Most patients with essential thrombocythemia (95.7%; 1184/1237) included in an analysis of the prospective, observational MOST study (NCT02953704) did not experience disease progression to myelofibrosis, but those who did were found to have had longer duration of disease, higher white blood cell counts, and lower hemoglobin levels at enrollment, according to findings presented at the 

Of the 4.3% (n = 53) of patients who progressed to myelofibrosis, a pathologic diagnosis of the disease or grade 2 or greater fibrosis was the most common indicator (49.1%; n = 26) of disease progression, followed by new or worsening splenomegaly coupled with a combination of high white blood cell counts and low hemoglobin levels and platelet counts (22.6%; n = 12). Additional indicators were death from myelofibrosis, myelodysplastic syndrome (MDS), or acute myeloid leukemia (AML; 11.3%; n = 6) and circulating blasts above 1% with new or worsening splenomegaly (5.7%; n = 3); patients also met at least 2 progression criteria (11.3%; n = 6).

“These findings and further analyses of MOST data will add insight into disease progression in patients with essential thrombocythemia and facilitate clinical management of this patient population,” lead study author Ruben A. Mesa, MD, FACP, president and executive director of Atrium Health Levine Cancer Institute and Atrium Health Wake Forest Baptist Comprehensive Cancer Center, and vice dean of cancer programs at Wake Forest University School of Medicine in Charlotte, North Carolina, and coauthors wrote in the poster.

Essential thrombocythemia is a myeloproliferative neoplasm characterized by clonal blood cell growth, constitutional symptoms, excessive platelet production, and increased risk of vascular symptoms. There is potential for disease transformation to myelofibrosis, however most documented cases of disease progression have been pulled from retrospective series. For this reason, investigators launched the longitudinal, noninterventional, observational MOST study allowing for prospective study of patients with essential thrombocythemia throughout the United States.

The study enrolled adult patients who received a clinical diagnosis of essential thrombocythemia and patients either were at least 60 years old; had a history of thromboembolic events; or were receiving essential thrombocythemia–directed therapy excluding aspirin monotherapy. Criteria for enrollment were confirmed through central and local assessment. Enrollment then began in November 2016 after which patients entered an observation period where physician-level data were collected during routine visits for at least 3 years. March 2022 marked the end of the study and observation period at which point investigators evaluated disease progression to myelofibrosis.

Patients were considered to have disease progression to myelofibrosis if they experienced any of the following criteria during the study period: bone marrow biopsy with fibrosis of grade 2 or greater or a pathologic diagnosis of myelofibrosis; death because of myelofibrosis, MDS, or AML; circulating blasts above 1% and new or worsening splenomegaly; and new or worsening splenomegaly. For new or worsening splenomegaly, patients also needed to have 2 of the following: white blood cell count above 11 × 10

/L, hemoglobin level below 10 g/dL, and platelet count below 100 × 10

A total of 1,237 patients with essential thrombocythemia were enrolled in MOST, all of whom were included in the present analysis. Only 14.2% (n = 176) and 76.0% (n = 940) of patients had bone marrow data and spleen records available, respectively. Regarding patient characteristics, the median time from essential thrombocythemia diagnosis to enrollment was 4.2 years (range, 0-42) and the median duration of enrollment was 4.8 years (range, 3.5-5.8).

“Compared with patients without progression, those with progression had longer duration of disease, higher white blood cell counts [10.4 × 10

 <.001], and lower hemoglobin [levels 12.5 g/dL vs 13.1 g/dL; 

 =.026] at enrollment. Mean platelet count was not significantly different [418.6 × 10

 =.466 and] symptom burden at enrollment [based on the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score] was similar between the 2 groups [with progression: mean, 17.2, standard deviation (SD), 13.4; without progression: mean, 16.9, SD, 15.6],” the authors wrote.

Patients with progression also had a prolonged time from essential thrombocythemia diagnosis to enrollment vs those without, at 7.9 years (range, 0-41) vs 4.2 years (range, 0-42), respectively (

Additionally, 94.8% of patients with progression and 94.3% of patients without progression were receiving essential thrombocythemia–directed therapy at enrollment; more patients without progression (91.1%) were receiving single-agent therapy vs those with progression (81.1%; 

 =.0142). However, there were some variations in the types of therapy received between the 2 groups, most notably for ruxolitinib (Jakafi; with progression, 11.3%; without progression, 3.0%; 

 =.0016), and anagrelide (17.0% vs 7.9%; 

 =.0198). Other types of therapy included interferon (1.9% vs 2.9%; 

 =.6723), aspirin monotherapy (5.7% vs 10.5%; 

Notably, disease duration at enrollment was prolonged in patients receiving ruxolitinib at 13.2 years (range, 4-41) compared with those receiving hydroxyurea at 8.7 years (range, 4-47; 

In addition to evaluating treatment at enrollment investigators performed mutational testing in 950 patients. Among patients with progression, 71.7% (n = 38) had at least 1 positive mutation test; common mutations included 

 (28.6%; n = 2/7); 2 of 4 patients were triple negative for the 3 aforementioned mutations and 5 (13.2%) had unknown status. Among patients without progression, 77.0% (n = 912) had at least 1 positive mutation test; common mutations included 

 (17.7%; n = 22/124). Further, 31.1% of patients (n = 14/45) were triple negative for the 3 aforementioned mutations and 274 (30.0%) had unknown status.

Study authors also noted that hemorrhagic events were slightly increased in patients with progression although thrombotic and hemorrhagic events were overall infrequent. The rates of thrombotic events, hemorrhagic events, and death from thrombotic or hemorrhagic events were 1.9% (n = 1), 7.5% (n = 4), and 0% in patients with progression, respectively, vs 3.7% (n = 44), 1.3% (n = 15), and 0.3% (n = 4) in patients without progression, respectively.

“One limitation of this study is the lack of bone marrow data for the majority of patients, which likely contributed to an underestimation of the rate of progression to myelofibrosis,” the authors noted.

 Dr Mesa reported consulting or advisory roles with Constellation Pharmaceuticals, La Jolla Pharmaceutical, Novartis, and Sierra Oncology. He also noted receiving institutional research funding from AbbVie, Celgene, Constellation Pharmaceuticals, CTI BioPharma, Genentech, Incyte Corporation, Mays Cancer Center, National Cancer Institute, Promedior, and Samus Therapeutics.

Mesa RA, Lyons RM, Braunstein EM, et al. Progression to myelofibrosis in patients with essential thrombocythemia: a real world analysis from the prospective MOST study. Presented at: 2024 EHA Congress; June 13-16, 2024; Madrid, Spain. Abstract P1030.

Articles

Most patients with essential thrombocythemia did not progress to myelofibrosis in the MOST study. Those who did had longer disease duration, higher white blood cell counts, and lower hemoglobin levels at enrollment. Indicators of progression included pathologic diagnosis, new or worsening splenomegaly, and death from related conditions. The study highlighted the importance of prospective data in understanding disease progression and managing essential thrombocythemia. Variations in therapy types and mutational profiles were also noted between patients with and without progression.

Patients with essential thrombocythemia who progressed to myelofibrosis had longer duration of disease, higher white blood cell counts, and lower hemoglobin levels at enrollment.

Prospective Analysis Highlights Patterns of Progression to Myelofibrosis Following Essential Thrombocythemia Diagnosis

The onset of new or worsening anemia following treatment induction with ruxolitinib (Jakafi) did not reduce the clinical benefit of the agent for patients with primary or secondary myelofibrosis, according to data from a post-hoc analysis of the phase 3b JUMP trial (NCT01493414) which were presented during the 

The median overall survival (OS) among baseline anemic patients with new or worsening anemia (n = 361) was 58.3 months (95% CI, 52.6-not evaluable [NE]) compared with NE (95% CI, 52.7-NE) in those without new or worsening anemia (n = 486; HR, 1.08; 95% CI, 0.77-1.51; 

 = .66). Similarly, patients who were baseline nonanemic with new or worsening anemia (n = 756) achieved a median OS of NE (95% CI, NE-NE) vs NE (95% CI, NE-NE) in those with no new or worsening anemia (n= 630; HR, 0.66; 95% CI, 0.45-0.99; 

In a poster presentation of the data, study authors noted that these findings were consistent with the results of a recent pooled data analysis of the phase 3 COMFORT-I (NCT00952289) and COMFORT-II (NCT00934544) studies, which both examined ruxolitinib for patients with myelofibrosis.

“Dose-dependent anemia is one of the adverse effects [AEs] of ruxolitinib therapy,” Haifa Kathrin Al-Ali, MD, lead study author, professor of hematology, and head of the Krukenberg Cancer Center, at the University Hospital Halle (Saale) in Germany, explained during the presentation. “A previous analysis of 2 phase 3 trials [showed that] new or worsening anemia did not diminish the clinical benefit of ruxolitinib therapy.”

“The objective of this current analysis was to validate these findings using data from JUMP, which is the largest trial [of ruxolitinib] in patients with myelofibrosis to date,” he explained.

JUMP is a global, single-arm expanded-access study that evaluated ruxolitinib treatment in patients with myelofibrosis in a setting comparable with routine clinical practice. In order to be eligible, patients needed to be at least 18 years old and have a diagnosis of primary or secondary myelofibrosis that is high, intermediate-2, or intermediate-1 risk according to International Prognostic Scoring System criteria. Patients with intermediate-1 risk disease must have palpable splenomegaly of at least 5 cm from the costal margin.

All patients received ruxolitinib twice daily at a starting dose of 5 mg for those with a platelet count of 50 x 109/L to less than 100 x 109/L; 15 mg for those with a platelet count of 100 x 109/L to 200 x 109/L; or 20 mg for those with a platelet count over 200 x 109/L. Patients were stratified in the post hoc analysis by baseline anemia and transfusion status, with nonanemic being defined as hemoglobin levels over 100 g/L; transfusion-requiring anemia was defined as hemoglobin levels less than 100 and having received at least 2 units of red blood cells over 8 weeks before the first dose of ruxolitinib; or non-transfusion-requiring anemia.

The primary end point of JUMP was safety. Secondary end points included percentage of participants with at least 50% reduction in spleen length, 5-year best overall response according to spleen length, and change in ECOG performance status from baseline to worst post-baseline up to 5 years.

The baseline characteristics of the new/worsening anemia (n = 1117) and no new/worsening anemia (n = 1116) groups were generally well balanced; the median age was 68.0 years (range, 18-89) vs 66.0 years (range, 20-89), respectively, and the median time since initial diagnosis was 24.9 months (range, 0-456) vs 26.9 months (range, 0-444). Most patients in both groups had a palpable spleen (93.8% vs 93.1%), a median platelet count of at least 200 x 109/L (65.0% vs 60.2%), were nonanemic (67.7% vs 56.5%), and had a mean hemoglobin of at least 100 g/L (66.7% vs 56.0%). The median palpable spleen length at baseline was 12.0 cm (range, 1-40) vs 12.8 cm (range, 0.5-45), respectively.1

Additional data showed that, at week 24, evaluable baseline nonanemic patients in the new/worsening anemia group (n = 473) and the no new/worsening anemia group (n = 394) experienced a spleen length reduction of at least 50% at respective rates of 31.5% vs 31.2% (

 = .93); these respective rates were 24.4% vs 27.9% (

 = .48) among patients with non-transfusion requiring anemia and transfusion-requiring anemia. In the with non-transfusion requiring anemia subgroup 127 patients experienced new/worsening anemia and 179 did not; these figures were 92 patients and 84 patients, respectively in the transfusion-requiring anemia subgroup.

At week 48, evaluable baseline nonanemic patients in the new/worsening anemia group (n = 289) and the no new/worsening anemia group (n = 257) experienced a spleen length reduction of at least 50% at respective rates of 35.6% vs 26.1% (

 = .02); these respective rates were 29.6% vs 27.2% (

 = .10) among patients with non-transfusion requiring anemia and transfusion-requiring anemia. In the with non-transfusion requiring anemia subgroup 81 patients experienced new/worsening anemia and 103 did not; these figures were 58 patients and 45 patients, respectively in the transfusion-requiring anemia subgroup.

In terms of symptom response, at week 24, baseline nonanemic patients in the new/worsening anemia group (n = 618) and the no new/worsening anemia group (n = 530) achieved a minimum 6.5-point increase in FACT-Lym total score at respective rates of 34.5% vs 34.% (

 = .86); these respective rates were 32.7% vs 29.6% (

 = .13) among patients with non-transfusion requiring anemia and transfusion-requiring anemia. In the with non-transfusion requiring anemia subgroup, 153 patients experienced new/worsening anemia and 243 did not; these figures were 120 and 109 patients, respectively in the transfusion-requiring anemia subgroup.

At week 48, baseline nonanemic patients in the new/worsening anemia group (n = 120) and the no new/worsening anemia group (n = 109) experienced a minimum 6.5-point increase in FACT-Lym total score at respective rates of 30.4% vs 23.3% (

 = .02); these respective rates were 26.4% vs 27.6% (

 = .91) among patients with non-transfusion requiring anemia and transfusion-requiring anemia. In the with non-transfusion requiring anemia subgroup, 106 patients experienced new/worsening anemia and 156 did not; these figures were 79 and 66 patients, respectively in the transfusion-requiring anemia subgroup.

Among evaluable patients in the new or worsening anemia (n = 1033) and no new or worsening anemia group (n = 1000) received a median dose exposure of 12.2 months (range, 0.2-59.7) and 12.5 months (range, 0-58.1) with ruxolitinib, respectively.

“These results are consistent with those obtained from a previous pooled analysis from the 2 phase 3 COMFORT trials,” Al-Ali concluded. “These results from JUMP based on a broad patient population in a real-world setting, including those with platelet counts of less than 100 x 109/L and lower-risk patients with myelofibrosis, support the use of ruxolitinib in patients with myelofibrosis regardless of baseline anemia or the development of treatment-related anemia.”

Al-Ali HK, Guglielmelli P, JE Hamer-Maansson, Braunstein E, Gupta V. The impact of new or worsening anemia on clinical outcomes in 2233 patients with myelofibrosis treated with ruxolitinib: results from the expanded-access jump study. Presented at: 2024 European Hematology Association Congress; June 13-16, 2024; Madrid, Spain. Abstract P1044.

INC424 for patients with primary myelofibrosis, post polycythemia myelofibrosis or post-essential thrombocythemia myelofibrosis. (JUMP). ClinicalTrials.gov. Updated April 26, 2019. Accessed June 14, 2024. https://clinicaltrials.gov/study/NCT01493414

New or worsening anemia following ruxolitinib treatment does not diminish its clinical benefits for myelofibrosis patients, as shown in the phase 3b JUMP trial. Median overall survival was comparable between patients with and without new or worsening anemia. These findings align with previous COMFORT trials, reinforcing ruxolitinib's efficacy regardless of anemia status. The JUMP trial, the largest of its kind, evaluated ruxolitinib in a real-world setting, confirming its safety and effectiveness across various patient subgroups, including those with lower platelet counts and lower-risk myelofibrosis.

Patients with new or worsening anemia from their myelofibrosis did not experience lessened clinical benefit of ruxolitinib treatment.

Anemia Does Not Diminish Benefit With Ruxolitinib Treatment in Myelofibrosis

Time from diagnosis to enrollment, elevated white blood cell (WBC) count, and variant allele frequency (VAF) were significantly associated with an increased risk of disease progression among patients with polycythemia vera (PV), according to data from the phase 4 prospective, observational REVEAL study (NCT02252159) presented at the 

“Five predictors of PV progression were identified: disease duration, thrombotic event [TE] history, WBC count of greater than 11 × 10

/L, hematocrit [HCT] level of 0.45 L/L or lower, and VAF. However, HCT [level] of 0.45 L/L or lower may be confounded by disease duration and cytoreductive treatment covariates. These results provide additional support for the use of disease duration and elevated WBC and VAF as risk factors for disease progression, and identify history of TEs as a potential novel risk factor,” Grunwald and coauthors wrote in a poster presentation of the findings. Grunwald is chief of the Leukemia Division at Atrium Health’s Levine Cancer Institute and director of the Transplantation and Cellular Therapy Program at Levine Cancer Institute in Charlotte, North Carolina.

At a median follow-up of 3.7 years, findings from REVEAL, the largest prospective, observational clinical study in patients with PV to date (n = 2023), showed that 6.7% of patients progressed to myelofibrosis (MF). Results from a univariate analysis of patients with vs without progression revealed that significant covariates consisted of time from PV diagnosis to enrollment (OR, 1.065; 95% CI, 1.040-1.090; 

 < .0001), history of TEs (yes vs no; OR, 1.722; 95% CI, 1.170-2.534; 

 = .0059), HCT levels of 0.45 L/L or lower (>0.45 vs ≤0.45 L/L; OR, 0.593; 95% CI, 0.410-0.858; 

 = .0056), and white blood cell (WBC) count of greater than 11 × 10

Investigators noted that each covariate remained significant in multivariate analyses with step wise model selection, including time from PV diagnosis to enrollment (OR, 1.059; 95% CI, 1.032-1.086; 

 < .0001), history of TEs (OR, 1.597; 95% CI, 1.062-2.401; 

 = .0246), HCT levels (OR, 0.579; 95% CI, 0.392-0.857; 

 = .0062), and WBC count (OR, 2.144; 95% CI, 1.475-3.117; 

“At enrollment, patients with HCT ≤0.45 L/L vs >0.45 L/L had a significantly longer duration from PV diagnosis, had higher PV risk, and were more likely to be receiving hydroxyurea or other cytoreductive treatment, which potentially confounds the HCT ≤0.45 L/L covariate. These confounders were not observed in patients with WBC >11×10

/L, disease duration, TE history, WBC count of greater than 11 × 10

/L, HCT of 0.45 L/L or lower, and VAF,” Grunwald and coauthors noted.

The real-world, multicenter, REVEAL study examined data from patients treated in US community and academic centers between 2014 and 2019. Of the 2510 patients included in the study, 2023 received a confirmed PV diagnosis; of these patients, 1524 had 

 p. V617F-positive disease confirmed by droplet digital polymerase chain reaction, 365 had a physician-reported 

 mutation, and 134 had PV confirmed by bone marrow aspirate/biopsy.

Among all patients with a confirmed diagnosis of PV, the median age at enrollment was 68.0 years (range, 22-95); most patients were male (51.2%), White (89.1%), and treated in a community practice setting (82.6%). Patients who experienced disease progression (n = 135) experienced a median time from diagnosis to enrollment of 7.2 years (range, 0.0-34.1) and the median follow-up for these patients was 3.4 years (range, 0.0-4.9). Patients who did not experience disease progression (n = 1888) had a median time from diagnosis to enrollment of 3.7 years (range, 0.0-38.5) and the median follow-up for these patients was 3.7 years (range, 0.0-5.0).

Among patients with disease progression vs without, PV risk at enrollment was high in a majority of patients (85.9% vs 78.7%). PV treatments received at enrollment were watchful waiting (6.7% vs 5.5%), phlebotomy (17.8% vs 27.8%), hydroxyurea (38.5% vs 31.1%), hydroxyurea plus phlebotomy (17.8% vs 27.3%), or other (19.3% vs 8.4%), respectively. Further, 29.6% vs 19.7% of patients had a history of TEs at enrollment, respectively.

Additional findings from a subset analysis revealed that of patients with quantitative allele burden data available, VAF was a significant covariate (

 < .0001), and VAF remained a significant covariate in multivariate analyses with stepwise model. WBC count was excluded from the multivariate analysis models because VAF and VWBC count of greater than 11 vs less than or equal to 11 × 10

 p. V617F VAF was higher in patients with vs without PV progression [

Grunwald M, Zwicker J, Gerds A, et al. A real-world evaluation of risk factors for disease progression in patients with polycythemia vera (PV) enrolled in REVEAL. Presented at: 2024 EHA Congress; June 13-16, 2024; Madrid, Spain. Abstract P1047.

The REVEAL study identified key predictors of disease progression in polycythemia vera (PV) patients, including disease duration, thrombotic event history, elevated white blood cell (WBC) count, hematocrit (HCT) levels, and variant allele frequency (VAF). The study, which followed 2023 patients over a median of 3.7 years, found that 6.7% progressed to myelofibrosis. Significant covariates for progression included time from diagnosis to enrollment, history of thrombotic events, HCT levels, and WBC count. VAF was also a significant predictor, independent of WBC count.

Time from diagnosis, elevated WBC count, and VAF were all significantly associated with an increased risk of disease progression of polycythemia vera.

Disease Duration, Elevated WBC Count, and VAF Predict Disease Progression in Polycythemia Vera

Among patients with low- or intermediate-risk myelofibrosis (MF), a majority were reported to have disease progression over 4 years, and the rate of progression increased over time, according to findings from the prospective observational MOST study (NCT02953704) presented in a poster session at the 2024 EHA Congress. These findings provide important insight into the rates of disease progression for patients with lower-risk MF, a patient group with limited prospective data available on this topic.

A total of 232 patients with MF were enrolled, with 205 patients considered low or INT-1 risk due to being aged over 65 years alone comprising cohort A and 27 patients considered low or INT-1 risk for factors other than age only being evaluated in cohort B. In cohort A, 58.5% (n = 120) of patients experienced disease progression during the study, with the most common progression criteria being hemoglobin below 10 g/dL (47.5%). Further, 12 patients (10.0%) died due to disease progression and 6 (5%) had leukemic transformation. In cohort B, 29.6% (n = 8) of patients had disease progression during the course of the study.

Laboratory-defined criteria for progression in the MOST study included hemoglobin below 10 g/dL, platelet count below 100 × 109/L, less than 1% blasts, white blood cell count above 25 × 109/L, and leukemic transformation with greater than 20% blasts. Physician-reported criteria for progression were constitutional symptoms (weight loss, fever, sweats), new or worsening splenomegaly, 1 red blood cell transfusion during the study, physician-reported leukemic transformation, and death due to disease progression. The presence of at least 1 criterion was considered disease progression.

Other progression criteria met in cohort A included a platelet count below 10 × 109/L in 31.7%, constitutional symptoms in 30.8%, and splenomegaly in 28.3%. Hemoglobin below 10 g/dL was present in 21 of 29 patients (72.4%) of those who had 3 or more progression criteria.

Importantly, the rate of progression appeared to increase over the course of the study. The median time to meeting criteria for first and second disease progression in cohort A was approximately 2 years for each (24.9 vs 28.2 months), whereas it was approximately 1 year (11.6 months) for reaching the third progression criteria.

Looking at patients with vs without progression during the study, in cohort A, more patients were over 65 at the time of diagnosis (53.3% vs 35.3%, 

=.0384). However, the median time from diagnosis to enrollment was similar between the groups, with a median of 1.9 vs 1.4 years (

 = .9997). There was also not a significant difference in the median duration of enrollment for patients in cohort A with or without disease progression (4.5 vs 4.3 years). Most patients in cohort A were receiving MF-directed therapy at the time of enrollment regardless of whether they experienced disease progression (59.2% vs 61.2%); however, more patients with progression were receiving ruxolitinib (Jakafi; 59.2% vs 14.1%, 

= .0078), and fewer patients with progression were receiving hydroxyurea (22.5% vs 36.5%, 

= .0913). In cohort B, the median time from diagnosis to enrollment was 1.9 years (range, 0-31), and the median duration of enrollment was 4.3 years (range, 3.6-5.4).

Of all patients enrolled in both cohorts, 186 were tested for at least 1 known driver mutation. In cohort A, 108 of 158 had a 

 mutation, and 66 of 93 patients had disease progression whereas 42 of 65 without progression had the JAK2 mutation. Of those evaluated for CALR mutation, 33 of 44 had a mutation with 16 of the 21 with disease progression having it and 17 of the 23 without progression having the mutation present. Five out of 31 had an 

 mutation, with 1 out of 6 having the mutation among those who experienced disease progression and 2 of 10 having it among those who did not experience disease progression.

Grunwald M, Gerds A, Agrawal A, et al. High rate of disease progression in patients with low-risk myelofibrosis (MF) enrolled in the prospective MOST study. Presented at: 2024 European Hematology Association Congress; June 13-16, 2024; Madrid, Spain. Abstract P1053.

The MOST study revealed that a significant proportion of patients with low- or intermediate-risk myelofibrosis (MF) experienced disease progression over four years, with the rate of progression increasing over time. The study included 232 patients, with 205 in cohort A (aged over 65) and 27 in cohort B (other risk factors). In cohort A, 58.5% experienced progression, primarily due to hemoglobin levels below 10 g/dL. The study also highlighted the role of JAK2, CALR, and MPL mutations in disease progression.

Over a 4-year period, most patients with lower-risk myelofibrosis experienced disease progression, according to the prospective MOST study. 

Observational Study Finds Progression Common in Lower-Risk Myelofibrosis

The addition of pelabresib (CPI-0610) and ruxolitinib (Jakafi) led to a significant and durable reduction in splenomegaly, showed a trend toward reduced tumor symptom score (TSS) from baseline, and improved anemia and bone marrow fibrosis at week 24 vs ruxolitinib alone in JAK inhibitor–naive patients with myelofibrosis, according to updated data from the phase 3 MANIFEST-2 study (NCT04603495) presented at the 

As previously presented at the 2023 ASH Annual Meeting, the trial met its primary end point when a higher percentage of those who received the doublet (n = 214) experienced a 35% or greater reduction in spleen volume (SVR35) at week 24 vs those given ruxolitinib alone (n = 216), at 65.9% and 35.2%, respectively (difference, 30.4; 95% CI, 21.6-39.3; 

 The mean percentage change in spleen volume at week 24 in the pelabresib/ruxolitinib arm was -50.6% (95% CI, -53.2% to -48.0%) vs -30.6% (95% CI, -33.7% to -27.5%) in the ruxolitinib-alone arm.

When looking at all responders who achieved SVR35 response, the proportion who lost response at any point in the pelabresib/ruxolitinib arm was 13.4% and more than double in the ruxolitinib-alone arm, at 27.8%. When examining the criteria of loss of SVR35 response plus a spleen volume increase greater than 25% from nadir, this occurred in 9.3% and 14.8% of patients, respectively. Notably, SVR35 response was consistently higher with the doublet vs the monotherapy across all predefined subgroups and across hematologic subgroups.

A strong trend for numerical decrease in absolute change in TSS from baseline at week 24 was observed with the doublet vs the monotherapy, at -15.99 and -14.05, translating to a mean difference of -1.94 points (95% CI, -3.92 to 0.04; 

= .0545). A higher proportion of patients who received the combination vs ruxolitinib alone achieved a 50% reduction in TSS (TSS50), at 52.3% vs 46.3% (difference, 6.0; 95% CI, -3.5 to 15.5; 

= .216); this difference did not reach statistical significance. A two-fold increase in patients who achieved both SVR35 and TSS50 responses was observed with pelabresib plus ruxolitinib vs ruxolitinib alone, at 40.2% and 18.5%, respectively.

At the meeting, Raajit K. Rampal, MD, PhD, of the Department of Medicine, Leukemia Service, at Memorial Sloan Kettering Cancer Center in New York, New York, shared additional findings from a modified TSS (mTSS) analysis, which he said partially addresses the ceiling effect that is pronounced for the fatigue domain and may help demonstrate the full potential of the doublet to impact disease-associated symptoms.

 Specifically, when utilizing mTSS, which does not include the fatigue subdomain, there is a numerical advantage with regard to reduction in TSS in favor of the combination regimen (mean difference, -2.10; 95% CI, -4.04 to -0.15; 

Additional updated data revealed a numerically higher proportion of patients who experienced hemoglobin response with the doublet vs the monotherapy. A hemoglobin response, defined as at least a 1.5-g/dL mean increase, was observed in 10.7% (95% CI, 6.60%-14.90%) of those in the pelabresib/ruxolitinib arm vs 6.0% (95% CI, 2.85%-9.19%) of those in the ruxolitinib-alone arm. In patients with anemia who had baseline hemoglobin of less than 10 g/dL, hemoglobin response was observed in 16.4% (95% CI, 7.55%-25.29%) and 14.1% (95% CI, 5.99%-22.18%) of patients in the doublet and monotherapy arms, respectively. Additionally, red blood cell transfusions (RBC) occurred in 30.3% of those who received the combination at any time during the first 24 weeks of therapy but in 40.3% of those who were given single-agent ruxolitinib.

With regard to hallmarks of the disease, bone marrow fibrosis was improved in 38.3% of those in the pelabresib/ruxolitinib arm vs 25.3% of those in the ruxolitinib-alone arm; it worsened in 17.0% and 27.7% of patients, respectively. Moreover, a significantly greater reduction in proinflammatory cytokine levels at week 24 from baseline were observed with the doublet vs the monotherapy.

“The combination of pelabresib and ruxolitinib showed significantly reduced splenomegaly, a trend toward improved symptom score, and improvements in multiple measures of anemia and in the bone marrow microenvironment compared with placebo plus ruxolitinib, impacting the four hallmarks of myelofibrosis,” Rampal said in a presentation of the data.

MANIFEST-2: Trial Design, Objectives, Baseline Disease Characteristics

The global, randomized, double-blind, active-control, phase 3 study enrolled patients with myelofibrosis who did not have prior exposure to JAK inhibitors, had a Dynamic International Prognostic Scoring System (DIPSS) score of intermediate-1 or higher, splenomegaly defined as at least 450 cm3 by CT or MRI, and a TSS of at least 10 and at least 3 for two symptoms per the Myelofibrosis Symptom Assessment Form v4.0.

Participants were randomly assigned 1:1 to receive ruxolitinib per label with a 5-mg twice daily lower starting dose on days 1 to 21 plus placebo or pelabresib at 125 mg on days 1 to 14 as part of 21-day cycles. Stratification factors included DIPSS risk category (intermediate-1 vs intermediate-2 vs high), platelet count (>200 x 109/L vs 100 to 200 x 109/L), and spleen volume (≥1800 cm3 vs <1800 cm3).

The primary end point was SVR35 response at week 24, and key secondary end points included absolute change in TSS from baseline at week 24 and TSS50 response at week 24. Safety was also evaluated.

The median patient age in both the doublet and monotherapy arms was 66 years (range, 19-88). Most patients were male (60.3% vs 56.5%) and White (74.8% vs 75.5%). Approximately half had primary myelofibrosis (50.0% vs 50.9%) and an ECOG performance status of 0 (50.0% vs 50.5%) Regarding DIPSS score in the doublet arm, 59.8% had intermediate-1 disease, 35.0% had intermediate-2 disease, and 5.1% had high-risk disease; these rates were 58.8%, 34.3%, and 6.9%, respectively, in the monotherapy arm. Slightly more than half of patients had a 

The median baseline hemoglobin level was 10.9 g/dL (range, 5.8-18.0) in the doublet arm and 11.0 g/dL (range, 6.7-17.9) in the monotherapy arm. The respective median platelet counts at baseline were 285 x 109/L (range, 99-1303) and 287 x 109/L (range, 66-1084). Mean peripheral blasts was 0.8 in both arms. Median spleen volume was 1308.89 (range, 200.24-7117.03) and 1382.97 (range, 277.87-5540.45). The percentage of patients who required RBC transfusions at baseline was 10.3% of those in the doublet arm and 9.7% of those in the monotherapy arm; 3.7% vs 0.9% of patients were transfusion dependent at the time of enrollment. The median TSS at baseline was 26.6 (range, 7.3-66.4) vs 24.7 (range, 9.0-68.4).

The combination of pelabresib and ruxolitinib at 24 weeks was reported to be generally comparable to what has been observed with ruxolitinib alone, according to Rampal.

Any-grade treatment-emergent adverse effects (TEAEs) occurred in 96.7% of those in the doublet arm vs 96.7% of those in the monotherapy arm; these effects were grade 3 or higher for 49.1% and 57.0% of patients, respectively. Serious AEs occurred in 29.7% and 29.4% of patients, respectively.

TEAEs led to dose reduction of pelabresib or placebo in 32.5% and 29.0% of patients, respectively, or dose reduction of ruxolitinib in 47.6% and 41.6% of patients, respectively. TEAEs led to dose interruptions of pelabresib or placebo for 32.1% and 22.9% of patients, respectively, or dose interruption of ruxolitinib for 23.1% and 16.4% of patients, respectively. TEAEs led to pelabresib or placebo discontinuation in 12.3% and 7.5% of patients, respectively, and ruxolitinib discontinuation for 9.9% and 6.1% of patients, respectively.

“Getting more granular, in terms of anemia, there was a higher proportion of anemia seen with ruxolitinib alone, including 36.5% of grade 3 or higher events. There was a higher proportion of thrombocytopenia seen with the combination therapy,” Rampal reported. “In terms of non-hematologic AEs, these were essentially similar in both arms with two notable exceptions. One is dysgeusia, which was seen with a higher proportion of the combination-treated patients but notably this was a dose-dependent effect and reducing the dose did attenuate this AE; only 1 patient withdrew due to that AE. The other notable thing is muscle spams occurring in 11% of patients on the combination.”

Accelerated and blast-phase progression occurred in 3.3% of those who received the combination vs 2.3% of those given ruxolitinib alone. “A higher proportion of patients treated with ruxolitinib progressed to accelerated-phase disease and higher proportion of patients treated with the combination progressed to blast-phase disease,” Rampal noted. “One important point to make here is that in terms of actual numbers, 5 patients [on the combination arm] progressed at first data cutoff to blast-phase disease vs 1 patient in the ruxolitinib arm. However, upon further adjudication, one of these blast-phase cases actually turned out to be diffuse large B-cell lymphoma, and thus, the actual number here is 4 patients vs 1 patient in the respective arms.”

Leukemic transformation continues to be followed up, Rampal concluded.

Rampal R, Grosicki S, Chraniuk D, et al. Updated safety and efficacy data from the phase 3 MANIFEST-2 study of pelabresib in combination with ruxolitinib for JAK inhibitor treatment-naive patients with myelofibrosis. 

. 2024;42(suppl 16):6502. doi:10.1200/JCO.2024.42.16_suppl.6502

Rampal R, Grosicki S, Chraniuk D, et al. Pelabresib in combination with ruxolitinib for Janus Kinase Inhibitor treatment-naïve patients with myelofibrosis: results of the MANIFEST-2 randomized, double-blind, phase 3 study. 

. 2023;142(suppl 1):628. doi:10.1182/blood-2023-179141

The addition of pelabresib and ruxolitinib (Jakafi) led to a significant and durable reduction in splenomegaly, among other improvements, vs ruxolitinib alone in JAK inhibitor–naive patients with myelofibrosis.

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