14 Practice-Changing Advances in MDS and MPN
14.1 Session Overview
| Session | Practice Changing Advances in Myelodysplastic Syndromes and Myeloproliferative Neoplasms |
| Speaker | Harinder Gill, MBBS, MD, FRCP, FRCPath |
| Affiliation | Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong |
| Time | Day 2, 4:30–5:00 p.m. |
Dr. Gill reviews four phase 3 readouts that are recalibrating frontline practice across myeloid neoplasms [slide p.1]. In lower-risk MDS, a post-hoc analysis of COMMANDS identifies the patients who benefit most from up-front luspatercept; in higher-risk MDS, the primary analysis of VERONA tempers expectations for azacitidine-based combinations [slide p.3]. On the MPN side, the VERIFY and ROP-ET trials introduce rusfertide for polycythemia vera and ropeginterferon alfa-2b for essential thrombocythemia patients ineligible for standard cytoreduction, highlighting pathway-directed agents that may alter disease biology [slide p.3].
14.2 Speaker Spotlight
Harinder Gill, MBBS, MD, FRCP, FRCPath is Clinical Associate Professor in the Department of Medicine, School of Clinical Medicine, The University of Hong Kong [slide p.1]. His clinical and research interests span the full spectrum of myeloid malignancies, with particular focus on MDS and MPN biology, molecular diagnostics, and the application of novel targeted and combination therapies to guide treatment decisions in the Asia-Pacific context.
14.3 What’s New in 2025–2026
14.3.1 MDS: Refining Up-Front Luspatercept in Lower-Risk Disease (COMMANDS Post-Hoc)
The phase 3 COMMANDS trial (NCT03682536) established luspatercept as preferred first-line therapy for ESA-naive, transfusion-dependent lower-risk MDS (LR-MDS), based on higher rates of red blood cell transfusion independence (RBC-TI) than epoetin alfa [slide p.6]. At ASH 2025, Santini and colleagues presented a post-hoc analysis (abs25-9166) asking which patients derive the greatest benefit, stratifying by baseline hemoglobin (Hb), serum erythropoietin (sEPO), and transfusion burden (TB) [slide p.5, p.7].
Eligible patients were ≥18 years old, had IPSS-R very low-, low-, or intermediate-risk MDS with or without ring sideroblasts and <5% marrow blasts, were ESA-naive with endogenous sEPO <500 U/L, and required 2–6 pRBC units every 8 weeks; patients with del(5q) were excluded [slide p.7]. Luspatercept was dosed at 1.0 mg/kg SC every 3 weeks with titration to 1.75 mg/kg, and epoetin alfa at 450 IU/kg weekly titrated up to 1050 IU/kg [slide p.7]. Post-hoc efficacy outcomes (data cutoff February 7, 2025) included RBC-TI ≥12 weeks and HI-E across Week 1–end of treatment, stratified by baseline Hb (≥8 vs <8 g/dL), sEPO (≤100, >100 to ≤200, >200 U/L), and TB (2 vs ≥4 pRBC U/8 weeks) [slide p.7].
Across every subgroup, patients with features of less advanced disease achieved higher response rates and longer response durations on luspatercept [slide p.8–10]:
| Subgroup | RBC-TI ≥12 wk (favorable stratum) | RBC-TI ≥12 wk (less favorable) | OR (95% CI) |
|---|---|---|---|
| Baseline Hb ≥8 vs <8 g/dL | 87.5% (63/72) | 69.1% (76/110) | 3.1 (1.4–7.0) [slide p.8] |
| sEPO ≤100 vs >200 U/L | 87.4% (90/103) | 54.1% (20/37) | 5.9 (2.5–14.0) [slide p.9] |
| TB 2 vs ≥4 U/8 wk | 86.4% (70/81) | 60.9% (39/64) | 4.1 (1.8–9.2) [slide p.10] |
Median duration of RBC-TI ≥12 weeks was 150.0 weeks for Hb ≥8 g/dL versus 108.3 weeks for Hb <8 g/dL (HR 0.62), and 143.3 versus 48.3 weeks for sEPO ≤100 versus >200 U/L (HR 0.41) [slide p.8–9]. HI-E rates by sEPO were particularly striking at 90.3% versus 62.2% (OR 5.7) [slide p.9]. The investigators concluded that initiating luspatercept early in the disease course—before advanced anemia, high sEPO, or heavy transfusion burden develops—may translate into deeper and more durable transfusion independence [slide p.11].
In ESA-naive LR-MDS, don’t wait for severe anemia or escalating transfusion needs. Higher baseline Hb, sEPO ≤100 U/L, and a lighter transfusion burden all predict markedly higher RBC-TI rates and response durations with luspatercept [slide p.11]. Early initiation is now supported by level 1b evidence.
14.3.2 Higher-Risk MDS: The VERONA Primary Analysis (Venetoclax + Azacitidine)
Higher-risk MDS remains an aggressive disease, with median OS of approximately 3, 1.6, and 0.8 years for intermediate-, high-, and very-high-risk patients on hypomethylating agents alone [slide p.13]. Building on a promising phase 1b signal, the phase 3 VERONA trial (NCT04401748) randomized 509 treatment-naive patients with newly diagnosed MDS (2016 WHO), IPSS-R score >3, and ECOG 0–2 to venetoclax 400 mg PO days 1–14 plus azacitidine 75 mg/m² IV/SC days 1–7 or to placebo plus azacitidine in 28-day cycles, stratified by IPSS-R, HSCT eligibility, and geographic region [slide p.13–14]. Note that venetoclax is discussed off-label in this indication [slide p.2].
Primary endpoint negative. At a median follow-up of 41.2 months, median OS was 22.2 months with Ven+Aza versus 21.7 months with Pbo+Aza (HR 0.908, 95% CI 0.733–1.126; stratified log-rank nominal P=0.38) [slide p.16]. The Kaplan-Meier curves essentially overlapped [slide p.16].
Secondary endpoints favor the combination. Modified overall response (mOR: CR + PR + mCR) was 76.2% with Ven+Aza versus 57.7% with Pbo+Aza (nominal P<0.0001), driven by higher mCR rates (57.8% vs 37.5%) [slide p.17]. RBC-TI rates among baseline transfusion-dependent patients were 55.7% (73/131) versus 33.6% (41/122), and platelet TI rates were 68.6% (24/35) versus 36.8% (14/38) [slide p.17]. More Ven+Aza patients proceeded to allogeneic HSCT (16.8% vs 13.0%) [slide p.19]. Subgroup analyses suggested mOR trends favoring Ven+Aza in patients aged <75 years, with higher blast counts, high/very-high IPSS-R, and ASXL1, TP53, or RUNX1 mutations at baseline [slide p.18, p.21].
Safety. No new safety signals were identified. Grade ≥3 neutropenia (77% vs 60%) and thrombocytopenia (66% vs 59%) were more common with Ven+Aza, as expected, while AEs leading to death occurred in 7.1% versus 8.1% [slide p.20].
VERONA is the latest in a series of phase 3 trials showing that layering novel agents onto azacitidine improves response rates without translating into an overall survival benefit [slide p.21]. Clinicians should interpret Ven+Aza in HR-MDS as a tool for maximizing response depth and bridging to transplant in selected younger, biologically aggressive patients (high blasts, high/very-high IPSS-R, adverse mutations), rather than as a universal replacement for single-agent HMA [slide p.21].
14.3.3 Polycythemia Vera: Rusfertide Durable Efficacy (VERIFY Phase 3)
Polycythemia vera is a JAK2-driven myeloproliferative neoplasm where guidelines recommend maintaining hematocrit (Hct) <45% to reduce thrombotic risk, yet frequent phlebotomy (PHL) is burdensome and often insufficient for durable Hct control [slide p.24]. Rusfertide is a first-in-class, self-administered subcutaneous peptide mimetic of hepcidin, the principal regulator of iron homeostasis [slide p.24].
The phase 3 VERIFY study (abstract presented by Kuykendall and colleagues) randomized 293 PV patients 1:1 to rusfertide plus current standard of care (CSC: phlebotomy ± cytoreductive therapy) or placebo plus CSC across a double-blind Part 1a (Weeks 0–32), followed by open-label Part 1b (Weeks 32–52) in which all patients received rusfertide, and long-term extension in Parts 2 and 3 [slide p.25, p.28].
Part 1a primary and secondary endpoints (Weeks 20–32). Rusfertide met its primary endpoint, with a clinical response (absence of PHL eligibility) in 76.9% (113/147) versus 32.9% (48/146) with placebo (P<0.0001) [slide p.26]. All four key secondary endpoints were met: fewer phlebotomies (mean 0.5 vs 1.8; P<0.0001), a higher proportion maintaining Hct <45% (62.6% vs 14.4%; P<0.0001), and statistically significant improvements in PROMIS Fatigue SF-8a and MFSAF TSS7 symptom scores [slide p.26].
Part 1b durability and placebo crossover (Weeks 32–52). Among rusfertide responders, 84.1% (95/113) maintained response through Week 52 [slide p.29]. Placebo patients who crossed over to rusfertide achieved a rapid 77.9% (109/140) response rate by Weeks 40–52—mirroring the original rusfertide arm—and hematocrit fell rapidly upon switching [slide p.28–29]. Rusfertide lowered hematocrit without exacerbating systemic iron deficiency: ferritin, serum iron, and transferrin saturation trended back toward normal ranges on treatment, and transferrin declined [slide p.30].
Safety. Most treatment-emergent adverse events were grade 1–2. Injection-site reactions were the most common (55.9% Part 1a), with grade ≥3 events uncommon (anemia, asthenia, hypertension each n=3) [slide p.31]. Serious AEs occurred in 3.4% (Part 1a) and 2.6% (Part 1b) of rusfertide-treated patients; only 2 thromboembolic events occurred across 189.6 patient-years of exposure [slide p.31]. Non-PV malignancies were infrequent and balanced between arms [slide p.32].
Based on data from the phase 2 REVIVE and phase 3 VERIFY studies, regulatory approval of rusfertide is being pursued [slide p.33].
For PV patients requiring frequent phlebotomy to maintain Hct <45%, rusfertide offers a mechanistically elegant alternative. By mimicking endogenous hepcidin, it restricts iron availability for erythropoiesis, controls hematocrit without worsening iron deficiency, and improves fatigue and MPN-related symptoms [slide p.26, p.33]. Expect this agent to enter routine practice upon approval.
14.3.4 Essential Thrombocythemia: Ropeginterferon Alfa-2b When Cytoreduction Fails (ROP-ET)
ROP-ET (NCT06514807) is an ongoing phase 3, prospective, multicenter, single-arm study of ropeginterferon alfa-2b in adults with ET (WHO 2016) who require cytoreduction but are intolerant, resistant, and/or ineligible for all locally approved cytoreductive therapies (hydroxyurea, anagrelide, busulfan, pipobroman) and are interferon alfa-naive [slide p.35]. Patients start at 125 µg SC every 2 weeks, with dose escalation to 250 µg and 500 µg for non-response and interval extension to 4 weeks permitted after month 12; total planned treatment duration is 36 months [slide p.35].
The primary endpoint was durable (≥3 months) composite hematologic and clinical response at 12 months per modified ELN criteria, requiring all of: peripheral blood count remission (platelets ≤400 × 10⁹/L and leukocytes <10 × 10⁹/L), absence of thrombotic/hemorrhagic events and disease progression, absence or non-progression of disease-related signs (splenomegaly), and symptom improvement on MPN-SAF TSS—benchmarked against a historical response rate of 40% [slide p.36].
Baseline characteristics (N=132). Median age was 56.5 years (range 22–87), 58.3% female, median platelet count 579 × 10⁹/L, and median MPN-SAF TSS 8.0 [slide p.37].
Primary endpoint met. At 12 months, 48.0% (95% CI 39.1–57.1) of patients achieved a durable response, exceeding the historical 40% benchmark [slide p.38]. Component response rates were: durable peripheral blood count remission 65.3% (77/118), absence of hemorrhagic/thrombotic events 96.2% (127/132), absence of disease progression 100% (132/132), absence or non-progression of splenomegaly 98.5% (130/132), and durable symptom improvement 84.2% (96/114) [slide p.38]. Median 2-weekly response-driven dose was 193.8 µg, indicating most patients achieved response at lower dose tiers [slide p.40].
Safety. Treatment-related AEs were mostly mild (68.9% grade 1) [slide p.38, p.39]. Grade ≥3 treatment-related AEs occurred in 5.3%, with only one serious AE (thrombocytopenia, neutropenia) and treatment-related toxicity leading to withdrawal in 2.3% [slide p.38, p.40]. The most common adverse drug reactions (≥10%) were ALT increase, headache, GGT increase, neutropenia, and pruritus (each 10.6–15.2%) [slide p.39]. Major thrombotic events occurred in 2 patients (1.5%); no major hemorrhagic events or disease progression were observed [slide p.40].
For ET patients intolerant, resistant, or ineligible for hydroxyurea, anagrelide, and other standard cytoreductives, treatment options have been limited. ROP-ET shows that ropeginterferon alfa-2b delivers a 48% durable composite response at 12 months with a favorable safety profile, positioning it as a rational salvage option in this difficult population [slide p.38, p.40].
14.4 Clinical Pearls
- Initiate luspatercept early in ESA-naive LR-MDS. COMMANDS post-hoc data show that higher baseline Hb (≥8 g/dL), lower sEPO (≤100 U/L), and a lower transfusion burden (2 U/8 wk) predict markedly higher RBC-TI rates and response durations with luspatercept, supporting earlier initiation before disease progresses [slide p.8–11].
- VERONA did not improve OS in higher-risk MDS. Venetoclax + azacitidine failed to beat azacitidine alone on the primary OS endpoint (22.2 vs 21.7 months, HR 0.908), but improved mOR (76.2% vs 57.7%), mCR, and transfusion independence [slide p.16–17]. Consider it primarily for biologically aggressive disease or as a bridge to transplant [slide p.21].
- Venetoclax in MDS is off-label. Any use of venetoclax-containing regimens in MDS must be framed as off-label and, where possible, within clinical trials [slide p.2].
- Rusfertide provides durable hematocrit control in PV. VERIFY met its primary endpoint (response 76.9% vs 32.9%) and key secondary endpoints, with durability to Week 52, rapid rescue of placebo patients on crossover, and improvements in iron parameters and symptom scores [slide p.26, p.29]. Regulatory approval is being pursued [slide p.33].
- Ropeginterferon alfa-2b fills the cytoreduction gap in ET. In ROP-ET, 48% of hydroxyurea/anagrelide-intolerant or ineligible ET patients achieved a durable composite ELN response at 12 months, with only 1.5% major thrombotic events and 5.3% grade ≥3 treatment-related AEs [slide p.38, p.40].
14.5 Key References
- Santini V, Della Porta MG, Komrokji RS, et al. Clinical benefit of luspatercept in erythropoiesis-stimulating agent-naive patients with early disease characteristics and very low-, low-, or intermediate-risk myelodysplastic syndromes: a post-hoc analysis from the COMMANDS trial. ASH 2025 abstract abs25-9166 [slide p.5].
- Della Porta MG, Garcia-Manero G, Santini V, et al. Luspatercept versus epoetin alfa in ESA-naive transfusion-dependent lower-risk MDS (COMMANDS). Lancet Haematol. 2024;11:e646–e658 [slide p.6–7].
- Garcia-Manero G, Platzbecker U, Fenaux P, et al. Subgroup analyses from the randomized phase 3 VERONA study of venetoclax with azacitidine versus placebo with azacitidine in patients with treatment-naive higher-risk myelodysplastic syndromes. ASH 2025 abstract abs25-13272 [slide p.12].
- Garcia JS, et al. Phase 1b venetoclax + azacitidine in higher-risk MDS. Blood. 2025;145:1126–1135 [slide p.13].
- Kröger N. Higher-risk MDS survival on HMAs. Haematologica. 2025;110(2):339–349 [slide p.13].
- Kuykendall AT, Bankar A, Pettit K, et al. Rusfertide or placebo plus current standard of care therapy for polycythemia vera: durability of response and safety results through Week 52 from the randomized controlled phase 3 VERIFY study. ASH 2025 [slide p.23].
- Kremyanskaya M, et al. Rusfertide in polycythemia vera (phase 2 REVIVE). N Engl J Med. 2024;390(8):723–735 [slide p.24].
- Kiladjian JJ, Al-Ali HK, Mayer J, et al. Ropeginterferon alfa-2b in essential thrombocythemia of all risk levels ineligible for standard cytoreduction: 12-month primary endpoint analysis from the ROP-ET phase 3 study. ASH 2025 abstract abs25-2199 [slide p.34].
- Kiladjian JJ, Marin FF, Al-Ali HK, et al. ROP-ET trial design rationale. Ann Hematol. 2024;103(7):2299–2310 [slide p.35].
- Yacoub A, Mascarenhas J, Kosiorek H, et al. Historical response benchmark in ET. Blood. 2019;134(18):1498–1509 [slide p.36].