Zhijian Xiao, M.D.

MDS and MPN Centre, Blood Diseases Hospital

Chinese Academy of Medical Sciences

Recent advances in treatment of MDS

Diagnosis, Prognosis(IPSS,IPSS-R), Objective(cure or care)

Age of the patientPerformance status of the patient

Comorbidity of the patientPredictive 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.

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).

Treatment strategy

(Higher risk MDS)

★Improve blood cytopenias

★ Improve quality of life

★ Delay disease progression

★ Prolong survival

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 agentsAzacitidine/(decitabine)

Lenalidomide,immunosuppressive Rx

HSCT = haemopoietic stem cell transplantation; QoL = quality of life.

陈悦丹 , 等。中华血液学杂志, 2012,33: 532-535

Overall survival probability

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 .

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.

Giagounidis et al. Cancer 2014;120:1838–46

Patients on the romiplostin are had great platelet response, fewer bleeding events ≥ grade2, and less need for platelet transfusion.

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.

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.

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 agentsAzacitidine/(decitabine)

Lenalidomide,immunosuppressive Rx

HSCT = haemopoietic stem cell transplantation; QoL = quality of life.

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.

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

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

The presense of BM progenitor cells with strong nuclear p53 expression may reflect anunderlying p53 mutations.

● Assessment of p53 by HIS shoud be integrated in the routine diagnostic work-up andfollow-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

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 agentsAzacitidine/(decitabine)

Lenalidomide,immunosuppressive Rx

HSCT = haemopoietic stem cell transplantation; QoL = quality of life.

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.

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.

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

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).

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).

Overall survival (OS) by TP53 and DNMT3A mutation status.

Bejar R et al. JCO 2014;32:2691-2698

Avoid SCT when patients not likely to benefit

● Advanced age/comorbidity

● Absence of suitable donor

● Very adverse molecular features