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Rebranding Langerhans Cell Histiocytosis

2017 USCAP/Society for Hematopathology

Carl Allen MD, PhD

ceallen@txch.org

Disclosure of Relevant Financial Relationships

USCAP requires that all planners (Education Committee) in a position to

influence or control the content of CME disclose any relevant financial

relationship WITH COMMERCIAL INTERESTS which they or their

spouse/partner have, or have had, within the past 12 months, which relates to

the content of this educational activity and creates a conflict of interest.

Disclosures

• Scientific Committee, NovImmune NI‐0501 (IFN‐gantibody) Clinical Trials.

• Consultant, Roche.

• There are no drugs approved for use in LCH.

Histiocytoses

• Histiocyte = “Tissue Cell”

• “Classification” is dynamic with changingunderstanding of biology.

• Classification based on presumed cell oforigin.

• Histiocytosis = Abnormal proliferation orfunction of a “histiocyte”

Classification of Histiocytoses

• DISORDERS OF VARIED BIOLOGICAL BEHAVIOR

• Dendritic Cell Proliferation

• Langerhans Cell Histiocytosis

• Xanthogranulomas

• Macrophage Proliferation

• Rosai‐Dorfman Disease• Sinus histiocytosis with massive lymphadenopathy

• Hemophagocytic Lymphohistiocytosis

• “HISTIOCYTIC” MALIGNANCIES

• Malignant Histiocytosis

• Histiocytic Sarcoma

• AML (M7)

Histiocyte Society Writing Group; Favara Med Ped Onc 1997

Neoplasms Derived from Histiocytes

M Lim, J Hematopath 2009

2001 WHO 2008 WHO

Histiocytic sarcoma Histiocytic sarcoma

LCH Tumors derived from LC (LCH and LC sarcoma)

LC sarcoma

IDC sarcoma/tumor IDC sarcoma

Follicular DC sarcoma/tumor Follicular DC sarcoma

DC sarcoma, NOS NOS + Indeterminate DC

Fibroblastic reticular

Disseminated JXG

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ICD10 “Histiocytoses”

Fernandes, Intl. Arch. Otorhinolaryngol 2009 North American Clinics in Hematology and Oncology, 1998

North American Clinics in Hematology and Oncology, 1998

“…LCH treatment “strategy” is based more on a roulette wheel than on scientifically based logic. Certainly part of the confusion and lack of consensus is derived from persisting ambivalence as to whether LCH is primarily a neoplastic disorder, an immunodysregulatory disorder, or a disorder with characteristics of both.”

Epidemiology

• Children:  5 cases/ 106

• Adults:   2 cases/ 106

•ALL 34/ 106

•NHL 9/ 106

•AML 7/ 106

•HD 5/ 106

•LCH 5/ 106

WHAT IS LCH?

“Langerhans Cell” Histiocytosis?

1868, On the Nerves of Human Skin

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LCH: 1900‐2010

What is LCH?

What is LCH? What is LCH?

What is LCH? What is LCH?

Hand‐Christian‐Schuller

Letterer‐Siwe

Eosinophilic granuloma

Hashimoto‐Pritzker

Histiocytosis X

Lichtenstein 1953

Pulmonary LCH

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Histiocytosis X

Langerhans Cell HistiocytosisNezelof et al., 1973

Photo courtesy of Dr. John Hicks

What is LCH?

Histology image courtesy of Dr. John Hicks

CD207 CD1A S100A Factor XIIFascin

Langerhans Cells  ‐ Basics

CD11c+CD207+CD1a+

TNFIFNIL1IL2IL6

CCR6CCR7

E-Cad

Draining LN

Epidermis

“Immature‐Activated” Model

CD11c+ CD207+CD1a+

TNFIFNIL1IL2IL6

CCR6CCR7

E-Cad

SkinBoneLiverLungLymph nodeBone marrowBrain

Epidermis

Survival: High vs Low Risk

High Risk Low Risk

LCHII – Histiocyte Society; Gadner , Blood 2008

Frequent “Reactivations”

Minkov et al., J. Pediatr, 2008

Low Risk

High Risk

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LCH: 2010‐2015

IsoAb

Iso Ab

CD207‐PE

CD1a‐FITC

Cell‐Specific Gene Expression Experiments

LCH CD207+ Transcriptome Suggests Immature Myeloid Phenotype

CD300LFITGAX (CD11c)ITGAM (CD11b)ICAM1 (CD54)CD33CD1dITGA4  (CD49d)ANPEP (CD13) 

Myeloid DC‐Associated Genes

Allen et al., JI, 2010

Epidermal LC LCH CD207+

Myeloid Dendritic Cell Precursors in LCH

Draining LN

Rolland et al., JI 2005Ginhoux et al., JEM 2007; Merad, Ginhoux, Collin, Nat Rev Imm 2008

Increased lin‐CD11c+ in LCHIncreased M‐CSF and Flt3L

CD207 is promiscuous‐Dermis, Lung, Kidney, Spleen

Epidermis

Dermis

Shifting Focus: The Myeloid Dendritic Cell in LCH

Draining LN

Epidermis

Dermis

•57% of LCH lesions with BRAFV600E• pMEK and pERK in all cases• No significant clinical correlation with genotype

BRAFV600E:A New Piece of the LCH Puzzle

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BRAFV600E in Texas: Clinical Correlations

•63% of patients with BRAFV600E

•No significant correlation:• high risk vs low risk • age (<2, 2-8, >8 years)• gender• single vs multifocal• overall survival

Berres et al., JEM 2014

BRAFV600E: Clinical Correlations

Pro

bab

ility

of

Rec

urre

nce

(Weeks)

Hazard Ratio: V600E Increased Risk of Recurrence 2.05 (95% CI: 0.99-4.25)

V600E

WT

Berres et al., JEM 2014

Circulating Cells with BRAF‐V600E in High Risk LCH

0% 13% 100%(0/26) (5/38) (12/12) Berres et al., JEM 2014

% C

ircu

latin

g C

ells

with

BR

AF

-V6

00

E A

llele

0

2

4

6

8

CD11c CD14 BDCA2 NF

MB0037

BRAF Bar‐Code:BRAFV600E in CD11c and CD14 cells

Berres et al., JEM 2014

0

2

4

6

8

10

12

14

16

CD34 CD14

%

Ce

lls

wit

h B

RA

F-V

60

0E

All

ele

BRAF Bar‐Code:BRAF‐V600E in CD34+ cells

Berres et al., JEM 2014

0

2

4

6

8

10

12

14

16

CD34 CD14

%

Ce

lls

wit

h B

RA

F-V

60

0E

All

ele

**50% of “normal” bone marrows had BRAF‐V600E+ CD34/precursors

Berres et al., JEM 2014

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Expressing V600E in langerin+ DCs BRAF in langerin+ DCs

BRAF in CD11c+ (pre)DCs  BRAF in CD11c+ (pre)DCs

Berres et al., JEM 2014

Misguided Myeloid DC Model of LCH

High-risk LCH(multisystem)

Low-risk LCH(multifocal)

Low-risk LCH(single lesion)

Self-renewingCD34+ stem/progenitor

(bone marrow)

Committed DCprecursors(BM-blood)

CD1a+/CD207+LCH Cells

Inflam

matio

nIn

flamm

ation

Inflam

matio

n

Committed DC precursors

(tissue)

Collin and Allen, HO Clinic NA 2015

Somatic mutation rate (Per MB x 10N )

Pediatriccancers

Median of ONE

somatic mutation per LCH sample0.03 muts/MB

VERY Low Mutation Frequency in LCH Patients

Chakraborty Blood 2014

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Recurrent MAP2K1 Mutations in LCH

BRAF-V600E MAP2K1 ?

Brown Blood 2014Chakraborty Blood 2014Nelson GCC 2015Diamond CancDisc 2015

More BRAF Mutations in LCH

Chakraborty Blood 2016

FUSION

INDELS

Genomic Landscape of LCH (2017)

RASRAS

RAFRAF

MEKMEK

ERKERK

65% BRAFV600E6% BRAF indel*BRAF Fusion*ARAF

15% MAP2K1

*ERBB3

LCH

11% Unknown

Genomic Landscape of Histiocytoses

Diamond et al., Canc Discovery 2016

+ Fusions: BRAF, ALK, NTRK1 in JXG/ECD

Toward Rationale Cure(s)

Standard of Care: How Are We Doing?

• LCH-III (High-Risk)• Poor response by Week 12: 30%• Reactivation within 3 Years: 29%

“EFS”=Cure with VBL/Pred: <41%

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LCH-IV (Histiocyte Society)

Open Now…

Front‐Line Randomized Trial

Phase III: Pred/Vbl (6MP) 1 vs 2 years

Pilot Trial (N=16) Front-line Cyatarabine: -100% EFS-93% 1 Year PFS

Open Now…(Texas Chidren’s and 12 Collaborating Sites)

Front‐Line Randomized Trial

LCH REASONPhase III: Pred/Vbl vs Ara-C Front-Line

N=120 to detect a 20% difference (60 vs 80%) in 1 yr PFS

Simko, BJH 2014

Can We Improve Chemotherapy?

Strategy PFS Survival Toxicity Citation

2-CdA (5mg/m2 x 5 day)

3% (6 month) RO+: 56% RO- : 90%

Minimal Weitzman 2009

2-CdA/Ara-C (9mg/m2; 1g/m2 x 5 day)

70% (3 year) RO+: 70% (7/10) Universal Bernard 2005

Ara-C (100-125 mg/m2 x 5 days)

60% (1 year) RO+: 100% (6/6) RO-: 100%

Minimal Simko 2015

Clofarabine (25mg/m2/day x 5 day)

75% (1 year) RO+: 67% (2/3) RO- : 100%

Minimal Simko 2014b

Goals: Eliminate myeloid neoplastic clone vs control “recurrence”?

CML >75%

Ware, R. Blood. 2010.

Hydroxyurea for LCH?

Example of Response to HU

Prior Treatment: • Ara-C• Clofarabine• 6MP/MTXLeft 9th ribRight T8 VertebraRight iliac crestSplenic uptakeNeedle biopsy = LCH

Zinn et al., Blood 2016

Vemurafenib in Adult ECD (Haroche JCO 2015)

Objective: Retrospective review of outcomes of patients with BRAF-V600E+ ECD

Primary Response: PET at 6 months-6/6 partial metabolic responders-Response durable with median 10.5 month follow-up

Toxicities:-6/6 with severe skin effects (Grade 2-3)-1/6 with squamous cell carcinoma

Salvage – BRAFV600E Inhibition

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Salvage – BRAFV600E Inhibition

Toxicity – “C/W other trials”

MSK Basket TrialHyman et al, NEJM 2015

Vem in Pediatrics

Heretier JAMA Oncology 2015“NAD” at 10 monthsNo toxicity reported

LCHIV Trial

LR Salvage: Pred/VCR/Ara-C with 6MP/MTX + Indomethacin

vsPred/VCR/Ara-C with 6MP/MTX

HR Salvage: Response after 2 courses Ara-C/2-CDA

Coming Soon…

NACHO-Clo: (Open)Clofarabine salvage for LR and HR

NCI COG MATCH: Vemurafenib (BRAF-V600E Inhibitor)Selumetinib (MEK Inhibitor)

BASKET:Multiple novel agents2nd Generation BRAF InhibitorsERK InhibitorsPD-1/PD-L1

Skin

It’s just LCH…

• Median time to biopsy: >3 mo• % patients with presumed skin-limited with multiystem: 50%

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Skin‐limited vs Multisystem

Simko J Peds 2014

Skin‐limited vs Multisystem

Simko J Peds 2014

CNS

CNS LCH

A

B

Skull Lesions: “Clean margins” impair remodeling

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Peripheral Blood Progenitors in LCH‐ND?

Peripheral Blood Progenitors in LCH‐ND?

Response to BRAFi in LCH‐ND

unpublished

Pt 1 Pt2 Pt3

Onset o

f ND

Pre‐BRAFi

On BRAFi

15 mo 2 mo 8 mo

4 years 10 years 2 years

PR PR NR

Model: LCH‐ND is LCH

CD34+ HSCCirculating

mDC precursorTissue-restricted

mDCCD1a+/CD207+LCH Lesion DC

High-risk LCH(multisystem)

Low-risk LCH(multifocal)

Low-risk LCH(single lesion)

Neurodegeneration

Implications: 1. Treat LCH to eradicate clone. 2. Look for LCH-ND in some systematic fashion (MRI/blood).3. Treat early

Lung

Lung LCH: A Case of Surgical Cure

Cytarabinex 12 months

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Cousins of LCH

Allen PBC 2015

Cousins of LCH

Allen PBC 2015

Juvenile Xanthogranuloma

Berres Adv Imm 2013; Simko PBC 2014; Chakraborty unpublished

Rosai‐Dorfman DiseaseSinus Histiocytosis with Massive Lymphadenopathy

Erdheim‐Chester Disease

Haroche et al., Current Opinion Rheumatology 2012; Haroche et al., JCO 2014

Evolving Models of Histiocytoses

Emile et al, Blood 2016; Frater Blood 2016

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Coffee Break Question

• LCH: (Inflammatory) Myeloid Neoplasia?

Vardiman et al., Blood 2009

Bonus Case

12 month male with history of skin rash and poor weight gain, now with fever and abdominal distension

Skin bx CD207

Images courtesy of Dr. Choladda Curry

Bonus CasePoor response to vinblastine/prednisone, recurrent fever, abdominal distention, sIL2Ra>10k, ferritin>10k

Bone marrow

CD163

Bonus Case: Bone Marrow

CD1a

CD163CD68

CD207CD1a

FactorXIIIa Fascin

Bonus Case: Back to Original SkinCD1a CD207

FascinFactorXIIIa

Bonus Case: Molecular Path

CD3 CD19 CD16 CD68 CD11c CD11c+CD14

no no yes yes yes yes

BRAF-V600E+• 3.1% of blood pbmc• 2.5% of bone marrow aspirate pbmc

Clinical Interpretation: Refractory BRAF-V600E+ mixed histiocytic myeloid neoplastic disorder (LCH + JXG) with reactive macrophage activation

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Coffee Break Question #2:

• CD1a, CD207, fascin, Factor XIIIa, CD163 for all “LCH”?

• BRAF qPCR (and/or sequencing) for all “LCH”?

Conclusions

Histiocytosis X

LCH

Histiocytosis X

Histiocytosis X

Histiocytosis Y

Histiocytosis Z

Back to Histiocytosis X,Y,Z… Pathways to LCH (JXG, ECD, RDD)

RAS

RAF

MEK

ERK

50-65% BRAF *ARAF

10-20% MAP2K1

*ERBB3

LCH

15-40% Unknown

CD207CD34

Newcastle UniversityMatthew Collin MD, PhDSingaporeFlorent Ginhoux PhDUPMCJennifer Picarcic MDFunding Sources:NCI Lymphoma SPORE (Heslop, PI)HistioCure FoundationNational Cancer Institute (5R01CA154489)St. Baldrick’s Consortium Award (NACHO)ASH Scholar AwardHistiocytosis AssociationBaylor COM Seed GrantTexas Children’s Hospital Pilot AwardThrasher Research Fund

TXCH Histiocytosis Program (BCM)Kenneth McClain, MD, PhDRikhia Chakraborty, PhDKaren Lim, MSBrooks Scull, MSDan Zinn MD, Amanda Grimes MDHarshal Abhyankar, MSErnesto Joubran MS, Aurora AlainisJohn Hicks MD, PhDPhillip Lupo PhD, Erin Peckham PhDChris Man PhD, Howard LinMunu Bilgi, Elizabeth PachecoWill Parsons MD, PhD, Oliver Hampton PhDDavid Wheeler PhDDolores Lopez-Terrada MD, PhD

Mt. Sinai SOMMiriam Merad MD, PhDMarie Berres MDJeremy PriceBrandon HogstadSergio Lira MD, PhDPoulikos Poulikakos PhDJuliana Idoyaga PhDUniversity of ZurichMarkus Manz MD, PhDUniversity Medical Center MainzBjorn Clausen