The document discusses recent advances in the treatment of myelodysplastic syndrome (MDS). It covers several key points: 1) Patient characteristics like age, performance status, and comorbidities are important considerations in determining treatment approach and ability to tolerate intensive therapies. 2) Treatment strategies for lower-risk and higher-risk MDS aim to improve blood counts, quality of life, delay disease progression, and prolong survival. 3) Supportive care focuses on reducing morbidity from low blood counts while active therapies aim to alter the natural history of MDS and improve survival. 4) Allogeneic stem cell transplantation remains the only potentially curative treatment but the decision to transplant requires considering age,

1. Zhijian Xiao, M.D.
MDS and MPN Centre, Blood Diseases Hospital
Chinese Academy of Medical Sciences
Recent advances in treatment of MDS

2. Diagnosis, Prognosis(IPSS,IPSS-R), Objective(cure or care)
Age of the patient
Performance status of the patient
Comorbidity of the patient
Predictive models for response
Decision about treatment
• The IPSS (R) category provides a risk-based evaluation of outcome
• The patient’s age, performance status and comorbidity are important
considerations, as they have an important influence on the ability of patients with
MDS to tolerate intensive treatments.

3. Treatment strategy
(lower risk MDS)
★Improve blood cytopenias
★ Improve quality of life
★ Delay disease progression
★ Prolong survival
The therapeutic strategy remains largely based on the IPSS(R).

4. Treatment strategy
(Higher risk MDS)
★Improve blood cytopenias
★ Improve quality of life
★ Delay disease progression
★ Prolong survival

5. Treatment of patients with MDS: goals and options
Clinically
significant
cytopenia(s)
Supportive care
Goals
● To reduce morbidity/mortality
due to cytopenias
● To improve QoL
Active therapy
Goals
● To alter the natural history
of MDS
● To improve survival
● To improve QoL
● To alleviate complications
Transfusions (+ iron chelation)
Growth factors
Treatment of infections
HSCT
Chemotherapy
• Intensive
• Low-dose
Hypomethylating agents
Azacitidine/(decitabine)
Lenalidomide,
immunosuppressive Rx
HSCT = haemopoietic stem cell
transplantation; QoL = quality of life.

6. 陈悦丹 , 等。中华血液学杂志, 2012,33: 532-535
Overallsurvivalprobability
Time(months)
Thrombocytopenia is a significant problem in MDS and many patients have issues with
bleeding and require repeated platelet transfusions.
Severe thrombocytopenia is an independent prognostic factors .

7. Giagounidis et al. Cancer 2014;120:1838–46
There is increasing off-label use of the TPO receptor agonists romiplostim and eltrobopag in
MDS. Recent data from a plocebo-controlled phase 3 trail of romiplostim in lower-risk MDS
patients with thrombocytopemia are somewhat reasuring.

8. Giagounidis et al. Cancer 2014;120:1838–46
Patients on the romiplostin are had great platelet response, fewer bleeding events ≥ grade
2, and less need for platelet transfusion.

9. Giagounidis et al. Cancer, 2014,120:1838–46
● using romiplostim may influence quality of life but not survival.
● Although romiplostin transiently increased peripheral blasts in a proportion of patients,
but the rate of progression to AML didn’t differ significantly between the study groups.

10. Sekeres et al.Br J Haematol, 2014, 167: 337–345
A model was proposed and validated using baseline endogenous EPO levels and initial red
blood cell transfusion needs to predict which patients were most likely to respond to ESAs.
For thrombocytopenic patients with lower-risk MDS, lower baseline THPO levels (<500
pg/ml) and limited platelet transfusion history predicted a greater likelihood of a
subsequent platelet response to romiplostim.

11. Treatment of patients with MDS: goals and options
Clinically
significant
cytopenia(s)
Supportive care
Goals
● To reduce morbidity/mortality
due to cytopenias
● To improve QoL
Active therapy
Goals
● To alter the natural history
of MDS
● To improve survival
● To improve QoL
● To alleviate complications
Transfusions (+ iron chelation)
Growth factors
Treatment of infections
HSCT
Chemotherapy
• Intensive
• Low-dose
Hypomethylating agents
Azacitidine/(decitabine)
Lenalidomide,
immunosuppressive Rx
HSCT = haemopoietic stem cell
transplantation; QoL = quality of life.

13. Mechanism of action of lenalidomide. (A) Lenalidomide directly inhibits Cdc25C, resulting
in G2/M arrest and apoptosis in del(5q) cells. (B) Reduced expression of RPS14 results in
binding of free ribosomal proteins (RP) to MDM2, allowing p53 accumulation.
Lenalidomide disrupts phosphatase PP2A, which results in hyperphosphorylation and
stabilization of MDM2. Despite continued binding of RP, p53 is degraded and effective
erythropoiesis is restored.

14. Unmutated TP53 status showed a tendency for haematological response (P = 0061).
Complete cytogenetic response was not observed in any of the mutated TP53 cases.
M. Mallo et al.Br J Haematol, 2013, 162, 74–86

15. 85 patients in the MDS-004 trail.
The strong P53 protein expression by IHC is the strong independent preditor of AML
Transformation, and also an independent predictor of overall survival and lower
Cytogenetic response in lower-risk del(5q) MDS patients treated with lenalidomide.
Saft L, et al. Haematologica, 2014,99(6):1041-9

16. The presense of BM progenitor cells with strong nuclear p53 expression may reflect an
underlying p53 mutations.
● Assessment of p53 by HIS shoud be integrated in the routine diagnostic work-up and
follow-up of del(5q) MDS patients.
● P53 mutational status should be included in the risk assessment of del(5q) MDS patients.
Saft L, et al. Haematologica, 2014,99(6):1041-9

17. Treatment of patients with MDS: goals and options
Clinically
significant
cytopenia(s)
Supportive care
Goals
● To reduce morbidity/mortality
due to cytopenias
● To improve QoL
Active therapy
Goals
● To alter the natural history
of MDS
● To improve survival
● To improve QoL
● To alleviate complications
Transfusions (+ iron chelation)
Growth factors
Treatment of infections
HSCT
Chemotherapy
• Intensive
• Low-dose
Hypomethylating agents
Azacitidine/(decitabine)
Lenalidomide,
immunosuppressive Rx
HSCT = haemopoietic stem cell
transplantation; QoL = quality of life.

18. SCT in myelodysplastic syndrome
★Indication and timing of SCT in MDS
★ Upfront transplantation, induction or low-intensity
therapy before SCT
★ Stem cell source
★ Conditions
The only potentially curative therapy for MDS remains allogenetic hematopoitic stem cell
transplatation. The decision to perform HSCT in patients with MDS can be challenging.

19. Illustration of the relationship between age in years and the hazard ratio for nonrelapse
mortality (NRM).
Sorror M L et al. JCO 2014;32:3249-3256
Age at transplantation was identified as one of the most important prognostic factors:
the older the age, the shorter the overall and disease-free survival.

20. Comparisons of outcome stratifications by the hematopoietic cell transplantation–
comorbidity index (HCT-CI) and the composite comorbidity/age index (HCT-CI/age).
Sorror M L et al. JCO 2014;32:3249-3256
(A, B) Cumulative incidences of nonrelapse mortality and (C, D) Kaplan-Meier
estimates of overall survival

21. Adjusted probability of overall survival in 701 adult MDS patients by donor source.
Saber W et al. Blood 2013;122:1974-1982
In multivariate analysis, the risk of all-cause mortality was significantly higher with 7 of
8 MUD HCT recipients compared with MRD and 8 of 8 MUD HCT recipients (RR 1.62
and 1.30, respectively). The risk was not different between 8 of 8 MUD and MRD
HCT recipients (RR 1.24).

22. Adjusted probability of DFS in 694 adult MDS patients by donor source.
Saber W et al. Blood 2013;122:1974-1982
In multivariate analysis, the risk of treatment failure (death or relapse) was significantly
higher with 7 of 8 MUD HCT recipients compared with MRD and 8 of 8 MUD HCT
recipients (RR 1.47 and 1.29 , respectively). The risk was not different between 8 of 8
MUD and MRD HCT recipients (RR 1.13).

23. Overall survival (OS) by TP53 and DNMT3A mutation status.
Bejar R et al. JCO 2014;32:2691-2698

25. Avoid SCT when patients not likely to benefit
● Advanced age/comorbidity
● Absence of suitable donor
● Very adverse molecular features