemia (ET), 23.1% had overt fibrotic phase primary myelofibrosis (PMF), 10.8% had post-ET myelofibrosis (MF), 8.2% had pre-fibrotic PMF, 8.2% had MPN-unclassifiable (MPN-U), 7.2% had polycythemia vera (PV), and 2.1% had post-PV MF.

Basophilia were present among 22% of patients. The lowest level of basophilia was present among patients with ET and PV at 8% compared with 35% among patients with pre-PMF, F-PMF, post-ET MF, post-PV MF, or MPN-U (P <.0001). There were 9% of patients who demonstrated basophilia in the bone marrow, but not the blood.

Of the patients without basophilia at baseline, researchers found that 12% developed basophilia within a median of 19.6 months after diagnosis. Older age (P <.001), higher white blood cell count (P <.001), higher reticulin grade (P =.0007), lower hemoglobin levels (P =.01), and lower platelet counts (P <.001) were significantly associated with basophilia.

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Options for MPN Treatment Are Expanding Rapidly With More on the Horizon

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December 24, 2024

Author(s): Laura Joszt, MA, Luke Halpern

The past few years have been an exciting time in myeloproliferative neoplasms (MPNs) with new treatments providing new options for patients and additional products in the pipeline that explore new mechanisms of action, explained Firas El Chaer, MD, associate professor of medicine, University of Virginia School of Medicine. At the American Society of Hematology annual meeting, El Chaer had presented research and been a coauthor on abstracts related to treatment for myeloproliferative neoplasms.

He discussed how MPNs are diagnosed, the current treatment landscape, and promising new therapies in the pipeline. When diagnosing for MPNs, particularly for myelofibrosis, a bone marrow biopsy is needed, but the challenge is that this can be “patchy,” he explained, and the amount of fibrosis present in the particular part of the bone marrow that is biopsied is what is relied upon to make the diagnosis.

The good news is that the approval of many new Janus kinase inhibitors has changed the treatment landscape of myelofibrosis dramatically in the last few years, El Chaer said, which has provided patients with additional options for treatment. In addition, there are new mechanisms of action that can improve anemia in this patient population.

“I’m very excited that currently we’re thinking about combination therapies,” he said, to improve anemia or that potentially have a disease-modifying capability. “Our field is expanding very quickly.”

He highlighted some of the new mechanisms of action being studied in myeloproliferative neoplasms, such as bromodomain molecules and TGF-β agonists, which can potentially be helpful for anemia and this patient population. He had presented phase 1/2 data on nuvisertib, or TP-3654, which is a highly selective PIM1 kinase inhibitor that has reduced spleen size and bone marrow fibrosis either alone or in combination with ruxolitinib. Nuvisertib has minimal cytopenia side effect and can be combined with other molecules for treatment. Currently, enrollment is ongoing in 3 arms of the study (NCT04176198) to continue to evaluate nuvisertib as a monotherapy and in combination with ruxolitinib and momelotinib.

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HMGA2 overexpression with specific chromosomal abnormalities predominate in CALR and ASXL1 mutated myelofibrosis

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Shivani Handa, Christoph Schaniel, Joseph Tripodi, Daiva Ahire, Md. Babu Mia, Sophie Klingborg, Douglas Tremblay, Bridget K. Marcellino, Ronald Hoffman & Vesna Najfeld

December 23, 2024

Abstract

Although multiple genetic events are thought to play a role in promoting progression of the myeloproliferative neoplasms (MPN), the individual events that are associated with the development of more aggressive disease phenotypes remain poorly defined. Here, we report that novel genomic deletions at chromosome 12q14.3, as detected by a high-resolution array comparative genomic hybridization plus single nucleotide polymorphisms platform, occur in 11% of MPN patients with myelofibrosis (MF) and MPN-accelerated/blast phase (AP/BP) but was not detected in patients with polycythemia vera or essential thrombocythemia. These 12q14.3 deletions resulted in the loss of most of the non-coding region of exon 5 and MIRLET7 binding sites in the 3’UTR of the high mobility group AT hook 2 (HMGA2), which negatively regulate HMGA2 expression. These acquired 12q14.3 deletions were predominately detected in MF patients with CALR and ASXL1 co-mutations and led to a greater degree of HMGA2 transcript overexpression, independent of the presence of an ASXL1 mutation. Patients with 12q structural abnormalities involving HMGA2 exhibited a more aggressive clinical course, with a higher frequency of MPN-AP/BP evolution. These findings indicate that HMGA2 overexpression associated with genomic deletion of its 3’UTR region is a newly recognized genetic event that contributes to MPN progression.

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Bromodomain and BET Inhibitor INCB057643 Shows Benefit for Patients With Myelofibrosis

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12/19/24

Emily Estrada

According to research presented by Justin Watts, MD, Sylvester Cancer Center Institute, University of Miami, Miami, Florida at the 2024 American Society of Hematology (ASH) Annual Meeting & Exposition in San Diego, California, INCB057643 may improve patient outcomes in the treatment of hematologic malignancies, including myelofibrosis (MF).

A small-molecular bromodomain and extra-terminal BET protein inhibitor, INCB057643, has shown safety and tolerability as monotherapy and combination with Janus kinase (JAK) 1 and 2 inhibitors among patients with MF in previous phases of the ongoing phase 1/2 clinical trial. In this dose-escalation and expansion portion of the trial, the dose of INCB057643 in patients with MF receiving monotherapy was increased from 4mg to 12mg and for patients with MF who had an inadequate response to ruxolitinib, combination therapy dosage was increased from 4mg to total maximum dosage.

The primary end points were safety and tolerability, as well as dose-limiting toxicities of INCB057643 at 24 weeks. The secondary end points included spleen volume reduction greater than 35% from baseline (SVR35), symptom reduction by greater than 50% from baseline via MPN-Symptom Assessment Form (TSS50), and anemia response of a hemoglobin increase at least 1.5 g/dL from baseline in patients that were not receiving transfusions or transfusion-free for at least 12 weeks for patients dependent on transfusions at baseline.

Patients with relapsed/refractory MF (84.1%%), essential thrombocythemia ([ET]; 4.5%), myelodysplastic syndromes (MDS), or myeloproliferative neoplasm (MPN) syndromes (11.4%). were included in the study. In total, 18 patients were treated with a monotherapy dose escalation and 10 patients received dose expansion. Combination therapy dose escalation was received by 16 patients whose median age was 71 years and whose median ruxolitinib dose was 22.4mg per day. The median duration of INCB057643 exposure was 195.5 days for patients in the monotherapy dose-escalation cohort and 139.0 days for patients in the dose-expansion cohort. As for patients who were in the combination therapy dose-escalation cohort, median INCB057643 exposure was 194.0  days.

At 24 weeks, 3 out of 16 patients who received monotherapy achieved SVR35 and 5 out of 14 achieved TSS50 with any dose of INCB057643, of which 3 received a dose of at least 10 mg. During any time of treatment, improvements in spleen volume and TSS50 best response were demonstrated by 13/19 and 12/15 patients, respectively. Among patients who received combination therapy of INCB057643 and ruxolitinib, 3 out of 12 patients achieved SVR35 and 6 out of 11 achieved TSS50 at any combo dose. Improvements were seen at any time during treatment for both SVR35 and TSS50 in 13 out of 16 and 10 out of 15 patients, respectively. Of patients not dependent on blood transfusions, an anemia response was demonstrated by 3 patients in both the monotherapy and the combination group. Additionally, of 6 patients who were blood transfusion dependent at BL, 2 achieved transfusion independence.

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Transforming Care With Collaboration, Individualized Treatment, and Novel Therapies

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Author(s): Laura Joszt, MA

December 20, 2024

Patients with chronic hematologic malignancies are living for decades, especially with new treatments, making it an important time to shape value-based treatments being offered to these patients, said Jennifer Vaughn, MD, during a fireside chat at the Cleveland Regional Institute of Value-Based Medicine (IVBM) event hosted by The American Journal of Managed Care.

Vaughn, a hematology specialist specializing in myelodysplastic syndromes at The Ohio State University, was joined by Akriti Jain, MD, a hematologist at Cleveland Clinic, to discuss quality care initiatives in rare hematological disorders.

With myelofibrosis, for example, the disease can be very high risk or very low risk, and there have been recently approved Janus kinase (JAK) inhibitors to treat the disease, with more coming. There are 4 approved JAK inhibitors1: ruxolitinib (Jakafi), fedratinib (Inrebic), pacritinib (Vonjo), and momelotinib (Ojjaara). With multiple treatments available, it’s important to understand the individual patient’s symptoms to choose the most effective therapy.

“One of the main things that we talk about these days is individualizing care, right? Not every patient is the same,” Jain said. “So, when I see a patient with myelofibrosis in clinic, the first question is: What are they presenting with?” If a patient has the typical symptoms of myeloproliferative neoplasms (MPNs), a JAK inhibitor is probably the right way to go, she said. If they don’t have those symptoms but they have anemia or thrombocytopenia, then a little more investigation is needed.In the polycythemia vera space, there are also a number of agents now available that can lead to a reduced risk of progression in the future. Vaughn explained that when she sees a younger patient, they now have the opportunity to take aspirin and go to the doctor for routine phlebotomies and labs or a treatment that they can manage and can limit time away from work and their kids.

“That’s been, now, a really interesting discussion in that patient population for me, because there are many of my patients who have actually opted to go on therapy,” she said. “We all think of phlebotomy as this very low-risk, easy [procedure] to undergo, but phlebotomy is just a real…pain for them. They can’t spend the time away.”

She added that “time toxicity” is being considered more and more, which is a way to evaluate how much time patients spend having to engage in their health care treatments.

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Combination of PXS-5505 With Standard Ruxolitinib Therapy Shows Potential Benefit for Patients With Myelofibrosis

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12/16/2024

According to data from an ongoing multicenter, open-label phase 1/2a trial, the addition of the pan-lysyl oxidase inhibitor PXS-5505 to standard Janus kinase (JAK) inhibitor therapy demonstrated safety and potential efficacy for patients with intermediate or high-risk myelofibrosis (MF).

Peter T Tan, MBSS, One Clinical Research Pty Ltd, Nedlands, Australia presented these findings at the 2024 American Society of Hematology (ASH) Annual Meeting & Exposition in San Diego, California.

Previous dose escalation and cohort expansion of PXS-5505 trial phases have established safety and tolerability of a monotherapy dose of 200 mg BID over 24 weeks in patients with MF. Researchers evaluated the safety and efficacy of a 200 mg BID dose of PXS-5505 as an add-on to standard JAK2 inhibitor, ruxolitinib (RUX), therapy among patients with MF.

Enrolled in the study were patients with MF with a Dynamic International Prognostic Scoring System (DIPPS) score of intermediate-2/high risk disease. Before initial PXS-5505 administration, patients had been under current RUX treatment for 12 or more weeks, with a stable dose for at least 8 weeks.  A bone marrow biopsy was completed within 3 months of start date for all patients. Patients received PXS-5505 for 52 weeks or until progressive disease, dose limiting toxicity, or unacceptable toxicity. Dosage of PXS-5505 remained consistent at 200 mg BID, however patients were entitled to change RUX dose or discontinue RUX therapy while continuing to receive PXS-5505.

In this add-on phase of the trial, 15 patients were included, of which 6 had primary MF, 2 had post-ET MF, 7 patients had post-PV MF, 3 patients were considered high risk, and all other patients were Int-2. Among patients, the median duration of RUX treatment was 26 months (range, 3.5-74) and a median of 58 months (range 6.5-120) since time of MF diagnosis. The median myeloproliferative neoplasms symptom asssessment form total symptom score (PMN-SAF TSS) was 22.5. The median baseline spleen volume was 1353 cm3 (n=14) and medial baseline hemoglobin was 94 g/dL.

Additionally, 11 patients had hemoglobin levels over 100 g/dL at baseline and almost half had platelet levels below 100×109/L, 2 of which were transfusion-dependent at the start of the study. Baseline mutation profiles for 11 patients revealed a JAK2 V617F mutation among 7 patients and 6 patients with more than 1 high risk mutation.

“The results from this trial using a novel combination of PXS-5505 and RUX will add to the existing safety profile of PXS-5505 and provide preliminary indicators of efficacy to help inform future investigations of PXS-5505 in patients with MF,” the researchers concluded.

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Patient-Reported Outcomes Drive Effective MPN Treatment

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December 16, 2o24

Author(s): Laura Joszt, MA

With patients with myeloproliferative neoplasms (MPNs) having long life expectancies, it’s important that treatments optimize quality of life and patient-reported outcomes, said Jennifer Vaughn, MD, hematologist-oncologist and assistant professor in the Division of Hematology at The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute.

This transcript has been lightly edited for clarity.

Transcript

How are patient-reported outcomes currently being used and incorporated into clinical practice to inform treatment for rare hematological conditions?

I think myeloproliferative neoplasms are an important area where patient-reported outcomes are so important. The drug ruxolitinib or Jakafi, which is a JAK [Janus kinase] inhibitor used in both polycythemia vera and myelofibrosis, was actually originally approved in myelofibrosis because of the improvement it led to in patient quality of life.

First of all, it was able to objectively reduce spleen volume, which led to improvement in patient symptoms, and it led to reductions in symptom scores on the MPN symptom assessment form, which is sort of the standard form we use now to assess how a patient is feeling over time. While there have been some data later on that suggests there may be an overall survival benefit in certain subsets of myelofibrosis, we really do decide to put patients on that treatment because of what they’re telling us about, how they feel. This was really one of the first models of using patient-reported outcomes in looking at whether or not a drug is valuable to society and to patients themselves.

Patients with MPNs become very symptomatic, and many of them will live [long] or have very excellent prognosis in terms of expected lifespan, but their quality of life is quite impeded by the symptoms of the disease. So, it’s really important for clinicians to be kind of reevaluating that on a regular, routine basis.

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Thrombosis Linked With Second Cancer Risk in MPNs

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Jonathan Goodman, MPhil
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Among patients with myeloproliferative neoplasms (MPNs), arterial thrombosis incidence appears to raise the risk of second cancers (SCs) and consequently, mortality, according to an analysis published in Blood Cancer Journal. Inflammatory biomarkers in these diseases suggest a more aggressive disease etiology, the authors added.

In the case of polycythemia vera (PV) or essential thrombocythemia (ET), previous research suggested that thrombosis may heighten the risk of progression to secondary myelofibrosis, which has a high mortality rate. For this retrospective analysis of MPN-patient data, researchers aimed to determine the elements of thrombosis that promote this risk.

Overall, data were evaluated from 1545 patients with PV, 891 patients with ET, 180 patients who were pre-primary myelofibrosis (PMF), and 707 patients with PMF. The median follow-up periods in the PV, ET, pre-PMF, and PMF groups were 5.6 months, 5.6 months, 6.1 months, and 2.92 months, respectively; 19%, 12%, 15%, and 7% of patients had a thrombosis event.

Future therapies should focus on targeting the complex mechanisms involved in both atherogenesis and thrombogenesis…and anti-inflammatory drugs for primary and secondary prevention of thrombosis.

Analysis of the patient data showed that arterial, but not venous or splanchnic, thrombosis was linked with a greater risk of SCs (odds ratio [OR], 2.53; 95% CI, 2.4-5.17). A white blood cell count of at least 11 x 109/L appeared to trend toward a greater risk of SCs, but this link was not significant (OR, 1.27; 95% CI, 0.96-1.67); this was also true of a PMF vs ET diagnosis (OR, 2.54; 95% CI, 0.97-6.61).

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OB756 Showcases Favorable Tolerability in JAK Inhibitor–Naive Myelofibrosis

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December 16, 2024

Author(s): Kristi Rosa

The investigative JAK2 inhibitor OB756 was found to be well tolerated and to elicit meaningful clinical activity in the form of rapid and durable spleen reduction in Chinese patients with myelofibrosis who did not have prior exposure to JAK inhibition, according to data from a phase 1/2 study (CTR20201950) presented during the 2024 ASH Annual Meeting.

In the phase 1 portion of the research, no dose-limiting toxicities were reported when the agent was administered at twice daily doses ranging from 8 mg to 32 mg. Investigators ultimately identified 16 mg and 20 mg twice daily as the recommended phase 2 dose (RP2D) according to p-STAT3 inhibited percentage in an Imax model.

Of 66 evaluable patients, 54.5% achieved a spleen volume reduction (SVR) of at least 35% (SVR35) at the end of cycle 6. Moreover, 59.1% of patients achieved SVR35 at the time of the last follow-up; at the end of cycle 12, 50.0% had achieved SVR35. SVR occurred early, with 7 of 28 patients experiencing a reduction of greater than 5 cm from baseline by week 1 of treatment. Additionally, a 50% or higher reduction in total symptom score (TSS50) was achieved by 51.4% of 55 patients at the end of cycle 3, 64.2% of 53 patients at the end of cycle 6, and 87.5% of 8 patients at the end of cycle 20.

“OB756 can be a promising treatment option for patients with myelofibrosis, but we still need to wait for the final data analysis results after all patients complete follow-up,” Yile Zhou, MD, of the Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, in Hangzhou, China, said in a poster presentation of the data.

In preclinical studies, OB756 was found to hinder cell proliferation and encourage cell apoptosis by acting on the JAK/STAT-signaling pathway. The open-label, multicenter, phase 1/2 study enrolled patients with primary myelofibrosis, post–polycythemia vera (post-PV) myelofibrosis, and post–essential thrombocytopenia (post-ET) myelofibrosis who were at least 18 years of age and whose disease was intermediate-1/2 or higher per the International Prognostic Scoring System (IPSS).

The trial utilized a 3+3 design for the dose-escalation portion of the research. OB756 was to be evaluated twice daily at the following 6 dosage levels: 8 mg, 16 mg, 24 mg, 32 mg, 40 mg, and 48 mg. The number of patients enrolled per dose level in phase 1 were as follows: 1 patient in the 8-mg group, 3 in the 16-mg group, 4 in the 24-mg group, and 1 in the 32-mg group.

The primary end point of phase 1 was to identify the maximum tolerated dose and the RP2D of OB756. For the second phase, investigators set out to determine the proportion of patients who achieved SVR35 from baseline at week 24. The key secondary end points in phase 2 included TSS50 from baseline at week 24, platelet and anemia improvements, and safety.

A total of 296 patients with myelofibrosis were assessed for eligibility between November 3, 2020, and May 16, 2024; 75 patients were enrolled and received the JAK2 inhibitor (phase 1, n = 9; phase 2, n = 66). The median age of patients included in the phase 2 portion of the research was 58 years (range, 55-69), and more than half were male (57.6%). Most patients had primary myelofibrosis (71.2%), and the remaining patients had post-PV disease (21.2%) or post-ET disease (7.6%). Regarding IPSS, 28.8% of patients had intermediate-1 disease, 39.4% had intermediate-2 disease, and 31.8% had high-risk disease. The median spleen volume was 1780.2 mL (range, 1132.5-2728.7). Moreover, 6.1% of patients had a history of red blood cell transfusion. Patients had EOG status of 0 (24.2%), 1 (68.7%), or 2 (6.1%). Most patients had JAK2 mutation (87.1%); other participants had CARL (12.1%) or MPL (1.6%) mutations. The mean MPN System Assessment Form TSS was 13.5 (range, 0-71). The mean number of days from diagnosis to enrollment was 298.5 (range, 4-4020).

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JAB-8263 Monotherapy Demonstrates Early Promise in Myelofibrosis

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December 13, 2024

Author(s): Kristi Rosa

The investigative BET inhibitor JAB-8263 was found to be well tolerated and to demonstrate preliminary efficacy in patients with myelofibrosis, according to data from a phase 1/2 study (NCT04686682) presented during the 2024 ASH Annual Meeting.1

Any treatment-emergent adverse effects (TEAEs) occurred in 93.8% of those who received the agent at any dose level (n = 16), with 37.5% experiencing grade 3 or higher TEAEs and 25.0% experiencing a serious TEAEs. Treatment-related AEs (TRAEs) occurred in 87.5% of patients, with 31.3% experiencing grade 3 or higher TRAEs, and 18.8% experiencing serious TRAEs. TRAEs led to dose interruption and reduction for 43.8% and 25.0% of patients, respectively. One patient experienced a TRAE that led to discontinuation of JAB-8263. No treatment-related events proved to be fatal.

Notably, 1 dose-limiting toxicity occurred in a patient who received the agent at a dose of 0.4 mg; this patient experienced grade 3 increases in alanine and aspartate aminotransferase levels.

In all evaluable patients (n = 13), the mean spleen volume reduction (SVR) was –19.95% (range, –39.4% to 3.6%) at week 24 and –26.16% (range, 56.6% to –11.0%) at best response. Notably, 2 patients achieved an SVR of 35% or higher, and 1 patient experienced an SVR of –34.9%. Moreover, at week 24, 60% of 10 patients had a tumor symptom score reduction of at least 50% (TSS50). Two of 8 patients who had received JAK inhibitors experienced a best response of SVR of –41.2% and 34.9%, respectively. Moreover, 50% of 6 evaluable patients who had received JAK inhibitors achieved TSS50 at week 24.

“JAB-8263 at 0.125 mg [once daily to] 0.3 mg [once daily] was well tolerated…Hematological and gastrointestinal AEs are mild with JAB-8263 continuous dosing [compared with] other BET inhibitors,” Junyuan Qi, MD, of the Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences, in Tianjin, China, and coauthors, wrote in the poster of the data. “The preliminary efficacy data in myelofibrosis for JAB-8263 monotherapy is promising. Most patients showed spleen reduction and TSS reduction.”

The early-phase study enrolled patients with confirmed primary myelofibrosis (PMF), post–polycythemia vera myelofibrosis (PV-MF), or post–essential thrombocytopenia myelofibrosis (ET-MF). Patients were at least 18 years of age, had spleen volume of at least 450 cm3, a Dynamic International Prognostic Score (DIPSS) of at least intermediate-1, and an ECOG performance status up to 2.

The median age in the 16 total patients was 62 years (range, 36-69) and 56.3% were female. All patients were Asian. Regarding ECOG performance status, 31.3% had a status of 0, 62.5% had a status of 1, and 6.3% had a status of 2. Regarding disease subtype, 68.8% of patients had PMF, 18.8% had PV-MF, and 12.5% had ET-MF. Half of patients had prior exposure to a JAK inhibitor. Most patients had a JAK2 mutation (93.8%). Regarding DIPSS, 68.8% had intermediate-1 disease and 25.0% had intermediate-2 disease. The median time since initial diagnosis was 13.5 months (range, 0.9-76.6).

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