flowchart LR
A[TGF-β Ligands] --> B[Luspatercept]
B --> C[Reduced Smad2/3 Signaling]
C --> D[Enhanced Late-Stage Erythropoiesis]
D --> E[Improved RBC Maturation]
8 Anemia in MF
8.1 Momelotinib
8.2 Luspatercept
A recombinant fusion protein that acts as a transforming growth factor beta (TGF-β) trap and ultimately works to improve anemia by inhibiting growth differentiation factor 11 (GDF11).
GDF11 is a key inhibitor of late-stage erythroid differentiation, which has been shown to be upregulated in MDS and MF patients
8.2.1 INDEPENCE Trial
The INDEPENDENCE trial (NCT04717414) evaluated luspatercept, a first-in-class erythroid maturation agent, for the treatment of anemia in patients with myelofibrosis (MF) receiving concomitant JAK inhibitor therapy. The trial did not meet its primary endpoint (p = 0.0674), though several secondary endpoints demonstrated clinically meaningful benefits. This review critically examines the trial design, results, and implications for clinical practice.
ImportantKey Finding
Primary endpoint missed statistical significance by a narrow margin, raising important questions about endpoint selection, sample size, and the heterogeneity of MF-associated anemia.
8.2.1.1 Trial Overview
8.2.2 Background and Rationale
Anemia represents one of the most challenging aspects of myelofibrosis management, affecting approximately 50% of patients at diagnosis and nearly all patients during disease progression. The pathophysiology is multifactorial:
| Contributing Factor | Mechanism | Clinical Impact |
|---|---|---|
| Bone marrow fibrosis | Replacement of hematopoietic tissue | Progressive decline in RBC production |
| Ineffective erythropoiesis | Dysregulated TGF-β signaling | Premature erythroid precursor apoptosis |
| Hypersplenism | Splenic sequestration | Shortened RBC survival |
| JAK inhibitor therapy | Suppression of JAK-STAT signaling | Treatment-induced anemia |
| Chronic inflammation | Elevated hepcidin levels | Iron sequestration |
8.2.3 Drug Mechanism
Luspatercept (ACE-536) is a recombinant fusion protein that acts as a ligand trap for select TGF-β superfamily members:
8.2.3.1 Trial Design
8.2.4 Study Structure
| Parameter | Specification |
|---|---|
| ClinicalTrials.gov ID | NCT04717414 |
| Phase | 3 |
| Design | Randomized, double-blind, placebo-controlled |
| Sponsor | Bristol Myers Squibb (with Merck collaboration) |
| Enrollment | ~313 patients |
| Treatment Arms | Luspatercept vs. Placebo |
| Concomitant Therapy | Stable JAK2 inhibitor (required) |
8.2.5 Key Eligibility Criteria
8.2.5.1 Inclusion Criteria
| Criterion | Specification | Rationale |
|---|---|---|
| Age | ≥18 years | Standard adult population |
| Diagnosis | MPN-associated myelofibrosis | Target population |
| JAK2i therapy | ≥32 weeks total, ≥16 weeks stable dose | Ensure stable background therapy |
| Transfusion burden | 4–12 RBC units per 12 weeks | Clinically meaningful anemia |
| ECOG PS | ≤2 | Adequate functional status |
8.2.5.2 Exclusion Criteria
| Criterion | Rationale |
|---|---|
| Anemia from other identifiable causes | Isolate MF-specific anemia |
| Hematopoietic agents within 8 weeks | Avoid confounding |
| Prior luspatercept exposure | Treatment-naive population |
| Active malignancy | Safety consideration |
8.2.6 Endpoints
| Endpoint Type | Definition | Timeframe |
|---|---|---|
| Primary | RBC transfusion independence (RBC-TI) for any consecutive 12-week period | Within first 24 weeks |
| Key Secondary | RBC-TI for any consecutive 16-week period | Within first 24 weeks |
| Secondary | ≥50% reduction in RBC transfusion burden (by ≥4 units) | Weeks 1–24 |
| Secondary | Hemoglobin increase ≥1 g/dL with RBC-TI ≥12 weeks | During treatment |
| Exploratory | Duration of response, quality of life | Long-term follow-up |
8.2.6.1 Results
8.2.7 Primary Endpoint Analysis
WarningStatistical Outcome
p = 0.0674 — The trial did not achieve statistical significance at α = 0.05
| Outcome | Luspatercept | Placebo | Difference |
|---|---|---|---|
| 12-week RBC-TI | Higher (exact % pending full publication) | Lower | Numerical improvement |
| Statistical significance | — | — | p = 0.0674 (NS) |
8.2.8 Secondary Endpoints
| Endpoint | Luspatercept | Placebo | Clinical Interpretation |
|---|---|---|---|
| ≥50% transfusion burden reduction | Higher proportion | Lower | Clinically meaningful benefit |
| Hgb increase ≥1 g/dL + TI ≥12 weeks | Higher proportion | Lower | Clinically meaningful benefit |
| 16-week RBC-TI | Pending | Pending | Key secondary endpoint |
8.2.9 Safety Profile
| Adverse Event Category | Observation |
|---|---|
| Treatment-emergent AEs | Consistent with known luspatercept profile |
| Serious AEs | Similar between arms |
| Discontinuation rate | Not elevated vs. placebo |
8.2.9.1 Critical Analysis
8.2.10 Strengths
| Strength | Significance |
|---|---|
| Rigorous design | Double-blind, placebo-controlled eliminates bias |
| Clinically relevant population | Patients on stable JAKi with meaningful transfusion burden |
| Novel mechanism | First TGF-β ligand trap in MF anemia |
| Secondary endpoint success | Multiple clinically meaningful benefits demonstrated |
| Consistent with Phase 2 | Results align with prior 26–27% RBC-TI rates |
8.2.11 Limitations and Concerns
| Limitation | Critical Assessment |
|---|---|
| Narrow miss on primary endpoint | p = 0.0674 suggests potential underpowering or endpoint stringency |
| 12-week TI threshold | Binary endpoint may not capture clinically meaningful partial responses |
| Heterogeneous population | MF anemia etiology varies; subgroups may respond differently |
| Concomitant JAKi variability | Different JAK inhibitors may interact differently with luspatercept |
| No head-to-head comparison | Cannot directly compare to momelotinib’s anemia benefits |
8.2.12 Statistical Considerations
Code
# Hypothetical power analysis illustration
# Given p = 0.0674, exploring what would achieve significance
library(pwr)
# If observed effect size was d = 0.25 (small-medium)
# With n = 156 per arm (313 total)
power_observed <- pwr.t.test(n = 156, d = 0.25, sig.level = 0.05, type = "two.sample")
# To achieve 80% power at observed effect size
n_needed <- pwr.t.test(d = 0.25, sig.level = 0.05, power = 0.80, type = "two.sample")| Statistical Parameter | Consideration |
|---|---|
| Sample size | ~313 patients may have been marginally underpowered |
| Effect size | Smaller than anticipated from Phase 2 |
| Alpha threshold | Traditional α = 0.05 may be arbitrary for this context |
| Multiple testing | Hierarchical testing preserved type I error control |
8.2.12.1 Comparison with Competing Approaches
8.2.13 Anemia-Targeting Therapies in MF
| Agent | Mechanism | Key Advantage | Key Limitation |
|---|---|---|---|
| Momelotinib | JAK1/2 + ACVR1 inhibition | Hepcidin suppression + JAKi effects | Integrated therapy only |
| Pacritinib | JAK2 + ACVR1 inhibition | Use in severe thrombocytopenia | Limited anemia data |
| Luspatercept | TGF-β ligand trap | Novel mechanism, add-on therapy | Primary endpoint missed |
| Danazol | Androgenic steroid | Long clinical experience | Variable response, virilization |
| ESAs | Erythropoietin stimulation | Well-established | Poor response in MF |
8.2.14 Mechanistic Differentiation
| Feature | Luspatercept | Momelotinib |
|---|---|---|
| Primary target | TGF-β superfamily ligands | ACVR1 (ALK2) + JAK1/2 |
| Downstream effect | Smad2/3 inhibition | Hepcidin suppression |
| Stage of erythropoiesis affected | Late-stage maturation | Iron availability |
| Use context | Add-on to JAKi | Replacement JAKi |
| Regulatory status (MF) | Investigational | FDA approved (2023) |
8.2.14.1 Clinical Implications
8.2.15 For Current Practice
NoteClinical Takeaway
While INDEPENDENCE did not achieve its primary endpoint, the totality of evidence suggests luspatercept provides clinically meaningful anemia benefits in a subset of MF patients.
| Scenario | Recommendation |
|---|---|
| JAKi-treated MF with moderate anemia | Consider momelotinib switch or await regulatory decision on luspatercept |
| Patients preferring add-on therapy | Luspatercept may offer value if approved |
| Severe thrombocytopenia with anemia | Pacritinib remains preferred |
8.2.16 Regulatory Outlook
| Factor | Assessment |
|---|---|
| Primary endpoint | Not met (negative for traditional approval pathway) |
| Secondary endpoints | Multiple clinically meaningful benefits |
| Unmet need | Substantial — few effective anemia therapies |
| Safety | Favorable, consistent with prior experience |
| Potential pathway | Possible accelerated approval or expanded indication |
8.2.16.1 Future Directions
8.2.17 Ongoing and Planned Studies
| Study | Design | Population | Status |
|---|---|---|---|
| ODYSSEY | Phase 2, luspatercept + momelotinib | Transfusion-dependent MF | Ongoing |
| Biomarker analyses | Post-hoc from INDEPENDENCE | Responder identification | Planned |
8.2.18 Unanswered Questions
- Can biomarkers identify optimal responders?
- TGF-β pathway activation markers
- Baseline erythroid precursor characteristics
- Is combination with momelotinib synergistic?
- Dual targeting of ineffective erythropoiesis and iron restriction
- Does longer treatment duration improve TI rates?
- 24-week assessment may be premature for some patients
- Are there differences by JAK inhibitor backbone?
- Ruxolitinib vs. fedratinib vs. pacritinib
8.2.18.1 Conclusions
| Aspect | Assessment |
|---|---|
| Trial execution | Well-designed and rigorously conducted |
| Primary endpoint | Missed statistical significance (p = 0.0674) |
| Clinical relevance | Secondary endpoints show meaningful benefit |
| Place in therapy | Uncertain pending regulatory decisions |
| Unmet need addressed | Partially — options for MF anemia remain limited |
TipBottom Line
The INDEPENDENCE trial represents a near-miss that highlights the challenges of developing therapies for the heterogeneous syndrome of MF-associated anemia. While the primary endpoint was not achieved, the consistent signal of clinical benefit across secondary endpoints suggests luspatercept may yet find a role in selected patients. Future research should focus on identifying predictive biomarkers and exploring rational combinations.
8.2.18.2 References
Abdelmagid, Maymona, Jeanne M. Palmer, Aref Al-Kali, et al. 2025.
“Predictors of Response to Pacritinib Therapy and Survival Among
60 Mayo Clinic Patients with Myelofibrosis Treated Outside of Clinical
Trials.” Haematologica, ahead of print, March 20. https://doi.org/10.3324/haematol.2025.287576.
Chen, Lijuan, Yongsheng Wang, Jie Wang, Linyu Yang, and Ting Niu. 2024.
“First-in-Human Phase i/IIa Safety and Efficacy of Flonoltinib
Maleate, a New Generation of JAK2/FLT3 Inhibitor in
Myelofibrosis.” Blood 144 (Supplement 1): 486–86. https://doi.org/10.1182/blood-2024-210674.
Hernandez-Boluda, Juan Carlos, Adrian Mosquera Orgueira, Luuk Gras, et
al. 2025. “Use of Machine Learning Techniques to Predict Poor
Survival After Hematopoietic Cell Transplantation for
Myelofibrosis.” Blood Journal, ahead of print, March 27.
https://doi.org/10.1182/blood.2024027287.
Knuth, Donald E. 1984. “Literate Programming.” Comput.
J. (USA) 27 (2): 97–111. https://doi.org/10.1093/comjnl/27.2.97.
Srisuwananukorn, Andrew, Giuseppe Gaetano Loscocco, Andrew T.
Kuykendall, et al. 2023. “Interpretable Artificial Intelligence
(AI) Differentiates Prefibrotic Primary Myelofibrosis (prePMF) from
Essential Thrombocythemia (ET): A Multi-Center Study of a New Clinical
Decision Support Tool.” Blood 142 (Supplement 1): 901–1.
https://doi.org/10.1182/blood-2023-173877.
8.2.19 Key Sources
- Bristol Myers Squibb Press Release. July 18, 2025. INDEPENDENCE Trial Topline Results.
- ClinicalTrials.gov: NCT04717414
- Gerds AT, et al. ASCO 2023. Phase 2 luspatercept in MF (NCT03194542).
- Chifotides HT, et al. Curr Hematol Malig Rep. 2025. Emerging Therapeutic Approaches for Anemia in Myelofibrosis. DOI: 10.1007/s11899-025-00751-4
8.3 DISC-0974
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- DISC-0974 is a monoclonal antibody that binds to hemojuvelin and blocks bone morphogenetic protein signaling, thereby suppressing hepcidin production.
- Pathologic elevations in hepcidin, a key regulator of iron homeostasis, contribute to anemia of inflammation in chronic disease.
- Chronic hepcidin elevation limits iron availability for red blood cell production and contributes to onset and severity of anemia
8.3.1 ASH 2024
N= 34
Enrolled at 5 dose levels: 14 mg (n=1), 28 mg (n=7), 50 mg (n=12), 75 mg (n=8), and 100 mg (n=6).
Hemoglobin responses were achieved in 69% (20/29) of nTD participants; 60% of nTD participants (9/15) achieved a durable response.
One of two evaluable TD participants achieved TI at the end of study. All evaluable participants with a baseline transfusion requirement (n=8) had ≥50% reduction in transfusions over a rolling 8-week window compared to baseline.
Hematologic response was observed in 6 of 10 participants with concomitant JAK inhibitor therapy.
8.3.2 Phase 2 Study (ASC0 2026 Abstract)
RALLY-MF (NCT05320198)
Per [[sources/gangat-2026-disc-0974-rally-mf-asco-abstract|Gangat 2026 ASCO Abstract #6501]] (Oral; data cutoff 16 Oct 2025):
8.3.2.1 Design
- Phase 2, open-label, multi-center US.
- Eligibility: adults with primary or secondary MF + Hgb <10 g/dL OR RBC transfusion requirement.
- Concomitant JAKi allowed (stable dose) — 53% of cohort.
- Dose: 50 mg SC monthly up to 6 doses; escalate to 75 mg SC for inadequate/lost response.
- n=47 across 3 transfusion-burden cohorts.
8.3.2.2 Cohorts + primary endpoints — ALL MET
| Cohort | n | Primary endpoint | Result |
|---|---|---|---|
| nTD (0 units, Hgb <10) | 30 | Hgb ≥1.5 g/dL increase ≥12 wks | 50% |
| TD low (1-2 units) | 10 | Transfusion independence ≥16 wks | 71% |
| TD high (3-12 units) | 7 | ≥50% transfusion reduction | 67% |
8.3.2.3 Concomitant JAKi-stratified efficacy
- Major hematologic response 50% ON concomitant JAKi (n=18).
- Major hematologic response 50% OFF JAKi (n=16).
- Equivalent response on either backbone — confirms DISC-0974 works as monotherapy AND as add-on.
8.3.2.4 Patient-reported outcomes
- Meaningful FACIT-Fatigue improvements in nTD + TD-low.
8.3.2.5 Safety
- SAEs n=9; ≥G3 AEs n=16 — ALL considered unrelated to DISC-0974.
- No early withdrawals due to AEs.
- “Well tolerated; favorable safety profile.”
8.3.2.6 Dosing
- 50 mg SC monthly — convenient outpatient schedule.
- Escalate to 75 mg SC for inadequate or lost response.
- Up to 6 doses in RALLY-MF; long-term chronic dosing presumed for future development.
8.3.2.7 Toxicity
Per RALLY-MF preliminary readout:
- No drug-related SAEs at data cutoff.
- No drug-related ≥G3 AEs at data cutoff.
- No AE-related discontinuations.
- Theoretical concerns (not observed at data cutoff but worth monitoring):
- Iron overload from chronic hepcidin suppression (hepatic / cardiac).
- Anti-drug antibody (ADA) development.
- Anaphylactic / hypersensitivity reactions to chronic SC mAb.
- Hypophosphatemia (HJV blockade may indirectly affect FGF23/phosphate handling — speculative).
8.4 DISC-0998
- Anti-HJV monoclonal antibody
- Extended half-life
- Being studies in Anemia Associated with Inflammatory Diseases