Tag Archives: Ruxolitinib

Ruxolitinib Plus Siremadlin Yielded Superior Spleen Volume Reduction in Patients With Myelofibrosis

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May 20, 2025

Author(s): Alexandra Gerlach, Associate Editor

Data from the ADORE trial (NCT04097821) suggest combining ruxolitinib (Jakafi; Incyte Corp) with novel agents such as siremadlin (HDM201, Novartis), rineterkib (LTT462; Novartis), sabatolimab (MBG453; Novartis), crizanlizumab (Adakveo; Novartis), or NIS793 (Novartis) was superior to ruxolitinib monotherapy in patients with myelofibrosis (MF). The investigators reported improved spleen volume reductions (SVR), which were greatest in patients treated with ruxolitinib in combination with siremadlin.1

3D visualization of red blood cells | Image Credit: © Thipphaphone – stock.adobe.com

MF is a disease that falls under the umbrella of myeloproliferative neoplasms, which is a group of diseases characterized by the overproduction of red blood cells, white blood cells, or platelets in the bone marrow. In MF, there is an ongoing reduced production of red blood cells that leads to bone marrow fibrosis, extramedullary hematopoiesis, recurrent splenomegaly, and anemia. Other symptoms can include fatigue, nocturnal sweats, bone pain, enlarged spleen, and weight loss. can arise as a main disease (primary MF) or as a subsequent condition to essential thrombocythemia (post-ET MF) and polycythemia vera (post-PV MF). In some cases, MF can progress to acute myeloid leukemia.2

Janus kinase (JAK) inhibitors, such as ruxolitinib, are the standard of care for treatment and management of MF-related complications and have yielded significantly favorable outcomes; however, they are associated with various adverse effects (AEs). Ruxolitinib was initially approved in 2011 for first-line treatment of patients with intermediate- and high-risk MF, but the agent is known to be highly associated with increased risk of persistent or worsening anemia. Despite its widespread use, approximately 70% of patients discontinue treatment after about 5 years, with a third citing an inadequate reduction in spleen volume as a key reason.3,4

ADORE is a randomized, open-label, phase 1/2 open platform study evaluating the safety and efficacy of 5 novel agents with ruxolitinib in patients with MF. The trial utilized an innovative open platform design and enrolled 44 patients in part 1 of the trial who were treated with ruxolitinib in combination with 1 of 5 investigational agents: siremadlin, rineterkib, sabatolimab, crizanlizumab, or NIS793. The largest cohort (n = 23) received the combination of ruxolitinib (orally at a dosage of 5 mg) and siremadlin (orally at a dosage of 10, 20, or 40 mg).1,4

Among those patients, the most common AEs were gastrointestinal issues, such as nausea and diarrhea, and hematologic toxicities, including thrombocytopenia, anemia, and neutropenia. Based on safety and efficacy findings, once-daily 30 mg siremadlin taken orally on days 1 through 5 of a 28-day cycle was chosen as the recommended phase 2 dose.4

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Seiter Explores Time of Initiation and Alternate Dosing of Ruxolitinib in Myelofibrosis

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By Targeted Oncology Staff
Fact checked by Jonah Feldman

During a live event, Karen Seiter, MD, discussed the role of the JAK/STAT pathway in myeloproliferative neoplasms and the use of ruxolitinib to treat myelofibrosis.

Karen Seiter, MD

Karen Seiter, MD

Professor of Medicine
New York Medical College
Director of  the Adult Leukemia Service
Westchester Medical Center
Valhalla, NY

CASE SUMMARY

  • A 68-year-old woman presented to her physician with symptoms of mild fatigue.
  • Spleen was palpable 6 to 7 cm below the left costal margin
  • Past medical history: no known comorbidities
  • Next-generation sequencing testing: JAK2 V617F mutation
  • Karyotype: 46,XX
  • Bone marrow biopsy: megakaryocyte proliferation and atypia with evidence of reticulin fibrosis
  • Blood smear: leukoerythroblastosis
  • Diagnosis: primary myelofibrosis

Risk

  • Dynamic International Prognostic Scoring System: intermediate-1
  • Mutation-Enhanced International Prognostic Scoring System for Transplantation-Age Patients: intermediate risk

Laboratory Values

  • Red blood cell count: 3.40 ×106/μL
  • Hemoglobin level: 9.7 g/dL
  • Hematocrit: 32.3%
  • Mean corpuscular volume: 94 μm3
  • White blood cell count: 23,000/μL
  • Platelet count: 450,000/μL
  • Peripheral blood blasts: <1%

Peers & Perspectives in Oncology: What disease states are currently classified as myeloproliferative neoplasms (MPNs)?

Seiter: The latest classification is the 2022 World Health Organization [WHO] classification.1,2 As a clinician, when we have myeloproliferative diseases, we think of MPNs [as meaning the patient] has too much of something: The WBC count is too high but with maturing myeloid and not with a lot of blasts, or the hemoglobin [level] is too high, or the [platelet count is] too high. That would be potentially chronic myelocytic leukemia [CML], polycythemia vera [PV], essential thrombocytopenia [ET], and for primary myelofibrosis, the most common presentation would be somebody with either anemia, with abdominal distension or early satiety from splenomegaly. The WBC count could be high; it could be low; platelets could be high, or they could be low.

When we’re working up patients with MPN, the first step is always to make sure that they don’t have CML, because CML can look like myelofibrosis because CML can present with a high platelet count. The first step is always to [test for] the Philadelphia chromosome and perform BCR::ABL1 testing to make sure it’s not CML.

Most of these patients are going to have a bone marrow [biopsy] done. There’s always the debate about, if you have somebody with a hemoglobin level of 20 g/dL, where it looks pretty clear that they have PV, do you need a bone marrow [biopsy] in order to formally diagnose the patient? You do because that’s part of the diagnostic criteria. But sometimes, if you have a much older patient with frailty, you have to consider the goals of care. Sometimes, there may be cases of patients who don’t get the bone marrow biopsy done. The only time it would be reasonable is if the hemoglobin level is high; for anything else, there are so many other things that [it] could be that it’s important to do the bone marrow biopsy for a diagnosis.

Mastocytosis used to be [listed among the] MPNs, but [the WHO] made it its own classification. MPNs with eosinophilia are a separate category. Now we have the myelodysplastic syndrome [MDS]/MPN overlap; that’s a separate category. Then, we have MDS, secondary myeloid neoplasms, and acute myeloid leukemia.

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As-Expected Ruxolitinib Starting Dose Outperforms Lower Dosage in Myelofibrosis

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By Bridget Hoyt
Fact checked by Kristie L. Kahl

Patients with myelofibrosis who were treated with the expected starting dose of ruxolitinib (Jakafi) demonstrated higher spleen response rates and a shorter median time to first response vs patients receiving a less-than-expected starting dose, per data from the ROMEI trial.

Additionally, overall survival (OS) was not reached in the as-expected group; however, patients in both groups reduced daily dosages over 12 months in the multicenter, observational, ongoing study, according to findings published in Cancer.

“To ensure optimal treatment with ruxolitinib, patients should be started on appropriate ruxolitinib doses and maintain the highest tolerated dose for maximum effectiveness,” wrote the study authors. “Patients who received the recommended doses showed a better trend in response.”

Trial Design and Key Data

The trial enrolled 508 adult ruxolitinib-naive patients who had been diagnosed with primary or secondary myelofibrosis across 51 centers in Italy between April 2017 and May 2022, at which time ruxolitinib was the only FDA-approved JAK inhibitor for myelofibrosis.

Patients with available baseline platelet counts were stratified into the as-expected (n = 174) and lower-than-expected (n = 132) dosage groups, resulting in 43% of patients receiving a lower-than-expected dose.

Changes in symptoms and health-related quality of life (HRQOL), assessed using Myeloproliferative Neoplasm 10 total symptom score (MPN-10 TSS) and EuroQol5-Dimension 5-Level (EQ-5D-5L), respectively, were primary end points of the study.

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New Trial Will Assess Safety and Efficacy of MF Drug

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Leonardo Jaimes, MD

Publish Date

A clinical trial aiming to determine the efficacy, safety, and pharmacokinetics of the experimental drug WJ01024 combined with ruxolitinib in patients with myelofibrosis (MF) is set to begin soon.

“Although the clinical efficacy of ruxolitinib tablets has been confirmed, only about half of MF patients can achieve the ideal therapeutic effect (≥35% reduction in spleen volume and ≥50% improvement in disease symptoms at 24 weeks),” the authors wrote. “Therefore, there is an urgent need for innovative drugs that can be combined with ruxolitinib tablets to enhance therapeutic efficacy and meet clinical needs,” they added.

WJ01024 aims to enhance the therapeutic efficacy of ruxolitinib through  XPO-1 inhibition. Previous in vitro studies have confirmed that the drug enhances ruxolitinib anti-cell proliferation activity, the researchers noted. Furthermore, preliminary studies on humans suggest that WJ01024 is effective as monotherapy for relapsing patients and those intolerant to JAK inhibitors, they added.

The trial will consist of a dose escalation and a dose extension phase (phase 1a and phase 2). Phase 1b will divide patients into three groups receiving 40 mg, 60 mg, and 80 mg of WJ01024, respectively. Phase 2 will be an open-label evaluation of the efficacy and safety of the recommended dose in combination with ruxolitinib.

The study will only include patients diagnosed with MF and with the international prognostic scoring system risk category of intermediate-1, intermediate-2, or high-risk. Patients in the accelerated blast phase or previous treatment with either JAK or XPO-1 inhibitors are not eligible for participation.

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Optimal Ruxolitinib Dosing in Myelofibrosis Critical for Improved Effectiveness, Survival in Real-World Setting

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March 27, 2025

Author(s): Luke Halpern, Assistant Editor

Patients with myelofibrosis (MF) started on appropriate and highest tolerated doses of ruxolitinib (Jakafii; Incyte Corporation) experienced better trends in response and improved health-related quality of life (HRQoL), highlighting the importance of proper ruxolitinib dosing, timing, and administration to ensure the most effective patient responses in terms of symptom relief, spleen size reduction, and improved overall survival (OS).1

Diagnosis of Myelofibrosis. Laboratory blood bottle (tube), glass slide with blood smear, hematology test, stethoscope lying on notebook with printed text hematological diagnosis

Ruxolitinib is effective at reducing symptoms in myelofibrosis. | Image Credit: © shidlovski – stock.adobe.com

It’s critical for treatment providers administering ruxolitinib for MF to know the expected real-world presentation of treatment complications. Patients being administered ruxolitinib face higher health care resource utilization and clinical burdens, including an increased risk of anemia development and adverse treatment events. Still, the treatment is highly effective when dosed and administered appropriately and when proper consideration of adverse events, such as anemia or graft-versus-host disease, is included in counseling.1,2

According to the investigators, the expected optimal starting dose for initiating ruxolitinib is based on a patient’s baseline platelet count. Further dose titration—up to 25 mg twice daily—can be utilized to maximize efficacy, which has been demonstrated to be dose-dependent. However, suboptimal adherence is consistently reported among patients treated with ruxolitinib, which could contribute to poor survival outcomes and undermine disease control.1,3

Poor adherence rates have been observed in the ongoing Ruxolitinib Observational Study in Myelofibrosis Treated Patients in Italy (ROMEI), an observational study of ruxolitinib-treated patients with MF in Italy. Twenty-four-week findings confirmed ruxolitinib’s therapeutic effects and a favorable safety profile but also indicated that up to one third (25% to 40%) of patients receiving ruxolitinib could have been undertreated despite their clinical presentation necessitating higher doses. An interim analysis, conducted by the current authors, was commissioned to investigate ruxolitinib dosing patterns and correlations with clinical outcomes in patients who completed the first 12 months of follow-up or prematurely discontinued the ROMEI trial.1

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Pelabresib Plus Ruxolitinib Improves Spleen Responses in Myelofibrosis

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By Roman Fabbricatore
Fact checked by Russ Conroy

Pelabresib (CPI 0610) in combination with ruxolitinib (Jakafi) significantly improved spleen responses and elicited robust clinical activity compared with placebo/ruxolitinib in patients with JAK inhibitor-naïve myelofibrosis, according to results from the phase 3 MANIFEST-2 trial (NCT04603495) published in Nature Medicine.1

Efficacy data from the trial revealed that the primary end point of spleen volume reduction of at least 35% at week 24 favored the investigational combination vs the placebo arm: 65.9% vs 35.2%, respectively (difference, 30.4%; 95% CI, 21.6%-39.3%; P <.001). Additionally, the mean percent change at week 24 in the respective arms was –50.6% (95% CI, –53.2% to –48.0%) vs –30.6% (95% CI, –33.7% to –27.5%). Spleen volume response was consistently higher with pelabresib vs placebo across predefined subgroups.

Furthermore, the hemoglobin response rate, defined as a 1.5 g/dl or greater mean increase, occurred in in 10.7% of the pelabresib arm (95% CI, 6.60%-14.90%) vs 6.0% of the placebo arm (95% CI, 2.85%-9.19%). Transfusions were received in the first 24 weeks of treatment in 27.6% and 37.5% of respective arms.

Greater reductions in NF-κB-regulated cytokines (–32.1% [95% CI, –34.9% to –29.2%] vs –19.4% [95% CI, –22.5% to –16.2%]), tumor necrosis factor (TNF; –43.5% [95% CI, –47.0% to –39.8%] vs –26.4% [95% CI, –30.5% to –22.1%]), and interleukin-6 (IL-6; –35.4% [95% CI, –44.2% to –25.2%] vs –14.5% [95% CI, –25.2% to –2.3%]) were seen in the investigational arm vs the placebo arm. Of note, a reduction in IL-8 levels was observed with pelabresib (–14.3% [95% CI, –22.3% to –5.5%]), but an increase was observed in the placebo arm (31.2% [95% CI, 17.5%-46.5%).

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Patients With MF Who Failed Ruxolitinib Treatment May Benefit From Fedratinib

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Özge Özkaya, MSc, PhD
Publish Date

Fedratinib treatment is effective in patients with myelofibrosis (MF) who discontinued ruxolitinib due to treatment failure, according to data from a real-world study published in the scientific journal Future Oncology.

The findings of this study offer a new option for patients with MF whose disease does not respond to ruxolitinib treatment.

To assess the real-world treatment patterns with fedratinib as well as clinical outcomes in patients with primary or secondary MF after ruxolitinib discontinuation, a team of researchers conducted a retrospective, noninterventional medical record review of 196 patients with MF in Germany, Canada, and the United Kingdom.

Data about the patients was provided by 70 physicians of whom 78.6% were primarily hematologists or oncologists.

Of these 196 patients, the majority (76.5%) had primary MF and started treatment with fedratinib at a mean age of 67.7 .

The median duration of treatment with fedratinib was 11.5  months and the median follow-up period was 13.8  months.  Almost half (49.5%) of patients started fedratinib at the dose indicated on the label, i.e. 400  mg per day.

Six months after the start of treatment with fedratinib, 77.7% of patients had symptom response and 66.8% had spleen response.

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Ruxolitinib Plus SOC Prophylaxis Is Associated With Lower Rates of GVHD in Myelofibrosis

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February 14, 2025

Author(s): Dylann Cohn-Emery

Fact checked by: Jonah Feldman

Treatment with the combination of ruxolitinib (Jakafi) and standard-of-care graft-vs-host disease (GVHD) prophylaxis led to a reduction in the rates of acute and chronic GVHD without compromising survival rates in patients with myelofibrosis undergoing hematopoietic stem cell transplantation (HCT), according to data from a phase 2 prospective study (NCT04384692) presented at the 2025 Transplantation and Cellular Therapy Meetings.1

The study conducted at Fred Hutchinson Cancer Center showed grade II to IV acute GVHD occurred in 32% of patients receiving peri-transplant ruxolitinib, whereas it occurred in 71% in a pre-transplant ruxolitinib group of a similar preliminary study. The percentage of patients with chronic GVHD at 1 year with peri-transplant ruxolitinib 12%, whereas it was 25% with pre-transplant ruxolitinib. These rates of GVHD also coincided with high overall survival (OS) rates at year 1 and 2 of 100% and 87%, respectively, in the peri-transplant ruxolitinib trial.

“The incidence of acute and chronic GVHD was markedly reduced without the expense of non-relapse mortality, relapse, or survival. It doesn’t appear that infections or transfusion needs were increased,” Rachel B. Salit, MD, associate professor at Fred Hutchinson Cancer Center, said in her presentation.

Janus kinase (JAK) inhibitors prevent activation of the JAK domain by binding to the kinase, in turn preventing STAT phosphorylation and translocation of the nucleus. This process reduces the production of pro-inflammatory cytokines. GVHD pathogenesis has shown to be affected by the JAK-STAT pathway, and JAK signaling is key in the process leading to tissue damage and inflammation.

In previous trials of ruxolitinib, such as COMFORT-I (NCT00952289) and COMFORT-II (NCT00934544), this JAK inhibition showed significantly better results in reducing symptoms and splenomegaly compared with best available therapy in patients with myelofibrosis. Additionally, the REACH1 (NCT02953678), REACH2 (NCT02913261), and REACH3 (NCT03112603) trials demonstrated significantly improved response with ruxolitinib vs best available therapy when treating patients with acute and chronic GVHD.

The preliminary study (NCT02251821) of ruxolitinib pre-transplant showed improved survival in this patient population. With a median time of 7 months on ruxolitinib, 38% of patients had more than a 10% decrease in spleen size and 36% were stable. In patients with symptoms prior to ruxolitinib, 55% had stable or improved symptoms by the time of HCT.

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Calreticulin Mutations Can Worsen Survival Outcomes in Ruxolitinib-Treated Patients With Myelofibrosis

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January 31, 2025

Author(s): Luke Halpern, Assistant Editor

Patients with myelofibrosis (MF) who harbor calreticulin (CALR) mutations begin treatment with ruxolitinib presenting severe disease with a longer median time from diagnosis, with inferior spleen responses and lower rates of symptom responses observed at 6-months, according to study results published in Annals of Hematology.1

3D illustration Virus DNA molecule, structure. Concept destroyed code human genome. Damage DNA molecule. Helix consisting particle, dots. DNA destruction due to gene mutation or experiment
CALR mutations in patients with myelofibrosis being treated with ruxolitinib can lead to worsened outcomes. | Image Credit: © rost9 | stock.adobe.com

CALR mutations can be found in around 20% of patients with primary and post-essential thrombocythemia (ET) MF. Patients who harbor CALR mutations often present with distinct clinical features compared with Janus kinase (JAK)2-mutated patients. Typically, they feature lower levels of hemoglobin and white blood cells, present at younger age, and are associated with better survival rates.1,2

Ruxolitinib (Jakfafi; Incyte) is a targeted therapeutic option for patients with MF that has shown efficacy regardless of the driver mutation in patients. However, new therapies continue to be developed that specifically target CALR, necessitating further research on therapies that are currently standard in CALR-positive patients, according to the investigators.1,3

The study authors reported the outcomes of a sub-analysis of the RUX-MF clinical trial, documenting 135 patients with CALR mutation who received ruxolitinib in a real-world setting. The analysis was performed with major considerations, including that the younger age of CALR-mutated patients compared with JAK2-mutated patients may influence survival outcomes, and that younger patients are eligible for allogeneic stem cell transplantation, which the investigators noted could meaningfully impact the treatment algorithm.1

In total, 786 patients from the RUX-MF trial were JAK2-mutated, while 135 had a CALR mutation. Only 78 CALR-mutated patients were evaluable, in which their mutation was type 1-like in 66.7% of the population, while 30.8% had type 2-like mutation. At the beginning of ruxolitinib initiation, CALR-mutated patients were younger, had higher percentages of peripheral blasts, and lower median hemoglobin levels compared with JAK2-mutated patients.1

Responses to ruxolitinib and patient outcomes according to mutation type were reported at 6 months. There were no major differences in spleen responses (CALR: 21.4%; JAK2: 25.7%), and there were comparable rates of treatment-emergent anemia (CALR: 35.7%; JAK2: 30.4%) and both overall and treatment-emergent thrombocytopenia. However, symptoms response was significantly lower in CALR-mutated patients (56.1% vs 66.7%), and overall anemia rates (60.3% vs 50.3%) were higher in this population compared with JAK2-mutated participants.1

Across the 135 patients with CALR mutation, there were no factors associated with spleen or symptom response. Notably, factors correlated with worse survival included hemoglobin below 10 g/dL and a high burden of symptoms. In the subgroup of 72 CALR-mutated patients who began ruxolitinib over 2 years following diagnosis, anemia (HR: 1.92; 95% CI, 1.02-3.79) and the use of a reduced ruxolitinib initiation dose (HR: 2.29; 95% CI, 1.15-4.56) were associated with poor overall survival.1

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Ruxolitinib Combinations in MPNs: Updates From ASH

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January 8, 2025

Author(s): Mary Caffrey

Following its approval in 2011 for myelofibrosis (MF), ruxolitinib (Jakafi, Incyte) became the backbone of treatment for MF and later for polycythemia vera (PV), 2 of the 3 common myeloproliferative neoplasms (MPNs).

But although ruxolitinib improves survival outcomes and quality of life, some patients may not respond to therapy, while others may stop due to genetic mutations, disease progression, or other factors. For years now, investigators have been studying the Janus kinase (JAK) inhibitor in combination with other drugs, both in first-line treatment and refractory disease. Abstracts and oral presentations at the recent 66th American Society of Hematology (ASH) Annual Meeting and Exposition, held December 7-10, 2024, in San Diego, California, offered updates on several combinations in the pipeline:

MANIFEST-2. Previous results from this phase 3 study (NCT04603495) of pelabresib, a selective bromodoman and extraterminal domain (BET) inhibitor, with ruxolitinib show it met its primary end point; in patients with MF not treated with a JAK inhibitor, a statistically significant higher proportion showed at least 35% reduction in spleen volume from baseline at week 24 with the combination vs ruxolitinib and placebo. Results presented at ASH showed those results were maintained after a median follow-up of 72 weeks, with a 48-week response rate of 57.0% for the combination vs 37.5% for ruxolitinib and placebo. An improvement in the Myelofibrosis Symptom Assessment Form total symptom score (TSS) by at least 50% was seen in 45.3% of patients receiving the combination vs 39.4% in the placebo group.1

Bomedemstat. An abstract at ASH reported on an ongoing phase 2 study (NCT05569538) involving bomedemstat combined with ruxolitinib in patients with advanced MF.2 Bomedemstat is an irreversible inhibitor of lysine-specific demethylase 1 (LSD1), which plays a role in gene regulation; blocking this enzyme alters cell differentiation and growth. In August 2024, Merck announced the second phase 3 trial of bomedemastat in another MPN, essential thrombocythemia (ET).

The abstract authors noted that about 50% of patients with MF stop ruxolitinib after 3 years, mostly due to disease progression or cytopenia; median OS after discontinuation is 14 months.2 LSD1, they write, is “critical for self-renewal” of cancerous stem cells, and has shown promise as a single agent. This study reported on 2 cohorts: Cohort A had a suboptimal response to ruxolitinib, and cohort B patients had MF and were treatment naive. Patients in cohort A remained on the entry dose of ruxolitinib while cohort B started 10 mg twice per day; all patients received a starting dose of 0.4 mg/kg/day of bomedemstat. Dose adjustments were permitted every 4 weeks to achieve an optimal platelet count; downward titrations were done at any time for safety reasons. After a median of 61.7 weeks, in 40 evaluable patients, at week 24, 11 patients had at least a 50% improvement in TSS, with 25.9% in cohort A and 30.7% in cohort B; 17.5% had at least 35% spleen volume reduction, with 7.4% in cohort A and 38.5% in cohort B; and 50% of patients had stable or improved hemoglobin (51.9% in cohort A and 46.3% in cohort B). There were no safety signals or deaths related to the drug, the authors said.2

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