Category Archives: Myelofibrosis

Momelotinib Improves Anemia in JAK Inhibitor-Naive Myelofibrosis

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Sabrina Serani

Treatment with momelotinib (Ojjaara) delivered benefits to anemia among patients with myelofibrosis who were naive to JAK inhibitors, regardless of their baseline hemoglobin level. Further, momelotinib provided significant anemia benefits compared with ruxoltinib (Jakafi), according to an analysis from the phase 3 SIMPLIFY-1 study (NCT01969838).

SIMPLIFY-3 randomized 432 patients with myelofibrosis who had not received JAK inhibitors toreceive momelotinib or ruxolitinib.In patients who were anemic and received momelotinib, mean hemoglobin levels increased by weeks 2 to 4 of treatment, and hemoglobin levels remained stable among patients who were not anemic.

Comparatively, patients who were anemic and nonanemictreated with ruxolitinib experienced an initial decrease in mean hemoglobin. This decrease stabilized after weeks 4 to 6 as patients received red blood cell transfusions. Patients receiving ruxolitinib were permitted to cross over to the momelotinib group, and mean hemoglobin levels increased after this change.

The study also evaluated patients at different levels of anemia. Among patient who were mildly anemic, with ahemoglobin levelbetween 10 and 12 g/dL, 90.4% of patients were transfusion-free at baseline, 93.9% of these patients remained transfusion-free while receiving momelotinib. Four patients who were not transfusion-free at baseline became transfusion-free while on treatment. In contrast, patients who were mildly anemic in the ruxolitinib arm became more dependent on transfusion; 50% of patients who were transfusion-free at baseline required a transfusion while on ruxolitinib.

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Serum Albumin Levels May Predict Survival Among Patients With Myelofibrosis Treated With Ruxolitinib

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Jonathan Goodman, MPhil

Serum albumin may function as a dynamic surrogate marker for clinical outcomes among patients with myelofibrosis treated with ruxolitinib, according to research published in JCO Precision Oncology. The utility of this surrogate measure may, however, vary by a given patient’s treatment status.

Previous work has established ruxolitinib, a JAK inhibitor, as a standard of care among patients with myelofibrosis. Yet although this treatment may help to reduce spleen size and symptom burden, it is unclear whether it improves overall survival (OS) rates.

New models, such as the RR6 model, have aimed to provide a prognostic surrogate measure for OS, though whether these models effectively distinguish high-risk disease from cases where there is no response to treatment is unclear. For this study, researchers aimed to evaluate whether serum albumin — which is linked with an anti-inflammatory response to treatment — is an effective surrogate marker for OS among patients with myelofibrosis.

Overall, data from 396 patients were included. In the cohort, among evaluable patients, 91 had received ruxolitinib while 305 were naïve to treatment, 58% of patients were male sex, and 72% of patients had primary myelofibrosis.

Analysis suggested that serum albumin levels frequently dropped among all patients, though this was less pronounced among patients treated with ruxolitinib. Relatedly, patients with a high serum albumin level at baseline had improved median OS periods (53.5 months) compared to patients with low levels (29.8 months; odds ratio, 1.95; P <.001).

The link between serum albumin levels and OS was independent of variables included in the dynamic international prognostic scoring system, though only among patients who were naïve to ruxolitinib.

Future efforts to incorporate serum albumin with other inflammatory markers into an inflammatory index and assess its relevance in the context of other JAK inhibitors and combinations are ongoing.

Furthermore, among patients treated with ruxolitinib, changes in serum albumin levels predicted OS. Among patients with stable levels or an increase, median OS was 82.7 months, compared with 64.1 months among patients with a decrease (P =.04).

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Genetics and Genetic Testing to Inform Myelofibrosis Clinical Management

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by Charles Bankhead, Senior Editor, MedPage Today May 1, 2024

The history of primary myelofibrosis dates back to 1951 and the description of four distinct clinicopathologic entitiesopens in a new tab or window that came to be known as myeloproliferative neoplasms (MPNs): chronic myeloid leukemia (CML), polycythemia vera, essential thrombocythemia, and myelofibrosis.

Discovery of the Philadelphia (Ph) chromosome in 1960opens in a new tab or window paved the way to identification of BCR/ABL as the principal genetic driver of CML. Another 45 years passed before the discovery of a first genetic driver of non-Ph MPNs, a mutation in the Janus kinase 2 (JAK2) gene,opens in a new tab or window which occurs in 50-60% of myelofibrosis cases.

“The identification of that particular pathway was foundational, and it has changed the face of how we treat patients,” said James Rossetti, DO, of the University of Pittsburgh. “The JAK2 mutation is not present in everyone with myelofibrosis, and there are other mutations as well.”

Researchers identified a third key driver in 2013opens in a new tab or window: calreticulin gene (CALR). The mutation is associated with about 25% of myelofibrosis cases.

Most studies have shown that JAK2, MPL, and CALR are mutually exclusiveopens in a new tab or window and do not occur together. However, a few studies have shown co-occurrence of the three key mutations. Even though JAK2, MPL, and CALR usually do not occur together, numerous other mutations have been identified in association with the three primary mutations. As many as 80% of patients with myelofibrosisopens in a new tab or window have one or more other mutations.

Historically, myelofibrosis treatment was palliative in nature, aimed at relieving specific symptoms. The discovery of the JAK2 driver mutation has transformed treatment. Since 2011 four JAK2 inhibitors have received FDA approval: ruxolitinib (Jakafi)opens in a new tab or window, fedratinibopens in a new tab or window (Inrebic), pacritinibopens in a new tab or window (Vonjo), and momelotinibopens in a new tab or window (Ojjaara). All four drugs demonstrated ability to reduce splenomegaly, a major clinical manifestation of myelofibrosis, as well as symptoms.

Some of the co-occurring mutations are targetable, creating interest in combination therapies that simultaneously target different signaling pathways, said Aaron Gerds, MD, of the Cleveland Clinic. One such combination was evaluated in a clinical trial that paired a JAK2 inhibitor with an IDH2 inhibitor.

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Dr Sekeres on the Rationale for the FDA Approval of Momelotinib in Myelofibrosis

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Mikkael A. Sekeres, MD, MS

Mikkael A. Sekeres, MD, MS, professor, medicine, chief, Division of Hematology, Leukemia Section, the University of Miami Health System, Sylvester Comprehensive Cancer Center, discusses the background on the FDA approval of momelotinib (Ojjaara) for the treatment of patients with anemic myelofibrosis.

At a recent OncLive® State of the Science Summit™ on hematologic malignancies, Sekeres and colleagues provided updates in the realm of myelodysplastic syndromes. Notably, one of these updates includes the FDA approval of momelotinib for the treatment of adult patients with intermediate or high-risk myelofibrosis with anemia. Originally, the phase 3 SIMPLIFY-1 (NCT01969838) and SIMPLIFY-2 (NCT02101268) trials investigated momelotinib compared with ruxolitinib (Jakafi) and momelotinib compared with best available therapy, respectively, Sekeres begins. In SIMPLIFY-2, although patients receiving momelotinib didn’t show a significant improvement in spleen response, they experienced a notable enhancement in symptom score, a benefit that is crucial for patients with myelofibrosis, he reports.

Subsequently, the phase 3 MOMENTUM trial (NCT04173494) was initiated, randomly assigning symptomatic patients with myelofibrosis in a 2:1 ratio to receive either momelotinib or danazol. Notably, significant improvement in symptom scores was observed with momelotinib, Sekeres states, saying that furthermore, substantial improvement in spleen size reduction was noted, forming the basis for momelotinib’s FDA approval. Additionally, there was a trend toward enhanced red blood cell transfusion independence rates among patients, Sekeres adds.

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Connecting Spleen Volume Reduction to Survival Outcomes in MF

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Targeted Oncology Staff

CASE SUMMARY

A 68-year-old woman presented to her physician with symptoms of mild fatigue. Her spleen was palpable 6-7 cm below the left costal margin​, but she had no known comorbidities. Next-generation sequencing revealed a JAK2 V617F mutation​, and her karyotype was46XX.​ A bone marrow biopsy showed megakaryocyte proliferation and atypia with evidence of reticulin fibrosis​, and a blood smear was positive for leukoerythroblastosis​.

Her laboratory values also led to a diagnosis of primary myelofibrosis (MF). Risk stratification based on the dynamic international prognostic scoring system gave her a score of intermediate-1, and based on the mutation-enhanced international prognostic score system for transplantation-age she was also determined to be at intermediate risk​.

DISCUSSION QUESTIONS

  • Did the overall survival data from the COMFORT-I trial (NCT00952289) and COMFORT-II trial (NCT00934544) impact the way you manage patients with MF?​
  • How do you monitor and manage anemia in patients with primary MF prior to starting Janus kinase (JAK) inhibitor therapy?​

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How the PERSIST-2 Results Show The Benefit of Pacritinib in MF

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Targeted Oncology Staff

Targeted Oncology: What was the make-up of the PERSIST-2 trial (NCT02055781) looking at pacritinib (Vonjo) in patients with myelofibrosis (MF)?

JOHN MASCARENHAS, MD: This was the more interesting of the 2 PERSIST studies. PERSIST-2 looked at patients with platelets of 100,000/µL or less.1 So, the cytopenic patient with MF could have been given a Janus kinase [JAK] inhibitor before being enrolled, and half did in this study…but these are patients that were hard to treat, which was opposite to the set-up of the COMFORT-1 [NCT00952289] and COMFORT-2 [NCT00934544] studies.2 [Patients in PERSIST-2 study] were given either 400 mg daily or 200 mg of twice daily pacritinib vs patients on best available therapy [BAT], which could also include ruxolitinib [Jakafi], with a coprimary end point of spleen volume reduction of 35% or more and reduction of the total symptom score at week 24.1

What stood out among patients enrolled in either arm of the study?

I think what’s important to appreciate is when asking the investigator what they would give to patients who were randomly assigned to the BAT arm is that there is a lack of options available. In the BAT arm, 45% of patients got low-dose ruxolitinib, 19% had no options, while some patients were getting hydroxyurea [19%], steroids [13%], and even interferons [2%], which I would argue don’t work in this setting.1 These were patients who had higher-risk disease, and half of them had hemoglobin counts less than 10 g/dL, and the median platelet count was somewhere around 50,000/µL [in a majority of patients in both arms].

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Parsaclisib Added to Ruxolitinib Decreases Spleen Volume and Improves Symptom Scores in Myelofibrosis

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Kyle Doherty

The PI3Kδ inhibitor parsaclisib added to a stable dose of ruxolitinib (Jakafi) reduced spleen volume and improved symptom scores for patients with myelofibrosis who experienced a suboptimal response to ruxolitinib, according to findings from a phase 2 study (NCT02718300) published in Blood Adv.

Final results of the study revealed that patients who received daily-to-weekly dosing of parsaclisib (n = 32) and those who received all-daily dosing of parsaclisib (n = 42) achieved a decrease in spleen volume of at least 10% at 12 weeks at rates of 28.0% and 59.5%, respectively. Moreover, patients achieved a 50% decrease or more at week 12 in Myelofibrosis Symptom Assessment Form symptom scores at rates of 14% and 28%, respectively; the rates of at least a 50% decrease at week 12 in Myeloproliferative Neoplasms Symptom Assessment Form symptom scores were 18% and 32%, respectively.

“Ruxolitinib reduces spleen volume, improves symptoms, and increases survival in patients with intermediate- or high-risk myelofibrosis. However, suboptimal response may occur, potentially because of signaling via the PI3K/protein kinase B pathway,” Abdulraheem Yacoub, MD, professor of Hematologic Malignancies and Cellular Therapeutics at KU Medical Center in Kansas City, Kansas, and coauthors wrote. “The addition of parsaclisib to stable-dose ruxolitinib can reduce splenomegaly and improve symptoms, with manageable toxicity in patients with myelofibrosis with suboptimal response to ruxolitinib.”

The study authors added that parsaclisib was designed with a different molecular structure than earlier-generation PI3K inhibitors—the orally bioavailable, potent, and highly selective next-generation inhibitor may in turn be able to limit both on- and off-target toxicities that were previously seen.

Additional findings from the study demonstrated that in the overall population evaluable for the primary end point (n = 65), the median change in spleen volume was −163.6 cm3 (range, −735.6 to 10173 cm3), with a median percentage change of −11% (range, −47% to 444%). At week 24, these figures were −192.0 cm3 (range, −2040 to 761.4 cm3) and −10% (range, −89% to 34%) among 49 evaluable patients. The median percentage change was greater among patients who received all-daily dosing compared with those who received daily-to-weekly dosing both at 12 weeks (−15.0% vs −2.0%) and 24 weeks (−19.0% vs −2.5%, respectively).

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Utilization of Momelotinib for Myelofibrosis With Anemia Can Result in Small Savings

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Laura Joszt, MA

Although momelotinib to treat myelofibrosis (MF) with anemia has a higher acquisition cost, it is partially offset by savings when transfusion-related costs are reduced, according to a poster being presented at the AMCP Annual Conference, held April 15-18, 2024, in New Orleans, Louisiana.1

MF is a rare cancer in the bone marrow that disrupts the production of blood cells.2 MF causes anemia because of the extensive scarring to bone marrow. This extensive scarring also causes patients to have a low number of platelets, increasing their risk of bleeding. Patients may also have an enlarged spleen.

Momelotinib inhibits Janus kinase (JAK) 1, JAK2, and activin A receptor type 1. In September 2023, the FDA approved momelotinib to treat patients with intermediate- or high-risk MF with anemia.3

The approval of momelotinib was based on data from the phase 3 MOMENTUM trial, which found clinically significant improvements for patients treated with momelotinib vs danazol.4 A quarter of patients treated with momelotinib had a 50% or greater reduction in total symptom score compared with only 16% of patients on danazol.

Since the approval, the National Comprehensive Cancer Network (NCCN) has added momelotinib5 to its Clinical Practice Guidelines in Oncology for Myeloproliferative Neoplasms. Momelotinib was added as a category 2A treatment for patients with high-risk MF. It was also added as a 2B category treatment for patients with lower-risk MF.

Patients with MF who have anemia and are dependent on transfusions have increased medical costs and poor prognosis, the authors of the AMCP poster noted. JAK inhibitors may provide improvements in symptoms and spleen size, but they could worsen or induce anemia. However, momelotinib has been shown to reduce spleen size.4

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Ryvu Therapeutics Presents Preclinical Data on RVU120 and Synthetic Lethality Programs at the 2024 AACR Annual Meeting

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10 Apr, 2024

  • Ryvu PRMT5 inhibitors show potential best-in-class profiles, including a strong antiproliferative effect on MTAP-deleted cell lines and a good safety window versus MTAP WT cells.
  • Ryvu’s WRN inhibitor program has demonstrated target engagement and selective potency with a synthetic lethal effect; in vivo efficacy studies exhibited pronounced tumor growth inhibition in an MSI-H colorectal cancer xenograft model.
  • Ryvu’s proprietary ONCO Prime discovery platform, which recently received a PLN 26 million (approx. USD 6.6 million) grant from the Polish Agency for Enterprise Development, has identified novel drug targets in KRAS-mutant patient-derived cells (PDCs) with therapeutic potential in colorectal cancer; the ONCO Prime platform has broad potential across multiple tumor types.
  • RVU120 shows efficacy both as a monotherapy and synergistically in combination with ruxolitinib in preclinical models of myeloproliferative neoplasms, including myelofibrosis and polycythemia vera.
  • MEN1703 (SEL24), presented by partner Menarini Group, shows cytotoxic activity in myelofibrosis cell lines as a monotherapy and synergistically in combination with ruxolitinib.

KRAKOW, Poland, April 10, 2024 /PRNewswire/ — Ryvu Therapeutics (WSE: RVU), a clinical-stage drug discovery and development company focusing on novel small molecule therapies that address emerging targets in oncology, presents preclinical data from its synthetic lethality pipeline, RVU120, and MEN1703 (SEL24) at the 2024 AACR Annual Meeting, April 5-10 in San Diego, California.

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Disease Progression for Patients With Low-Risk Myelofibrosis Participating in the MOST Study

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Grace Taylor

03/26/2024

A group of researchers presented data on disease progression for patients with low-risk myelofibrosis (MF) participating in the prospective observational Myelofibrosis and Essential Thrombocythemia Observational Study (MOST) at the 2023 ASH Annual Meeting & Exposition.

In order to qualify for the MOST study, participants were required to have a physician-reported diagnosis of MF (primary myelofibrosis [PMF], post progression of polycythemia vera [post-PV], or post essential thrombocythemia [post-ET). They also could not have any risk factors per the Dynamic International Prognostic Scoring System (DIPSS) criteria. However, participants could be aged 65 years or older. The number of patients with MF enrolled in the study was 232. Of this population, 205 met the study criteria and were included in cohort A. Although the remaining 27 patients had  ≥1 DIPSS risk factor, they were included in the study in a separate cohort B.

For the study, disease progression was defined by the worsening of clinical or laboratory parameters, which included one or more of the following criteria: hemoglobin (Hb) <10 g/dL, platelets <100×109/L, presence of constitutional symptoms (weight loss, fever, or sweats), new or worsening splenomegaly, blasts >1%, white blood cell count >25×109/L, death due to disease progression, leukemic transformation (LT), or >1 red blood cell transfusion. The median follow-up was 52.9 months (42-68).

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