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Therapeutic Options in Myelodysplastic Syndromes Following Hypomethylating Agent Failure

Authors:

Abigail Belasen ,

Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
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Shyamala Navada

Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, NY
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Abstract

How to Cite: Belasen, A. and Navada, S., 2020. Therapeutic Options in Myelodysplastic Syndromes Following Hypomethylating Agent Failure. Journal of Scientific Innovation in Medicine, 3(3), p.1. DOI: http://doi.org/10.29024/jsim.62
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  Published on 17 Jul 2020
 Accepted on 09 Jun 2020            Submitted on 09 Jun 2020

Background

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.

Methods

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.

Results

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.

Conclusions

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.

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