For more than a decade, myelofibrosis therapy has run on a single axis: JAK inhibition. Ruxolitinib proved the concept, shrinking spleens, easing the constitutional symptoms that erode quality of life, and validating JAK-STAT signaling as a druggable target in a disease that had few. Later JAK inhibitors expanded treatment options, including for patients in whom anemia or thrombocytopenia complicates therapy.
But one limitation has been stubbornly resistant: controlling the manifestations of MF is not necessarily the same as changing its underlying course.
That gap between managing symptoms and actually modifying the disease is largely why the field has moved toward combination approaches, trying to hold onto what JAK inhibition does well while adding something that addresses the rest of the biology.
Why JAK Inhibition Alone Has Not Been Enough
Constitutive JAK-STAT activation is central to MF, whether driven by JAK2, CALR, MPL, or other molecular events. This makes JAK inhibition logical, but MF is not maintained by one signaling pathway alone. Abnormal megakaryopoiesis, inflammatory cytokine signaling, ineffective hematopoiesis, progressive stromal changes, and clonal evolution all contribute to the disease phenotype.
The limitations are clinically visible. In the phase III COMFORT studies that established ruxolitinib, spleen volume reduction of at least 35% (SVR35) and improvement in symptoms became important benchmarks for treatment efficacy. These endpoints remain highly relevant, but they do not fully capture anemia, fibrosis, clonal burden, leukemic transformation, or survival.
A regimen that produces more spleen responses than ruxolitinib alone is clearly more active against one manifestation of the disease. Whether it changes the natural history of MF requires a higher evidentiary threshold.
Why Combine BET and JAK Inhibition?
Pelabresib, a bromodomain and extraterminal domain (BET) inhibitor, became one of the most advanced tests of this strategy. Preclinical studies suggested that the inhibition could reduce inflammatory cytokine expression and bone marrow fibrosis while complementing JAK inhibition.
That possibility first gained meaningful clinical support in MANIFEST.
MANIFEST: The Signal That Took Pelabresib Into Phase III
MANIFEST, a multicohort phase II study, tested pelabresib across different MF settings. Its most closely watched arm, Arm 3, enrolled 84 JAK inhibitor–naïve patients on pelabresib plus ruxolitinib. The early results looked strong: 68% reached SVR35 and 56% reached TSS50 by week 24, and those responses held up over time, with SVR35 rates of 61% at week 48 and 54% at week 60.
What stood out, though, was evidence of change beyond the spleen and symptoms. On central review, bone marrow fibrosis improved by at least one grade in 31% of patients and stayed stable in another 48%. Inflammatory cytokines shifted, and JAK2V617F allele burden dropped, though not by more than what’s already been reported with ruxolitinib alone.
MANIFEST-2 Put the Combination Against Ruxolitinib
MANIFEST-2 put pelabresib to the test in a more rigorous setting. The phase III trial randomized 430 JAK inhibitor-naïve patients with MF to pelabresib plus ruxolitinib or placebo plus ruxolitinib, allowing investigators to see what pelabresib actually added to JAK inhibition.
The spleen response was clear. At week 24, 65.9% of patients on pelabresib plus ruxolitinib achieved SVR35, compared with 35.2% on ruxolitinib alone (P<0.001), an absolute difference of about 30 percentage points.
The symptom benefit was less clear. TSS50 was achieved in 52.3% with pelabresib–ruxolitinib vs 46.3%, while the difference in mean TSS change did not reach statistical significance. MANIFEST-2 therefore met its primary endpoint convincingly, but the benefit was not uniform across measures of MF response.
What Does Disease Modification Actually Mean in Myelofibrosis?
“Disease modification” gets used a lot in MF these days, but there’s no agreed-upon endpoint that actually proves a therapy has achieved it. A framework recently proposed in Cancer sets the bar higher: true disease modification should mean a meaningful effect on survival and/or restored normal blood cell production, alongside improved marrow fibrosis and a durable drop in clonal burden.
That’s what makes certain findings from combination trials worth a second look. In MANIFEST, pelabresib plus ruxolitinib showed both fibrosis improvement and JAK2V617F VAF reduction in some patients.
But none of these signals stands on its own, so the test is whether they ultimately connect to better long-term outcomes: delayed progression, less leukemic transformation, longer PFS, longer OS.
Why Longer Follow-Up Matters
The 96-week update offers a longer view. At a median follow-up of about 116 weeks, spleen responses remained durable. There were 28 vs 32 deaths and 22 vs 34 PFS events with pelabresib-ruxolitinib vs placebo-ruxolitinib, corresponding to HR of 0.986 for OS and 0.746 for PFS. However, the study was not powered for OS or PFS, and the confidence intervals remain wide, so these findings are signals rather than evidence of a survival benefit.
Leukemic transformation occurred in 5.1% vs 3.7% of patients, respectively. The earlier numerical imbalance narrowed with longer follow-up, but there is currently no evidence that pelabresib reduces leukemic progression. For now, MANIFEST-2 provides signals consistent with the possibility of disease modification
Pelabresib Is Part of a Broader Combination Strategy
Other combinations are testing this principle through different mechanisms. One example is selinexor, an XPO1 inhibitor that affects nuclear export and pathways involved in malignant cell survival and inflammatory signaling.
Phase III SENTRY randomized 353 JAK inhibitor-naïve patients to selinexor plus ruxolitinib or placebo plus ruxolitinib. At week 24, 49.8% achieved SVR35 with the combination versus 28.0% with ruxolitinib alone (P<0.0001). However, the symptom co-primary endpoint was not met, with similar TSS improvement in both groups. An early OS signal was observed (HR 0.43), but follow-up remains short and the finding should not yet be interpreted as a survival benefit.
A similar pattern has emerged in the phase III TRANSFORM-1 trial, where adding the BCL-XL/BCL-2 inhibitor navitoclax to ruxolitinib substantially increased SVR35, although symptom improvement was not significantly different between treatment groups.
Moving Beyond JAK Inhibition Does Not Mean Moving Away From It
The combination era reframes what “beyond JAK inhibition” actually means. JAK inhibition remains central. Pacritinib and momelotinib show the class itself still has room to evolve, extending coverage to thrombocytopenia and anemia. What’s shifting is the bar treatment is held to.
Early JAK inhibitor trials proved MF could be controlled without eliminating the malignant clone. Combination trials now push further, trying to make that control deeper and more durable. That’s where disease modification gets decided: not by attaching the term to a mechanism or biomarker, but by showing biological effects that actually change outcomes over time.
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