First-Line Ruxolitinib Combinations Boost Benefit Over Single Agent in Myelofibrosis

Get Permission

In two international phase III trials in myelofibrosis, drugs given in combination with the Janus kinase (JAK) inhibitor ruxolitinib in JAK inhibitor–naive patients significantly improved outcomes vs ruxolitinib alone. Both studies were presented at the 2023 American Society of Hematology Annual Meeting & Exposition.

MANIFEST-2 evaluated the addition of pelabresib, an oral small-molecule BET inhibitor that can also decrease BET-mediated gene expression involved in myelofibrosis pathogenesis.1 TRANSFORM-1 assessed the benefit of adding the BCL2 inhibitor navitoclax to the standard of care, ruxolitinib.2 In both studies, the combinations led to an approximate doubling in the proportion of patients achieving ≥ 35% spleen volume reduction (SVR35) at 24 weeks.

JAK inhibitors are the current standard of care in patients with intermediate- and high-risk myelofibrosis. Although these drugs have revolutionized the care of these patients, they have not led to cures. There is an unmet need to improve the depth and durability of responses with therapy, as well as reduce toxicities.

MANIFEST-2: Pelabresib Plus Ruxolitinib

At a median follow-up of 45 weeks, MANIFEST-2 met its primary endpoint by showing a significant reduction in SVR35 at 24 weeks with the addition of pelabresib: 66% with the combination vs 35% with ruxolitinib and placebo (P < .001), with responses consistently higher across all predefined subgroups. Ruxolitinib/pelabresib also demonstrated strong trends in reducing symptom score and improving symptomatic response, and it doubled the percentage of patients who met both splenomegaly and symptom endpoints, according to Raajit Rampal, MD, a leukemia specialist at Memorial Sloan Kettering Cancer Center, New York.

We believe these results [with ruxolitinib plus pelabresib] support a potential paradigm shift in the treatment of patients with myelofibrosis.
— Raajit Rampal, MD

Tweet this quote

“There were fewer anemia adverse events, a higher rate of hemoglobin response, and fewer patients with transfusion requirements on combination therapy…. Pelabresib in combination with ruxolitinib also showed a reduction of pro-inflammatory cytokines, and improvement in bone marrow fibrosis and anemia response—addressing the four hallmarks of myelofibrosis. As such, we believe these results support a potential paradigm shift in the treatment of patients with myelofibrosis,” Dr. Rampal said.

The study enrolled 430 patients with primary myelofibrosis or post–essential thrombocythemia/polycythemia vera myelofibrosis and no prior treatment with a JAK inhibitor. Patients had a Dynamic International Prognostic Scoring System (DIPSS) score of intermediate-1 or higher, splenomegaly of at least 450 cm3, and a Total Symptom Score (TSS) ≥ 10 (or ≥ 3 for two symptoms). Nearly 60% of patients had intermediate-1 disease, and 35% had intermediate-2 disease; 6% had high-risk disease. About 16% of patients on pelabresib required red blood cell (RBC) transfusions at baseline vs 12% of those on the ruxolitinib/placebo arm. The median spleen volume was 1,308.89 cm3 with pelabresib/ruxolitinib and 1,382.97 cm3 with placebo/ruxolitinib. Median TSS was 26.6 and 24.7, respectively.

Patients were randomly assigned 1:1 to receive oral pelabresib at 125 mg daily on days 1 to 14 plus ruxolitinib at a starting dose of 10 mg or 15 mg twice daily on days 1 to 21 or placebo plus ruxolitinib in 21-day cycles. Although the ruxolitinib dose was lower than the labeled starting dose, dose escalation was required if patients met certain hematologic parameters. The primary endpoint was SVR35 at week 34.

Multiple Endpoints Improved With Combination

The key findings for pelabresib/ruxolitinib vs ruxolitinib alone at week 24 were:

  • SVR35 response was seen in 65.9% vs 35.2% (P < .001), a 30.4% improvement.
  • Mean percentage change in spleen volume was −50.6% vs −30.6%, a 30.6% improvement.
  • TSS change from baseline was −15.99 vs −14.05 (P = .0545), an improvement of 1.94 points.
  • TSS50 (≥ 50% reduction in TSS from baseline) was achieved in 52.3% vs 46.3% (P = .216), a numerical improvement, with benefit balanced across all TSS domains (fullness after eating, bone pain, pain under left rib, abdominal discomfort, itching, night sweats, fatigue).
  • Twice the number of patients on the combination achieved both SVR35 and TSS50 (40.2% vs 18.5%).
  • More patients on the combination had a hemoglobin increase ≥ 1.5 g/dL (9.3% vs 5.6%), and fewer patients required red blood cell transfusions (30.8% vs 41.2%).
  • More patients on the combination had an improvement of reticulin fibrosis grade and a reduction in inflammatory cytokines.

Safety Profile

Treatment-related adverse events of grade ≥ 3 were observed in 49% of the combination arm and 57% of the placebo arm, with serious adverse events reported for about 29% of each arm. Approximately 3% of patients per arm died as a result of these events. Approximately 27% and 25% of patients, respectively, discontinued double-blind treatment due to toxicities.

“Overall, there were no new treatment-emergent adverse events seen in the combination arm above what was seen with ruxolitinib alone,” Dr. Rampal noted. “Drilling down to adverse events of special interest, there was actually a higher proportion of anemia with ruxolitinib alone (56% vs 44%), and this includes grade 3 events (36% vs 23%). A slightly higher proportion of thrombocytopenia occurred with the combination (32% vs 23%); however, grade 3 events were less than 10% (9% vs 6%).”

The incidence of nonhematologic adverse events was largely balanced except for more diarrhea with the combination (23% vs 19%) and more dysgeusia (18% vs 4%). “It’s important to note the dysgeusia was dose-dependent for pelabresib and responded to dose reductions. Only one patient withdrew because of it,” Dr. Rampal said.

TRANSFORM-1: Navitoclax Plus Ruxolitinib

In TRANSFORM-1, the addition of navitoclax to ruxolitinib significantly improved SVR35 at 24 weeks, from 32.1% with ruxolitinib alone to 63.2% with the combination (P < .0001). Spleen volume reduction at any time during treatment was achieved by 77% vs 42%, respectively. The median time to first spleen volume reduction response was similar between the arms, approximately 12 weeks.

“This study marks a notable achievement in the field of myelofibrosis, as one of the first reported global phase III front-line randomized combination clinical trials in our field. The primary endpoint was met—the spleen volume reduction was doubled and this was highly statistically significant, no question,” said Naveen Pemmaraju, MD, Associate Professor, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston.

Rationale for the Study

With JAK inhibitors alone, the primary endpoint of most studies, SVR35 at 24 weeks, has ranged from only 29% to 42% in most monotherapy trials, according to Dr. Pemmaraju.

Navitoclax is an orally available inhibitor of antiapoptotic B-cell lymphoma 2 proteins (BCLXL, BCL2, BCLW). Dr. Pemmaraju explained that this particular inhibitor differs from the more broadly used venetoclax in that it also targets the BCLXL pathway, which appears to be upregulated in myelofibrosis. In vitro studies have shown that navitoclax by itself, and more so in combination with ruxolitinib, can overcome JAK resistance. “We hypothesized that if we could combine a JAK inhibitor with a second agent that works through a different pathway, we could improve clinical outcomes,” he said.

This was tested in TRANSFORM-1, which by data cutoff had randomly assigned 252 patients with intermediate-2 or high-risk myelofibrosis and measurable splenomegaly, evidence of myelofibrosis-related symptoms, and no prior JAK2 inhibitor treatment. Patients received navitoclax (starting dose = 100–200 mg) or placebo plus ruxolitinib (label dose) and were followed a median of 14.9 months. Demographics were similar, and, importantly, almost half the patients had high–molecular risk mutations. Most earlier studies did not differentiate the population by mutation risk, he indicated.

Additional Findings

Median time to SVR35 response was 12.3 weeks (range = 10.1–48.3 weeks) with navitoclax and ruxolitinib vs 12.4 weeks (range = 11.3–72.3 weeks) with ruxolitinib monotherapy. Median duration of SVR35 was not reached with the combination and was 19.4 months in the control arm.

As for symptom reduction at 24 weeks, a secondary endpoint, there were no significant differences between the groups according to a the seven-item myeloproliferative neoplasm symptom assessment instrument MFSAF v4.0.  Mean change in TSS from baseline was −9.7 with the combination vs −11.1 with ruxolitinib alone (P = .2852).  “There may be multiple reasons for this,” Dr. Pemmaraju said. “Ruxolitinib is a good drug for symptom improvement, and when you add a second drug you are improving outcomes, but you may be introducing a bit more toxicity.”

The adverse events occurring with the combination were manageable and consistent with previous trials. Grade ≥ 3 adverse events were experienced by 85% of patients with navitoclax plus ruxolitinib and 70% with ruxolitinib alone, most commonly thrombocytopenia, anemia, diarrhea, and neutropenia. Serious adverse events were reported for 26% and 32%, respectively. Navitoclax was dose-reduced in 81%, and doses were interrupted in 70% of patients. Of all enrolled patients, 33% discontinued study treatment.

[TRANSFORM-1] marks a notable achievement in the field of myelofibrosis, as one of the first reported global phase III front-line randomized combination clinical trials in our field.
— Naveen Pemmaraju, MD

Tweet this quote

“This data set now opens the door for additional research and investigation into combination therapies to treat myelofibrosis and, importantly, highlights a potential new era of investigating disease modification for patients,” Dr. Pemmajuru concluded. He added that additional outcomes in TRANSFORM-1, including disease modification, are being evaluated.

DISCLOSURE: Dr. Rampal reported financial relationships with Celgene-BMS, Kartos, Dainippon, Karyopharm, CTI BioPharm Corp, Galecto, MorphoSys, Sumitomo, PharmaEssentia, Servier, GSK-Sierra, Zentalis, and Incyte. Dr. Pemmaraju reported financial relationships with Cancer.Net, PharmaEssentia, Neopharm, ImmunoGen, Novartis, Curio Science, Stemline, Protagonist Therapeutics, Incyte, CareDx, EUSA Pharma, Menarini Group, Medscape, Dan’s House of Hope, Aplastic Anemia & MDS International Foundation, CTI BioPharma, Cimeio Therapeutics AG, ClearView Healthcare Partners, Pacylex, Celgene, Dava Oncology, Imedex, Harborside Press, Magdalen Medical Publishing, Intellisphere, OncLive, Patient Power, PeerView,  Physician Education Resource (PER), AbbVie, Astellas, Blueprint, Aptitude Health, and Bristol Myers Squibb.


1. 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 ASH Annual Meeting & Exposition. Abstract 628. Presented December 10, 2023.

2. Pemmaraju N, Mead AJ, Somervaille TCP, et al: Transform-1: A randomized, double-blind, placebo-controlled, multicenter, international phase 3 study of navitoclax in combination with ruxolitinib versus ruxolitinib plus placebo in patients with untreated myelofibrosis. 2023 ASH Annual Meeting & Exposition. Abstract 620. Presented December 10, 2023.

Related Articles

Expert Point of View: Prithviraj Bose, MD

Prithviraj Bose, MD, Professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, Houston, shared his thoughts on MANIFEST-2 and TRANSFORM-1 with The ASCO Post. While both were international phase III trials that showed similar benefits with two different...