International

LCH Study Reference CenterDAL HX 83/90 Studies (1983-1991)

LCH I-II-III Studies (1991-1998)

LCH-IV Study since 2012

Outline

o Overview on LCH clinical aspects

o Diagnostic approach

o Standard frontline therapy for SS-LCH and MS-LCH

o Empiric second-line options for high-risk LCH

o New insights into the LCH pathobiology and its

implications

LCH: Historical perspective

10.12.2018 3

1890 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990

Hand-Schüller-Christian Syndrome

Letterer-Siwe disease

Eosinophilic granuloma

Histiocytosis X

2000

S. Farber

L. Lichtenstein

C. Nezelof

2010

LCH

MAPK

Mutations

B. Rollins

Prospective clinical trials

Histiocyte Society

4

The Worldwide Histiocytosis Network

LCH Study Reference CenterDAL HX 83/90 Studies (1983-1991)

LCH I-II-III Studies (1991-1998)

LCH-IV Study since 2012

10.12.2018 5

International LCH Study Center

1983-2018

Cumulative database n>3600

EPIDEMIOLOGY

any age group

incidence 4-5 / 1Million children / year

(1/ 20 000 children by age 15)

incidence in adults ?

male:female 1:1 to 2:1

AGE DISTRIBUTION OF LCH

ORGAN INVOLVEMENT IN LCHn=275

BONE LESIONS

BONE LESIONS

BONE LESIONS

SKIN LESIONS

SOFT TISSUE

Proptosis Soft Tissue Swelling

PULMONARY DISEASE

Cerebellum

CNS-LCH

Basal ganglia

HISTOPATHOLOGICAL

DIAGNOSIS OF LCH

Light microscopy Immunohistochemistry

Electron microscopy

DEFINITIVE DIAGNOSIS

CD1a +

Birbeck granules

CD207 + (Langerin)

Physical examination Complete examination, special attention to:

skin and mucosal lesions, floating teeth,

proptosis, chronic otitis, aural discharge,

cough, dyspnea, enlarged liver, spleen, or

LN

Laboratory tests CBC, ALT, AST, γ-GT, ALP, bilirubin, total

protein, albumin, coagulation (aPTT, TT,

fibrinogen), urine specific gravity and

osmolality

Imaging Skeletal survey, chest x-ray, abdominal

ultrasound

OBLIGATORY CLINICAL AND

LABORATORY EVALUATION

Reference: Haupt R, et al. Langerhans Cell Histiocytosis (LCH): Guidelines for Diagnosis, Clinical Work-Up,

and Treatment for Patients Till the Age of 18 Years. Pediatr Blood Cancer, 2013;60:175–184

EVALUATION UPON INDICATION

Test Indication

HLA-typing and donor search Involvement of risk organs

Bone marrow tap and trephine biopsy Anemia, leukopenia, thrombocytopenia

Respiratory function test, HRCT Dyspnea, changes on thorax x-ray

Lung biopsy (if BAL negative) Dyspnea, changes on thorax x-ray (Cave

opportunistic infections)

Gut endoscopy (biopsy?) chronic, diarrhea, malabsorption, weight loss

Liver biopsy Liver dysfunction (discrimination between active

disease and cirrhosis)

Panoramic x-ray of the jaw Floating teeth, lumps or mucosal lesions

Skull CT Suspected orbital, temporal or other skull base

lesion

MRI of the brain Neurological or endocrine abnormalities

Consult endocrinologist DI, growth failure, other endocrine abnormalities

Consult neurologist/psychologist DI, neurological signs and symptoms, abnormal

MRI

Consultation ENT specialist, audiogram Chronic otitis, otorrhea, hearing loss

Consult ophthalmologist Proptosis, orbital lesions

CLINICAL CLASSIFICATION

SINGLE SYSTEM DISEASE

Single or Multiple Site

Bone

Skin

Lymph node

(CNS, Lungs, Thyroid)

MULTISYSTEM DISEASE

> 2 organs involved

± risk organ involvement

DATA OF THE DAL-HX STUDIES

on single-system LCH

Overall survival: 100%

Event-free survival: 82%

Reactivations 18%

Permanent consequences: 25%*

* 50% of the PC present at diagnosis

Ref.: Titgemeyer C. et al., MPO, 2001, 37:108-114

STANDARD OF CARE

FOR

SINGLE-SYSTEM LCH

CURRENT RECOMMENDATIONS

CURRENT RECOMMENDATIONS

SS-LCH

Skeleton Skin Lymph nodes

multifocal

Lo

cal

Th

era

py,

«w

ait

& s

ee»

Syste

mic

Th

era

py

Lo

cal

or

syste

mic

T

hera

py

Syste

mic

Th

era

py

unifocal multifocal

Resecti

on

unifocal

95% 5% <1%

PROSPECTIVE CLINICAL TRIALS

OF THE HISTIOCYTE SOCIETY

LCH I Study 1991-1995

LCH II Study 1996-2000

LCH III Study 2001-2008

MULTISYSTEM LCH

(≥ 2 involved organs / systems)

± “Risk Organs”

LCH IV Study 2012- ongoing

n=1074

Blood, 2013, 121(25):5006-5014

J Pediatr. 2001,138(5):728-34

MULTISYSTEM LCH

Overall Survival: RO+ MS-LCH

Patients Events 5-yrs. OS p-value

HX 83/90 53 15 0.72±0.06 0.000

LCH-I 108 38 0.63±0.05 .

LCH-II 172 55 0.66±0.04 .

LCH-III 248 32 0.86±0.02

LCH-III

Relapses after NAD: All MS-LCH

Reactivations Deaths without

reactivation

No event

Patients events 5 yrs. CIR Deaths 5-yrs. p 5-yrs. p

HX 83/90 72 23 0.33±0.06 0 0.00±0.00 0.67±0.06

LCH-I 127 64 0.51±0.05 1 0.01±0.01 0.48±0.05

LCH-II 236 101 0.45±0.03 1 0.00±0.00 0.55±0.03

LCH-III 365 115 0.35±0.03 2 0.01±0.01 0.64±0.03

P-value . . 0.000 . 0.702 0.000

33-35%

INITIAL TREATMENT COURSE 1 INITIAL TREATMENT COURSE 2

NAD procede to continuation therapy arm A

A

NAD procede to

AD better AD better continuat. tx arm A

AD intermediate

AD intermediate procede to salvage

AD worse

RX

AD worse procede to salvage

NAD

B NAD procede to

AD better continuat. tx arm B

AD better

AD intermediate

AD intermediate procede to salvageAD worse

AD worse procede to salvage

day 1 8 15 22 29 36

w eek 1 2 3 4 5 6 7 8 9 10 11 12

PDN 40 mg/m2/d orally day 1-28 PDN 40 mg/m2/d orally day 1 - 3; weekly for 6 weeks

afterwards weekly reduction

MTX 500 mg/m² q 2 weeks(+Ca-folate rescue) MTX 500 mg/m² q 2 weeks (+Ca-folate rescue)

VBL 6 mg/m2 i.v. bolus; day 1,8,15,22,29,36 VBL 6 mg/m2 i.v. bolus; day 43,50,57,64,71,78

w eek

procede to continuation therapy arm B

6 WKS

EVALUATION EVALUATION

12 WKS

LCH IIIRO+: INITIAL TREATMENT

Introduction of Initial Treatment Course 2 for Intermediate Responders

STANDARD

FRONTLINE TREATMENT

FOR MS-LCH

OUTSIDE OF CLINICAL TRIALS

GENERAL APPROACH

• INITIAL THERAPY

• intensive, duration 6-12 weeks

• CONTINUATION THERAPY

• non-intensive, duration at least 12 months

VBL 6 mg/m2 i.v.bolus

PRED 40 mg/m2/day

orally; weekly; tapering

after week 4

VBL 6 mg/m2 i.v.bolus

PRED 40 mg/m2/day

orally; weekly day 1-3

Initial Treatment

Continuation Treatment

87 50Week 519 10 11 12 13 49

VBL 6 mg/m2 i.v.bolus

PRED 40 mg/m2/day

orally; day 1-5 q 3 week

21 3 4 5 6

87 9 10 11 12

52

Week

Week

MS-LCH: STANDARD TREATMENT

MS-LCH: Challenges

MORTALITY

Progression

10% of all MS-LCH

or

20% of RO+MS-LCH

MORBIDITY

Relapses

~40% of the SURVIVORSPermanent Consequences

Liver/Lung fibrosis <1%

Diabetes insipidus 20%

Anterior pituitary dysfunction 10%

Neurodegeneration 10%

Ref.: Gadner H al., Blood, 2013, 121: 5006-5014

Beyond standard treatment:

progression or relapse

HIGH-RISK(mostly progression)

NON-RISK(mostly incomplete response

or relapse within 2 years)

Hematologic dysfunction:

Hb <7.0 g/dl and/or transfusion dependency

PLT <20 x109/L and/or transfusion dependency

(both criteria have to be fulfilled)

AND/OR

Liver dysfunction:

Total protein <55 g/L or substitution dependency

Albumin <25 g/L or substitution dependency

(at least one of the two criteria to be fulfilled)

Active LCH in non-risk organs, e.g.:

Skin, Bone, Pituitary (DI)

Challenging scenarios:

- Newly manifested DI ± bone lesions

- Relapse after multiple chemotherapies

- Sclerosing cholangitis

- Neurodegenerative CNS-LCH

LCH IV Registry & Stratification

STRATUM II: n=400

2nd-line Therapy for

Non-risk LCH

STRATUM III: n=30

Salvage Therapy for

Risk LCH

STRATUM VII:

Long-term Follow up

STRATUM IV:

n=25

LCH-HSCT

Lack of response,

Progression,

in risk organs

STRATUM I: n=1200 (800 rand.)

1st-line Therapy

(Group 1 & 2)

Progression,

Reactivation,

in non-risk organs

Other single system

LCH

Multisystem, multifocal bone,

and special single system LCH

STRATUM VI: n=450

Natural history and

Management of

“other” SS-LCH

NAD

Lack of response,

Progression,

in risk organs

Progression,

Reactivation

STRATUM V: n=50

Monitoring & Treatment of

CNS-LCH

Isolated tumorous

LCH of the brain

LCH-IV: Participating countries

22

countries

LCH-IV: Patient accrual

(August 1st, 2018)

Total IT RU

AU

DE

NL

US

AT

BE

RS

BY

DK

GB

NZ

ES

CH

NO

CZ

SE

KR

PL

Total649 111 88 64 47 42 34 31 27 27 26 25 23 23 21 15 14 13 13 4 1

Accrual by year:

2013 6 . 5 . . . . 1 . . . . . . . . . . . . .

2014 52 . 16 6 2 12 . 6 7 . . . . 3 . . . . . . .

2015 103 13 26 14 8 7 . 6 5 9 4 1 . 4 . 4 2 . . . .

2016 175 40 18 17 25 8 1 12 7 11 8 7 . 8 . 4 4 4 1 . .

2017 183 27 18 18 7 11 11 5 8 5 6 11 14 7 8 4 6 4 9 4 .

2018 130 31 5 9 5 4 22 1 . 2 8 6 9 1 13 3 2 5 3 . 1

Treatment options for high-risk

MS-LCH

Hematopoietic stem cell transplantation

(HSCT)

Intensive myeloid-directed chemotherapy

(2-CdA/Ara-C)

Clofarabine

BRAF (MEK) inhibitors

HSCT

Risky but curative:

Best conditioning and

graft source debatable:

Donor availability remains

an issue:

Survival: 7/9 (78%)

RIC-HSCT

Ref.: Steiner M. et al., BMT, 2005, 36:215-225

-8

Fludarabin 5 x 30 mg/m2

Melphalan 1 x 140 mg/m2

MabCampath 5 x 0.2 mg/kg

CSA

MMF

-7 -6 -5 -4 -3 -2 -1 0

Prophylaxis of GvHD/ Rejection from

day -3 if indicated

HSCT

Summary:

1.) Available knowledge is derived from salvage of patients with

otherwise incurable severe, active MS-LCH disease.

2.) Role for a definitive cure in MS-LCH patients brought into

remission by BRAF/MEK inhibitors still not explored

2-CdA/ARA-C REGIMEN

Day 1 Day 2 Day 3 Day 4 Day 5 Day 6

Ara-C

2-CdA

Ara-C 500 mg/m2 q12 h (2-hr infusion)

2-CdA 9 mg/m2 qday (2-hr infusion)

x 2 COURSES

Ref.: Bernard F. et al., Eur J Cancer, 2005, 41:2682-9

2-CdA / Ara-C

Summary:

1.) An effective curative treatment for most severe MS-LCH.

2.) Highly myelotoxic and requires maximal supportive care.

3.) Difficult to justify in patients with less severe disease

4.) Long-term effects unknown

2-CdA / Ara-C

Clofarabine

n=6

n=11

Breaking new ground…

The first somatic mutation

Activated MAPK

Ref.: Chakraborty R et al., Blood, 2014, 124:3007-3015

Legend:

ERBB3 gene codes for Receptor tyrosine-protein kinase erbB-3,

also known as HER3 (human epidermal growth factor receptor 3),

a membrane bound protein

Ref.: Brown NA et al., Blood, 2014, 124:1655-1658

Genomic landscape of LCH

Reference: Durham BH. Semin Cell Dev Biol (2018), https://doi.org/10.1016/j.semcdb.2018.03.002

What is currently known

about LCH?

Abnormal proliferation and dissemination of clonal dendritic

cells of myeloid origin, which surface antigen profile similar to

that of normal Langerhans cells

LCH is driven by activating mutations of the MAPK pathway

Granuloma formation (various proportions of T-lymphocytes,

granulocytes, monocytes and eosinophils) and abundance of

cytokines evidence inflammatory reaction

Any organ (bone, skin, liver, lungs, spleen, lymph node,

brain, etc.) can be involved

Wide spectrum of clinical presentation with variable course

Putative Model on LCH

Pathobiology

Ref.: Zinn DJ et al., Oncology, 2016, 30(2): 122-132

Pathogenetic role of MAPK-Activation

Current View on

LCH Pathogenesis

Lymphocyte/macrophage

recruitment and activation

Myeloid neoplastic

clone with inflammatory

properties

Cytokine/chemokine

production

Granuloma formation±systemic inflammation

Tissue damage (e.g. osteolysis)

Fever, cytopenia, organ dysfunction

Somatic mutations:

BRAF, MAP2K1,

ARAF, other

(Modified from Arceci RJ, „Atypical cellular disorders“, Hematology 2002, 297 ff)

Myeloid

dendritic

precursors

Implications of the New Knowledge

o Characterizing the cell of origin

o Liquid biopsies

o Assessment of disease burden (staging) and

treatment response evaluation (MRD)

o Targeted treatment

Implications of the New Knowledge

Implications of the New Knowledge

Implications of the New Knowledge

Own observation

Kolenova et al, Blood Advances, 2017

e.g. vemurafenib, dabrafenib

MEK 1/2

RAF

ERK 1/2

P

P

P

P

GRB2

P

P

e.g. trametinib, cobimetinib

pipe line

nucleus

P

P

P

PRAS

P P

Targeting MAPK Pathway

Ref.: Zinn DJ et al., Oncology, 2016, 30(2): 122-132

Experience in Adults

Experience in Adults (2)

Toxicity of MAPK Inhibitors

Adult patients with ECD/LCH n=46

DRESS 2

Squamous carcinoma 1

Basal cell carcinoma 2

Melanoma 1

Hepatitis 1

Agranulocytosis 1

Side-effects universal with the „melanoma“ dose!

(Source: J. Haroche, personal communication)

Experience in Adults (3)

14/18 pts relapsed, but responded again after drug re-

introduction. After up to 4 years of teatment no resistance so far.(Source: J. Haroche, personal communication)

How long should one treat?

Experience in Adults (4)

Reference: Heretier S. et al. JAMA Oncol. 2015;1(6):836-838

8-month-old girl with BRAF V600E–mutated LCH: skin, bone, gut, lymph node, spleen involvement and hematological dysfunction (DAS, 5).

Pre-treatment: 2 vinblastine-steroid inductions followed by 1 course of cladribine (failure, DAS 10).

Treatment: Off-label treatment with the BRAF inhibitor vemurafenib was started at an initial dose of 120 mg twice daily (33.8 mg/kg/d) for 60

days after written informed consent from the parents. The tablets were split, crushed, and suspended in water for oral administration. To

assess the efficacy of treatment, the DAS was determined twice per week, and we also performed computed tomographic (CT) scans.

Effect:

On day 3, the patient’s general health improved with apyrexia, oral feeding, decreased skin lesions, and tumoral syndrome.

On day 7, the biological inflammatory syndrome disappeared, and hypoalbuminemia and anemia showed improvement (Figure).

On day 14, all signs of disease activity had disappeared (DAS, 0), and CT scan showed partial remission.

A CT scan at day 60 showed complete remission, and vemurafenib therapy was discontinued.

Vemurafenib Use in an Infant for High-Risk

Langerhans Cell Histiocytosis

Skin toxicity: (cutaneous eruption, WHO grade 2) occurred on day 20, and vemurafenib dose was reduced to 60 mg once daily (8.5 mg/kg/d)

without adverse events.

On day 90, skin relapse was diagnosed (DAS, 1). Vemurafenib was resumed at 120 mg once daily (13.3 mg/kg/d) for 2 months and was

effective (DAS, 0) without adverse effects. Five months after the second discontinuation of vemurafenib therapy, the patient remains in

complete remission without any sequelae (total follow up 10 months).

Experience with Vemurafenib in

pediatric LCH

International survey (unpublished data):Schedule: 20mg/kg/d BID for at least 8 weeks

MS-LCH: 50

Risk-organ involvement: 41/50

Median age at diagnosis: 0.9 years

Previous treatment: at least PRED/VBL

Median age at vemurafenib: 1.9 years

Median treatment duration: 10.7 months

Response at 8 weeks: 100% (32 NAD; 18 AD better)

Experience with Vemurafenib in

pediatric LCH (2)

International survey (unpublished data):

Schedule: 20mg/kg/d BID for at least 8 weeks

Response sustainability:

95% of those who discontinued VEM relapsed within 0.12 months

All were responsive to VEM re-inroduction

Toxicity:

80%, limited to skin (Grade I and II) and reversible

Proven activity in patients with a BRAFV600E mutation

Rapid response

Resistance not observed so far

? Cure with monotherapy possible?

? Optimal treatment duration unknown

? Long-term side-effects unknown

Well designed prospective studies needed

Vemurafenib

Summary:

LCH IV Registry & Stratification

Non-response / Progression in RO

STRATUM I

1st-line Therapy (Group 1 & 2)

Multisystem, multifocal bone,

and special single system LCH

STRATUM V

Monitoring & Treatment of CNS-LCH

Isolated tumorous CNS-

LCH or ND-CNS-LCH

Lack of response / Progression

Targeted Therapy

Testing for known (MAPK) mutations

BRAF+ BRAF-

Vemurafenib Cobemetinib

(Trametinib,

Selumetinib)

or Combo?

Lack of response / Progression/

Relapse in non-risk organs

STRATUM II

2nd-line Tx for

Non-risk LCH

Non-response / Progression/

multiple Relapses

in non-risk organs

* or as a first-line option

Acknowledgments:

All contributing countries and clinics

Histiocytosis Association of America

HistiozytoseHilfe e.V.

and

all other sponsors

of the LCH Study Reference Center

November 4 - 5, 2019Pre-Meeting: November 3, 2019

Memphis, Tennessee USARegistration opens in April – www.histiocytesociety.org/2019mtg

35th Annual Meeting