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) Score Prognostic variable 0 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 *Karyotype: good: normal, -Y, del(5q), del(20q); poor: complex (≥ 3 abnormalities) or chr 7 anomalies; and intermediate: other abnormalities. Score IPSS subgroup Median survival (years) 0 Low 5.7 Low R 0.5–1.0 Int-1 3.5 1.5–2.0 Int-2 1.2 High R >= 2.5 High 0.4 Hb < 10.0 g/dL; ANC < 1.8 × 10 9 /L; platelet count < 100 × 10 9 /L Greenberg et al. Blood 1997
WHO classification-based Prognostic Scoring System (WPSS) Variable 0 1 2 3 WHO RA, RARS, del5q− RCMD, RAEB-1 RAEB-2 Karyotype Good Intermediate Poor – RBC no yes – – * Karyotype: good: normal, -Y, del(5q), del(20q); poor: complex (≥ 3 abnormalities, chr 7 anomalies); and intermediate: other abnormalities. Score WPSS group Median OS (mon) Median OS (mon) Italian cohort German cohort 0 Very low 103 141 1 Low 72 66 Low R 2 Intermediate 40 48 3–4 High 21 26 High R 5–6 Very high 12 9 Malcovati L, et al. J Clin Oncol. 2007;25:3503-10.
Goals of Treatment • Improve cytopenias Low R • Improve QoL • Delay disease progression High R • Prolong survival
Therapeutic options in MDS IPSS/WPSS scoring approved Not approved but active LOW RISK HIGH RISK trials Fe-chelation del5 q Len ATG/Cam Valproic EPO<500 Epo G-CSF TPO-R HDAC +/- Len +/- Epo +/- 5-AZA
The real MDS case 2008 Dx RCMD, 46XY, RBC TD 2010 RAEB-2
Therapeutic options in MDS IPSS/WPSS scoring approved Not approved but active LOW RISK HIGH RISK trials 5-Aza Fe-chelation Intensive CTx/allo Tx del5 q Len ATG/Cam Valproic EPO<500 Epo G-CSF TPO-R HDAC +/- Len +/- Epo +/- 5-AZA
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)
Therapeutic options in MDS IPSS/WPSS scoring approved Not approved but active LOW RISK HIGH RISK trials 5-Aza Fe-chelation Intensive CTx/allo Tx del5 q Decitabine Clofarabine Len ATG/Cam Valproic EPO<500 Epo G-CSF TPO-R 5-Aza q14d HDAC +/- Len +/- Epo +/- 5-Aza + Len 5-Aza/DAC + HDAC 5-AZA
Conclusion • Great clinical heterogeneity of MDS • Scoring systems • Low-risk vs. High-risk • Paucity of approved drugs (EU) • Need of (further) prognostic variables ;
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