Current State and Challenges in Development of Targeted Therapies in Myelodysplastic Syndromes (MDS)
Abstract
:1. Introduction
2. Currently Available Therapies
2.1. Low-Risk MDS
2.2. High Risk MDS
3. Emerging Therapeutics
3.1. Low Risk MDS
3.1.1. Imetelstat
3.1.2. Luspatercept
3.1.3. Roxadustat
3.1.4. New Hypomethylating Agents
3.2. High Risk MDS
3.2.1. Pevonedistat (NEDD8)
3.2.2. Immunotherapies
3.2.3. Venetoclax
3.2.4. Isocitrate Dehydrogenase (IDH) Inhibitors
3.2.5. New Hypomethylating Agents
3.2.6. Other Targeted Therapies
4. Limitations in Preclinical Models
4.1. Cell Lines
4.2. Mouse Models
Xenograft Mice
4.3. Emerging Technology and Advances
4.3.1. CRISPR/Cas9
4.3.2. Induced Pluripotent Stem Cells
4.3.3. Genetically Engineered Mice
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Drug Candidate | Design | MOA | FDA Indication | NCT # | Primary Endpoint | Approval Date | Notes |
---|---|---|---|---|---|---|---|
Lenalidomide (MDS-003) | Single-arm, open-label (phase 2) | Immuno-modulator | TDA in LR-IR Del (5q) MDS | NCT00065156 | 67% TI > 8 weeks | 28 December 2005 | Long term f/u shows TI > 8 weeks has OS benefit (4.3 vs. 2.0 years) |
Lenalidomide (MDS-004) | RCT | Immuno-modulator | TDA of LR- and IR- MDS with Del(5q) Chromosomal Abnormality | NCT00179621 | 56.1% transfusion independence > 26 weeks vs. 5.9% placebo (p < 0.001) | 28 December 2005 | Unable to assess; early crossover to lenalidomide in non-responders |
Luspatercept (MEDALIST) | RCT | TGF-ß family ligand trap | TDA in LR-MDS-RS and failed/unlikely to respond to ESA | NCT02631070 | 38% TI > 8 weeks vs. 13% placebo (p < 0.001) | 3 April 2020 | * Excluded del(5q), prior HMA, IMID * Progression to HR-MDS or AML: 5.2% in luspatercept vs. 5.3% in placebo |
Azacitidine | Randomized, parallel group,-open-label | HMA | LR/HR-MDS patients ineligible for BMT | NCT00071799 | OS 24.5 months in AZA vs. 15 months SOC (HR = 0.58, p < 0.0001) | 19 May 2004 | * Time to AML transformation: 17.8 mos AZA vs. 11.5 mos SOC * ORR: 77% AZA vs. 41% SOC |
Decitabine | Randomized, open-label | HMA | LR/HR-MDS patients ineligible for BMT | N/A | * ORR: 17% DAC vs. 0% BSC (p < 0.001) * Time to AML or death: 12.1 months DAC vs. 7.8 months BSC (p < 0.16) | 1 May 2006 | * HI: 13% DAC vs. 7% BSC (p < 0.001) * Subgroup of IPS-2/HR-MDS has time to AML/death benefit (12.0 vs. 6.8 months, p < 0.03) |
ASTX-727 (ASCERTAIN) | Randomized, open-label, crossover study | Oral DAC + Cytadine deaminase inhibitor | IR/HR-MDS | NCT03306264 | AUC of oral DAC-cedazuridine vs. IV DAC; AUC ratio of 98.9% | 7 July 2020 | * Excludes prior treatment with HMA |
Drug Candidate | Phase/Design | MOA | NCT # | Primary Endpoint | Date Complete | Status | Notes |
---|---|---|---|---|---|---|---|
Imetelstat | Phase 3 RCT | Telomerase Inhibitor | NCT02598661 | Percentage of TI during any consecutive 8-week period over 2 years | 22 August | Recruiting | Excludes ESA within 4 weeks of study entry |
Luspatercept (COMMANDS) | Phase 3 RCT | TGF-β family ligand trap | NCT03682536 | TI for 24 weeks | 22 November | Recruiting | Excludes prior ESA use, del(5q), SF3B1 subtype |
Roxadustat (MATTERHORN) | Phase 3 RCT | HIF Stabilizer | NCT03263091 | TI ≥ 56 consecutive days | 22 January | Recruiting | No restrictions on prior ESA use, excludes del(5q) |
ASTX727 | Phase 1/2 Randomizedopen-label, dose-finding | Oral HMA + Cytadine deaminase inhibitor | NCT03502668 | Normalization of baseline cytopenia | 21 December | Recruiting |
Drug Candidate | Phase + Design | MOA | Single or Combo | NCT # | Primary Endpoint | Completion Date | Status | Notes |
---|---|---|---|---|---|---|---|---|
Pevonedistat (PANTHER) | Phase 3 RCT open-label | NEDD8-i | Combo w/HMA | NCT03268954 | EFS | 22 July | Active, not recruiting | Treatment naïve HR-MDS/CMML, and low-blast AML |
Magrolimab (ENHANCE) | Phase 3 RCT | Anti-CD47 MAB | Combo w/HMA | NCT04313881 | *CR *OS | 25 February | Recruiting | Treatment naïve HR-MDS |
MBG453 (STIMULUS-MDS2) | Phase 3 RandomizedDouble-blind, active comparator | TIM-3-i | Combo w/HMA | NCT04266301 | OS | 21 August | Recruiting | HMA naïve HR-MDS/CMML |
Venetoclax (VERONA) | Phase 3 RCT active comparator | BCL2-i | Combo w/HMA | NCT04401748 | *OS *CR | 25 February | Recruiting | Treatment naïve HR-MDS |
Ivosidenib | Phase 2 Multi-cohort, open-label | IDH1-i | Single | NCT03503409 | Overall HI | 22 January | Recruiting | *Patients with IDH1-mutated MDS *Arm 1: R/R HMA *Arm 2: HMA-naïve *Arm 3: LR-MDS |
Enasidenib | Phase 2 Multi-cohort, open label | IDH2-i | Single | NCT03744390 | Overall HI | 23 February | Recruiting | *Patients with IDH2-mutated MDS *Arm 1: R/R HMA *Arm 2: HMA-naïve *Arm 3: LR-MDS |
Enasidenib | Phase 2 Non-randomized, parallel assignment | IDH2-i | Single and combo w/HMA | NCT03383575 | *Incidence of AE *ORR | 22 February | Recruiting | *Patients with IDH2-mutated MDS *Arm 1: HMA-naïve *Arm 2: HMA R/R |
ASTX030 | Multi-phase, dose-escalation followed by an open-label, randomized, crossover study | Oral AZA + Cytadine deaminase inhibitor | Single | NCT04256317 | AUC oral ASTX030 vs. SC AZA | 23 April | Recruiting | HMA naïve HR-MDS/CMML/AML |
ASTX727 | Phase 1/2a: Single arm, open label | Oral DAC + Cytadine deaminase inhibitor | Combo w/venetoclax | NCT04655755 | *Phase 1: Safety/tolerability *Phase 2: ORR | 22 July | Not yet recruiting | Treatment naïve HR-MDS/CMML |
Selinexor | Phase 2 Single arm, open label | XPO1-i | Single | NCT02228525 | ORR | 21 August | Complete | HR-MDS R/R to HMA |
APR-246 | Phase 3 Randomizedopen label, active comparator | TP53 modulator | Combo w/HMA | NCT03745716 | CR rate of APR-246 + AZA vs. AZA alone | 20 November | Active, not recruiting | HMA naïve, TP53 mutated MDS |
Rigosertib (INSPIRE) | Phase 3 Randomizedopen label, controlled study | TKI | Single | NCT02562443 | *OS *OS of IPSS-R very high-risk group | 20 December | Complete | *R/R to HMA *OS failed [64] |
Criteria Number | Guidelines for MDS in Mice |
---|---|
1 | Neutropenia, Thrombocytopenia, and Anemia found in peripheral blood without leukocytosis and erythrocytosis |
2 | Non-lymphoid hematopoietic cells showed dysgranulopoiesis, dyserythropoiesis, or dysplastic megakaryocytes with or without increased non-lymphoid immature forms or blasts |
3 | Non-lymphoid leukemia had been excluded out |
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Stanchina, M.; Chaudhry, S.; Karr, M.; Taylor, J. Current State and Challenges in Development of Targeted Therapies in Myelodysplastic Syndromes (MDS). Hemato 2021, 2, 217-236. https://doi.org/10.3390/hemato2020013
Stanchina M, Chaudhry S, Karr M, Taylor J. Current State and Challenges in Development of Targeted Therapies in Myelodysplastic Syndromes (MDS). Hemato. 2021; 2(2):217-236. https://doi.org/10.3390/hemato2020013
Chicago/Turabian StyleStanchina, Michele, Sana Chaudhry, Matthew Karr, and Justin Taylor. 2021. "Current State and Challenges in Development of Targeted Therapies in Myelodysplastic Syndromes (MDS)" Hemato 2, no. 2: 217-236. https://doi.org/10.3390/hemato2020013
APA StyleStanchina, M., Chaudhry, S., Karr, M., & Taylor, J. (2021). Current State and Challenges in Development of Targeted Therapies in Myelodysplastic Syndromes (MDS). Hemato, 2(2), 217-236. https://doi.org/10.3390/hemato2020013