How should we treat a 60y old with MDS ? - Conventional Therapy - - - PowerPoint PPT Presentation

How should we treat a 60y old with MDS ?

• Conventional Therapy -

Uwe Platzbecker Medical Clinic and Polyclinic I University hospital Dresden Germany

The real MDS case

2008 Dx RCMD, 46XY, RBC TD, PLT60, EPO 480

IPSS (international prognostic scoring system)

Greenberg et al. Blood 1997

Score Prognostic variable 0.5 1.0 1.5 2.0 Bone marrow blasts (%) < 5 5–10 11–20 21–30 Karyotype* Good Intermediate Poor Cytopenias 0/1 2/3 Score IPSS subgroup Median survival (years) Low 5.7 0.5–1.0 Int-1 3.5 1.5–2.0 Int-2 1.2 >= 2.5 High 0.4

*Karyotype: good: normal, -Y, del(5q), del(20q); poor: complex (≥ 3 abnormalities) or chr 7 anomalies; and intermediate: other abnormalities. Hb < 10.0 g/dL; ANC < 1.8 × 109/L; platelet count < 100 × 109/L

Low R High R

WHO classification-based Prognostic Scoring System (WPSS)

Variable 1 2 3

WHO RA, RARS, del5q− RCMD, RAEB-1 RAEB-2 Karyotype Good Intermediate Poor – RBC no yes – –

Malcovati L, et al. J Clin Oncol. 2007;25:3503-10.

Score WPSS group Median OS (mon) Italian cohort Median OS (mon) German cohort

Very low 103 141 1 Low 72 66 2 Intermediate 40 48 3–4 High 21 26 5–6 Very high 12 9

* Karyotype: good: normal, -Y, del(5q), del(20q); poor: complex (≥ 3 abnormalities, chr 7 anomalies); and intermediate: other abnormalities.

Low R High R

Goals of Treatment

• Improve cytopenias
• Improve QoL
• Delay disease progression
• Prolong survival

Low R High R

LOW RISK HIGH RISK

Therapeutic options in MDS

IPSS/WPSS scoring

trials Not approved but active approved

Valproic Epo

Fe-chelation

EPO<500

Len

del5 q

G-CSF TPO-R Len +/- Epo +/- HDAC +/- 5-AZA ATG/Cam

The real MDS case

2008 Dx RCMD, 46XY, RBC TD 2010 RAEB-2

LOW RISK HIGH RISK

Therapeutic options in MDS

IPSS/WPSS scoring

trials Not approved but active approved

Fe-chelation Intensive CTx/allo Tx 5-Aza

Valproic Epo

EPO<500

Len

del5 q

G-CSF TPO-R Len +/- Epo +/- HDAC +/- 5-AZA ATG/Cam

Clinical prognostic factors with DNMT-I

• Comorbidities/ECOG
• Heavily transfusion dependent
• Peripheral blasts
• Adverse cytogenetics

Itzykson R et al. ASH 2009

Genetic prognostic factors with DNMT-I

Mufti et al. ASH 2009

Molecular prognostic factors with DNMT-I

• Early epigenetic changes do not predict clinical response to 5-aza

and HDAC-I combination (Fandy T et al. Blood 09)

• A methylation score predicts clinical response to DAC (Shen L et al. JCO 10)
• Reduction in phosphoinositide-phospholipase C beta 1 methylation

predicts response to 5-aza (Follo MY et al. PNAS 09)

• High levels of miR-29b associated with response to DAC (Blum W et al. PNAS 10)

LOW RISK HIGH RISK

Therapeutic options in MDS

IPSS/WPSS scoring

trials Not approved but active approved

Fe-chelation

Decitabine

Intensive CTx/allo Tx

5-Aza + Len

5-Aza

5-Aza/DAC + HDAC Clofarabine 5-Aza q14d Valproic Epo

EPO<500

Len

del5 q

G-CSF TPO-R Len +/- Epo +/- HDAC +/- 5-AZA ATG/Cam

Conclusion

;

• Great clinical heterogeneity of MDS
• Scoring systems
• Low-risk vs. High-risk
• Paucity of approved drugs (EU)
• Need of (further) prognostic variables