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 

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; 

< .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; 

 < .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; 

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; 

 < .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; 

 < .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; 

“[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. 

 for the treatment of adult patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis, and anemia.

 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.

 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.

Eligible patients had myelofibrosis and had received momelotinib or BAT as second-line therapy. BAT comprised hydroxyurea, danazol, corticosteroids, erythropoiesis-stimulating agents, and other investigational agents beyond momelotinib. The comparison was performed among patients in the chronic phase, thereby excluding those in the accelerated or blast phase. The anemic subgroup was defined as patients who had hemoglobin levels less than 10 g/dL.

Patients who had received momelotinib were reweighted to match the BAT population using 2 models with different matching factors. Models 1 and 2 both used patient age, male sex, BMI above 25 kg/m

, myelofibrosis subtype, and Dynamic International Prognostic Dynamic International Prognostic Scoring System for Myelofibrosis risk score as matching factors. Model 1 also utilized hemoglobin levels less than 10 g/dL, white blood cell counts above 25 x 10

/L, spleen length of at least 10 cm, and total symptom score as matching factors.

The mean patient age at baseline across the BAT group, model 1, and model 2 was 71.5 years. Most patients in each group were male (58.4%), had primary myelofibrosis (51.7%), and had hemoglobin levels less than 10 g/dL (65.2% in BAT group; 65.2% in model 1; 67.3% in model 2). High-risk disease was present in 15.4% of patients in each arm; 51.7% of patients in each arm had intermediate-2-risk disease.

Additional findings from the MAIC analysis revealed that, when patients randomly assigned to ruxolitinib in SIMPLIFY-1 were excluded from the sensitivity analysis, there was still a median OS benefit with momelotinib over BAT with both model 1 (HR, 0.479; 95% CI, 0.292-0.786;

 = .004) and model 2 (HR, 0.512; 95% CI, 0.330-0.797; 

 = .003). These data were excluded to remove potential survival effects from patients who were JAK inhibitor–naive or received ruxolitinib for 24 weeks prior to the study.

There was also a median OS benefit with momelotinib compared with BAT using model 1 (HR, 0.551; 95% CI, 0.379-0.800; 

 = .002) and model 2 (HR, 0.521; 95% CI, 0.366-0.742; 

 < .001) with population matching when patients randomly assigned to receive momelotinib in MOMENTUM were excluded. These data were excluded to remove the potential effects of COVID-19 on survival outcomes.

In the anemia subgroup, there was a median OS benefit with momelotinib over BAT using model 1 (HR, 0.502; 95% CI, 0.335-0.754;

 = .001) and model 2 (HR, 0.503; 95% CI, 0.351-0.722; 

 < .001) with population matching when data from SIMPLIFY-1 were excluded. Similarly, there was a median OS benefit with momelotinib compared with BAT using model 1 (HR, 0.678; 95% CI, 0.457-1.005; 

 = .053) and model 2 (HR, 0.546; 95% CI, 0.394-0.757; 

 < .001) with population matching when data from MOMENTUM were excluded.

“Together with the results of SIMPLIFY-2 trial and MOMENTUM, these data further support the use of momelotinib as a standard of care in patients with myelofibrosis and anemia in this setting,” Palandri concluded.

Palandri F, Kapetanakis V, Dobi B, et al. Overall survival with momelotinib vs best available therapy in patients with ruxolitinib-experienced myelofibrosis: a matching-adjusted indirect comparison. 

. 2024;144(suppl 1):3187. doi:10.1182/blood-2024-205973

Ojaara (momelotinib) approved in the US as the first and only treatment indicated for myelofibrosis patients with anaemia. News release. GlaxoSmithKline. September 15, 2023. Accessed December 10, 2024. https://www.gsk.com/en-gb/media/press-releases/ojjaara-momelotinib-approved-in-the-us-as-the-first-and-only-treatment-indicated-for-myelofibrosis-patients-with-anaemia

Articles

Momelotinib has shown improved overall survival compared to best available therapy (BAT) in patients with myelofibrosis previously treated with ruxolitinib. This was demonstrated through a matching-adjusted indirect comparison (MAIC) analysis presented at the 2024 ASH Annual Meeting. The analysis included data from the MOMENTUM, SIMPLIFY-1, and SIMPLIFY-2 trials, and a real-world study. The FDA approved momelotinib in September 2023 for treating intermediate or high-risk myelofibrosis with anemia, based on these findings. The study supports momelotinib as a standard of care in this patient population.

Momelotinib improved OS vs best available therapy in patients with ruxolitinib-experienced myelofibrosis, according to data from a MAIC analysis.

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

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 

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 (

 = .021). The median platelet count at the start of therapy was 141 x 10

 = .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 (

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 (

 = .402). The median platelet count at the start of therapy was 65 x 10

 = .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 (

“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.

, the FDA granted accelerated approval to pacritinibfor the treatment of adult patients with intermediate or high-risk primary or secondary myelofibrosis with a platelet count below 50,000/µL.

To conduct their real-world study, investigators analyzed data from the first 50 patients treated at Moffitt Cancer Center with pacritinib or momelotinib.

 Study authors collected treatment history, demographic, hematologic, and genetic data. Hematologic values and transfusion requirements were assessed every 3 months. The objective of the study was to gain a better understanding of the hematologic responses, duration of therapy, and other real-world data with pacritinib or momelotinib following their FDA approvals.

The median age in the momelotinib group was 75.5 years, the median disease duration was 6.5 years, and the median number of prior lines of therapy was 2. Most patients (75%) had splenomegaly at the start of therapy and 47% had high-risk mutations. The median duration of treatment was 8.2 months and 22% of patients had RBC transfusion dependence at the start of therapy. Seven patients discontinued therapy due to non-hematologic/gastrointestinal (GI) toxicity and 3 discontinued treatment due to thrombocytopenia.

In the pacritinib group, the median age was 77 years, the median disease duration was 3.7 years, and the median number of prior lines of therapy was 2.5. Most patients had high-risk mutations (52%) and splenomegaly at the start of therapy (78%). Thirty percent of patients were RBC transfusion dependent at the start of therapy and the median duration of treatment was 3.3 months. Seven patients discontinued treatment due to GI toxicity and another 6 did so due to death.

Additional data from the real-world study demonstrated that the 6-month overall survival (OS) rates among patients who received momelotinib and pacritinib were 96% and 73%, respectively. The 9-month OS rates were 96% and 64%, respectively (

Patients who were transitioning off ruxolitinib (Jakafi) in the momelotinib arm experienced a median change in hemoglobin of 1.42 g/dL at 3 months compared with 0.42 g/dL among patients who did not receive ruxolitinib within 2 months of receiving momelotinib (

 = .177). In the pacritinib group, patients who were transitioning off ruxolitinib experienced a median change in hemoglobin of 0.3 g/dL at 3 months compared with –0.4 g/dL among those who did not receive recent ruxolitinib treatment (

The median change in platelet count was 33 x 10

/L among patients who were transitioning off ruxolitinib in the momelotinib group compared with 10 x 10

/L among patients who did not recently receive ruxolitinib (

 = .223). In the pacritinib group, the median change in platelet count was –40 x 10

/L among patients transitioning off ruxolitinib compared with 5 x 10

/L among those who did not receive recent treatment with ruxolitinib (

“Future considerations for this [research] are to create a multicenter project with longer follow-up,” DiGennaro said in conclusion.

DiGennaro JV, Concepcion G, Al Ali NH, et al. Post-approval utilization of pacritinib and momelotinib in patients with myelofibrosis and analysis of early treatment outcomes. 

. 2024;144(suppl 1):4561. doi:10.1182/blood-2024-202579

FDA approves drug for adults with rare form of bone marrow disorder. FDA. Updated March 1, 2022. Accessed December 9, 2024. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-drug-adults-rare-form-bone-marrow-disorder

Ojjaara (momelotinib) approved in the US as the first and only treatment indicated for myelofibrosis patients with anaemia. News release. GlaxoSmithKline. September 15, 2023. Accessed December 9, 2024. https://www.gsk.com/en-gb/media/press-releases/ojjaara-momelotinib-approved-in-the-us-as-the-first-and-only-treatment-indicated-for-myelofibrosis-patients-with-anaemia

Pacritinib and momelotinib both demonstrated favorable real-world effects on anemia and transfusion requirements among patients with myelofibrosis.

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

Treatment with momelotinib (Ojjaara) improved anemia, and increased rates of transfusion independence (TI) in patients with myelofibrosis; the agent also alleviated symptoms and controlled splenomegaly for those previously exposed to a JAK inhibitor, according to real-world data from a retrospective study presented at the 

Among patients who were symptomatic at baseline (n = 126), 92% experienced improvement in disease-related symptoms, including asthenia (76%), anorexia (65%), weight loss (51%), abdominal discomfort (47%), and pruritis (75%). Improvements were sustained at 3-, 6-, 9- and 12-month assessments.

Moreover, the mean hemoglobin level increased from 8.0 g/dL at baseline to 9.3 g/dL at 3 months and was maintained at 9.2 g/dL at 6 months. At 3 months of follow-up, 48.4% of patients who were transfusion dependent (TD) prior to treatment with momelotinib (n = 108) achieved TI; these rates were 45.7%, 42.9% and 44.4% at 6, 9, and 12 months, respectively. Furthermore, the rate of TI was 49.3% among JAK inhibitor–exposed patients vs 31.6% in JAK inhibitor–naive patients. Among patients who remained TD, the median number of red blood cell (RBC) units per month decreased from 4 to 2.25.

Further analysis of transfusion intensity during the treatment period showed that 50.8% of patients transitioned to a lower category. Conversely, 41.1% remained in the same transfusion intensity category, and 8.1% moved to a higher category.

Of those evaluable for spleen response (n = 45), 62.2% of patients experienced an improvement in spleen size with a median reduction of 5 cm. However, only 24.4% of patients met the European LeukemiaNet (ELN) International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria for spleen response, and these patients had a median reduction of 10 cm). Notably, 26.7% of patients (n = 12) evaluable for spleen response maintained stable splenomegaly without a significant decrease; 3 patients showed refractoriness, and 2 experienced an increase in spleen size.

“Momelotinib significantly improves anemia in patients with myelofibrosis, achieving high rates of TI [that are] more pronounced in JAK inhibitor–exposed than JAK inhibitor–naive patients,” lead study author Lucía Pérez-Lamas, MD

 of Ramón y Cajal University Hospital in Madrid, Spain, and colleagues wrote in a poster presentation of the data. “Momelotinib [also] effectively alleviates symptoms and controls splenomegaly in patients previously treated with ruxolitinib [Jakafi], maintaining an acceptable safety profile.”

 for the treatment of adult patients with intermediate or high-risk myelofibrosis and anemia, based on data from the phase 3 MOMENTUM trial (NCT04173494) and data for a subpopulation of adult patients with anemia enrolled in the phase 3 SIMPLIFY-1 trial (NCT01969838).

 In both trials, momelotinib produced a significant improvement in anemia and addressed both disease-related symptoms and splenomegaly in patients previously exposed to JAK inhibitors. Momelotinib also improved anemia and transfusion burden as first-line therapy vs ruxolitinib in the phase 3 SIMPLIFY-2 trial (NCT02101268).

 However, data regarding the agent’s real-world benefit were lacking.

Therefore, investigators conducted a multicenter, observational, retrospective study of 154 patients with myelofibrosis who received momelotinib through a managed-access program in Spain from March 2023 to July 2024 across 74 centers.

Both JAK inhibitor–naive and –exposed patients were included in the retrospective study, and patients were also required to have splenomegaly or symptoms and anemia, defined as a hemoglobin value of less than 11 g/dL for men and less than 10 g/dL for women. Anemia assessment was based on revised 2024 IWG-ELN criteria in myelofibrosis, and splenomegaly was assessed according to 2013 ELN IWG-MRT criteria. Patients with a baseline splenomegaly of more than 5 cm below the left costal margin (LCM) were evaluable for spleen response. Response criteria included a baseline splenomegaly palpable at 5 cm to 10 cm below the LCM that becomes not palpable, or baseline splenomegaly palpable at 10 cm below the LCM that decreases by 50%. TD was defined at least 1 RBC unit per month or at least 3 units in the past 12 weeks.

Patients with follow-up of more than 1 month were considered efficacy evaluable; all patients who received the agent at any dose level were included in the safety analysis.

The median age was 73 years (interquartile range [IQR], ±10.7) at the start of treatment with momelotinib, and most patients were male (61.7%). Primary myelofibrosis was the most common subtype (60%) followed by after essential thrombocythemia (29%) and after polycythemia vera (10%); subtype data were not available for 1 patient. The most frequently observed driver mutation was 

(5.8%), and not available (2%). Prior receipt of a JAK inhibitor was reported in 76.6% of patients vs 23.4% who were JAK inhibitor–naive.

The median number of prior lines of therapy was 1 (IQR, ±1). Regarding Dynamic International Prognostic Scoring System risk category, most patients had intermediate-2 (43.5%) or high-risk (42.9%) disease; 3.9% of patients had intermediate-1 disease, and data were not available for 9.7% of patients. Among patients with available cytogenetic data (n = 94), 11.78% had unfavorable-risk cytogenetics, and 5.3% had very high–risk cytogenetics. Data on additional mutations by next-generation sequencing were available in 108 patients; they included 

The baseline median hemoglobin was 8.0 g/dL (range, 4.7-13.5); median platelet count was 16 x 10

 μL (range, 3-1812); median leukocyte count was 6.3 x 10

 μL (range, 0.5-101). The median number of peripheral blasts was 1 (range, 0-13). TD patients required a median of 3 RBC units per month (range, 1-8)

After a median follow-up of 5.48 months (range, 1-14), 79% of patients continued treatment. Treatment discontinuations were attributed to hematopoietic stem cell transplant (n = 3), lack of efficacy (n = 5), disease progression (PD; n = 2), transformation of disease to acute myeloid leukemia (n = 5), toxicity (n = 6), and death (n = 11). Deaths occurred due to infections (n = 5), severe hemorrhages (n =3), PD (n = 2), and unknown cause (n = 1). Dose reductions were required in 26 patients, and 10 temporarily discontinued treatment, primarily due to infections or cytopenias.

The most common adverse effects (AEs) included diarrhea (any grade, 11.7%; grade 1/2, 9.7%; grade 3/4, 2.1%), thrombocytopenia (10%; 4.1%; 6.2%), infections (9%; 4.8%; 2.8%), nausea (6.2%; 5.5%; 0.7%), hepatotoxicity (5.5%; 2.8%; 2.8%), and dizziness (5.5%; 4.1%; 0.7%). Other AEs observed were peripheral neuropathy (4.8%; 4.1%; 0.7%), anemia (4.2%; 2.1%; 2.1%), abdominal pain (2.8%; 2.8%; 0%), hypotension (2.1% 1.4%; 0.7%), renal impairment (2.1% 1.4%; 0.7%), headache (1.4%; 0.7%; 0.7%), dyspnea (0.7%; 0.7%; 0%), and edema (0.7%; 0.7%; 0%).

Perez-Lamas L, Diaz AS, Delgado RG, et al. Real-world outcomes of momelotinib as an alternative therapy to other JAK inhibitors in myelofibrosis patients with anemia. 

. 2024;144(suppl 1):1790. 10.1182/blood-2024-200698

Ojaara (momelotinib) approved in the US as the first and only treatment indicated for myelofibrosis patients with anaemia. News release. GlaxoSmithKline. September 15, 2023. Accessed December 9, 2024. https://www.gsk.com/en-gb/media/press-releases/ojjaara-momelotinib-approved-in-the-us-as-the-first-and-only-treatment-indicated-for-myelofibrosis-patients-with-anaemia

Momelotinib has shown efficacy in improving anemia and increasing transfusion independence in myelofibrosis patients, particularly those previously treated with JAK inhibitors. The treatment also alleviates symptoms and controls splenomegaly, with sustained improvements over 12 months. A retrospective study involving 154 patients demonstrated significant benefits, including increased hemoglobin levels and reduced transfusion needs. The study highlighted a higher transfusion independence rate in JAK inhibitor-exposed patients compared to naive ones. Momelotinib was well-tolerated, with manageable adverse effects, and maintained an acceptable safety profile.

Real-world treatment with momelotinib led to high transfusion independence rates among patients with JAK inhibitor–exposed and –naive myelofibrosis. 

Momelotinib Shows Real-World Improvements in Anemia, Symptoms, and Spleen Response in Myelofibrosis

Selinexor (Xpovio) in combination with ruxolitinib (Jakafi) showed encouraging efficacy with a manageable safety profile in patients with myelofibrosis who previously received ruxolitinib, according to data from the phase 2 SENTRY trial (NCT04562389) presented during the 

Preliminary findings from the study showed that, among efficacy-evaluable patients (n = 30), 26 patients (86.67%) experienced alleviation of their symptoms, 9 (40.91%) achieved a 50% reduction in either total symptom score (TSS) or clinical-assessed symptom response, and 1 (3.33%) achieved symptom resolution. Additionally, 4 of the 9 patients who were transfusion-dependent achieved transfusion independence after treatment with the combination.

“At ASH 2023, we presented promising efficacy and safety data in the real-world setting for selinexor in combination with ruxolitinib in patients with myelofibrosis. Here we will report the efficacy and safety of the regimen in patients in a prospective clinical trial who received prior treatment with ruxolitinib,” Minghui Duan, PhD, of the Department of Hematology at Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College in Beijing, China, said during a presentation of the data.

The prospective, open-label, multicenter phase 2 study enrolled a total of 38 patients.

 By July 2024, all 38 patients received at least 1 dose of selinexor, and at a 6-month analysis, 88% of patients had a reduction in spleen length and 36% achieved a spleen response, Duan stated. Spleen response was defined as a reduction in length that is more than 50% per the International Working Group-Myeloproliferative Neoplasms Research and Treatment and European LeukemiaNet response criteria.

In total, there were 27 patients who received a 60-mg dose of selinexor, 10 who received a 40 mg dose, and 1 patient who received a 20-mg dose. The frequency of dose administration was weekly across all doses.

The primary end point of the trial was spleen response. This was assessed by palpation or CT and MRI. The secondary end points were anemia response, symptom response, and safety.

The median age across all patients was 65.5 years (range, 22-84), and 17 patients (44.74%) were male. The mean duration of prior ruxolitinib treatment was 20.5 months (range, 3.6-138.0).

Across all 38 patients, 25 (65.79%) harbored a 

 mutation, and 2 patients (5.26%) had triple-negative myelofibrosis. Data were missing for 3 patients (7.89%), and data for the remaining patients were unspecified. According to the Dynamic International Prognostic Scoring System model, 23 patients (60.53%) were classified as intermediate risk, 10 (26.32%) as high risk, and 5 (13.16%) as unknown. In addition, 36 patients (94.74%) had splenomegaly at diagnosis.

Regarding safety, the median treatment duration with selinexor was 151 days (range, 16–696), and this was consistent across both the 40-mg and 60-mg doses. In total, 18 patients discontinued treatment: 6 due to disease progression, 4 to enroll in another trial, 5 due to toxicity, 2 for economic reasons, and 1 to undergo transplantation. The most common any-grade adverse effects (AEs) were anemia and nausea (both 36.8%), followed by vomiting (23.7%). For grade 3 or 4 AEs, the most frequent were anemia (18.4%), thrombocytopenia (5.3%), and gastrointestinal symptoms, including nausea and vomiting (both 2.6%).

“Unlike the [phase 1] ESSENTIAL study [NCT03627403],” Duan began, which showed sustained spleen responses with selinexor as a single agent in myelofibrosis refractory to a JAK inhibitor, “this combination of selinexor and ruxolitinib may achieve similar therapeutic effects without requiring higher doses.” He also noted that “patients with myelofibrosis require more comprehensive methods for assessing efficacy than a 35% reduction in spleen volume or a 50% reduction in the total symptom score.”

Phase 3 of the SENTRY trial is currently enrolling patients with myelofibrosis who are naive to a JAK inhibitor.

Duan M, Ma L, Wu Q, et al. The efficacy and safety of selinexor in combination with ruxolitinib in ruxolitinib-treated myelofibrosis patients: the interim analysis of a prospective, open-label, multicenter, parallel-cohort, phase 2 study. 

. 2024;144(suppl 1):1002-1002. doi:10.1182/blood-2024-201204

Duan M, Ma L, Wu Q, et al. A real-world study to evaluate the efficacy and safety of selinexor in combination with ruxolitinib in patients with myelofibrosis. 

. 2023;7(53):e15697cd. doi:10.1097/01.HS9.0000971104.15697.cd

Selinexor in myelofibrosis refractory or intolerant to JAK1/2 inhibitors (ESSENTIAL). ClinicalTrials.gov. Updated September 10, 2024. Accessed December 10, 2024. https://clinicaltrials.gov/study/NCT03627403

Selinexor combined with ruxolitinib demonstrated promising efficacy and a manageable safety profile in myelofibrosis patients previously treated with ruxolitinib, as shown in the phase 2 SENTRY trial. Among 30 efficacy-evaluable patients, 86.67% experienced symptom alleviation, with 40.91% achieving significant symptom reduction. The trial's primary endpoint was spleen response, with 88% of patients showing spleen length reduction. Common adverse effects included anemia and nausea. The study suggests that this combination may offer therapeutic benefits without requiring higher doses, and phase 3 trials are underway for JAK inhibitor-naive patients.

Selinexor plus ruxolitinib showed activity in patients with myelofibrosis who were treated with ruxolitinib.

Selinexor Plus Ruxolitinib Displays Activity in Ruxolitinib-Pretreated Myelofibrosis

Navtemadlin monotherapy was found to be safe and effective in patients with myelofibrosis (MF) who were relapsed or refractory (R/R) to treatment with JAK inhibitors, according to findings from the randomized, multicenter, global phase 3 BOREAS study (NCT03662126) evaluating navtemadlin against best available therapy (BAT).

 showed that at a data cut-off of September 30, 2024, regarding spleen volume reduction by 35% (SVR35), patients treated with navtemadlin experienced a 3-fold increase in SVR35 (15%; n = 18/123) vs BAT (5%; n = 3/60) at week 24.

Concerning total symptom score reductions of at least 50% (TSS50), patients treated with navtemadlin saw a 2-fold increase in TSS50 (24%; n = 30/123) compared with BAT (12%; n = 7/60) at week 24. In the intention-to-treat population, the mean absolute TSS change from baseline to week 24 was -4.6 in the navtemadlin group compared with 0.9 in the BAT group (

 = .0078; least square mean difference -5.5; 95% CI, -9.6 to -1.5).

In the navtemadlin cohort, treatment-emergent adverse effects (TEAEs) included gastrointestinal (GI) events such as nausea (any grade, 42%; grade 3/4, 4%), diarrhea (41%; 6%), and vomiting (25%; 2%). These had median times to onset of 4 (range, 1-530), 8 (range, 1-384), and 30 (range, 1-477) days, respectively, and had median times to resolution of 9 (range, 1-348), 7 (range, 1-338), and 4 (range, 1-24) days.

Hematologic TEAEs of note included anemia (any grade, 36%; grade 3/4 29%), neutropenia (30%; 25%), and thrombocytopenia (46%; 37%). The median times to onset were 30 (range, 1-289), 29 (range, 8-176), and 29 (range, 8-253) days, respectively, and times to resolution of 8 (range, 1-369), 9 (range, 2-169), and 14 (range, 1-387) days, respectively.

“Expecting GI toxicity, this is mostly grade 1 and 2, … rarely grade 3 and 4, rarely a reason for discontinuation,” said John O. Mascarenhas, MD, of the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, in a presentation of the data at the conference.“Very importantly, the time to onset for GI toxicity was pretty predictable. The drug is dosed days 1 to 7 out of a 28-day cycle, [and] you almost always would see the GI toxicity days two to nine. But very important, if you look at time to resolution, the measuring in days, 9, 4, and 7. So, this is reversible toxicity, very importantly. In a drug that's given repeatedly, this is reversible toxicity, not [felt] through the constant 28 days of the cycle. [It’s the] same thing with hematologic toxicity, [which was] very predictable in its occurrence and very fleeting in its duration.”

Among its 183 participating patients, they were a median of 48.1 (range, 0.4-368.3) months from initial diagnosis in the navtemadlin cohort and 45.2 (range, 5-292.3) months from diagnosis in the BAT cohort. They had received a median of 1 prior line of therapy in both cohorts (ranges, 1-6 and 1-5, respectively).

“The BOREAS study is undoubtedly the first study in the relapsed, refractory setting as a single-agent, JAK inhibitor failure to show results,” Mascarenhas concluded. “Here today, [with these] clinical results, I think you'll see that there is clinically relevant efficacy and safety ... [with the] tripling of SVR35 and doubling of TSS50.

“And, the next step for the evaluation of navtemadlin is going to be the [phase 3] POIESIS study [NCT06479135]...This is going to be evaluating navtemadlin in the sub-optimal responders to see if we can move the drug even further up in its development pathway and benefit patients earlier on.”

Mascarenhas JO, Popov VM, Mohan S, et al., Results from the Randomized, Multicenter, Global Phase 3 BOREAS Study: Navtemadlin Versus Best Available Therapy in JAK Inhibitor Relapsed/Refractory Myelofibrosis, Presented at: 2024 American Society of Hematology Annual Meeting; December 7-10, 2024; San Diego, California. Abstract 1000.

Navtemadlin monotherapy demonstrated safety and efficacy in myelofibrosis patients who were relapsed or refractory to JAK inhibitors, as shown in the phase 3 BOREAS study. The study revealed a threefold increase in spleen volume reduction and a twofold increase in total symptom score reduction with navtemadlin compared to best available therapy. Treatment-emergent adverse effects were mostly mild and reversible, with predictable onset and resolution times. The study marks a significant advancement in the treatment of relapsed/refractory myelofibrosis, with further evaluation planned in the phase 3 POIESIS study.

Navtemadlin monotherapy was safe and effective among patients with myelofibrosis who were relapsed or refractory to treatment with JAK inhibitors.

Navtemadlin Reduces Spleen Size and Symptom Score in R/R Myelofibrosis

Pelabresib (CPI-0610) plus ruxolitinib (Jakafi) demonstrated improvements in spleen volume, total symptom score, anemia, and the bone marrow microenvironment at week 48 vs placebo plus ruxolitinib in patients with JAK inhibitor–naive myelofibrosis, according to results from the phase 3 MANIFEST-2 study (NCT04603495).

 showed that at a median follow-up of 72 weeks, the primary end point of spleen volume reduction of 35% (SVR35) was maintained, with a 48-week response rate of 57.0% with pelabresib and ruxolitinib vs 37.5% with ruxolitinib plus placebo. Total symptom score (TSS) improvement of at least 50% at week 48 was 45.3% vs 39.4%, respectively. Fewer patients required red blood cell transfusions, and bone marrow fibrosis improvement of at least 1 grade was reported in 41.0% vs 15.0%, respectively.

“Results at 48 weeks showed deep and sustained SVR35 response with biomarker evidence suggesting additional benefit of the combination of pelabresib plus ruxolitinib vs ruxolitinib alone,” said John O. Mascarenhas, MD, director of the Center of Excellence for Blood Cancers and Myeloid Disorders at Mount Sinai, in his poster presentation.

Pelabresib is an investigational small molecule BET inhibitor that can decrease the BET-mediated gene expression associated with MF.

The phase 3 MANIFEST-2 trial is a global, randomized, double-blind study that assigned 430 patients to receive ruxolitinib twice daily plus pelabresib or placebo once daily for 14 consecutive days of 21-day cycles. At the 2023 ASH meeting, the MANIFEST-2 trial investigators reported that it had met its primary end point of 24-week SVR. Key secondary end points were absolute change in TSS and 50% or greater reduction in TSS from baseline (TSS50) at week 24, with other end points including SVR35 at week 48, hemoglobin response, bone marrow fibrosis, and safety.

Patients had to have intermediate-1 or higher risk myelofibrosis by Dynamic International Prognostic Scoring System (DIPSS), platelet count of at least 100,000/μL, spleen volume of at least 450 cm

, TSS of 10 or greater (≥3 for 2 symptoms), and ECOG performance status of 2 or lower. The study arms were balanced in terms of age and DIPSS risk status.

At the data cutoff of March 29, 2024, 126 of 214 patients (58.9%) receiving the combination and 134 of 216 patients (62.0%) receiving ruxolitinib plus placebo were still being treated in a double-blind fashion.

In addition to a higher number of patients showing SVR35 response at week 48, only 13.1% of patients had a loss of SVR35 response and increase of 25% from nadir with pelabresib vs 20.0% with placebo, or 21.0% vs 36.8%, respectively by alternate definition of loss of SVR35 response. The mean change was -54.5% with the combination vs -33.5% with ruxolitinib plus placebo, and 82.2% had a response at any time with the combination vs 57.9% with ruxolitinib plus placebo.

The absolute change from baseline TSS was -15.99 for pelabresib plus ruxolitinib vs -14.05 for ruxolitinib plus placebo at week 24, and -16.24 vs -14.11, respectively at week 48. TSS individual domain scores were similar between the 2 arms and similar to national norms for people without MF, according to the investigators. An analysis of Myelofibrosis Symptom Assessment Form excluding fatigue showed a least square mean change from baseline of -16.19 with pelabresib plus ruxolitinib vs -13.86 with placebo plus ruxolitinib. Mascarenhas said that “additional symptom benefit of pelabresib could be difficult to detect due to a ceiling effect in TSS, especially in the fatigue domain.”

When looking at patients who had both SVR35 and TSS improvement of 50%, there were 77 (36%) who received the combination vs only 41 (19%) in the placebo arm.

A hemoglobin response as defined as a 1.5 g/dL or greater mean increase from baseline in the absence of transfusions in the past 12 weeks was observed in a numerically greater proportion of patients who received pelabresib (13.1% vs 7.9%), and hemoglobin levels rose and approached baseline in patients with anemia. In the combination arm, 27.6% required transfusion in the first 24 weeks and 21.8% required it in the next 24 weeks, compared with 38.6% and 33.2%, respectively, in the placebo plus ruxolitinib arm.

At week 48, bone marrow fibrosis had improved in 41.0%, remained unchanged in 45.0%, and worsened in 14.0% of those receiving pelabresib vs improving in 15.0%, remaining unchanged in 54.2%, and worsening in 30.8% of those receiving placebo. The improvement of bone marrow fibrosis of at least 1 grade at week 24 was 38.3% vs 25.3% in the respective arms, showing that the difference widened at week 48.

Based on a descriptive analysis of an exploratory end point, disease-relevant proinflammatory cytokines showed a numerically greater reduction at week 48 in the pelabresib plus ruxolitinib arm. The level of proinflammatory cytokines was lower in those who had an SVR35 response, regardless of which treatment they received.

Another exploratory end point was change in mutant clone burden in peripheral blood samples by next-generation sequencing. At week 48, there was greater reduction in the pelabresib plus ruxolitinib group, with a variant allele frequency reduction of 50% in 15% vs 9.0% of those receiving placebo plus ruxolitinib. The mean change from baseline was -24.1% vs -16.3% in the respective arms, and a correlation was found between SVR35 response and reduced mutation clone burden.

In terms of safety, grade 3 or higher treatment-emergent adverse events (TEAEs) were reported in 57.1% of the pelabresib plus ruxolitinib arm vs 62.1% of the placebo plus ruxolitinib arm. Grade 3 or higher anemia was reported in 25.9% and 38.3%, respectively, and grade 3 or higher thrombocytopenia was reported in 15.1 and 6.1%, respectively. The most common nonhematologic TEAEs including diarrhea, constipation, dysgeusia, cough, and nausea. Death occurred in 20 of 214 patients (9.3%) in the pelabresib plus ruxolitinib arm and 18 of 216 (8.3%) in the placebo plus ruxolitinib arm.

Accelerated and blast-phase progression to leukemia transformation was reported in 6.1% of the pelabresib plus ruxolitinib arm and 4.2% of the placebo plus ruxolitinib arm at a data cutoff of August 30, 2024. Newly acquired mutations were detected in 26% and 22%, respectively, and high molecular risk (HMR) mutations were seen in 4% and 2%, respectively. Mutations were no longer detectable in 11% and 12%, and HMR mutations were no longer detectable in 3% and 1%, respectively. Investigators proposed that the similar number of patients indicated that pelabresib does not have an additional mutagenic effect when combined with ruxolitinib.

The investigators intend to present longer follow-up data from MANIFEST-2 at future medical congresses. “Rates of grade 3 or greater TEAEs were similar in both arms and leukemia transformation continues to be followed up closely,” said Mascarenhas.

Mascarenhas JO, Grosicki S, Chraniuk D, et al. Updated Results from the Phase 3 Manifest-2 Study of Pelabresib in Combination with Ruxolitinib for Janus Kinase Inhibitor-Naïve Patients with Myelofibrosis. 

. 2024;144(suppl 1):3178. doi:10.1182/blood-2024-193193

Pelabresib combined with ruxolitinib shows promising results in treating JAK inhibitor-naive myelofibrosis, as evidenced by the phase 3 MANIFEST-2 study. At 48 weeks, the combination achieved significant improvements in spleen volume reduction, symptom scores, anemia, and bone marrow fibrosis compared to ruxolitinib alone. The study also noted a reduction in proinflammatory cytokines and mutant clone burden. Safety profiles were comparable between the two treatment arms, with similar rates of grade 3 or higher adverse events and leukemia transformation. Further follow-up data is anticipated.

Improvements in the 4 hallmarks of myelofibrosis were observed with pelabresib plus ruxolitinib vs placebo plus ruxolitinib in JAK inhibitor-naive disease. 

Pelabresib Plus Ruxolitinib Leads to Sustained Responses in JAK Inhibitor–Naive Myelofibrosis 