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In recent years, advances in sequencing and in our understanding of the genomic landscape of disease has advanced targeted therapeutic approaches for the highly heterogeneous group of hematopoietic stem cell disorders known as myelodysplastic syndromes (MDS).1,2 

For people with MDS, the selection of treatment strategies is dependent on risk stratification, with therapies for low-risk MDS (LR-MDS) primarily aiming to improve anemia or thrombocytopenia, decrease dependency on transfusions, improve quality of life (QoL), prolong overall survival (OS), and reduce the risk of disease progression.3 Meanwhile, treatments for high-risk MDS (HR-MDS) aim to prolong survival and reduce the risk of transformation into acute leukemia.3 

Novel approaches for low-risk MDS


In 2020, the FDA approved luspatercept, an erythroid maturation agent, for the treatment of anemia in certain adult patients with very low- to intermediate-risk MDS with ring sideroblasts (MDS-RS).4 The approval was based on data from the MEDALIST trial (NCT02631070), a randomized, multi-center, double-blind, placebo-controlled trial in 229 patients.4 

At the 2022 ASH Annual Meeting and Exposition, Uwe Platzbecker, MD, of the University of Leipzig, Leipzig, Germany, discussed the latest results of this trial. 



Highlighting the ability of luspatercept to induce transfusion independence (TI), the primary trial endpoint, it was revealed that red blood cell (RBC)-TI  ≥ 8 weeks was observed in 74/153 (48.4%) of patients treated with luspatercept and 12/76 (15.8%) of patients who received placebo during MEDALIST.5 Many patients experienced multiple distinct periods of RBC-TI ≥ 8 weeks; 52/74 (70.3%) luspatercept responders and 4/12 (33.3%) placebo responders experienced ≥ 2 episodes, with the greatest number of response periods reported in a single patient being ten with luspatercept and three with placebo.5

Commenting on the findings, Dr Platzbecker notes that, if a patient with a ring-sideroblastic phenotype on luspatercept experiences TI and then a transfusion event, “it is worth continuing the therapy in order to observe a consecutive second, third or even fourth period of TI.”

A second abstract on the MEDALIST study evaluated OS or progression-free survival (PFS), finding no significant difference between luspatercept and placebo (OS P < 0.9604 and PFS P = 0.3514).6 However, luspatercept responders were found to have statistically significantly longer OS than luspatercept non-responders at week 25 (hazard ratio 0.319; P = 0.0003).6


The Phase II IMerge trial (NCT02598661) is evaluating the investigational telomerase inhibitor imetelstat in those with RBC-TD, erythropoiesis-stimulating agents relapsed/refractory (ESA-R/R) LR-MDS. At ASH, results were shared on a subset of 38 patients who were non-del(5q) and lenalidomide/hypomethylating agent (HMA)-naïve; 11 (29%) achieved > 1-year sustained TI, ten of which had MDS-RS.7  

The median duration of sustained transfusion independence was 92.4 weeks (95% CI, 69.6-140.9).7 After a median follow-up of 51.5 months, median PFS was 34.2 months (95% CI, 25.1-39.2), median OS was 57.0 months (95% CI, 29.4 to NE), and none of the 11 patients progressed to acute myeloid leukemia (AML).7 Safety findings were consistent with those of the overall population and the most frequent adverse events were reversible thrombocytopenia and neutropenia.7 

Novel therapies for high-risk disease

Anti-CD47 antibodies – magrolimab

In this video, Naval Daver, MD, University of Texas MD Anderson Cancer Center, Houston, TX, discusses the importance of targeting CD47 in HR-MDS: “CD47 is an immune checkpoint that inhibits the macrophages… By blocking this inhibitory interaction, we release the macrophages from this dampening signal, and they are then able to attack the tumor cells, whether they are lymphoma, leukemia, or maybe even solid tumors. 

CD47 has been identified as an important therapeutic target in three disease areas; MDS, AML and lymphomas.8,9 Dr Daver explains that so far in MDS, anti-CD47 antibodies have been evaluated in single-arm studies, but a randomized Phase III study of magrolimab, the most advanced candidate, in combination with azacitidine has just finished enrollment and will hopefully confirm the importance of this target (ENHANCE; NCT04313881).  



Amer Zeidan, MBBS, Yale University and Yale Cancer Center, New Haven, CT presented results of the randomized Phase II STIMULUS-MDS1 trial (NCT03946670) in patients with HR-MDS at ASH 2022.10 The trial enrolled 127 very high, high or intermediaterisk patients with MDS to receive HMA with placebo or HMA with sabatolimab.10 Sabatolimab is a monoclonal antibody targeting the immune receptor TIM-3, expressed by both innate and adaptive immune cells, as well as hematopoietic stem cells.11 


The trial failed to meet its primary endpoints of complete remission (CR) rate and PFS; median PFS was 11.1 months in the sabatolimab group versus 8.5 months for placebo (P=0.102, 1-sided).10 Primary CR rate based on data up to seven months after the last patient’s first visit was 21.5% (14/65) versus 17.7% (11/62) respectively (P=0.769, 1-sided). Updated CR rate at primary analysis was 23.1% versus 21.0%, respectively.10 

OS was among the secondary endpoints, and was 19.0 versus 18.0 months, respectively (HR: 0.905 [95% CI: 0.565, 1.450]).10

“In terms of toxicity and safety evaluation, it was very similar to the earlier studies; we did not pick up any new signals, generally the drug was well tolerated, and immune-related adverse events were generally rare,” states Dr Zeidan. 

He goes on to suggest that, as is typical with immune therapies, when assessed with a longer duration of response there may be a delayed-onset benefit with sabatolimab, and that exploratory analyses indicate that the greatest benefit may be for those with lower disease burden (< 10% blasts) or stratified to the lower risk groups.  

The ongoing Phase III STIMULUS-MDS2 trial (NCT04266301) has completed accrual and is expected to provide definitive answers on the role of sabatolimab in MDS.10 

CAR-T therapy

There were also results from the Phase I/Ib study (NCT03927261) of PRGN-3006 UltraCAR-T in R/R AML and HMA failure HR-MDS at ASH 2022. Commenting on the study, David Sallman, MD, of the Moffitt Cancer Center, Tampa, FL, states: “Although there has been a paradigm shift in the use of CAR-T therapies for other hematological malignancies, this really has not been the case for AML. The timing of treatment, since these patients can progress rapidly, is quite critical, so rapid manufacturing as well as novel CAR-T therapy are somewhat urgently needed.” 

PRGN-3006 is a novel autologous CAR-T product expressing a CD33-CAR, membrane bound IL-15 (mbIL15) and a kill switch.12 Made in a decentralized fashion, without ex vivo expansion, this enables the patient to go from apheresis to infusion within two days, explains Dr Sallman. 

The completed Phase I dose escalation data revealed that PRGN-3006 infusion at up to 1×106 cells/kg was well tolerated, with no deaths, dose-limiting toxicities, or unexpected on-target/off-target toxicities.12 There were a few Grade 3 cytokine release syndrome (CRS) events, but they were transient.  

At data cut-off, almost a third of AML patients had responded to PRGN-3006, including one patient that had been bridged to transplant and was alive for over 18 months, and several additional patients who had achieved complete remission, though Dr Sallman notes the durability of remission remains a challenge. 

Expansion Phase Ib is now ongoing using a dose level of >3×105 but ≤106 cells/kg delivered in a two-dose regimen, where patients receive cells around day 0 and approximately two weeks later so long as there are no toxicity issues.12 

With so many novel therapies advancing through development, the future seems bright for people with both low- and high-risk MDS. However unmet need remains, and with the addition of a wider array of therapeutic options, patient selection will become an increasingly important aspect of the treatment paradigm.




  1. Gallazzi M, Ucciero MA, Faraci DG, et al. New frontiers in monoclonal antibodies for the targeted therapy of acute myeloid leukemia and myelodysplastic syndromes. International Journal of Molecular Sciences. 2022 Jul 7;23(14):7542.  
  2. Brunner AM, Leitch HA, van de Loosdrecht AA, et al. Management of patients with lower-risk myelodysplastic syndromes. Blood Cancer Journal. 2022 Dec 14;12(12).  
  3. Scalzulli E, Pepe S, Colafigli G, et al. Therapeutic strategies in low and high-risk MDS: What does the future have to offer? Blood Reviews. 2021 Jan;45:100689.  
  4. US Food and Drug Administration. FDA approves luspatercept-aamt for anemia in adults with MDS [Internet]. U.S. Food and Drug Administration.  Available from: here. (Last accessed 8/02/2023) 
  5. Platzbecker U, Santini V, Komrokji RS, et al. Multiple episodes of transfusion independence with luspatercept treatment and the impact of dose escalation in patients with lower-risk myelodysplastic syndromes from the medalist study. Blood. 2022 Nov 15;140(Supplement 1):6971–3.   
  6. Santini V, Fenaux P, Zeidan AM, et al. Overall survival and progression-free survival of patients following LUSPATERCEPT treatment in the medalist trial. Blood. 2022 Nov 15;140(Supplement 1):4079–81.  
  7. Platzbecker U, Komrokji RS, Fenaux P, et al. IMETELSTAT achieved prolonged, continuous transfusion independence (TI) in patients with heavily transfused Non-Del(5Q) lower-risk myelodysplastic syndrome (LR-MDS) relapsed/refractory (R/R) to erythropoiesis stimulating agents (esas) within the IMERGE phase 2 study. Blood. 2022 Nov 15;140(Supplement 1):1106–8.   
  8. Eladl E, Tremblay-LeMay R, Rastgoo N, et al. Role of CD47 in hematological malignancies. Journal of Hematology & Oncology. 2020 Jul 16;13(1).  
  9. Chao MP, Takimoto CH, Feng DD, et al. Therapeutic targeting of the macrophage immune checkpoint CD47 in myeloid malignancies. Frontiers in Oncology. 2020 Jan 22;9.  
  10. Zeidan AM, Ando K, Rauzy O, et al. Primary results of stimulus-MDS1: A randomized, double-blind, placebo-controlled phase II study of tim-3 inhibition with Sabatolimab added to hypomethylating agents (HMAS) in adult patients with higher-risk myelodysplastic syndromes (MDS). Blood. 2022 Nov 15;140(Supplement 1):2063–5. 
  11. Rezaei M, Tan J, Zeng C, et al. Tim-3 in leukemia; immune response and beyond. Frontiers in Oncology. 2021 Sep 30;11.  
  12. Sallman DA, Elmariah H, Sweet K, et al. Phase 1/1B safety study of PRGN-3006 ultracar-T in patients with relapsed or refractory CD33-positive acute myeloid leukemia and higher risk myelodysplastic syndromes. Blood. 2022 Nov 15;140(Supplement 1):10313–5. 
Written by Hannah Balfour
Edited by Thomas Southgate & Elitsa Kamberska

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