Category Archives: Myelofibrosis

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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MAIC Points to Improved OS With Momelotinib in Ruxolitinib-Pretreated Myelofibrosis

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December 13, 2024

Author(s): Caroline Seymour, Kyle Doherty

Fact checked by: Courtney Flaherty

Momelotinib (Ojjaara) demonstrated improved overall survival (OS) vs best available therapy (BAT) in patients with ruxolitinib (Jakafi)–pretreated myelofibrosis, according to data from a matching-adjusted indirect comparison (MAIC) analysis that were presented at the 2024 ASH Annual Meeting & Exposition.1

Data from an unmatched analysis demonstrated that the median OS favored patients who received momelotinib (n = 383) compared with those who received BAT (n = 267; HR, 0.373; 95% CI, 0.297-0.469; P < .001). In the base case model (model 1), the median OS also favored momelotinib (n = 89) vs BAT (HR, 0.512; HR, 0.358-0.732; P < .001). In the alternative adjustment model (model 2), the median OS again favored momelotinib (n = 117) vs BAT (HR, 0.484; 95% CI, 0.347-0.675; P < .001).

Additionally, patients in the anemia subgroup who received momelotinib (n = 255) experienced a median OS benefit compared with those treated with BAT (n = 174; HR, 0.384; 95% CI, 0.293-0.504; P < .001). Data from model 1 also showed that patients treated with momelotinib in this subgroup (n = 98) achieved a median OS benefit vs those in the BAT arm (HR, 0.542; 95% CI, 0.387-0.759; P < .001). Findings from model 2 demonstrated a median OS benefit with momelotinib (n = 146) vs BAT (HR, 0.487; 95% CI, 0.360-0.660; P < .001).

“[Although] the trials used in this analysis do no provide long-term outcomes, this MAIC suggests that momelotinib may offer a greater OS benefit than BAT in patients with myelofibrosis previously treated with ruxolitinib, both in the overall cohort and the anemic population,” Francesca Palandri, MD, PhD, lead study author and an adjunct professor in the Department of Medical and Surgical Sciences at the University of Bologna in Italy, said in a poster presentation of the data.

In September 2023, the FDA approved momelotinib for the treatment of adult patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis, and anemia.2 The regulatory decision was supported by findings from the phase 3 MOMENTUM (NCT04173494) and SIMPLIFY-1 trials (NCT01969838).

To conduct their analysis, Palandri and colleagues performed a MAIC analysis comparing patients who received momelotinib during MOMENTUM, SIMPLIFY-1, or the phase 3 SIMPLIFY-2 trial (NCT02101268) with 267 patients who received BAT across 26 European hematology centers in the real-world, retrospective RUX-MF study.1 Notably, the overall study included 1055 patients treated with ruxolitinib across 26 European hematology centers from 2013 until death or the data cutoff of February 2, 2024.

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Pacritinib and Momelotinib Display Positive Real-World Impact on Anemia and Transfusion Needs in Myelofibrosis

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December 12, 2024

Author(s): Kyle Doherty

Fact checked by: Caroline Seymour

Although long-term follow-up was limited, treatment with the JAK2 inhibitors pacritinib (Vonjo) and/or momelotinib (Ojjaara) led to favorable effects on anemia and transfusion requirements among patients with myelofibrosis, according to findings from a real-world study presented in a poster during the 2024 ASH Annual Meeting.1

Patients who received momelotinib (n = 32) had a median hemoglobin count of 8.7 g/dL (range, 6.5-1.2) at the start of therapy which increased to 9.0 g/dL after 3 months of treatment (P = .021). The median platelet count at the start of therapy was 141 x 109/L (range 15 x 109-504 x 109) and increased to 116 x 109/L after 3 months (P = .317). Patients required a mean of 1.9 red blood cell (RBC) units/month at the start of therapy and 0.47 units/month after 3 months of treatment (P = .015).

Patients treated with pacritinib (n = 27) had a median hemoglobin count of 8.5 g/dL (range, 6.9-12.9) at the start of treatment and a median count of 9.1 g/dL following 3 months of therapy (P = .402). The median platelet count at the start of therapy was 65 x 109/L(range, 18 x 109-441 x 109) compared with 31 x 109/L after 3 months of treatment (P = .303). Patients required a mean of 2.4 RBC units/month at the start of therapy vs 0.75 RBC units/month after 3 months of therapy (P = .099).

“The goal of this project was to [examine] the patients who have been treated so far at Moffitt Cancer Center with either pacritinib and/or momelotinib to gain a better understanding of the hematologic responses of these therapies, the duration of treatment, and other real-world data regarding these agents after they got their approvals,” Jeremy DiGennaro, MD, said during the presentation. “Patients receiving momelotinib and pacritinib are typically older with extended disease duration, multiple prior lines of therapy, high-risk mutations, and cytopenia. Pacritinib-treated patients have more prominent baseline thrombocytopenia. [However], there were favorable impacts on anemia and transfusion requirements [with both agents], although we still do need more long-term follow-up.”

DiGennaro is an internal medicine resident physician at the University of South Florida Morsani College of Medicine in Tampa.

In February 2022, the FDA granted accelerated approval to pacritinib for the treatment of adult patients with intermediate or high-risk primary or secondary myelofibrosis with a platelet count below 50,000/µL.2 Momelotinib was approved by the FDA in September 2023 for the treatment of adult patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis, and anemia.3

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Optimizing Myelofibrosis Care in the Age of JAK Inhibitors

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December 12, 2024|Hematology and Oncology
Douglas Tremblay, MD

Myelofibrosis is a rare but serious bone marrow disorder that disrupts blood cell production and often leads to debilitating symptoms. In this interview, Douglas Tremblay, MD, Assistant Professor at the Tisch Cancer Institute, discusses the process for selecting the best treatment pathway for patients – from evaluating disease prognosis to navigating treatment resistance and intolerance.

Dr. Douglas Tremblay

How do you assess a patient’s prognosis at the time that they are diagnosed with myelofibrosis?
In the clinic, we use several scoring systems that have been developed based on the outcomes of hundreds of patients with myeloproliferative neoplasms (MPNs) to try to predict survival from time of diagnosis. Disease features associated with a poor prognosis include anemia, elevated white blood cell count, advanced age, constitutional symptoms, and increased peripheral blasts. Some of these scoring systems also incorporate chromosomal abnormalities as well as gene mutations to further refine prognostication.1

Determining prognosis can be important to creating a treatment plan, particularly to decide if curative allogeneic stem cell transplantation is necessary. However, I always caution patients that these prognostic scoring systems cannot tell the future and that each patient may respond differently to treatment.

How do you monitor for disease progression?
I will discuss with patients how they are feeling in order to determine if there are any new or developing symptoms that could be a sign that their disease is progressing. I will also review their laboratory work looking for changes in blood counts that could be a signal of disease evolution.

For instance, development of anemia or thrombocytopenia may signal worsening bone marrow function or progression to secondary acute leukemia. If there are concerning signs or symptoms, I will then perform a bone marrow biopsy with aspirate that will include assessment of mutations and chromosomal abnormalities to determine if their disease is progressing.

What are the first-line treatment options for a patient newly diagnosed with myelofibrosis, and how do you determine the best course of action?
For patients with myelofibrosis, the first-line treatment options include Janus kinase (JAK) inhibitors, which are effective at improving spleen size and reducing symptom burden. The US Food and Drug Administration (FDA) has approved 4 JAK inhibitors for the treatment of myelofibrosis: ruxolitinib, fedratinib, pacritinib, and momelotinib (Table).2-13 In general, ruxolitinib is the first-line treatment option unless there is thrombocytopenia, in which case pacritinib is more appropriate. In patients with baseline anemia, momelotinib may be the best choice.

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Navtemadlin Reduces Markers of Disease Burden in Relapsed/Refractory Myelofibrosis

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December 9, 2024

Author(s): Morgan Bayer

Treatment with navtemadlin (KRT-232) lowered the levels of biomarkers of disease burden in patients with relapsed/refractory myelofibrosis, according to findings from the phase 3 BOREAS trial (NCT03930732) that were presented at the 2024 ASH Annual Meeting.1

“I want to emphasize the biology that drives this approach. MDM2 is a negative regulator of wild-type p53, which is a master determinant of cell fate, and this becomes very critical when you consider its influence over the 4 hallmarks of myelofibrosis: CD34-positive myelofibrosis cell proliferation, myelofibrosis driver gene variant allele frequency (VAF), bone marrow fibrosis, and pro-inflammatory cytokines,” said John O. Mascarenhas, MD, during a presentation of the data.

Mascarenhas is professor of medicine, hematology and medical oncology, director of the Center of Excellence for Blood Cancers and Myeloid Disorders, and director of the Adult Leukemia Program at the Mount Sinai Tisch Cancer Center in New York, New York.

In the randomized, multicenter, global phase 3 BOREAS trial, navtemadlin monotherapy was compared with best available therapy (BAT) that included hydroxyurea, peginterferon, immunomodulatory drugs, or supportive care. Patients included in the trial had TP53 wild-type myelofibrosis and were refractory or had relapsed on prior therapy with a JAK inhibitor. The data cutoff date was September 30, 2024.

In the study, 183 patients were randomly assigned 2:1 to receive navtemadlin (n =1 23) at 240 mg 7 days in a row for a 28-day cycle (with 21 days of drug holiday) or 1 cycle of BAT (n = 60) for 28 days. “The patients who were on a JAK inhibitor at the time had a 28-day washout period so that from a spleen and symptom perspective they were clear on day 1 of navtemadlin dosing,” Mascarenhas explained.

“What we saw in terms of biomarkers was a very significant potent, rapid reduction in circulating CD34 cells as a hallmark of myelofibrosis even within 12 weeks and sustained over 24 and 36 weeks,” Mascarenhas stated. At 12 weeks, CD34-positive cells showed a median reduction of 68% from baseline in 50 patients in the navtemadlin arm and 52% in 25 patients in the BAT arm. This trend continued at 24 weeks (n = 48, 70% reduction vs n = 19, 38% reduction) and at 36 weeks (n = 21, 76% reduction vs n = 9, 33% reduction).

The reduction in driver gene VAF by 50% or greater was observed in 21% (n = 17/82) of patients in the navtemadlin arm and 12% (n = 4/33) of patients in the BAT arm at 24 weeks, “nearly doubling the molecular response at 24 weeks,” Mascarenhas noted.

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Myelofibrosis symptom assessment form total symptom score version 4.0: measurement properties from the MOMENTUM phase 3 study

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November 25, 2024

Christina Daskalopoulou, Boris Gorsh, Gerasimos Dumi, Samineh Deheshi, Chad Gwaltney, Jean Paty, Catherine Ellis, Jun Kawashima & Ruben Mesa

Abstract

Purpose

The Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0) comprises 7 common MF symptom items (fatigue, night sweats, pruritus, abdominal discomfort, pain under the left ribs, early satiety, bone pain) and is the first patient-reported outcome (PRO) instrument designed to assess MF symptom burden. Given that information on the psychometric properties of this instrument has been limited, we sought to evaluate its measurement properties and validate its use in the phase 3 MOMENTUM trial.

Methods

Data were pooled to assess MFSAF item distribution, structural validity, reliability (test-retest and internal consistency), construct validity (convergent, divergent, and known-groups), and sensitivity to change. Other PRO measures included Patient Global Impression of Severity/Change (PGIS/PGIC), EORTC QLQ-C30, PROMIS Physical Function Short Form 10b, and ECOG performance status.

Results

Participants (N = 195) showed high completion rates (> 93%) across 24 weeks. Moderate to strong Spearman correlation coefficients among items were mostly observed at baseline (range, 0.289–0.772) and week 24 (range, 0.391–0.829), which supported combining items into a multi-item scale and total score. Internal consistency (Cronbach’s α, 0.877 at baseline and 0.903 at week 24) and test-retest reliability (intraclass correlation coefficient, > 0.829) were satisfactory across selected time intervals. Reliability was also supported by McDonald’s omega (ω) coefficient (> 0.875). MFSAF moderately correlated with PRO measures of similar content, differentiated between PGIS and ECOG groups (P < .001), and was able to detect change over time.

Conclusions

The MFSAF v4.0 is a valid tool to assess MF symptom burden, supporting its use in future trials in similar populations.

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Ojjaara (momelotinib) approved in Canada for the treatment of myelofibrosis in adults who have moderate to severe anemia

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  • Ojjaara (momelotinib) is the only approved treatment for newly diagnosed and previously treated myelofibrosis patientsi who have moderate to severe anemia and other key manifestations associated with the disease.ii
  • This approval underscores GSK’s commitment to help drive progress for people living with complex blood cancers.

MISSISSAUGA, ON, Nov. 12, 2024 /CNW/ – GSK announced today that Health Canada has approved Ojjaara (momelotinib) for the treatment of splenomegaly and/or disease-related symptoms, in adult patients with intermediate or high-risk primary myelofibrosis (MF), post polycythemia vera MF or post essential thrombocythemia MF who have moderate to severe anemia.iii Ojjaara is the first and only approved medication globally, and now in Canada, that treats both the anemia and other key manifestations of myelofibrosis (newly diagnosed and previously treated).iv

“Treatment options for myelofibrosis-related anemia have been limited. We are proud to offer this treatment alternative for Canadian patients to address this critical unmet need and other myelofibrosis symptoms. With most myelofibrosis patients becoming anemic over time, Ojjaara’s approval represents a significant milestone to improve the outcomes of these patients while also highlighting GSK’s commitment to making an impact in Canada’s hematology oncology space through innovative new treatments,” said Michelle Horn, Interim Country Medical Director, GSK Canada.

Myelofibrosis is a rare blood cancer part of the broader myeloproliferative neoplasms (MPNs) diseases. MPNs have an incidence rate of 2.05 new cases per 100,000 Canadians.v Currently there are between 1,400-2,177 estimated people living with this type of disease in Canada.vi Anemia is a common symptom of myelofibrosis and a major unmet needvii, but awareness among Canadians is low. A 2024 survey shows that 90% of Canadians have heard of anemia but almost 50 per cent do not know about blood cancer related anemia.viii Canadians also have low knowledge of anemia with over 40 per cent of the same respondents saying they know little to nothing about this condition.ix

“Anemia and related transfusions significantly affect the quality of life, prognosis and survival for anemic myelofibrosis patients,” said Cheryl Petruk, CEO of HEAL Canada. “We are excited to witness progress in this rare disease space and to see Ojjaara approved in Canada. This new treatment has the potential to help improve the lives of patients while addressing the disease’s main challenges, namely anemia and other major symptoms.”

Ojjaara is the only once-a-day, oral JAK1/JAK2 and activin A receptor type 1 (ACVR1) inhibitor.x The approval of Ojjaara by Health Canada is supported by data from the pivotal MOMENTUM Phase III trial, which demonstrated significant improvements in Total Symptom Score (TSS), Transfusion Independence, and Splenic Response Rate.xi Additional support came from a subset of patients in the SIMPLIFY-1 Phase III trial, reinforcing Ojjaara’s efficacy in treating moderate to severe anemia and related symptoms in myelofibrosis patients.xii

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Dr DeAngelo on the Integration of JAK Inhibitors in Myelofibrosis Management

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November 11, 2024

Author(s): Daniel J. DeAngelo, MD, PhD

Daniel DeAngelo, MD, PhD, professor, medicine, Harvard Medical School, chief, Division of Leukemia, institute physician, Dana-Farber Cancer Institute, discusses the integration of JAK inhibitors into clinical practice for patients with myelofibrosis. Lower third needs to be updated

When incorporating JAK inhibitors, such as ruxolitinib (Rituxan), into clinical practice, it is essential to understand both their benefits and the challenges they present, particularly regarding anemia, DeAngelo begins. The phase 3 COMFORT-I (NCT00952289) and COMFORT-II (NCT00934544) trials, which initially sought to address symptom control and spleen reduction, demonstrated a notable survival advantage with ruxolitinib over placebo in patients with intermediate-2 or high-risk myelofibrosis, or intermediate-1 disease with symptomatic splenomegaly, he reports. These results led to ruxolitinib becoming the standard of care for high-risk or symptomatic patients, especially as allogeneic transplantation remains limited to select candidates, DeAngelo shares.

A primary consideration with ruxolitinib is its tendency to induce a hemoglobin level drop of approximately 2 points during the first 2 months of treatment due to on-target JAK2 inhibition, which affects erythropoiesis, he continues. Although newer agents are now approved by the FDA specifically for patients with baseline anemia, clinicians using ruxolitinib should anticipate this hemoglobin level decline, he states. Importantly, the initial drop in hemoglobin level does not indicate treatment failure but is a manageable effect that is often misunderstood, leading some oncologists to discontinue or reduce dosing with the drug prematurely, DeAngelo notes.

He goes on to state that his advice for integrating JAK inhibitors into myelofibrosis management plans is to proactively address these expected effects with patients. Patients can be supported through transfusions, growth factors, or alternative JAK inhibitors if needed, according to DeAngelo. In most cases, hemoglobin levels tend to stabilize and improve after the first few months, typically between months 3 and 4, he notes. Setting clear treatment expectations helps ensure patient adherence to therapy and optimizes outcomes when using JAK inhibitors in clinical practice, DeAngelo concludes.

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Frequent Testing for Driver Mutations Critical in Myelofibrosis

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Nov 12, 2024

Researchers from the Munich Leukemia Laboratory in Germany have developed a model that uses 12 genetic markers to accurately stratify patients with myeloproliferative neoplasms (MPNs), according to a study published online ahead of print in Leukemia.

The WHO categorizes classical MPNs—using cytomorphology, bone marrow biopsy, grading of fibrosis, blood counts, and a handful of molecular markers—into four individual entities: chronic myeloid leukemia (CML) and the BCR::ABL1 negative MPNs polycythemia vera (PV), primary myelofibrosis (PMF), and essential thrombocythemia (ET).

“However, overlaps, borderline findings, or transitions between MPN subtypes occur, and incomplete clinical data often complicates diagnosis,” Manja Meggendorfer, PhD, and the study coauthors wrote.

The researchers analyzed 355 patients with MPN to use the results to stratify MPN entities and provide prognostic information. The investigation revealed the presence of genetically distinct subgroups with different cytogenetic abnormalities, mutations, and JAK2 allele statuses.

“Notably, differences in JAK2 allele status (heterozygous/homozygous) correlated with diverse EFS [event-free survival] and OS [overall survival] outcomes, potentially due to additional prognostic mutations,” the researchers reported. “In contrast, groups with cytogenetic aberrations and additional mutations generally had shorter EFS and poorer OS regardless of the diagnosed entity, aligning with studies on the impact of karyotype and mutation count on survival.”

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Lower Pharmacy Costs Give Ruxolitinib Edge for Patients With MF and Anemia

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November 9, 2024

Author(s): Mary Caffrey

The clinical benefits and lower transfusion costs of momelotinib (Ojjaara) are not enough to offset its higher pharmacy costs compared with an older therapy for patients with myelofibrosis (MF) and anemia who rely on transfusions, according to a recent cost-effectiveness analysis.

The results were presented in a poster at the 16th International Congress on Myeloproliferative Neoplasms, held in Brooklyn, New York, October 24-25, 2024.1

Aaron T. Gerds, MD, MS | Image Credit: Cleveland Clinic

Led by Aaron T. Gerds, MD, MS, assistant professor of Medicine, Cleveland Clinic Taussig Cancer Institute, the authors presented data based on a predictive model that computed per-patient total cost of care for 6-month, 1-year, and 2-year periods, comparing the Janus kinase (JAK) inhibitors ruxolitinib (Jakafi), and momelotinib (Ojjaara). Both inhibit the JAK/STAT pathway, with momelotinib additionally targeting a pathway that can result in improved iron-restricted anemia.

As the poster authors stated, ruxolitinib is indicated for patients with intermediate- or high-risk MF, including those with primary MF, post-polycythemia vera MF, post–essential thrombocythemia MF. Momelotinib is indicated for patients with intermediate- or high-risk MF, including those with primary MF, post-polycythemia vera MF, and post–essential thrombocythemia MF in in adult patients with anemia.1

The SIMPLIFY-2 study showed that patients switching from ruxolitinib to momelotinib took less time to achieve transfusion in dependence.2

This analysis presented in Brooklyn was based on the SIMPLIFY-1 study, which compared ruxolitinib and momelotinib in patients who had not previously received a JAK inhibitor.3 The authors, many of whom worked SIMPLIFY-1, found that the difference in pharmacy costs is $11,095 per month, with momelotinib being more expensive. Although transfusion costs for ruxolitinib were projected to cost an additional $10,854 over a 6-month period, the total cost of care still favored ruxolitinib, Results were as follows:

  • At the 6-month mark, the total cost of care favored ruxolitinib by$46,388.
  • At the 1-year mark, the total cost of care favored ruxolitinib by $84,239.
  • At the 2-year mark, the total cost of care favored ruxolitinib by $144,539.

Assumptions in the model. Authors wrote that the model assumed patients remained on therapy for the entire duration of the study or until death. It was limited to pharmacy- and transfusion-related costs, “to isolate costs associated with reductions in transfusion; other costs of care were assumed similar between ruxolitinib and momelotinib.”

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