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 thorsten.zenz@nct-heidelberg.de

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

Hairy Cell Leukemia

• Rare leukemia

• Cytopenia, massive splenomegaly

• Very responsive to Purine Analogues

Lig

ht chain

CD

25

CD

103

CD

11c

CD20

Cyclin D1

CD20 DBA.44

Diagnosis Hairy Cell Leukemia

M. Hundemer, M. Andrulis

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, Glimm et al, NEJM 2012

Therapeutic Options

No trials available

CD22 immunoconjugate

Campath (anti-CD52 Ab)

Splenectomy

Interferon alpha

Tiacci, NEJM 2011

BRAF V600E

c.T1799A, p.V600E

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!)

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

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

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

d0

Effect of BRAF inhibition in vivo

d6 d36

Dietrich et al, JCO in press

Peripheral blood counts :

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

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

Issues remaining

• Dosing?

• When to stop treatment?

• How to develop a practice changing trial in a very rare disease

with very effective standard treatment?

HCL - unique testing ground for rational clinical 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 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