Myelodysplastic Syndromes in the Postgenomic Era and Future Perspectives for Precision Medicine
Abstract
:Simple Summary
Abstract
1. Epidemiology
2. Pathophysiology
2.1. Recurrent Somatic Leukemia-Associated Driver Mutations and Clonal Hematopoiesis
2.2. The Role of Adaptive and Innate Immunity in MDS
3. General Aspects of MDS Patient Management
4. Diagnostic Approach and Risk-Stratification
4.1. WHO Classification and Minimal Diagnostic Criteria for MDS
4.2. Role of NGS in MDS Diagnosis, Follow-Up and Risk-Stratification
4.3. Hypoplastic MDS and Aplastic Anemia
4.4. Disease-Based Risk Stratification
4.5. Patient-Based Risk Stratification
4.6. Patient-Reported Outcomes (PROs)
5. Therapeutic Approach
5.1. Lower-Risk MDS Patients
5.1.1. Watchful Observation and General Supportive Treatment
5.1.2. Treatment of Anemia
5.1.3. Treatment of Thrombocytopenia
5.1.4. Treatment of Neutropenia and Infection Prophylaxis
5.1.5. Disease Modifying Treatments in Specific Subsets of Lower-Risk MDS
5.1.6. Hypomethylating Agents
5.2. Higher-Risk MDS Patients
5.2.1. Hypomethylating Agents
5.2.2. Induction Chemotherapy
5.2.3. Allogeneic Hematopoietic Stem Cell Transplantation
6. Ongoing Clinical Trials with Targeting Compounds
6.1. Lower-Risk MDS
6.2. Higher-Risk MDS
7. Future Perspectives for Precision Medicine
7.1. Clinical Management Using Guideline-Based Indicators (GBIs)
7.2. Diagnosis and Risk-Assessment
7.3. Patient Selection for Targeted Therapies
7.4. Understanding Clonal Heterogeneity at Single Cell Resolution
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
ACMG | American College of Medical Genetics |
Allo-HCT | Allogeneic hematopoietic stem cell transplantation |
ARCH | Age-related clonal hematopoiesis |
ATG | Antithymocyte globulin |
AML | Acute myeloid leukemia |
BM | Bone marrow |
CCUS | Clonal cytopenia of undetermined significance |
CGH | Comparative Genomic Hybridization |
CHIP | Clonal hematopoiesis of indeterminate potential |
CsA | Cyclosporine A |
EMA | Erythroid Maturation Agents |
EPO | Erythropoietin |
ESA | Erythropoietin Stimulating Agents |
FISH | Fluorescent in situ hybridization |
GBIs | Guideline-based indicators |
G-CSF | Granulocyte Colony-Stimulating Factor |
G/Rs | Guidelines and recommendations |
HCT-CI | Hematopoietic Cell Transplantation Comorbidity Index |
HI | Hematological improvement |
HMA | Hypomethylating agents |
HSPC | Hematopoietic stem and progenitor cells |
HU | Hydroxyurea |
ICI | Immune checkpoint inhibitor |
ICUS | Idiopathic cytopenia of undetermined significance |
IDUS | Idiopathic dysplasia of undetermined significance |
IP | Immunophenotyping |
IPSS | International Prognostic Scoring System |
IPSS-R | Revised International Prognostic Scoring System |
IST | Immunosuppressive treatment |
LD-AraC | Low-dose cytarabine |
LEN | Lenalidomid |
LUSPA | Luspatercept |
MDS | Myelodysplastic syndromes |
MRD | Measurable residual disease |
NGS | Next generation sequencing |
OS | Overall survival |
PB | Peripheral blood |
RBC | Red blood cell concentrates |
sAML | Secondary AML |
SLADMs | Somatic leukemia-associated driver mutations |
TC | Thrombocyte concentrates |
TLR | Toll-like receptor |
TPO-RA | Thrombopoietin receptor agonists |
QoL | Quality of life |
VAF | Variant allele frequency |
WHO | World Health Organization |
WPSS | WHO Prognostic Scoring System |
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Class | Gene | Approx. Frequency (%) |
---|---|---|
RNA-splicing factors | SF3B1 * | 25–30 |
SRSF2 | 10–15 | |
U2AF1 | 5–10 | |
ZRSR2 | 5 | |
SF3A1 | 1–2 | |
SF1 | 1–2 | |
U2AF65 | 1–2 | |
PRPF40B | 1–2 | |
Epigenetic regulators | TET2 | 20–25 |
DNMT3A | 15 | |
ASXL1 | 10–15 | |
EZH2 | 5 | |
IDH1 | 1–2 | |
IDH2 | 1–2 | |
Transcription factors | RUNX1♯ | 10–20 |
SETBP1 | 1–2 | |
ETV6♯ | 2 | |
CEBPA♯ | 1–2 | |
GATA2♯ | 1–2 | |
Cell-cycle regulators | TP53 | 5–10 |
PTEN | 1 | |
Cohesin complex factors | STAG1 | 1 |
STAG2 | 6 | |
RAD21 | 1 | |
Cell-signaling molecules | NRAS/KRAS | 5–10 |
NPM1 | 1–2 | |
JAK2 | 1–2 | |
FLT3 | 2 | |
CBL | 1–2 |
|
|
|
|
If relevant cytopenia in PB is present, consider CCUS (minimal diagnostic criteria for MDS are not fulfilled) or MDS (minimal diagnostic criteria are fulfilled). Annual risk of progression to hematologic neoplasm: 0.5–1% |
CHIP [20,21,22] | AA [25,26] | CCUS | MDS [10,11] | |
---|---|---|---|---|
Frequency | ~2% (40–49 years) ~3% (50–59 years) ~6% (60–69 years) ~10% (70–79 years) ~15% (80–89 years) | 19–47% (median age 44 years) | 35% of ICUS | 70–80% (median age 72 years) |
Most common mutations | DNMT3A, TET2, ASXL1, JAK2 | Younger patients: PIGA BCOR/BCORL1 Older patients: DNMT3A, ASXL1 | TET2, DNMT3A, ASXL1, TP53 | SF3B1, TET2, ASXL1, DNMT3A, SRSF2, RUNX1 |
Prognosis | Increased risk for hematological neoplasm, coronary heart disease, ischemic stroke, diabetes mellitus type 2 | Good prognosis: PIGA, BCOR/BCORL1 Poor prognosis: ASXL1, DNMT3A | Increased risk for MDS/AML | Good prognosis: SF3B1 Poor prognosis: TP53, ASXL1, RUNX1, ETV6, EZH2 Neutral: all others |
Mean VAF (%) | 9% | 20% (10% in 40% of patients) | 30% | 30% |
Mean number of mutations per patient | 1 (93% of individuals) | 1 (64–90% of patients) | 1 | 3 (range 0–12) |
Subtype 1 | Number of Dysplastic Lineages | Number of Cytopenic Lineages 2 | % RS of All Erythroid Cells in BM | % Blasts in PB or BM AR: Auer Rods | Conventional Cytogenetics | |||
---|---|---|---|---|---|---|---|---|
wtSF3B1 | mSF3B1 | BM | PB | AR | ||||
MDS-SLD | 1 | 1 or 2 | 15 | 5 | 5 | 1 | - | |
MDS-MLD | 2 or 3 | 1–3 | 15 | 5 | 5 | 1 | - | |
MDS-RS-SLD | 1 | 1 or 2 | ≥15 | ≥5 | 5 | 1 | - | |
MDS-RS-MLD | 2 or 3 | 1–3 | ≥15 | ≥5 | 5 | 1 | - | |
MDS del(5q) | 1–3 | 1 or 2 | n.a. | n.a. | 5 | 1 | - | Isolated del(5q) with or without one additional cytogenetic aberration without del(7) or −7 |
MDS-EB-1 | 0–3 | 1–3 | n.a. | n.a. | 5–9 | 2–4 | - | |
MDS-EB-2 | 0–3 | 1–3 | n.a. | n.a. | 10–19 | 5–19 | + | |
MDS-U | 15 | 5 | 5 | 1 | - | |||
(a) 1% blasts in PB | 1–3 | 1–3 | n.a. | n.a. | 5 | 1 3 | - | |
(b) SLD with pancytopenia | 1 | 3 | n.a. | n.a. | 5 | 1 | - | |
(c) defining cytogenetic aberration | 0 | 1–3 | 15 4 | n.a. | 5 | 1 | - | MDS defining cytogenetic aberration |
RCC | 1–3 | 1–3 | 15 | ≤5 | 5 | 1 | - |
Peripheral Blood |
|
|
Bone marrow |
|
|
Criteria | Diagnostic Test |
---|---|
1. Mandatory criteria (both have to be fulfilled) | |
Persistent cytopenia(s) for more than 4 months * | PB counts and morphological assessment |
Exclusion of other disease(s) that may cause cytopenia/dysplasia | BM aspirate and biopsy, cytogenetics, flow cytometry, molecular genetics, other relevant investigations ** |
2. MDS-defining criteria (at least one has to be fulfilled) | |
Morphological criteria of dysplasia 10% in at least one cell lineages investigated in the BM | PB, BM aspirate and biopsy |
Blasts 5–19% in BM or 2–19% in PB | PB, BM aspirate and biopsy |
Ring sideroblasts ≥15% or ≥5% with SF3B1 mutation | Iron staining, sequencing |
MDS-defining cytogenetic alterations *** | Conventional metaphase cytogenetics, interphase fluorescence in situ hybridization, array comparative genomic hybridization |
3. Co-criteria (for patients with 1. but not 2., two have to be fulfilled) | |
Abnormal findings in histologic and/or immunohistochemical studies of supporting the diagnosis of MDS **** | BM biopsy sections with immunohistochemistry |
Abnormal immunophenotype of BM cells with aberrant immunophenotype indicative for a monoclonal population | Flow cytometry |
Clonality of myeloid cells revealing MDS-related mutations | Molecular genetics, next generation sequencing |
Requisite Criteria | Score |
---|---|
BM blasts AND/OR CD34+ cells ≥5% | 2 |
BM blasts AND/OR CD34+ cells 2–4% | 1 |
Fibrosis grade 2–3 | 1 |
Dysmegakaryopoiesis | 1 |
Co-criteria | |
Ring sideroblasts ≥15% | 2 |
Ring sideroblasts 5–14% * | 1 |
Severe dysgranulopoiesis | 1 |
Karyotype (co-criterion) | |
Presumptive cytogenetic abnormality * | 2 |
Somatic mutation (co-criterion) | |
Specific high-risk mutation pattern ** | 1 |
Compound | Study Design | Efficacy * | Safety * | NCT |
---|---|---|---|---|
Erythropoiesis maturating agents | ||||
TGFβi luspatercept | Phase 3 (ongoing), open-label, randomized study: efficacy and safety of luspatercept (ACE-536) versus epoetin alpha for the treatment of anemia due to IPSS-R very low, low or intermediate risk according to IPSS-R MDS in ESA naïve subjects requiring red blood transfusions (COMMANDS) | ongoing 38% vs. 13% TI for 8 weeks or longer | AE:
| NCT03682536 [125] |
Hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHi) | ||||
roxadustat (FG-4592) | Phase 3, randomized double-blind placebo-controlled study investigating the efficacy and safety of roxadustat (FG-4592) for treatment of anemia in patients with lower risk MDS with low RBC transfusion burden | ongoing | ongoing | NCT03263091 [127] |
Telomerase inhibitor | ||||
imetelstat | Phase 2/3 (phase 3 part ongoing), double-blind, randomized study to evaluate imetelstat (GRN163L) versus placebo in transfusion-dependent subjects with IPSS low or intermediate-1 risk MDS that is relapsed/refractory to ESA treatment (IMERGE) | TI in 8- and 24-week: 37%, respectively 23%, median duration of 65 weeks phase 3 ongoing | AE:
| NCT02598661 [133] |
Spliceosome modulators | ||||
H3B-8800 | Phase 1 (ongoing), open-label trial to evaluate the safety, pharmacokinetics and pharmacodynamics of splicing modulator H3B-8800 for subjects with MDS, AML and CMML | decreased RBC or TC requirement in 14% | AE:
| NCT02841540 [135,136] |
DNA-methylation | ||||
guadecitabine (SGI-110) | Phase 1/2, dose escalation, dose escalation, randomized study of two regimens of SGI-110, in subjects with intermediate or high-risk MDS or AML | ORR 40% with 60 mg/m2 d1-d5 q28d ORR 55% with 90 mg/m2 d1-d5 q28d | AE:
| NCT01261312 [112] |
guadecitabine (SGI-110) | Phase 3, randomized, open-label study of SGI-110 versus treatment choice in adults with MDS or CMML previously treated with hypomethylating agents | primary endpoint (OS): no statistically significant improvement secondary endpoints: analysis ongoing | comparable to previous studies | NCT02907359 [138] |
oral AZA/ cedazuridine (CDZ) (ASTX030) | Phase1 (ongoing), multi-phase, dose-escalation followed by an open-label, randomized, crossover study of oral ASTX030 versus subcutaneous azacytidine in subjects with MDS, CMML or AML | parenteral and oral AZA + CDZ similar pharmacokinetic profiles and efficacy against human AML cells | n.a. | NCT04256317 [139] |
oral DEC/CDZ (ASTX727) | Phase1/2 pharmacokinetic guided dose-escalation and dose-confirmation study of ASTX727 (oral cytidine deaminase inhibitor E7727 with oral decitabine) in subjects with MDS | no difference in pharmakokinetics, pharmacodynamics and efficacy between p.o. and i.v. formulations | similar between p.o. und i.v. | NCT02103478 [112] |
Immune checkpoint inhibitors | ||||
CD47-Ab magrolimab | Phase 1b Trial of magrolimab monotherapy versus in combination with azacytidine in patients with hematological malignancies | TI: 58% (MDS), 64% (AML) objective response (CR, marrow CR, HI): 91% (MDS) | AE:
| NCT03248479 [142] |
TIM3-Ab sabatolimab (MBG453) | Phase 1b, multi-arm, open-label study of PDR001 and/or MBG453 in combination with decitabine in patients with AML or high risk MDS | AML: ORR 41.2% MDS: ORR 62.9% | AE: Grad 3/4 (AML/MDS):
| NCT03066648 [143] |
Proapoptotic agents | ||||
BCL-2i venetoclax + AZA | Phase 1b/2 (ongoing), dose escalation study evaluating the safety and pharmacokinetics of venetoclax in combination with azacytidine in subjects with treatment-naïve higher-risk MDS | 18 months: OS 74%, HI 50% | AE, grade 3/4:
| NCT02942290 [147] |
BCL-2iv enetoclax + AZA | Phase 1b study (ongoing) evaluating the safety and pharmacokinetics of venetoclax as a single-agent and in combination with azacytidine in subjects with relapsed/refractory MDS | median FU 4.7 months:
| Grade 3/4:
| NCT02966782 [148] |
NEDD8i pevonedistat | Phase 2, randomized, controlled, open-label, study of the efficacy and safety of pevonedistat plus azacytidine versus single-agent azacytidine in patients with higher-risk MDS, CMML and low-blast AML | Combination vs. single-arm
| Grade 3/4 adverse events similar (69% vs. 63% in single-arm)
| NCT02610777 [149] |
NEDD8i pevonedistat | Phase 3, randomized, controlled, open-label, study of pevonedistat plus azacytidine versus single-agent azacytidine as first-line treatment for patients with Higher-Risk MDS, CMML or low-blast AML (PANTHER) | ongoing | ongoing | NCT03268954 [150] |
TP53 reconforming agents | ||||
eprenetapopt (APR-246) | Phase 1b/2 (ongoing) study to evaluate the safety and efficacy of APR-246 in combination with azacytidine for the treatment of TP53 mutant myeloid neoplasms | ongoing | Grade 3/4 (phase 1b):
| NCT03588078 [154] |
Epigenetic inhibitors | ||||
IDH1i ivosidenib (AG-120) | Phase 1, open-label, dose-escalation and expansion, safety, pharmacokinetic, pharmacodynamic, and clinical activity study of orally administered AG-120 in subjects with advanced hematologic malignancies with an IDH1 mutation | CR2 plus CRh2: 42.4% CR2 30.3% FU 23.5 months: median OS 12.6 months TI in 9 of 21 TD (42.9%) IDH1 mutation clearance in 9/14 patients | AE:
| NCT02074839 [157] |
IDH2i enasidenib (AG-221) | Phase 1/2 (ongoing), open-label, dose-escalation and expansion, safety, pharmacokinetic, pharmacodynamic and clinical activity study of orally administered AG-221 in subjects with advanced hematologic malignancies with an IDH2 mutation | phase 1: ORR 53% median duration 9.2 months OS 16.9 months phase 2 ongoing | Grade 3/4 (phase 1):
| NCT01915498 [158] |
RAS-pathways inhibitors | ||||
FLT3i quizartinib (AC220) | Phase 1/2 study of the combination of quizartinib (AC220) with 5-azacytidine or low-dose cytarabine for the treatment of patients with AML and MDS | quizartinib/AZA-arm vs quizartinib/LD-AraC-arm:
| AE grade 3/4, quizartinib/AZA-arm vs. quizartinib/LD-AraC-arm:
| NCT01892371 [161] |
Bispecific antibodies | ||||
CD3/CD123 Flotetuzumab (MGD006) | Phase 1/2, first in human, dose escalation study of MGD006, a CD123 × CD3 DART® bi-specific antibody based molecule, in patients with relapsed or refractory AML or intermediate-2/high risk MDS | CR/CRh: 26.7% median OS 10.2 months ORR (CR/CRh/CRi): 30% | most frequent AE:
| NCT02152956 [163] |
CD3/CD33 (AMG 330) | A Phase 1 first-in-human study evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of AMG 330 administered as continuous intravenous infusion in subjects with myeloid malignancies | ongoing | ongoing | NCT02520427 [154] |
Domain 1 Diagnosis (n = 14) | Domain 2 Therapy (n = 8) | Domain 3 Provider/Infrastructural Characteristics (n = 7) |
---|---|---|
Diagnostic work-up:
| Supportive care:
| Personnel:
|
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Chanias, I.; Stojkov, K.; Stehle, G.T.; Daskalakis, M.; Simeunovic, H.; Njue, L.M.; Schnegg-Kaufmann, A.S.; Porret, N.A.; Allam, R.; Rao, T.N.; Benz, R.; Ruefer, A.; Schmidt, A.; Adler, M.; Rovo, A.; Balabanov, S.; Stuessi, G.; Bacher, U.; Bonadies, N., on behalf of the Swiss MDS Study Group. Myelodysplastic Syndromes in the Postgenomic Era and Future Perspectives for Precision Medicine. Cancers 2021, 13, 3296. https://doi.org/10.3390/cancers13133296
Chanias I, Stojkov K, Stehle GT, Daskalakis M, Simeunovic H, Njue LM, Schnegg-Kaufmann AS, Porret NA, Allam R, Rao TN, Benz R, Ruefer A, Schmidt A, Adler M, Rovo A, Balabanov S, Stuessi G, Bacher U, Bonadies N on behalf of the Swiss MDS Study Group. Myelodysplastic Syndromes in the Postgenomic Era and Future Perspectives for Precision Medicine. Cancers. 2021; 13(13):3296. https://doi.org/10.3390/cancers13133296
Chicago/Turabian StyleChanias, Ioannis, Kristina Stojkov, Gregor Th. Stehle, Michael Daskalakis, Helena Simeunovic, Linet Muthoni Njue, Annatina S. Schnegg-Kaufmann, Naomi A. Porret, Ramanjaneyulu Allam, Tata Nageswara Rao, Rudolf Benz, Axel Ruefer, Adrian Schmidt, Marcel Adler, Alicia Rovo, Stefan Balabanov, Georg Stuessi, Ulrike Bacher, and Nicolas Bonadies on behalf of the Swiss MDS Study Group. 2021. "Myelodysplastic Syndromes in the Postgenomic Era and Future Perspectives for Precision Medicine" Cancers 13, no. 13: 3296. https://doi.org/10.3390/cancers13133296