Jonah Feldman

Pelabresib plus Jakafi delivered stronger, clinically meaningful benefits versus Jakafi alone for people with untreated myelofibrosis.

The 96-week results from the MANIFEST-2 phase 3 trial show that adding pelabresib to Jakafi (ruxolitinib) can provide stronger, clinically meaningful benefits for people with myelofibrosis who have not yet received a JAK inhibitor, compared with Jakafi alone, according to data presented by Dr. Raajit Rampal of Memorial Sloan Kettering Cancer Center at the 2025 ASH Annual Meeting and Exposition.

The pelabresib plus Jakafi combination demonstrated deep and durable improvements across primary and secondary efficacy end points compared to Jakafi monotherapy.

In patients who were evaluable at week 96 combination therapy was associated with at least a 35% reduction in spleen volume in 91.5% of patients versus 57.5% with Jakafi plus placebo indicating a sustained benefit from previous evaluation at week 24. At week 24 the reduction in spleen volume was 82.9% with the combination versus 41.8% with placebo plus Jakafi. The median duration of spleen response was not reached in the combination arm versus 138.3 weeks in the placebo arm.

In the intent-to-treat population reduction in spleen volume was maintained at week 96 by 45.3% in the pelabresib plus Jakafi arm versus 30.1% in the placebo plus Jakafi arm. At week 24 the reduction in spleen volume for the respective arms were 65.9% and 35.2%.

Patients in the intent-to-treat population receiving pelabresib plus Jakafi experienced a greater and more durable improvement in their total symptom score. The absolute change from baseline in total symptom score was negative 15.07 in the pelabresib plus Jakafi arm versus negative 12.48 in the placebo plus Jakafi arm. The difference in the arms was negative 2.59 which was greater than the negative 1.96 difference at week 24. A reduction in total symptom score from baseline of at least 50% was achieved by 36.9% of patients in the pelabresib plus Jakafi arm versus 28.2% in the placebo plus Jakafi arm.

The rate of achieving both a significant reduction in spleen volume and a significant symptom improvement was more than double in the combination therapy arm: 31.8% of patients in the pelabresib plus Jakafi arm versus 15.7% in the placebo plus Jakafi arm. This maintained the dual response benefit seen at week 24.

The pelabresib plus Jakafi combination demonstrated favorable effects on anemia, a common and challenging complication of myelofibrosis. In the pelabresib plus Jakafi arm the hemoglobin response was 17.8% versus 11.6% in the placebo plus Jakafi arm. Red blood cell transfusions were required up to week 96 in 33.1% of patients in the pelabresib plus Jakafi arm versus 39.9% in the placebo plus Jakafi arm.

Although the study was not statistically powered for survival end points the longer-term follow-up showed numerically fewer deaths and progression-free survival events in the pelabresib plus Jakafi arm.

In the pelabresib plus Jakafi arm there were 28 deaths versus 32 in the placebo plus Jakafi arm. In the pelabresib plus Jakafi arm the number of progression-free survival events was 22 versus 34 in the placebo plus Jakafi arm.

Bone marrow fibrosis was improved in 52.5% of evaluable patients with pelabresib plus Jakafi versus 27.5% with placebo plus Jakafi and there were also greater reductions in bone marrow morphology seen with the combination. Similar reductions in variable allele frequency of JAK2 V617F CALR and MPL were seen in both arms.

Pelabresib Plus Jakafi Shows Favorable Long-Term Safety and Manageable Side Effects

The long-term safety profile of pelabresib plus Jakafi was comparable to that of placebo plus Jakafi. Treatment-emergent side effects were mainly low grade and remained similar between the arms over the follow-up period.

Any-grade treatment-emergent side effects occurred in 99.5% of patients in the pelabresib plus Jakafi arm versus 98.1% in the placebo plus Jakafi arm. Grade 3 or higher treatment-emergent side effects occurred in 67.5% of patients in the pelabresib plus Jakafi arm versus 70.1% in the placebo plus Jakafi arm.

Externally and independently adjudicated cases of leukemic transformation were reported in both arms. The frequency was noted to be in line with what is historically seen in myelofibrosis and an early imbalance between the arms decreased over time.

Study Design Supports Robust Evaluation of Combination in Myelofibrosis

The MANIFEST-2 study is a double-blind randomized phase 3 trial designed to assess the efficacy and safety of combining pelabresib with Jakafi in patients with myelofibrosis who have not previously been treated with a Janus kinase inhibitor.

Standard-of-care treatment with Janus kinase inhibitor monotherapy improves splenomegaly and symptom burden but provides responses of limited depth and durability. There is a significant need for new combination strategies that can address the underlying biology of the disease and improve long-term clinical outcomes.

Patients were randomized to receive either pelabresib or a placebo once daily in combination with Jakafi administered twice daily.

The data cut off for this analysis was March 2, 2025, with a median follow-up period of 115.9 weeks.

At the cut off approximately half of the patients in both arms remained on their assigned treatment. A total of 56.5% of patients in the pelabresib plus Jakafi arm and 59.3% in the placebo plus Jakafi arm completed 96 weeks of the assigned treatment.

The most common reasons for treatment discontinuation included side effects, physician decision, withdrawal of consent, and protocol-defined disease progression.

The findings strongly suggest that the pelabresib plus Jakafi combination provides clinically meaningful benefits over the standard of care for Janus kinase inhibitor–naive patients with myelofibrosis.

“The week 96 results from the phase 3 MANIFEST-2 trial of pelabresib and Jakafi versus placebo and Jakafi constitute the longest follow-up to date of a randomized combination trial in Janus kinase inhibitor-naive patients with myelofibrosis” concluded Rampal.

"Durable efficacy and long-term safety with pelabresib plus ruxolitinib in JAK inhibitor-naive myelofibrosis: 96-week results from the phase III MANIFEST-2 study," by Dr. Raajit Rampal. 

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The MANIFEST-2 phase 3 trial results indicate that combining pelabresib with Jakafi offers significant clinical benefits for myelofibrosis patients who have not previously received a JAK inhibitor. The combination therapy showed superior efficacy in reducing spleen volume and improving symptom scores compared to Jakafi alone. Additionally, the combination demonstrated favorable effects on anemia and bone marrow fibrosis, with a comparable safety profile to Jakafi monotherapy. The study underscores the potential of pelabresib plus Jakafi as a promising treatment strategy for enhancing long-term outcomes in myelofibrosis.

New Data Support Pelabresib Combination in Untreated Myelofibrosis  

Among fit patients with acute myeloid leukemia, azacitidine plus Venclexta was shown to be superior to intensive chemotherapy.

Among fit patients with acute myeloid leukemia, the combination of azacitidine plus Venclexta (venetoclax) was associated with a significantly improved event-free survival (EFS) compared with intensive induction chemotherapy, study results have shown.

Results from the phase 2 PARADIGM trial were presented at the 2025 ASH Annual Meeting. In the trial, patients receiving azacitidine/Venclexta had a 39% reduction in risk of progressive disease, persistent disease prompting therapy change, relapse, hospice or death compared with those receiving conventional intensive induction chemotherapy. Patients also had improved quality of life (QOL) with azacitidine/Venclexta.

Induction chemotherapy with cytarabine plus anthracycline has been the standard of care for decades but is not tolerable in older or less fit patients and can still yield suboptimal long-term outcomes in fitter patients. The hypomethylating agent (HMA) azacitidine plus the BCL2 inhibitor Venclexta was established as the regimen of choice for patients who were not eligible for induction chemotherapy based on the phase 3 VIALE-A trial, but no prospective randomized trials have shown an advantage with direct comparison.

Event-Free Survival (EFS): The length of time after treatment during which a patient has no major problems related to the cancer—such as the disease coming back, getting worse, or needing new treatment.

Mucositis: Soreness and inflammation of the lining of the mouth or digestive tract. It can cause mouth sores, pain, and difficulty eating, and is a common side effect of some cancer treatments.

Complete Response (CR): When all signs of cancer disappear on tests after treatment. It does not always mean the cancer is cured, but it means doctors cannot detect it.

CR with Partial Hematologic Recovery (CRh): A type of complete response where the cancer is gone, but blood counts—especially platelets and certain infection-fighting cells—have only partially recovered.

CR with Incomplete Hematologic Recovery (CRi): A type of complete response where the cancer is gone, but some blood counts are still below normal. Patients may still need monitoring and support while blood levels improve.

Hematopoietic Cell Transplant: A procedure that replaces damaged or diseased blood-forming cells with healthy ones. The cells may come from the patient (autologous transplant) or from a donor (allogeneic transplant). This helps rebuild the blood and immune system after intensive treatment.

“Intensive induction chemotherapy comes with substantial burden and cost,” said Dr. Amir Fathi, program director of the Center for Leukemia at the Massachusetts General Hospital Cancer Center, in a press briefing. “It’s associated with significant morbidity, including deep and prolonged marrow suppression, weeks’ long hospitalizations, frequent infections and bleeding complications, mucositis, malnutrition, deleterious psychosocial effects, and an increased risk of cardiac injury and secondary malignancies.”

The open-label, multicenter, investigator-initiated PARADIGM clinical trial randomly assigned 172 patients with previously untreated AML at nine centers in the United States to receive induction chemotherapy or azacitidine/Venclexta. Patients were excluded if they were below 60 years old and had NPM1 mutations, or if they had core binding factor fusions or FLT3 mutations.

The median age was 64 years in the experimental arm and 65 years in the comparator arm, and 55% versus 60% were male in these respective arms. Seventy-two percent had adverse risk with 15% having intermediate and 12% having favorable risk status. The arms were balanced for risk status as well as TP53, NPM1 and IDH1/IDH2 mutations.

The induction chemotherapy used was a 7+3 regimen (cytarabine plus an anthracycline) in 54% with the remaining 46% receiving liposomal daunorubicin plus cytarabine (CPX351).

Results were reported as of July 25, 2025. The median number of treatment cycles was four with azacitidine/Venclexta versus two with induction chemotherapy.

The overall response rate was 88% with azacitidine/Venclexta versus 62% with the comparator. The rate of complete response (CR), CR with partial hematologic recovery and CR with incomplete hematologic recovery was 81% versus 55%, respectively. Although these were statistically significant, the CR rates were not significantly different (59% versus 50%). Both arms were allowed to proceed to hematopoietic cell transplant (HCT); 52 patients (61%) received HCT after azacitidine/Venclexta versus 34 patients (40%) after induction chemotherapy. HCT had a significant protective effect for EFS, but after adjustment in univariate and multivariate models, azacitidine/Venclexta still showed protective effect on EFS.

The median EFS was 14.6 months for azacitidine/Venclexta versus 6.2 months for induction chemotherapy, and the one-year rate of EFS was 53% versus 39%, respectively.

Fathi stated that overall survival improvement was not statistically significant, but this was a difficult end point to interpret compared with EFS because patients could benefit from receiving the trial regimens as subsequent therapy. “Even if we were to do a larger phase 3 study, overall survival, in my opinion is going to be fraught with challenge because of this extensive crossover in both directions, but mainly from intensive therapy to azacitidine/[Venclexta],” he said.

In terms of side effects, there were similar rates of grade 3 (severe) or 4 (life-threatening) treatment-related side effects, which were mainly hematologic. Grade 3 or 4 lung infections were reported in 12% in the experimental arm versus 15% in the comparator arm, and grade 3/4 sepsis occurred in 7% versus 11%, respectively. There was no 30- and 60-day mortality with azacitidine/Venclexta, whereas 30-day mortality was 3.5% and 60-day mortality was 4.7% with induction chemotherapy.

Quality of life was also assessed, with patients in the experimental arm reporting significantly better QOL in the first two weeks. Symptom burden and depression symptoms were also significantly improved.

Intensive care unit care during index hospitalization was not needed in any patients receiving azacitidine/Venclexta compared with 9.8% with induction chemotherapy. They also had fewer days of inpatient index hospitalization versus those receiving induction chemotherapy (15 versus 36) and fewer days hospitalized in the first six months (41 versus 58).

Fathi noted that those with favorable risk, such as CEBPA-associated AML and those with targetable mutations, were excluded to maintain equipoise and characterize the patient population who would likely receive HCT as consolidation. “This was really a study aimed at patients who were transplant eligible for consolidation, and in that patient population, it met its primary end point,” he said.

“We therefore believe these data support the use of azacitidine and [Venclexta] in functionally fit patients eligible for transplant with intermediate or adverse risk, FLT3 wild-type AML,” Fathi concluded.

1. “Results from paradigm - a phase 2 randomized multi-center study comparing azacitidine and venetoclax to conventional induction chemotherapy for newly diagnosed fit adults with acute myeloid leukemia,” by Dr. Amir Fathi et al., 

The combination of azacitidine and Venclexta significantly improved event-free survival (EFS) in fit acute myeloid leukemia (AML) patients compared to intensive induction chemotherapy, as demonstrated in the phase 2 PARADIGM trial. This regimen also enhanced quality of life and reduced hospitalization duration. Despite similar overall survival rates, azacitidine/Venclexta showed a protective effect on EFS, even after hematopoietic cell transplant adjustments. The trial highlighted the tolerability and reduced side effects of azacitidine/Venclexta, supporting its use in transplant-eligible patients with intermediate or adverse risk AML.

Azacitidine Plus Venclexta Superior to Chemo in Acute AML

Treatment with Brukinsa was associated with improved efficacy in patients with treatment-naïve CLL or SLL. 

Patients with treatment-naive chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) experienced long-term improved efficacy when treated with Brukinsa (zanubrutinib) compared with bendamustine plus Rituxan (rituximab), study results have shown.

Findings from a five-year follow-up of the phase 3 SEQUOIA trial were presented at the 2024 ASH Annual Meeting.

In cohort 1 of the trial, patients who were randomly assigned to Brukinsa (241 patients) experienced improved progression-free survival (PFS) regardless of disease risk status and COVID-19 impact compared with patients randomly assigned to Rituxan (238 patients). Brukinsa also showed better overall response rate (ORR) and adverse event (AE, side effects) incidence.

Progression-free survival: the time a patient lives without their disease spreading or worsening.

Overall response rate: patients who responded partially or completely to treatment.

Complete response: the disappearance of cancer.

Overall survival: how long a patient lives, regardless of disease status.

Neutropenia: low count of neutrophils, a type of white blood cell.

Atrial fibrillation: Irregular and often rapid heart rate, according to the Mayo Clinic.

Bruton tyrosine kinase (BTK) inhibitors offer improved outcomes for patients with CLL/SLL, and the next-generation BTK inhibitors such as Brukinsa are designed for better efficacy and tolerability through increased potency, greater BTK specificity and more exposure coverage.

“With a median study follow-up of 61.2 months, [Brukinsa] has been shown to offer a sustained superior PFS over [Rituxan] in [patients with] treatment-naive CLL with 71% reduction of the risk of progression or death,” Dr. Mazyar Shadman, medical director of cellular immunotherapy at Fred Hutchinson Cancer Center, said in his presentation of the data.

Median PFS was not reached in patients given Brukinsa versus 44.1 months in those given Rituxan. The 54- and 60-month PFS rates were 80.1% and 75.8% with Brukinsa versus 44.6% and 40.1% with Rituxan, respectively.

Additionally, the degree of PFS difference was similar when the investigators adjusted for the impact of COVID-19 on the treatment outcomes, with 83.2% versus 45.2% 54-month PFS rates and 78.7% versus 40.6% 60-month PFS rates for Brukinsa versus Rituxan, respectively.

Regardless of IGHV status, Brukinsa showed consistent PFS benefit. However, treatment with Rituxan displayed lower PFS rates which were affected by IGHV status. Shadman noted that in prior reports from cohort 2 of the SEQUIOA trial, patients with deletion 17p (del[17p]) and TP53 mutations showed similar PFS rates in those without the high-risk features. “This suggests that the treatment with [Brukinsa] may overcome negative prognostic factors such as IGHV [mutation], del(17p) or TP53 mutation,” he said.

The ORR with long-term follow-up was 97.5% with Brukinsa versus 88.7% with Rituxan. With Brukinsa, the complete response (CR)/CR with incomplete bone marrow recovery (CRi) rates was 20.7% compared with Rituxan at 23.5%. The CR/CRi rate is the highest reported with an inhibitor monotherapy, according to Shadman.

In total, 34 deaths occurred in each arm at the time of follow-up. The estimated overall survival (OS) rates at 54 and 60 months with Brukinsa were 87.7% and 85.5%, respectively; after adjusting for COVID-19, it was 91.3% and 89.4%. For treatment with Rituxan, the estimated 54- and 60-month OS rates were 86% and 85%; then with COVID-19 adjustment, 87.8% and 86.8%.

In terms of toxicity, Brukinsa was well tolerated over the extended treatment period in these patients with CLL/SLL. The most common grade 3 (severe) or higher treatment-emergent and post-treatment AEs included COVID-19 (Brukinsa, 9% versus Rituxan, 2%), hypertension (12% versus 6%) and neutropenia (10% versus 41%).

There were “low rates of atrial fibrillation/flutter [afib/flutter], infections or AEs that limit daily living activities like [gastrointestinal] toxicities,” Shadman explained.

In the original readout of the SEQUOIA trial, Brukinsa showed statistically significant and clinically meaningful improvement in PFS over Rituxan in patients with CLL/SLL without del(17p) at 26.2 months median follow-up.

Brukinsa was given at 160 milligrams twice daily until disease progression or intolerable toxicity and Rituxan was given for a maximum of six cycles. The primary end point was PFS, with ORR and CR rate as the key secondary end points. Crossover was allowed after progression and prior to starting any other therapy for CLL/SLL.

The median treatment duration with Brukinsa at the 61.2-month follow-up was 60.5 months, with 163 patients (67.6%) still receiving treatment. For Rituxan, 79% completed all six cycles of treatment and 13% discontinued early due to AEs. Fifty-nine patients overall crossed over from Rituxan to Brukinsa after experiencing disease progression.

“The result of this extended follow-up support the use of [Brukinsa] as the standard first-line treatment option for patients, regardless of the disease risk factors,” Shadman concluded.

“Sustained superiority of zanubrutinib vs bendamustine + rituximab in treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma: 5-year follow-up of cohort 1 from the SEQUOIA study” by Dr. Mazyar Shadman et al., 

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Brukinsa (zanubrutinib) demonstrated superior long-term efficacy over bendamustine plus Rituxan (rituximab) in treatment-naive chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) patients, as shown in the five-year SEQUOIA trial follow-up. Brukinsa improved progression-free survival (PFS) and overall response rate (ORR), with a 71% reduction in progression or death risk. It was well tolerated, with fewer severe adverse events compared to Rituxan. The study supports Brukinsa as a standard first-line treatment, overcoming negative prognostic factors like IGHV mutation, del(17p), or TP53 mutation.

Patients with treatment-naive CLL/SLL experienced long-term improved efficacy when treated with Brukinsa compared with bendamustine plus Rituxan.

Brukinsa Supported as First-Line Treatment for Patients With CLL/SLL

Aspects of myelofibrosis, such as spleen size, were improved after receiving pelabresib plus Jakafi. 

Pelabresib (CPI-0610) plus Jakafi (ruxolitinib) continued to reduce splenomegaly, anemia, symptoms and bone marrow fibrosis in patients with JAK inhibitor-naive myelofibrosis, recent study findings demonstrated.

Results from the phase 3 MANIFEST-2 study were presented in a poster during the 

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% with pelabresib and Jakafi versus 37.5% with Jakafi plus placebo. Total symptom score (TSS) improvement of at least 50% at week 48 was 45.3% versus 39.4%, respectively. Fewer patients required red blood cell transfusions, and bone marrow fibrosis improvement of at least one grade was reported in 41% versus 15%, respectively.

BET inhibitor: a treatment that targets BET proteins, which play a role in regulating gene expression.

Nadir: the lowest point a blood cell count reaches after a course of chemotherapy.

Proinflammatory cytokines: small proteins secreted by immune cells that play a role in the body’s inflammatory response.

Mutant clone burden: the proportion of cells in a tumor that contains a specific genetic mutation.

Variant allele frequency reduction: the decrease in the proportion of tumor cells that carry a specific genetic mutation within a tumor sample.

Thrombocytopenia: lower than normal number of platelets in the blood.

Accelerated and blast-phase progression: worsening stages of certain types of blood cancers.

“Results at 48 weeks showed deep and sustained SVR35 response with biomarker evidence suggesting additional benefit of the combination of pelabresib plus [Jakafi] versus [Jakafi] alone,” said Dr. John O. Mascarenhas, 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.

 is a study that assigned 430 patients to receive Jakafi 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, platelet count of at least 100,000/μL, spleen volume of at least 450 cm

, TSS of 10 or greater (≥3 for two symptoms), and ECOG performance status of 2 or lower.

At the data cutoff of March 29, 2024, 126 of 214 patients (58.9%) receiving the combination and 134 of 216 patients (62%) receiving Jakafi plus placebo were still being treated.

In addition to a higher number of patients showing SVR35 response at week 48, 13.1% of patients had a loss of SVR35 response and an increase of 25% from nadir with pelabresib versus 20% with placebo, or 21% versus 36.8%, respectively by alternate definition of loss of SVR35 response. The mean change was -54.5% with the combination versus -33.5% with Jakafi plus placebo, and 82.2% had a response at any time with the combination versus 57.9% with Jakafi plus placebo.

The absolute change from baseline TSS was -15.99 for 

 versus -14.05 for Jakafi plus placebo at week 24, and -16.24 versus -14.11, respectively at week 48. TSS individual domain scores were similar between the two groups and similar to national norms for people without MF, according to the investigators. An analysis of the Myelofibrosis Symptom Assessment Form excluding fatigue showed a least square mean change from baseline of -16.19 with pelabresib plus Jakafi versus -13.86 with placebo plus Jakafi. 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 versus only 41 (19%) in the placebo group.

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% versus 7.9%), and hemoglobin levels rose and approached baseline in patients with anemia. In the combination group, 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 Jakafi group.

At week 48, bone marrow fibrosis had improved in 41%, remained unchanged in 45%, and worsened in 14% of those receiving pelabresib versus improving in 15%, remaining unchanged in 54.2%, and worsening in 30.8% of those receiving placebo. The improvement of bone marrow fibrosis of at least one grade at week 24 was 38.3% versus 25.3% in the respective groups, showing that the difference widened at week 48.

Disease-relevant proinflammatory cytokines showed a numerically greater reduction at week 48 in the pelabresib plus Jakafi group. 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 the change in mutant clone burden in peripheral blood samples by next-generation sequencing. At week 48, there was greater reduction in the pelabresib plus Jakafi group, with a variant allele frequency reduction of 50% in 15% versus 9% of those receiving placebo plus Jakafi. The mean change from baseline was -24.1% versus -16.3% in the respective groups, and a correlation was found between SVR35 response and reduced mutation clone burden.

In terms of safety, grade 3 (severe) or higher treatment-emergent side effects were reported in 57.1% of the pelabresib plus Jakafi group versus 62.1% of the placebo plus Jakafi group. 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 treatment-emergent side effects include diarrhea, constipation, dysgeusia, cough and nausea. Death occurred in 20 of 214 patients (9.3%) in the pelabresib plus Jakafi group and 18 of 216 (8.3%) in the placebo plus Jakafi group.

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

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

The combination of pelabresib and Jakafi demonstrated significant efficacy in reducing splenomegaly, anemia, symptoms, and bone marrow fibrosis in JAK inhibitor-naive myelofibrosis patients. The MANIFEST-2 study showed sustained spleen volume reduction and symptom improvement at 48 weeks, with fewer transfusions and better bone marrow fibrosis outcomes compared to Jakafi alone. Safety profiles were comparable, with similar rates of severe side effects and leukemia transformation. The study also indicated a reduction in proinflammatory cytokines and mutant clone burden, suggesting additional benefits of the combination therapy.

Adding pelabresib to a JAK inhibitor may improve multiple aspects of myelofibrosis, including spleen size, symptoms and bone marrow fibrosis.

Jonah Feldman

New Data Support Pelabresib Combination in Untreated Myelofibrosis

Azacitidine Plus Venclexta Superior to Chemo in Acute AML

Brukinsa Supported as First-Line Treatment for Patients With CLL/SLL

Pelabresib Plus Jakafi Maintains Efficacy in JAK-Naive Myelofibrosis

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