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Exploiting genetic lesions in leukemia
Thorsten Zenz Dept. of Translational Oncology, National Center for Tumor Diseases (NCT) / German Cancer Research Center (DKFZ), Heidelberg Dept. of Haematology / Oncology / Rheumatic Disease, University Hospital Heidelberg [email protected]
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Leukemia – therapeutic targets
CML: Tyrosine Kinase Inhibitors
CLL: Antibodies, BTK, PI3K Inhibitors
AML/APL: Kinase Inhibitors, Retinoic Acid
ALL: Kinase Inhibitors (BCR/ABL)
cMPS: JAK-Inhibitors
Hairy Cell Leukemia
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Hairy Cell Leukemia
• Rare leukemia
• Cytopenia, massive splenomegaly
• Very responsive to Purine Analogues
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Lig
ht chain
CD
25
CD
103
CD
11c
CD20
Cyclin D1
CD20 DBA.44
Diagnosis Hairy Cell Leukemia
M. Hundemer, M. Andrulis
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Refractory HCL Bone Marrow Findings Lack of response to chemotherapy
P P C P + 8 x R
02/09 4/11 06/09 09/11 11/11
CD
20+
cells
C: Cladribin; P: Pentostatin; R: Rituximab Dietrich, Glimm et al, NEJM 2012
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Blood Counts
Dietrich, Glimm et al, NEJM 2012
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Therapeutic Options
No trials available
CD22 immunoconjugate
Campath (anti-CD52 Ab)
Splenectomy
Interferon alpha
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Tiacci, NEJM 2011
BRAF V600E
c.T1799A, p.V600E
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BRAF mutations
• More than 30 mutations of the BRAF gene associated with human cancers have been identified.
• In 90% of the cases, thymine is substituted with adenine at nucleotide 1799. This leads to valine (V) being substituted by glutamic acid (E) at codon 600 (now referred to as V600E) in the activation segment that has been found in human cancers.
• The frequency of BRAF mutations varies widely in human cancers:
• 50% in melanomas
• 45% in papillary thyroid carcinoma
• 1-3% in lung cancers
• 5% in colorectal cancer
• 100% of cases of hairy cell leukaemia
(all V600E!)
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P P C + 8 x R C Vemurafenib
0
1,000
2,000
3,000
4,000
0
1,000
2,000
3,000
4,000
2009 2010 2011 2012
0
50,000
100,000
150,000
200,000
2009 2010 2011 2012
0
50,000
100,000
150,000
200,000
2009 2010 2011 2012
10
12
14
2009 2010 2011 2012
10
12
14
2009 2010 2011 2012
Pla
tele
ts/ µ
l H
em
oglo
bin
(g/d
l)
leucocytes
neutrophils
Response to B-RAF inhibitor
Dietrich, Glimm et al, NEJM 2012
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Bo
ne
ma
rro
w
infi
ltra
tio
n (
CD
20
)
CD
103+
CD20+
32% 1.04% <0.02%
0 20 40 60 80
0
480
960
1440
1920
d 17 d 70 d 36
Days
Ve
mu
rafe
nib
(m
g)
Imm
un
op
he
no
typ
ing
peri
ph
era
l b
loo
d
<0.02%
d 0 d 17 d 36 d 70
d 0 d 17 d 36 d 70
20x
Dietrich, Glimm et al, NEJM 2012
BRAF inhibition in HCL
Melanoma dose
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Ultrasound
Spleen
24,8 x 8,3 cm 13,8 x 5,7 cm 18,8 x 5,8 cm
d 0 d 6 d 36
BRAF inhibition in HCL
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0
10000
20000
30000
1 2 3 4 5 6 7 8
0 480 960
1440 1920
1 2 3 4 5 6 7 8
0
1000
2000
3000
4000
5000
1 2 3 4 5 6 7 8
8
10
12
14
16
18
1 2 3 4 5 6 7 8
0
50000
100000
150000
200000
250000
1 2 3 4 5 6 7 8
Continued response off treatment
Pla
tele
ts/µ
l H
em
og
lob
in (
g/d
l)
sC
D2
5 (
U/l
) C
ell
s/µ
l V
em
ura
fen
ib (
mg
)
Dietrich et al, JCO in press
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d0
Effect of BRAF inhibition in vivo
d6 d36
Dietrich et al, JCO in press
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Peripheral blood counts :
Vemurafenib
Days of Vemurafenib Follows et al, BJH 2012
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Pre treatment Post treatment
MR
Cases: Cambridge, Nice
Follows et al, BJH 2012
Peyrade et al, Haematologica 2013
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HCL - unique testing ground for rational clinical development
Very rare & efficient standard treatment
Easy access to tissue
Response assessment / Biomarker
Multiple companies with BRAF/MEK Inhibitors
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Issues remaining
• Dosing?
• When to stop treatment?
• How to develop a practice changing trial in a very rare disease
with very effective standard treatment?
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HCL - unique testing ground for rational clinical development
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Carolin Blume Jennifer Hüllein Alexander Jethwa Olaf Merkel Leopold Sellner Tatjana Stolz Mikolaj Slabicki Stefan Fröhling Manfred Schmidt Hanno Glimm Christof von Kalle
Sascha Dietrich Anthony Ho Anna Jauch Mindaugas Andrulis David Capper Michael Hundemer Julia Meissner Nicola Lehners
Addenbrooks Hospital George Follows
University of Nice Frederic Peyrade
University of Giessen Till Acker
Hairy Cell Leukemia Consortium Michael Grever
Axel Benner Benedikt Brors Peter Lichter Jan Meier Daniel Mertens Chris Oakes Christoph Plass Martin Sill Martina Seiffert Stephan Wolf Marc Zapatka