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Julien Haroche Service de Médecine Interne 2
Centre de Référence des Histiocytoses
Groupe Hospitalier Pitié-Salpêtrière
Targeted Therapies in histiocytoses in 2019 : are we there yet ?
Tel-Aviv 6/2/2019
I have no disclosures
Macrophage : a chamaleon cell
hemophagocytosis Siderophage Touton cell
(xanthogranuloma)
Virchows cell
(leprosy) Lipophage
Langhans cell
(tuberculosis)
Most importantly
Langerhans cell histiocytosis: systematic histology
review ?
H&E
CD1a
Baby 1 month old with diffuse cutaneous involvement
Scabies infection
Differential Diagnosis LCH • Eosinophils and histiocytes:
• Hodgkin lymphoma
• T cell lymphoma
• Infection (among which leprosy)
• Non specific and/or surrounding a tumor
• Bone: chronic osteitis, schwanoma (CD68+ S100+)
• Lymph nodes: dermatopathic lymphadenitis
• Pituitary gland: germ cell tumor, sarcoidosis
• Meningeal : glioma
• Liver: sclerosing cholangitis, parasite (liver fluke)
• Lung: no diagnosis on BAL fluid
RAS-RAF-MEK-ERK pathway BRAF V600E activating mutation
• Melanoma 50 %
• Colon cancer 5%
• Hairy cell L 100%
• Histiocytosis
LCH 50-60 %
ECD 55-70% (droplet PCR)
Haroche et al Blood 2012; 120: 2700
Classification taking into account molecular alterations
Rosai-Dorfman-Destombes Disease Polymorph histiocytosis first described in 1965 by the French pathologist Pierre Paul Louis Lucien Destombes
1912-2002
Then in 1969 by the US Rosai and Dorfman
≈ 2000 known cases
Characterized by massive infiltration of lymph
nodes, often in children or young adults
General status conserved
Within the histiocytic infiltration, nuclei of lymphocytes in the
cytoplasm of histiocytes
= emperipolesis
Bilateral painless neck nodes ~ 90%
Inguinal/axillary ~ 20%; Mediastinum/upper para-aortic ~10-15%
43% Extranodal – skin, upper respiratory, tonsil, hearing abnormalities and
bone
Orbit & sinuses Kidney, lungs, testes and thyroid
GI – liver: sclerosing cholangitis (IgG4-related?)
Rarely CNS (5%)
Clinically highly heterogeneous
Association with a biological inflammatory syndrome, hypergammaglobulinemia & auto-immunity (15%)
Review by Pulsoni et al Am J Hematol 2002:
40/80 patients did not require any treatment - MRD was self limiting
Treatment needed for:
Massive nodal disease causing life-threatening complications
Extra-nodal RDD with vital organ compromise
Patients with high & recurrent fevers: non-infection related, affecting quality of life
Steroids, 2CDA, rituximab, MTX, imatinib, INF alpha, thalidomide
Surgery sometimes needed
RDD Treatment – no consensus
Virchows Arch Pathol Anat 1930; 279: 561-602
Erdheim-Chester disease
Bone scintigraphy (99 Tc)
"Hairy kidney aspect" and peri-renal infiltration
(96%) (≈ 60%)
Between 1000 & 1500 cases since 1930
Histology is mandatory: xanthelasma / peri-kidney = preferred sites
Natural history unknown
• Asymtomatic forms of the disease
• Multisystemic & life-threatening forms of the disease
• 3 ♂︎ / 1 ♀︎
• Mean age at diagnosis: 56.1 yr (14.4), range: 5-80
• Increased levels of acute inflammatory protein (CRP) : 87 pts (71%)
• 1st symptom extremely variable (bone pain 10%, diabetes insipidus 16%) but also exophthalmos, seizures, sinusitis…
Extra-osseous involvement ≈ 98% of patients
• Xanthelasma 43 pts (26%) • Exophthalmos 36 pts (22%) • Diabetes insipidus 46 pts (28%) • Central nervous system (CNS) 60 pts (37%) Cerebellar 28 pts (17%) • Pulmonary involvement 58 pts (36%) • Peri-renal (“hairy kidney”) 95 pts (58%) • “Retro-peritoneal fibrosis” / HN 40 pts (25%) • “Coated aorta” 75 pts (46%) • Reno-vascular hypertension 29 pts (18%) • Pericardial 51 pts (31%) • Pseudo-atrial tumor 61 pts (37%)
Pitié-Salpêtrière, 165 Patients (Avril 2016)
Rheumatologic manifestations
Bone pain: 56 pts (38%) Bone involvement often latent
37% pts « pseudo-tumoral » infiltration of RA
Circulation 2009
CNS involvement and treatment with interferon-alpha are independant prognostic
factors in Erdheim-Chester disease: a multicenter survival analysis of 53 patients
Arnaud, Hervier, Haroche, et al. Blood 2011
2nd line
Anakinra Aouba Blood 2010 Cohen-Aubart Blood 2016
Remicade Cohen-Aubart ARD 2018
Sirolimus Gianfreda Blood 2015
05/2007 04/2008
01/2009
Man, 30-year-old, referred to our institution in October 2006 ECD diagnosed on bone biopsy in September 2002 CNS involvement only with sus and retro-sellar infiltration with diabetes insipidus, hypogonadism and complex partial seizures Major side effects to vinblastine in 2002 IFN alpha 9 M x 3 per week initiated in October 2006
Impaired Th1/Th2 balance Production of IFN- (source ?)
Histiocyte recruitment via MCP-1 ?
Identification of a cytokine « signature »
Blood 2011
Erdheim-Chester Haroche, et al. Blood 2012
Diamond, et al. Blood 2013
Go, et al. Histopathology 2014
Emile, Diamond, et al. Blood 2014
O’Malley, et al. Ann Diagn Pathol 2015
Brown RA, et al. Blood 2015
Kordes, et al. Leukemia 2015
Diamond, Durham, Haroche, et al. Cancer
Discovery 2016
Durham, et al. Curr Opin Hematol. 2016
Shanmugan, et al. Head Neck Pathol. 2016
Lee, et al. JCI Insight 2017
Charkraborty et al. Oncotarget 2017
Techavichit, et al. Hum Pathol. 2017
Garces, et al. Mod. Pathol. 2017
Bentel et al. BMJ Case Report 2017
Demographic and clinical characteristics of 217 patients with ECD, including 182 patients with BRAF genotyping
BRAF inhibitors Vemurafenib April 2012 (France)
Approved for unresectable or metastatic melanoma with the BRAF V600E mutation Advised posology 960 mg twice /d (4 tablets x 2)
Duration of treatment: untill progression of disease or unacceptable toxicity occurs
Reproducible and sustained efficacy of targeted therapy with Vemurafenib in Eight patients with BRAFV600E mutated Erdheim-Chester disease
Haroche J Clin Oncol, 2015
All patients were in PMR at M6
•All patients were PMR at M6 of vemurafenib, and the median SUVmax reduction was 63.5 % (range: 41.3 - 86.9) •Evaluation of cardiac and aortic infiltrations showed that 7 patients had a partial response, and 1 was in stable disease according to RECIST criteria •Persistent response to vemurafenib, with a median follow up of 10.5 months (range: 6-16) Haroche et al J Clin Oncol, 2015
Xanthelasma
M0 M12
Haroche et al J Clin Oncol, 2015
Neurologic regression
Haroche J Clin Oncol, 2015
A
B
C
D
E F G H
PET at M4 : total disappearance of suprasellar and lung hypermetabolism
Cohen-Aubart, Neurology 2014
Marked efficacy of vemurafenib in suprasellar Erdheim-Chester disease
BRAF inhibition 2012-2018 • MSKCC: Basket Trial: 18 histiocytoses (mainly ECD)
published in NEJM august 2015, close to 40 pts currently • Italy: 10 pts treated by Augusto Vaglio (Parma) • Italy: Lorenzo Dagna (Milano) : 10 - 15 pts • Israel: 5 pts treated • Germany at least 1 patient (ICU) • Norway: 2 cases • Sweden: at least one case with CNS • EU group & Jean Donadieu LCH children 54 VMF • Houston Group : 5 – 10 LCH children pts • PITIE-SALPETRIERE : 88 patients (May 2018)
> 200 patients worldwide adults & children with ECD, ECD + LCH and LCH
Baseline Last0
5
10
SU
V
A
B
C
Baseline Last0
2
4
6
SU
V
Baseline Last0
5
10
15
20
25
SU
V
Patient 1 Patient 2 Patient 3
Cohen-Aubart, BJH 2016
MEK inhibition (MSKCC & Paris) > 2015
In May 2018: 88 pts with histiocytosis have received targeted therapy at PITIE SALPETRIERE Cohen-Aubart, Blood 2017
Cohen-Aubart, Blood 2017 Since 2016: + 3 melanomas; 1 adeno K pancreas KRAS mutated; 2 pancreatitis; 2 MDS
Erdheim-Chester + LCH D1-C18 VEMURAFENIB AcSé VEMU
6/6/2018
Infiltrant squamous cell carcinoma requiring surgery and radiotherapy (treatment discontinuation)
Haroche, J Clin Oncol 2015
Sarcoidosis under vemurafenib
Severe acneic rash under
cobimetinib
The LOVE study : relapses after treatment interruption
0 10 20 300
50
100
Months
Su
rviv
al w
ith
ou
t re
lap
se
15/20 patients relapsed (75%)
Cohen-Aubart, Blood 2017
" Cobimetinib for BRAF-wild-type histiocytoses : a randomized, placebo-controlled, double blind study"
PHRC National 2017 Etude COBRAH
Vaglio & Diamond, Blood 2017
No difference in survival V600E / WT (p = 0.4)
August 2018 217 ECD patients
Median survival BRAF 146 months WT 174 months
In 2018 prognosis of ECD is better than in « older series »
published in 1996 & 2004 ≈ 60% death at 3 yrs
August 2018 217 ECD patients
August 2018 217 ECD patients
Cohen-Aubart Am J Hematol 2018
Langerhans cell histiocytosis • 1868 : description of the cells by Paul Langerhans
• 1900-1950 : description of the different entities
– 1893-1919 : Hand, Schuller and Christian : exophthalmos, diabetes insipidus, bone lytic lesions
– 1924-1933 : Letterer and Siwe : hematologic disease of new born
– 1953 : gathering = histiocytosis X
– 1973 : « the langerhans cell histiocytosis » (C Nezeloff)
Histologic definition : eosinophil granuloma Confirmed by immuno-histochemistry (or EM)
CD1a
In children 50-55 cases/year in France 300 cases/year in Europe
LCH a highly proteiform disease
• Sclerosing cholangitis
• Neuro degenerative
• Pulmonary involvement
Organ repartition in pediatric series of LCH
n=684, 31/12/01
Organs %
Bone 80
Skin 37
ENT 20
Nodes 10
Hyphophyse 25
CNS 5
Hematology Lung Liver Other
14 15 17 10
Day 1 D14 after Vemurafenib
Héritier JAMA Oncol 2015
-20
0
20
40
60
80
100
120
140
160
180
16/04/2014 06/05/2014 26/05/2014 15/06/2014 05/07/2014 25/07/2014 14/08/2014 03/09/2014
Alb
CRP
Hb
120mg x2 /d 60mg x1 /d
Vemurafenib administration
Day 0 Day 14 Day 60 Day 105
Héritier JAMA Oncol 2015
Update on EU study of vemurafenib in LCH 54 PATIENTS TREATED IN EU AND LEBANON
Submitted (Jean Donadieu)
Héritier JAMA Oncol 2015
Badalian-Very, et al. Blood 2010
Kansal, et al. Genes Chrom Cancer 2013
Nelson, et al. Blood 2014
Brown NA, et al. Blood 2014
Chakraborty, et al. Blood 2014
Nelson, et al. Genes Chrom Cancer 2015
Chakraborty et al. Blood 2016
Lee, et al. JCI Insight 2017
Zarnegar, Durham, et al. Pediatr Blood Cancer. 2017
Héritier, et al. Mol Cancer. 2017
Papo, Blood 2017
23 LCH + ECD
Diagnosis
7 before (4 years
[1-22])
6 simultaneously
6 after (1 year [1-
4])
Patient Histiocytosis Sex Age Mutationnal status histiocytosis Haematological disease Mutationnal status MPN/MDS
#1 ECD, LCH, RDD M 64 BRAF WT MPN (MF) JAK2 p.V617F
#2 ECD M 60 BRAFV600E MPN (ET) CALR
#3 ECD, LCH M 56 BRAFV600E MPN (ET) JAK2 p.V617F TET2 K95X
#4 ECD M 73 BRAF WT CMML JAK2 p.V617F NRAS G12S
TET2 L757fsX56 U2AF1
#5 ECD M 68 BRAFV600E MPN (PV), AML JAK2 p.V617F
#6 ECD M 73 BRAF WT MPN (MF) -
#7 ECD M 71 BRAFV600E CMML ASXL1 Q592X
#8 ECD, RDD M 71 BRAF WT CMML -
#9 ECD M 63 BRAFV600E MPN (ET) JAK2 p.V617F
#10 ECD, LCH M 51 BRAF WT MDS -
#11 ECD, LCH F 83 BRAFV600E MDS -
#12 ECD M 52 MAP2K1 p.K57N MPN (ET) JAK2 p.V617F
#13 ECD M 66 NRAS p.Q61R CMML NRAS p.Q61R
#14 ECD M 73 BRAFV600E CMML JAK2 p.V617F IDH2 R140Q
#15 ECD F 64 BRAFV600E CMML NRAS p.G13D ASXL1 1Q733X
#16 ECD M 75 BRAFV600E CMML -
#17 ECD M 55 BRAFV600E MDS -
#18 ECD M 78 BRAFV600E CMML ASXL1 1A733X TET2 Q904X TET2 Q321X TET2 N1387S
#19 ECD, LCH M 70 BRAFV600E
AML IDH2R140Q TP53N131K
MH
31,5
%
BRAF
V600E
63,2%
NRAS
MAP2K1
JAK2
V617F
36,8% CALR
NRAS
ASXL1
TET2
U2AF1
IDH2
TP53
NRAS p.Q61R
• In CD34 BM cells, BRAF mutation are less frequent than the mutations in genes
involved in MPN/MDS such as TET2, SRSF2 or JAK2
• The mutations of TET2, SRSF2 or JAK2 can also be detected within peripheral
tissues involved by ECD.
Clonal hematopoiseis of indeterminate potential (CHIP)
Since end of 2016 analysis of 121 BM aspiration / ECD & mixed histiocytosis + 31 follow-up BM aspiration under targeted therapy NGS panel of 36 myeloid genes Most frequently mutated genes : TET2, ASXL1, DNMT3A and NRAS CHIP increased by 40% compared to a population same age
ASH 2017, SFH 2018 0 20 40 60 80 100
0
2
4
6
8
Nu
mb
er
of m
uta
tio
ns
The presence & the number of mutations per patient are correlated with age (p=0.0055 and p=0.0001)
Cluster analysis
CHIP / ECD
• High prevalence (38-43%) of somatic mutations other than BRAF in patients with ECD
• Under estimation of hemopathies ?
• Clonal hematopoiesis is associated with a vascular phenotype (linked to TET2 or BRAF status ?)
• Perspectives : adaptation (?) of therapies depending on the presence of mutations ? Hematologic outcome - particulary risk of occurrence of AML ?
And at the end of the pathway…
Frequency of mutations found in a cohort of 218 histiocytosis patients
MSKCC
Take home messages (I)
• LCH & ECD often associated, group « L » from the revised WHO 2016 classification = myeloid inflammatory neoplam
• Systematic centralized review essential / clinical context + looking for BRAF (+/- pddPCR) & NGS for genes of the MAPkinases pathway
• BRAFV600E mutation is associated with cardiac & neurologic phenotype in ECD
• BRAFV600E has (currently) no influence on the survival of ECD patients (≠ pediatric forms of LCH)
• Interferon-alpha & targeted therapies (BRAF and/or MEK inhibitors) improve survival of ECD patients.
Take home messages (II) • LOVE Study : 75% ECD & mixed histiocytosis relapse Cohen-Aubart, Blood 2017
• No resistance to BRAF inhibitors in ECD or mixed histiocytosis after >
6 years, no resistance to MEK inhibitors with follow-up period of 3
years; ≈ 100 adults treated at Pitié-Salpêtrière
• Only treat severe patients: heart and/or CNS (SAE frequent)
• What is the place for COMBOTHERAPIES in ECD and mixed
histiocytosis (by analogy with metastatic melanoma) ?
• PHRC COBIMETINB vs Placebo for histiocytoses of the « L » group
(opens in Paris in March 2019)
• Where are the mutations in RDD ? Phospo-ERK is expressed and MEK
inhibitors are efficaccious
Thank you
Fleur Cohen-Aubart Zahir Amoura All the residents Frédéric Charlotte Jean-François Emile Groupe d’Etude des Histiocytoses Jean Donadieu Eli Diamond, Ben Durham, Omar Abdel-Wahab, MSKCC, New York The patients Kathy Brewer and the ECD global alliance Histiocyte Society
+33 6 30 04 02 88 [email protected]
