Accepted on 09 Jun 2020
Submitted on 09 Jun 2020
Hypomethylating agents (HMA) azacitidine and decitabine are standard of care for the treatment of myelodysplastic syndromes (MDS). Although HMA have revolutionized the treatment of MDS, only approximately half of patients respond to these agents with variable duration of effect, known as primary and secondary HMA failure, respectively.
Therapeutic options following HMA failure remain limited; however, growing understanding of the pathogenesis underlying MDS has resulted in the development of multiple targeted therapies showing varying degrees of success in clinical trials.
Drugs that target molecular alterations (such as abnormal histone regulation, IDH mutations, and spliceosome gene mutations), abnormal signaling pathways (such as the multikinase inhibitor rigosertib), cellular apoptosis (such as the Bcl2 inhibitor venetoclax), and immune checkpoint inhibition are under development (Table 1). Agents recently approved for use in higher-risk acute myeloid leukemia, such as FLT3-inhibitors and CPX-351, are also being studied in MDS. Several more agents, including two first in class agents, a novel immune regulator targeting CD47, and pevonedistat, a NEDD8-activating enzyme inhibitor, are under investigation.
Table 1
Agents under active investigation in patients with myelodysplastic syndromes (MDS).
| Mechanism | Agent | NCT identifier | Phase | Relevant study population | Status |
|---|---|---|---|---|---|
| Epigenetic regulators | |||||
| Hypomethylating agents | Guadecitabine | #NCT02935361 | II | Int-1 or HR-MDS + HMAf | Recruiting |
| #NCT02131597 | II | HR-MDS | Active, not recruiting | ||
| #NCT02907359 | III | MDS + HMAf | |||
| Histone deacetylase inhibitors | Vorinostat, mocetinostat, panobinostat, etc. | No active studies in this population | |||
| Mutant IDH1/2 inhibitors | Enasidenib | #NCT03383575 | II | mIDH2 MDS +/– HMAf | Recruiting |
| #NCT03744390 | II | ||||
| Ivosidenib | #NCT02074839 | I | mIDH1 r/r MDS | ||
| #NCT03471260 | Ib/II | IDH1-mutant MDS | |||
| #NCT03503409 | II | mIDH1: HR-MDS, treatment-naïve MDS, ESA-resistant LR-MDS | |||
| LSD1 inhibitors | Tranylcypromine | #NCT02273102 | I | R/r MDS | Active, not recruiting |
| #NCT02717884 | II | Int-/HR-MDS + HMAf | Recruiting | ||
| GSK2879552 | No active studies | ||||
| Signal transduction regulators | |||||
| TGF-beta signaling modulators | Galunisertib | No active studies in this population | |||
| Sotatercept | |||||
| Luspatercept | #NCT02631070 | II | Very low, low, or int-risk MDS refractory to ESA | Active, not recruiting | |
| #NCT03682536 | III | Very low, low, or int-risk MDS in ESA-naïve | Recruiting | ||
| TLR inhibitors | Tomaralimab (OPN-305) | No active studies in this population | |||
| Multi-kinase inhibitors | Rigosertib | #NCT01926587 | I/II | Int-1, Int-2 (Int-2) or HR-MDS | Active, not recruiting |
| #NCT01904682 | II | LR or Int-1 risk-MDS | |||
| #NCT01928537 | III | MDS+excess blasts + HMAf | |||
| #NCT01241500 | III | ||||
| #NCT02562443 | III | Very high-risk MDS + HMAf | Recruiting | ||
| FLT-3 inhibitors | Midostaurin | #NCT00819546 | I | R/r MDS and AML | Active, not recruiting |
| Gilteritinib | No active studies in this population | ||||
| Sorafenib | #NCT02728050 | II | HR-MDS | Recruiting | |
| Immunotherapy | |||||
| PD-1 inhibitors | Nivolumab | #NCT02530463 | II | MDS +/– HMAf | Recruiting |
| #NCT02464657 | II | ||||
| #NCT03417154 | II | ||||
| Durvalumab | #NCT02775903 | II | Treatment naïve, HR-MDS | Active, not recruiting | |
| #NCT02281084 | II | MDS + HMAf | |||
| Pembrolizumab | #NCT02936752 | I | MDS +/– HMAf | Recruiting | |
| #NCT03094637 | II | Int-1 or HR-MDS +/– HMAf | |||
| Atezolizumab | #NCT02935361, see guadecitabine | ||||
| CTLA-4 inhibitors | Ipilimumab | #NCT02530463, see nivolumab | |||
| #NCT02890329 | I | MDS +/– HMAf | Recruiting | ||
| Anti-CD47 antibody | Hu5F9-G4 | #NCT03248479 | I | R/r and treatment-naïve MDS | Recruiting |
| Bispecific T cell engaging antibodies | MCLA-117 | No active studies in this population | |||
| AMG330 | |||||
| AMV564 | #NCT03516591 | I | Int-2 or HR-MDS with HMAf or standard AML CTX | Active, not recruiting | |
| Cell death regulators | |||||
| Bcl-2 inhibitors | Venetoclax | #NCT02966782 | I | HR-MDS + HMAf | Active, not recruiting |
| #NCT04017546 | I | MDS with ≥10% blasts | Recruiting | ||
| #NCT02942290 | I | Treatment-naïve HR-MDS | |||
| #NCT03113643 | I | HR-MDS | |||
| #NCT04160052 | I/II | HR-MDS +/– HMAf | |||
| #NCT03404193 | II | HR-MDS + HMAf | |||
| #NCT02115295 | II | MDS with ≥10% blasts | |||
| NEDD 8 activating enzyme | Pevonedistat | #NCT03772925 | I | HR-MDS + HMAf | Recruiting |
| #NCT03813147 | I | HR-MDS | |||
| #NCT03459859 | I | MDS +/– HMAf | |||
| #NCT03814005 | I | HR-MDS + HMAf | |||
| #NCT03238248 | II | MDS+ HMAf | |||
| #NCT02610777 | II | HR-MDS | Active, not recruiting | ||
| #NCT03268954 | III | HR-MDS | Recruiting | ||
| Other agents | |||||
| RNA splicing modulators | H3B-8800 | #NCT02841540 | I | HR-MDS + HMAf, LR-MDS refractory to ESA | Active, not recruiting |
| Cytotoxic agents | CPX-351 | #NCT02019069 | I | HR-MDS + HMAf | Recruiting |
| #NCT03896269 | I | ||||
| #NCT03957876 | II | MDS + HMAf | |||
| #NCT03672539 | II | HR-MDS + HMAf | |||
CTX = chemotherapy, ESA = erythropoiesis-stimulating agents, HMAf = hypomethylating agent failure, HR = high risk Int = intermediate, LR = low risk, MDS = myelodysplastic syndromes, mIDH = mutant IDH, R/r = relapsed/refractory, TLR = toll-like receptor.
In the absence of established therapeutic approaches following HMA failure, decisions in therapy should be based on the type of HMA resistance as well as the patient’s clinical and molecular characteristics. As targeted therapies continue to be developed, a comprehensive re-evaluation of the patient including the mutational profile at the time of HMA failure may reveal new treatment options. Here, emerging therapeutic approaches to HMA failure in MDS are reviewed.
