1. Targeted therapies in leukaemia:
New avenues
Stephan Metzelder
Ascona, 13.06.2011

2. τὸ λευκὸν αἷμα
White Blood
18 year old patient Healthy donor
500.000 leukocytes 5.000 leukocytes

3. Targeted Therapies
Principle:
Targeting genetic lesions involved in tumorigenesis
Characteristics:
effective
tumour-specific
reduced treatment associated toxicities
(economic)

4. „Older new Avenues“

5. All-trans retinoic acid in acute promyelocytic leukemia:
long-term outcome and prognostic factor analysis from
the North American Intergroup protocol
Disease-Free Survival
Induction-Consolidation / Maintenance
ATRA-Dauno/AraC / ATRA
Dauno/AraC / ATRA
ATRA-Dauno/AraC / none
Dauno/AraC / none
Tallman M et al. Blood 2002;100:4298

6. Arsenic Trioxide Monotherapy
Four cycles consolidation
One cycle consolidation
Ghavamzadeh A et al. J Clin Oncol 2011; Jun 6 Epub

7. Arsenic Trioxide
Zhang XW et al. Science 2010;5975:240

8. The „Magic Cancer Bullet“
1845 RudolfVirchow
1960 Peter Nowell
David Hungerford
1973 Janet Rowley
1987 Owen Witte
David Baltimore
1999 Nick Lydon
Alex Matter
Jürg Zimmermann
Elisabeth Buchdunger
Brian Druker

9. BCR-ABL:
The CML
oncogene

10. CML Survival 1983 - 2009
The Swiss / German CML study group
N=3140
Imatinib:
Percent survival
92% after 5 years (> 2001)
Interferon or stem cell transpl.
71% after 5 years
Interferon: 53% after 5 years
Busulfan: 38% after 5 years
Years after diagnosis

11. New tyrosine kinase inhibitors: Are they better?
Nilotinib/Dasatinib approved in Germany as first line
treatment in CML chronic phase
Compared to Imatinib:
- Faster MMR/CCyR
- Less Acceleration/Blastcrisis
Some limitations:
- Faster MMR not correlated with better OS
- Higher rate of progress to AP/BC for Imatinib:
3,5% Dasision, 4,2% ENESTnd, vs. 1,5% IRIS
Saglio G et al. NEJM 2010;362:2251
Kantarjian H et al. NEJM 2010;362:2260

12. TKIs cure CML? STIM – Stop Imatinib
41% CMR after 1y
Mahon FX et al. Lancet Oncology 2010;11:1029

13. Interferon: Signal transduction via IRFs

14. ICSBP (=IRF8): A potential tumor suppressor of CML
32D/BA-v 32D/BA-ICSBP
Days after Inj.
All Good Poor Schmidt et al., Blood 1998
Schmidt et al., J Clin Oncol 2000
Resp. Resp. Schmidt et al., Blood 2001
Burchert et al., Blood 2004

15. Interferon after Imatinib
Relapse free survival after STOP Imatinib
Burchert et al., J Clin Oncol 2010

16. Model
BCR/ABL dep. Imatinib IFN-a
HSC no - +
GMP yes + -
CMP

17. CML study V
Flow chart
First diagnosis CML
Randomisation
TK-Inhibitor
Induction TK-Inhibitor
Interferon
Maintenance TK-Inhibitor Interferon

19. FLT3-ITD positive Acute Myeloid Leukemia
• ∼20-30% in AML < 60J,
∼5% in AML > 60J.
• High-Risk:
- ∼90% relapse after
conventional chemotherapy
within 12 mo.
- poor survival
• Relapse after allogenic
transplantation: desperate
situation
Kindler T et al. Blood 2010;116:5089

20. Sorafenib in vitro

21. Sorafenib in vivo: ♀, 40a therapy refractory FLT3-ITD+ AML
Sorafenib p.o.
before Sorafenib d+12 Sorafenib
Metzelder S et al. Blood 2009;113:6567

22. Sorafenib in vivo: ♀, 40a therapy refractory
FLT3-ITD+ AML, Relapse post allo-SCT
relapse molecular no detectable FLT3-ITD Sorafenib p.o. allo-PBSCT

23. Patients characteristics

24. Patients characteristics

25. Sorafenib in FLT3-ITD positive AML
Only good when combined with graft vs leukemia
Design of SORMAIN
FLT3 ITD
AML
Allogen.
BMT
Random
Placebo Sorafenib

26. Summary
• Arsenic is effective as monotherapy in APL and
recruits PML-RARa to proteasomal degradation
• IFNa therapy may deepen molecular remission in
maintenance of CML (by IRF8 ?)
• Sorafenib monotherapy might have curative potential
in AML with FLT3-ITD (especially after BMT)

27. „New Avenues grow old?“
Andreas Neubauer
Andreas Burchert
Colleagues in Marburg
Colleagues providing
patient data