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Exploiting genetic lesions in leukemia: BRAF inhibition in HCL
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]
BRAF V600E
c.T1799A, p.V600E
Targeting BRAF
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
Blood Counts
Dietrich et al, NEJM in pressDietrich, Glimm et al, NEJM 2012
Therapeutic Options
No trials available
CD22 immunoconjugate
Campath (anti-CD52 Ab)
Splenectomy
Interferon alpha
„At this time, our compassionate use program is
restricted to metastatic melanoma. This is in line
with ....policy, which restricts compassionate use to
indications for which we have strong evidence of
activity. We have no data to support use of …. in
patients with HCL.”
Obtaining a BRAF inhibitor
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 BRAF inhibitor
Dietrich, Glimm, et al, NEJM 2012
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
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
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
Dietrich, JCO in press
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
)
Effect of BRAF inhibition in vivo
Dietrich et al, JCO in press
d0
Effect of BRAF inhibition in vivo
d6 d36
Dietrich et al, JCO in press
Hairy cell leukaemia: A
Targeted Haircut?
Cambridge Cancer Center
Hannah Sims
George Follows
Peripheral blood counts since Vemurafenib
Days of Vemurafenib Follows et al, BJH 2012
Pre treatment Post treatment
MR
Cases: Cambridge, Nice
Follows et al, BJH 2012
Peyrade et al, Haematologica 2013
Pla
tele
ts/µ
l s
CD
25 (
U/l)
M0nths Days
0 20 40 60 0
5000
10000
15000
20000
25000
0 2 8 16
0 20 40 60 0
50
100
150
200
0 2 8 16
4 x R
Vemurafenib
2x240 mg
Heidelberg Patient Nr. 2
before d19
Patient Nr. 3
0 50 100 150 0
50
100
Time (days)
0 50 100 150 0
100000
200000
300000
400000
500000
Time (days)
Pla
tele
ts (
/µl)
%
Red
uc
tio
n o
f s
CD
25
(IL
2-R
)
Combined experience Heidelberg
Combined experience Heidelberg, Nice, Cambridge
PLT before
day PLT >
100 PLT
WBC
before WBC
day Neut >
1000 Hb before Hb
54.000 14 140.000 1650 5200 42 10,5 13,2
36.000 28 118.000 840 4150 13 10 13,4
15.000 25 137.000 1100 570 na 7,7 13,5
24.000 33 473.000 14.000 4100 35 6,9 12,6
57.000 11 310.000 3000 3700 11 9,4 12,3
20.000 35 193.000 600 3800 GCS-F 13,2
HCL - unique testing ground for
rational drug development
Very rare & efficient standard treatment
„Easy“ access to tissue
Response assessment / Biomarker
Multiple companies with BRAF/MEK Inhibitors
Major Issues remaining
• Dosing
• When to stop treatment
• How to develop a practice changing trial in a very rare
disease with very effective standard treatment
• Cost
HCL - unique testing ground for
rational drug development
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 David Capper Mindaugas Andrulis Julia Meissner Michael Hundemer Nicola Lehners
Addenbrooks Hospital George Follows
Nice Frederic Peyrade
Neuropathologie Giessen Till Acker Boyan K. Garvalov
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