Ruxolitinib Combinations Reduce Spleen Volume in Myelofibrosis

Derick Alison
Derick Alison
8 Min Read

SAN DIEGO — Combining the Janus kinase (JAK) inhibitor ruxolitinib (Jakafi) with either navitoclax or pelabresib led to more patients with myelofibrosis achieving reductions in spleen volume, two phase III studies showed.

In the TRANSFORM-1 trial, the combination of the BCL-XL/BCL-2 inhibitor navitoclax and ruxolitinib doubled the number of patients who achieved a 35% or greater reduction in spleen volume (SVR35) by week 24 (63.2% vs 31.5%, P<0.0001) compared with patients who were treated with ruxolitinib plus placebo, reported Naveen Pemmaraju, MD, of the University of Texas MD Anderson Cancer Center in Houston.

This difference in response was more pronounced over time, with 76.8% of patients achieving SVR35 at any time on study with the combination compared with 41.7% of patients in the control arm (P<0.0001), Pemmaraju said at the American Society of Hematology annual meeting.

These preliminary data are “encouraging,” and additional evaluations are continuing to assess other outcomes, including overall survival, as well as responses in subgroups, Pemmaraju said.

Results from the MANIFEST-2 study evaluating the bromodomain and extra-terminal (BET) inhibitor pelabresib plus ruxolitinib were similar to those of TRANSFORM-1, with 66% of patients treated with the combination achieving SVR35 at week 24 versus 35% of patients given ruxolitinib and placebo (P<0.001), reported Raajit Rampal, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City.

Patients treated with the combination experienced a reduction in pro-inflammatory cytokines, and improvement in bone marrow fibrosis and anemia response, “addressing the four hallmarks of myelofibrosis,” he said. “We believe these results support a potential paradigm shift in the treatment of patients with myelofibrosis.”


In explaining the rationale behind the trial, Pemmaraju noted that while JAK inhibitors have “revolutionized” the care of patients with myelofibrosis, they “by and large, have not led to a cure, and response rates — with the primary endpoint usually being spleen volume reduction at 35% at week 24 — of only 29% to 42% in monotherapy trials with JAK inhibitors.”

However, navitoclax in combination with ruxolitinib was shown to have pronounced antitumor activity in patients with myelofibrosis in the phase II REFINE trial.

In the international, randomized, double-blind, multicenter TRANSFORM-1 trial, Pemmaraju and colleagues further evaluated whether the combination could improve clinical outcomes in myelofibrosis patients.

The study included 252 JAK inhibitor-naive patients with intermediate-2- or high-risk myelofibrosis with measurable splenomegaly and evidence of myelofibrosis symptoms.

Median participant age was 69-70 years, and most were men. Most patients in both arms had intermediate-2-risk disease (83% in the combination arm and 87% in the placebo arm). Slightly less than half had high-molecular-risk mutations (48% and 43%, respectively). Median follow-up was about 15 months.

TRANSFORM-1’s key secondary endpoint was the change in total symptom score (TSS) as measured with the Myelofibrosis Symptom Assessment Form version 4.0, which focuses on seven items — fatigue, weight loss, bone pain, fever, pruritus, night sweats, and symptomatic splenomegaly — with a total score of 0-70.

TSS was reduced in both arms, but with a difference that was not statistically significant — a 9.7 reduction from baseline with the combination at week 24 compared with an 11.1 reduction with ruxolitinib plus placebo (P=0.2852).

Pemmaraju said there could be multiple reasons for the divergence between the primary outcome result and the change in total symptom burden. “Ruxolitinib alone is a nice drug for symptom improvement,” he noted. “But when you add in a second drug, you’re improving the outcomes for the patient, but may be introducing a bit more toxicity or side effects — so the statistical significance may not have come out because of that.”

The most common adverse event was thrombocytopenia, which was “expected by the mechanism of action,” he said, followed by anemia and neutropenia — adverse events that were manageable with dose modifications.

The most common non-hematologic side effects were gastrointestinal-related, including diarrhea, with grade 3 events occurring in 5% of patients in the combination arm compared with none in the control arm. Serious adverse events occurred in 26% and 32% of patients, respectively.


In the case of pelabresib, Rampal noted that preclinical data support the potential of combining it with therapies targeting overlapping pathways, such as JAK/STAT, and MANIFEST-2 was initiated based on compelling data from the ongoing phase II MANIFEST study.

In MANIFEST-2, 430 JAK inhibitor-naive patients were randomized to either pelabresib plus ruxolitinib or ruxolitinib plus placebo. The median follow-up was 45.4 weeks.

Median age of the patients was 66 years, and most were men. The majority in both arms had intermediate-1-risk disease (59.8% in the combination arm and 58.8% in the control arm), while about one-third had intermediate-2-risk disease (35% and 34.3%, respectively).

On the secondary endpoint of absolute change from baseline in TSS at 24 weeks, there were improvements in both arms (-15.99 in the combination arm and -14.05 in the control arm), resulting in a mean difference of -1.94 in favor of the combination, but not quite reaching statistical significance (P=0.0545).

The proportion of patients achieving ≥50% reduction in symptom score (TSS50) at 24 weeks was 52.3% in the combination arm versus 46.3% in the placebo arm — a difference that again did not reach statistical significance (P=0.216).

The number of patients who achieved both SVR35 and TSS50 at 24 weeks was doubled with the combination versus ruxolitinib plus placebo (40.2% vs 18.5%, respectively).

Patients receiving pelabresib in combination with ruxolitinib reported fewer anemia adverse events compared with placebo plus ruxolitinib, and fewer patients in the combination arm required red blood cell transfusions.

  • author['full_name']

    Mike Bassett is a staff writer focusing on oncology and hematology. He is based in Massachusetts.


TRANSFORM-1 was sponsored by AbbVie.

MANIFEST-2 was sponsored by Constellation Pharmaceuticals.

Both Pemmaraju and Rampal reported multiple relationships with industry.

Primary Source

American Society of Hematology

Source Reference: Pemmaraju N, 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” ASH 2023; Abstract 620.

Secondary Source

American Society of Hematology

Source Reference: Rampal R, et al “Pelabresib in combination with ruxolitinib for Janus kinase inhibitor treatment-naive patients with myelofibrosis: results of the MANIFEST-2 randomized, double-blind, phase 3 study” ASH 2023; Abstract 628.

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