POIESIS Trial Evaluates Navtemadlin/Ruxolitinib Combo in Myelofibrosis

The phase 3 POIESIS trial is investigating navtemadlin as an add-on therapy to the JAK inhibitor ruxolitinib (Jakafi) in patients with JAK inhibitor-naive myelofibrosis who experience a suboptimal response to ruxolitinib.

Myelofibrosis, a chronic leukemia, is a rare hematologic malignancy characterized by scar tissue formed in a patient’s bone marrow. The disease is a chronic leukemia that produces excess abnormal blood cells that replace normal cells, causing anemia and spleen enlargement in patients with the disease.¹

Anemia is a condition characterized as a deficiency of red blood cells that can deprive your tissues of oxygen and cause symptoms like fatigue, weakness and shortness of breath. An enlarged spleen, or splenomegaly, can cause a sensation of fullness or discomfort in the upper left section of your abdomen. Myelofibrosis affects the body in many ways, causing other signs and symptoms like thrombocytopenia (a deficiency of platelets), extramedullary hematopoiesis (abnormal growth of blood-forming cells outside of your bone marrow, in organs such as the spleen, liver or lungs) and constitutional symptoms, such as night sweats, itching, bone pain and fever, which are experienced by the majority of patients with myelofibrosis. The presence of these signs and symptoms, in turn, create an unmet medical need across the treatment landscape of myelofibrosis.

To address these unmet needs, investigators have launched clinical trials that aims to combat the disease and its signs and symptoms. One of these is the phase 3 POIESIS trial (NCT06479135), which is investigating navtemadlin as an add-on therapy to the JAK inhibitor ruxolitinib (Jakafi), compared with placebo plus ruxolitinib in patients with JAK inhibitor-naive myelofibrosis who experience a suboptimal response to ruxolitinib.² The POIESIS study is a randomized, double-blind, placebo-controlled, multicenter, global clinical trial.

The most recent presentation of information on navtemadlin in myelofibrosis was shared at the American Society of Hematology Annual Meeting and Exposition in December 2024. In an article published before the meeting in Blood, first study author, Pankit Vachhani, MD, wrote, “POIESIS has an innovative and unique design that aligns with [myelofibrosis] treatment approaches adopted in routine clinical practice: treat, when necessary, with add-on therapy.”³

Vachhani serves as an associate professor of hematology and oncology at the University of Alabama at Birmingham O’Neal Comprehensive Cancer Center.

Phase 3 POIESIS Trial

To understand the clinical benefit the POIESIS trial may offer, it's important to first recognize the significant unmet medical needs faced by patients with myelofibrosis, particularly those who have a suboptimal response to ruxolitinib. According to the official POIESIS trial website, JAK inhibitors are the only approved treatment options for patients with myelofibrosis.⁴ JAK inhibitors like ruxolitinib inhibit a key pathway (JAK-STAT) that drives myelofibrosis cancer cell proliferation. Because JAK inhibitors are the only approved treatment option, once progression occurs, patients have limited treatment options.

“There are currently no approved therapies for patients who have not optimally responded to treatment with a JAK inhibitor,” the POIESIS trial website explains.

With the POIESIS trial, it is hoped that navtemadlin, the oral therapy under investigation, may provide additional benefit to ruxolitinib treatment compared with ruxolitinib alone. Navtemadlin targets the MDM2 protein; MDM2 decreases the activity of p53, a critical tumor suppressor protein that plays an important role in the body’s natural defenses against cancer, making MDM2 an important target. Notably, in myelofibrosis, MDM2 levels abnormally increase, preventing p53 from carrying out its usual cancer-fighting functions.

Based on this background information, investigators rationalize that because navtemadlin treatment inhibits MDM2 to allow p53 to kill cancer cells, it may eventually offer a potential new treatment for patients with myelofibrosis.

The POIESIS trial is comprised of 2 treatment periods, the first being a run-in period which is set to enroll approximately 600 patients, according to Blood.³ Patients who consent to participate in the study will receive ruxolitinib treatment for 18 to 24 weeks, with the dosage determined by the study doctor. If patients show a suboptimal response to ruxolitinib or if the treatment proves insufficiently effective, they will move on to the second phase of the study: the randomized add-on period, involving approximately 180 participants.

Conversely, if ruxolitinib treatment is effective in shrinking the spleen and reducing symptoms, patients may continue their current therapy but will no longer be part of the study, as stated on the POIESIS trial website.⁴ Notably, if the patient does not respond at all to treatment with ruxolitinib, the study doctor will work with that individual to determine their optimal treatment approach following study cessation.

Natasha Johnson, MSN, APRN, AOCNP, a nurse practitioner at the malignant hematology clinic at Moffitt Cancer Center in Tampa, Florida, who treats patients enrolled in POIESIS, discussed the importance of providing prophylactic regimens ahead of experiencing possible but rare adverse effects.

“In general, ruxolitinib is tolerated very well,” explained Johnson. “As far as adverse events with the POIESIS trial, gastrointestinal adverse effects are something that can occur. … Prophylactic antiemetics help prevent nausea and vomiting, and antidiarrheals [are important] because if we can manage those gastrointestinal adverse effects well, patients tolerate the medication better.”

During the randomized add-on period, eligible participants will receive either navtemadlin or a placebo, in addition to their current ruxolitinib dose from the run-in period. The trial’s website states that investigators intend to enroll 180 patients who will be randomly assigned in a 2:1 fashion to receive either navtemadlin (120 patients) or placebo (60 patients) treatment. This means patients have a 2 in 3 chance of receiving the navtemadlin treatment.

Moreover, this portion of the study is blinded to everyone involved, meaning that patients and doctors will not know which add-on treatment is being used: either navtemadlin or placebo.

Prior to treatment initiation, patients must undergo complete clinical evaluations, including providing blood samples, spleen volume measurement via imaging scans (such as MRI or CT), as well as fill out questionnaires that assess the severity of each patient’s related symptoms. Upon enrollment and consent for study participation, these procedures and measurements will be ongoing until either the end of the 28th week of the randomization period or end of treatment, whichever is later.

Importantly, the POIESIS trial website states that, “For both periods of the study [run-in period and add-on period], patients remain on study unless they cannot tolerate the treatment or their disease progresses.”

The primary end points of the study will be evaluated 24 weeks after the start of the randomized add-on period. Efficacy will be assessed by comparing navtemadlin to placebo for their effects on spleen volume reduction (measured by MRI or CT) and symptom score reduction, as reported in the daily 7-symptom questionnaire. To ensure accurate results, it is crucial for patients to attend all imaging appointments and record their daily symptom scores accurately.

Jhada-Kai Hunter, a clinical trial coordinator for POIESIS, spoke to the role of nurses in the trial.

“Being there to remind the patient, give them a phone call in the first set of days when the patient is starting off, to remind them to keep doing the questionnaires and explain to them what the purpose of these questionnaires are and how they work [is an important role of nurses in the POIESIS trial],” said Hunter. “I’ve seen a few patients who, because they may have had this disease and its symptoms for a while … to them today [their symptom score] is a 1 out of 10, because it has been worse before. But [nurses can encourage patients to] try and remember back to before they had some of these symptoms, so that the patient gets a good gauge [of how they are feeling in comparison].”

Johnson touched on the importance of explaining to patients that improvement may not be immediate. “It goes back to educating that when we start trials or treatment, it’s not often a quick fix. Patients better handle it when they know upfront that we’re really assessing how the patient responds … 12 to 24 weeks [from now] to see how the patient is really doing,” said Johnson.

“When they come back in 2 to 4 weeks later, they say, ‘My counts are getting worse. I’m not feeling much better.’ But if they know upfront that we don't anticipate improvement right away, they can respond better.”

Discussing Clinical Trial Participation

Participation in clinical trials such as the POIESIS study is necessary because these trials help researchers identify new standard-of-care medications that are more effective and safer than currently available options, thus improving the survival and quality of life of countless future patients, according to the POIESIS trial website; in some trials, it may even lead to the discovery of a curative treatment option.

According to the Fred Hutch Cancer Center website, patients should inquire about clinical trials which are applicable to their type and stage of cancer with their care team. Moreover, the clinicaltrials.gov website houses information on thousands of trials which are active and currently enrolling, as well as those which have been completed. Patients can find information for clinical studies on the website by filtering through condition, treatment, location or investigator name on the website’s home page. Patients can also access the study status, eligibility criteria and specific institutions which are conducting the clinical trial.

Although clinical trials are vital in the treatment landscape, participation is never required and is a big decision for those participating. Therefore, Fred Hutch Cancer Center website encourages patients who have a caregiver, partner or adult family member, to share their thoughts with them and include them in discussions with the care team about clinical trials. Of note, the National Institute of Mental Health encourages patients to bring questions to their care team which cover topics such as: the study’s purpose and duration, possible risks and benefits, participation and care, and personal and cost concerns.

Notably, the POIESIS trial website also encourages patients to find more information about clinical trials through other resources such as the American Cancer Society, National Cancer Institute, European Federation of Pharmaceutical Industries and Associations, MPN Research Foundation, and MPN Advocacy & Education International.

Of note, the POIESIS trial is currently enrolling patients with JAK inhibitor-naive myelofibrosis. Patients with prior exposure to a JAK inhibitor will be excluded from enrollment on the trial.

POIESIS is expected to be conducted in more than 250 cancer centers across multiple countries, including up to 70 community and academic centers in the United States. In the United States, study sites are located in over 90 cities in both academic and community practice settings. For a full list of participating sites please visit www.poiesis-trial.com.

Editor’s note: For more information on trial participation, you can contact your nearest participating center for more information or send an email to POIESIS-trial@kartosthera.com, as well as find more information on the clinicaltrials.gov website.

References

1. Myelofibrosis. Cleveland Clinic. Updated June 27, 2025. Accessed July 30, 2025. https://my.clevelandclinic.org/health/diseases/15672-myelofibrosis
2. Study of navtemadlin add-on to ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis who have a suboptimal response to ruxolitinib (POIESIS). ClinicalTrials.gov. June 28, 2024. Updated December 24, 2024. Accessed July 29, 2025. https://clinicaltrials.gov/study/NCT06479135
3. Vachhani P, Rampal R, Bradley T, et al. POIESIS: a randomized, double-blind, placebo-controlled, multicenter, global phase 3 study of navtemadlin as add-on to ruxolitinib in JAK inhibitor-naïve patients with myelofibrosis who have a suboptimal response to ruxolitinib. Blood (2024) 144 (Supplement 1): 1808.2. doi: 10.1182/blood-2024-200966
4. POIESIS: a clinical trial for patients with myelofibrosis. Kartos Therapeutics, Inc. 2025. Accessed July 29, 2025. https://poiesis-trial.com/