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Rebranding Langerhans Cell Histiocytosis
2017 USCAP/Society for Hematopathology
Carl Allen MD, PhD
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