Myelodysplastic Syndrome Clinical Trial Landscape

Active Phase 2 and Phase 3 recruiting trials — Myelodysplastic Syndromes

The table below reflects key recruiting and active trials on ClinicalTrials.gov for myelodysplastic syndromes as of early 2026, organized by risk category. DataLookout monitors for new registrations and status changes daily.

Sources: ClinicalTrials.gov. DataLookout monitors for new registrations and status updates daily. Table reflects recruiting and active trials as of early 2026.

MDS: a genomically complex disease with a rapidly evolving treatment landscape

Myelodysplastic syndromes represent one of the most genomically characterized hematologic malignancies, with >90% of patients harboring at least one somatic mutation identifiable by comprehensive NGS. The most commonly mutated genes — SF3B1, TET2, SRSF2, ASXL1, DNMT3A, RUNX1, TP53 — have driven a wave of molecularly targeted trials that are now producing Phase 3 results. The approval of imetelstat in June 2024 was the most significant regulatory event in lower-risk MDS in over a decade, establishing a new mechanism of action for ESA-refractory patients.

The MDS treatment paradigm bifurcates sharply by risk category. Lower-risk MDS patients (IPSS-R low, very low, intermediate) primarily suffer from symptomatic anemia requiring red blood cell transfusions, with low risk of near-term AML transformation. Treatment goals are transfusion independence (TI) and quality of life. Higher-risk MDS patients face high AML transformation rates and short survival without treatment; the goals are disease modification, AML-free survival, and bridging to allogeneic stem cell transplant for eligible patients.

Lower-risk MDS: the erythropoiesis-focused pipeline

Luspatercept (Reblozyl, BMS/Acceleron) — the COMMANDS data

Luspatercept is an activin receptor ligand trap that inhibits Smad2/3 signaling and promotes late-stage erythroid differentiation. It was approved in April 2020 for ESA-refractory anemia in adults with lower-risk MDS with ring sideroblasts (MDS-RS) or MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T). The registration trial (MEDALIST Phase 3, NCT02631070) showed TI rate at ≥8 consecutive weeks of 37.9% versus 13.2% with placebo in ESA-refractory patients.

The COMMANDS Phase 3 trial (NCT04971408) compared luspatercept head-to-head with epoetin alfa (ESA) in ESA-naive lower-risk MDS with ring sideroblasts. Results showed superiority: 58.5% TI rate with luspatercept vs. 31.2% with epoetin alfa (p<0.0001). This expanded the luspatercept indication to ESA-naive MDS-RS patients and positioned it as the preferred front-line agent in the ring sideroblast subgroup — a meaningful commercial expansion for BMS beyond the ESA-refractory niche.

Imetelstat (Rytelo, J&J/Geron) — the IMerge approval

Imetelstat received FDA approval in June 2024 for ESA-refractory transfusion-dependent anemia in lower-risk MDS — the first new MDS therapy in nearly 15 years. The approval was based on the Phase 3 IMerge trial (NCT02598661), which enrolled 178 patients with ESA-refractory lower-risk MDS (not limited to ring sideroblasts) and demonstrated a TI rate of 39.8% at ≥8 weeks versus 15.0% with placebo.

Importantly, imetelstat showed activity in patients without ring sideroblasts (who would not qualify for luspatercept under prior labeling), and it demonstrated a longer-duration TI response: 17% of imetelstat patients achieved ≥1-year TI versus 0% in the placebo arm. The mechanism — telomerase inhibition in dysplastic hematopoietic clones — is entirely distinct from ESAs, luspatercept, and hypomethylating agents, providing a rationale for use post-ESA and potentially post-luspatercept failure.

Higher-risk MDS: the venetoclax era and the Phase 3 battleground

Azacitidine + venetoclax (VERONA): the AML/MDS cross-indication thesis

The most anticipated Phase 3 result in higher-risk MDS is the VERONA trial (NCT04266795), comparing azacitidine + venetoclax versus azacitidine alone. This combination is FDA-approved in newly diagnosed AML ineligible for intensive chemotherapy (VIALE-A Phase 3: CR+CRi rate 66.4% vs. 28.3%; OS HR 0.66), generating the hypothesis that the same BCL-2 targeting strategy could benefit higher-risk MDS, where AZA monotherapy response rates (~40–50% complete or partial response) are limited and short-lived.

The biological rationale is supported by the shared dependence of dysplastic blasts on anti-apoptotic BCL-2 signaling and the high rate of gene mutations overlapping between MDS and AML (TP53, IDH1/2, RUNX1, SRSF2). If VERONA is positive, it would represent the first new regulatory approval in higher-risk MDS since azacitidine/decitabine's approvals in the mid-2000s — a transformative commercial event for AbbVie (venetoclax) and potentially repositioning higher-risk MDS treatment toward AML-like regimens.

Magrolimab (anti-CD47, ENHANCE-2): the macrophage checkpoint thesis

Magrolimab (Gilead) is a monoclonal antibody that blocks CD47 — a "don't eat me" signal on tumor cells — enabling macrophage-mediated phagocytosis of MDS blasts. The ENHANCE-2 Phase 3 trial (NCT04093570) tests magrolimab + azacitidine versus azacitidine alone in higher-risk MDS. Phase 1b data showed a complete response (CR) rate of 35% in the combination arm (with higher rates in TP53-mutant patients), motivating the Phase 3 investment. Anti-CD47 therapy in MDS is scientifically appealing because TP53-mutant MDS — the highest-risk subgroup with fewest treatment options — overexpresses CD47 and may be particularly dependent on this immune evasion mechanism.

TIM-3 targeting (sabatolimab, STIMULUS-MDS2): the innate immune checkpoint

Sabatolimab (MBG453, Novartis) targets TIM-3, an immune checkpoint expressed on T cells and, importantly, on leukemic stem cells and AML/MDS blasts. Unlike PD-1/PD-L1 checkpoint inhibitors (which have limited activity in MDS), TIM-3 targeting in MDS may work through dual mechanisms: reinvigorating anti-tumor immunity via T-cell derepression, and directly eliminating TIM-3-expressing leukemic stem cells via ADCC. The STIMULUS-MDS1 Phase 2 trial showed improved CR rates with sabatolimab + AZA versus AZA alone, motivating the Phase 3 STIMULUS-MDS2 (NCT04401748) with overall survival as a co-primary endpoint. This is one of the first Phase 3 trials of an immune checkpoint inhibitor specifically in MDS, where prior PD-1 attempts were disappointing.

Molecularly targeted strategies: IDH inhibitors and TP53-directed therapy

IDH1 (ivosidenib) and IDH2 (enasidenib) in higher-risk MDS

IDH1 and IDH2 mutations each occur in ~5–10% of MDS patients. Both enzymes are targeted by approved drugs in AML: ivosidenib (Tibsovo, Servier) for IDH1-mutant AML and enasidenib (Idhifa, BMS) for IDH2-mutant AML. The Phase 3 trials extending these approvals to IDH-mutant higher-risk MDS are underway, applying the same differentiation-inducing mechanism to MDS blasts that are IDH-mutation dependent. IDH inhibitors work by blocking the production of 2-hydroxyglutarate (2-HG), an oncometabolite that inhibits TET2 and other alpha-KG-dependent enzymes critical for normal hematopoietic differentiation.

TP53-targeted therapy: the hardest problem in MDS

TP53-mutant MDS represents the most refractory MDS subgroup — TP53 mutations (~8–10% of MDS) are associated with very short survival, high rates of AML transformation, and poor response to standard HMA-based therapy. Eprenetapopt (APR-246, Aprea Therapeutics) is a small molecule that reactivates mutant p53 to wild-type conformation; Phase 2 data with eprenetapopt + azacitidine in TP53-mutant MDS/AML showed CR rates of 36–47%, motivating the Phase 3 trial (NCT04179864). However, regulatory and competitive challenges — including a complex FDA review and competition from magrolimab's TP53-enriched signal — make this a closely watched program.

MDS and AML: the clinical trial overlap

A significant fraction of MDS clinical trials enroll MDS/AML combined populations, reflecting the biological continuum between the two diseases. MDS with excess blasts (MDS-EB, 5–20% blasts) shares genomic features with AML and is often treated on AML-like protocols. This overlap has important BD implications: drugs that succeed in AML often have MDS trials as adjacent programs, and BD teams tracking either indication should monitor the overlapping trial registrations. DataLookout's keyword matching captures this overlap by monitoring 'MDS', 'myelodysplastic', 'myeloid neoplasm', and AML-adjacent terms in trial condition fields.

Related clinical trials and monitoring resources

MDS is part of the broader hematologic malignancy landscape. DataLookout monitors related areas including:

• Blood cancer clinical trials — comprehensive hematologic oncology pipeline
• AML clinical trials — biologically adjacent to MDS; shared molecular targets and treatment strategies
• Multiple myeloma clinical trials — active Phase 3 pipeline with bispecific antibodies and CAR-T
• CLL clinical trials — BTK inhibitors, BCL-2 inhibitors; overlapping agents with MDS

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