Rebranding Langerhans Cell Histiocytosis

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1 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 g antibody) Clinical Trials. Consultant, Roche. There are no drugs approved for use in LCH. Histiocytoses Histiocyte = Tissue Cell Classification is dynamic with changing understanding of biology. Classification based on presumed cell of origin. Histiocytosis = Abnormal proliferation or function 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 2001 WHO 2008 WHO Histiocytic sarcoma LCH LC sarcoma IDC sarcoma/tumor Follicular DC sarcoma/tumor DC sarcoma, NOS Histiocytic sarcoma Tumors derived from LC (LCH and LC sarcoma) IDC sarcoma Follicular DC sarcoma NOS + Indeterminate DC Fibroblastic reticular Disseminated JXG M Lim, J Hematopath

2 ICD10 Histiocytoses Fernandes, Intl. Arch. Otorhinolaryngol 2009 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/ 10 6 Adults: 2 cases/ 10 6 ALL 34/ 10 6 NHL 9/ 10 6 AML 7/ 10 6 HD 5/ 10 6 LCH 5/ 10 6 North American Clinics in Hematology and Oncology, 1998 Langerhans Cell Histiocytosis? WHAT IS LCH? 1868, On the Nerves of Human Skin 2

3 What is LCH? LCH: What is LCH? What is LCH? What is LCH? What is LCH? Hand Christian Schuller Eosinophilic granuloma Letterer Siwe Hashimoto Pritzker Pulmonary LCH Histiocytosis X Lichtenstein

4 Histiocytosis X What is LCH? CD207 CD1A S100A Fascin Factor XII Photo courtesy of Dr. John Hicks Langerhans Cell Histiocytosis Nezelof et al., 1973 Histology image courtesy of Dr. John Hicks Langerhans Cells Basics Immature Activated Model CD11c+ CD207+ CD1a+ CD11c+ CD207+ CD1a+ Epidermis TNF IFN IL1 IL2 IL6 CCR6 CCR7 E-Cad Draining LN Epidermis TNF IFN IL1 IL2 IL6 CCR6 CCR7 E-Cad Skin Bone Liver Lung Lymph node Bone marrow Brain Survival: High vs Low Risk Frequent Reactivations High Risk Low Risk High Risk Low Risk LCHII Histiocyte Society; Gadner, Blood 2008 Minkov et al., J. Pediatr,

5 Cell Specific Gene Expression Experiments LCH: Iso Ab CD207 PE Iso Ab CD1a FITC LCH CD207+ Transcriptome Suggests Immature Myeloid Phenotype Myeloid DC Associated Genes Myeloid Dendritic Cell Precursors in LCH Increased lin CD11c + in LCH Increased M CSF and Flt3L CD300LF ITGAX (CD11c) ITGAM (CD11b) ICAM1 (CD54) CD33 CD1d ITGA4 (CD49d) ANPEP (CD13) Epidermis Dermis Draining LN Epidermal LC LCH CD207+ Allen et al., JI, 2010 CD207 is promiscuous Dermis, Lung, Kidney, Spleen Rolland et al., JI 2005 Ginhoux et al., JEM 2007; Merad, Ginhoux, Collin, Nat Rev Imm 2008 Shifting Focus: The Myeloid Dendritic Cell in LCH BRAFV600E: A New Piece of the LCH Puzzle Epidermis Dermis Draining LN 57% of LCH lesions with BRAFV600E pmek and perk in all cases No significant clinical correlation with genotype 5

6 BRAFV600E in Texas: Clinical Correlations BRAFV600E: 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 Probability of Recurrence V600E WT (Weeks) Hazard Ratio: V600E Increased Risk of Recurrence 2.05 (95% CI: ) Berres et al., JEM 2014 Berres et al., JEM 2014 Circulating Cells with BRAF V600E in High Risk LCH BRAF Bar Code: BRAFV600E in CD11c and CD14 cells 0% 13% 100% (0/26) (5/38) (12/12) Berres et al., JEM 2014 % Circulating Cells with BRAF-V600E Allele MB0037 CD11c CD14 BDCA2 NF Berres et al., JEM 2014 BRAF Bar Code: BRAF V600E in CD34+ cells **50% of normal bone marrows had BRAF V600E+ CD34/precursors % Cells with BRAF-V600E Allele CD34 CD14 Berres et al., JEM 2014 % Cells with BRAF-V600E Allele CD34 CD14 Berres et al., JEM

7 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 VERY Low Mutation Frequency in LCH Patients Self-renewing Committed DC Committed DC CD34+ stem/progenitor precursors precursors (bone marrow) (BM-blood) (tissue) CD1a+/CD207+ LCH Cells Somatic mutation rate (Per MB x 10 N ) High-risk LCH (multisystem) Low-risk LCH (multifocal) Low-risk LCH (single lesion) Inflammation Inflammation Inflammation Median of ONE somatic mutation per LCH sample 0.03 muts/mb Pediatric cancers Collin and Allen, HO Clinic NA 2015 Chakraborty Blood

8 Recurrent MAP2K1 Mutations in LCH More BRAF Mutations in LCH FUSION BRAF-V600E MAP2K1? INDELS Brown Blood 2014 Chakraborty Blood 2014 Nelson GCC 2015 Diamond CancDisc 2015 Chakraborty Blood 2016 Genomic Landscape of LCH (2017) Genomic Landscape of Histiocytoses *ERBB3 RAS 11% Unknown RAF MEK 65% BRAFV600E 6% BRAF indel *BRAF Fusion *ARAF 15% MAP2K1 ERK LCH + Fusions: BRAF, ALK, NTRK1 in JXG/ECD Diamond et al., Canc Discovery 2016 Standard of Care: How Are We Doing? LCH-III (High-Risk) Poor response by Week 12: 30% Reactivation within 3 Years: 29% Toward Rationale Cure(s) EFS =Cure with VBL/Pred: <41% 8

9 Front Line Randomized Trial LCH-IV (Histiocyte Society) Open Now Phase III: Pred/Vbl (6MP) 1 vs 2 years Front Line Randomized Trial Pilot Trial (N=16) Front-line Cyatarabine: -100% EFS -93% 1 Year PFS LCH REASON Phase III: Pred/Vbl vs Ara-C Front-Line Open Now (Texas Chidren s and 12 Collaborating Sites) N=120 to detect a 20% difference (60 vs 80%) in 1 yr PFS Simko, BJH 2014 Can We Improve Chemotherapy? Hydroxyurea for LCH? Goals: Eliminate myeloid neoplastic clone vs control recurrence? Strategy PFS Survival Toxicity Citation 2-CdA (5mg/m2 x 5 day) 3% (6 month) RO+: 56% RO- : 90% Minimal Weitzman CdA/Ara-C (9mg/m2; 1g/m2 x 5 day) Ara-C ( mg/m2 x 5 days) 70% (3 year) RO+: 70% (7/10) Universal Bernard % (1 year) RO+: 100% (6/6) RO-: 100% Minimal Simko 2015 CML >75% Clofarabine (25mg/m2/day x 5 day) 75% (1 year) RO+: 67% (2/3) RO- : 100% Minimal Simko 2014b Ware, R. Blood Prior Treatment: Ara-C Clofarabine 6MP/MTX Left 9 th rib Right T8 Vertebra Right iliac crest Splenic uptake Needle biopsy = LCH Example of Response to HU Salvage BRAFV600E Inhibition 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 Zinn et al., Blood

10 Salvage BRAFV600E Inhibition Vem in Pediatrics MSK Basket Trial Hyman et al, NEJM 2015 Toxicity C/W other trials NAD at 10 months No toxicity reported Heretier JAMA Oncology 2015 LCHIV Trial Coming Soon LR Salvage: Pred/VCR/Ara-C with 6MP/MTX + Indomethacin vs Pred/VCR/Ara-C with 6MP/MTX HR Salvage: Response after 2 courses Ara-C/2-CDA NACHO-Clo: (Open) Clofarabine salvage for LR and HR NCI COG MATCH: Vemurafenib (BRAF-V600E Inhibitor) Selumetinib (MEK Inhibitor) BASKET: Multiple novel agents 2 nd Generation BRAF Inhibitors ERK Inhibitors PD-1/PD-L1 It s just LCH Median time to biopsy: >3 mo % patients with presumed skin-limited with multiystem: 50% Skin 10

11 Skin limited vs Multisystem Skin limited vs Multisystem Simko J Peds 2014 Simko J Peds 2014 CNS CNS LCH Skull Lesions: Clean margins impair remodeling A B 11

12 Peripheral Blood Progenitors in LCH ND? Peripheral Blood Progenitors in LCH ND? Response to BRAFi in LCH ND Model: LCH ND is LCH Pt 1 Pt2 Pt3 Onset of ND High-risk LCH (multisystem) CD34+ HSC Circulating Tissue-restricted mdc precursor mdc CD1a+/CD207+ LCH Lesion DC Pre BRAFi 2 years 4 years 10 years Low-risk LCH (multifocal) Low-risk LCH (single lesion) 15 mo 8 mo 2 mo Neurodegeneration On BRAFi PR PR NR unpublished Implications: 1. Treat LCH to eradicate clone. 2. Look for LCH-ND in some systematic fashion (MRI/blood). 3. Treat early Lung LCH: A Case of Surgical Cure Lung Cytarabine x 12 months 12

13 Cousins of LCH Cousins of LCH Allen PBC 2015 Allen PBC 2015 Juvenile Xanthogranuloma Rosai Dorfman Disease Sinus Histiocytosis with Massive Lymphadenopathy Berres Adv Imm 2013; Simko PBC 2014; Chakraborty unpublished Erdheim Chester Disease Evolving Models of Histiocytoses Haroche et al., Current Opinion Rheumatology 2012; Haroche et al., JCO 2014 Emile et al, Blood 2016; Frater Blood

14 Coffee Break Question LCH: (Inflammatory) Myeloid Neoplasia? Bonus Case 12 month male with history of skin rash and poor weight gain, now with fever and abdominal distension Skin bx CD207 Vardiman et al., Blood 2009 Images courtesy of Dr. Choladda Curry Bonus Case Poor response to vinblastine/prednisone, recurrent fever, abdominal distention, sil2ra>10k, ferritin>10k CD1a CD1a Bonus Case: Bone Marrow CD207 Bone marrow FactorXIIIa CD68 Fascin CD163 CD163 CD1a Bonus Case: Back to Original Skin CD207 Bonus Case: Molecular Path BRAF-V600E+ 3.1% of blood pbmc 2.5% of bone marrow aspirate pbmc FactorXIIIa Fascin CD3 CD19 CD16 CD68 CD11c CD11c+CD14 no no yes yes yes yes Clinical Interpretation: Refractory BRAF-V600E+ mixed histiocytic myeloid neoplastic disorder (LCH + JXG) with reactive macrophage activation 14

15 Coffee Break Question #2: CD1a, CD207, fascin, Factor XIIIa, CD163 for all LCH? BRAF qpcr (and/or sequencing) for all LCH? Conclusions Back to Histiocytosis X,Y,Z Pathways to LCH (JXG, ECD, RDD) *ERBB3 RAS RAF 50-65% BRAF *ARAF CD34 CD % Unknown MEK 10-20% MAP2K1 Histiocytosis X ERK LCH LCH Histiocytosis X Histiocytosis X Histiocytosis Y Histiocytosis Z TXCH Histiocytosis Program (BCM) Kenneth McClain, MD, PhD Rikhia Chakraborty, PhD Karen Lim, MS Brooks Scull, MS Dan Zinn MD, Amanda Grimes MD Harshal Abhyankar, MS Ernesto Joubran MS, Aurora Alainis John Hicks MD, PhD Phillip Lupo PhD, Erin Peckham PhD Chris Man PhD, Howard Lin Munu Bilgi, Elizabeth Pacheco Will Parsons MD, PhD, Oliver Hampton PhD David Wheeler PhD Dolores Lopez-Terrada MD, PhD Mt. Sinai SOM Miriam Merad MD, PhD Marie Berres MD Jeremy Price Brandon Hogstad Sergio Lira MD, PhD Poulikos Poulikakos PhD Juliana Idoyaga PhD University of Zurich Markus Manz MD, PhD University Medical Center Mainz Bjorn Clausen Newcastle University Matthew Collin MD, PhD Singapore Florent Ginhoux PhD UPMC Jennifer Picarcic MD Funding Sources: NCI Lymphoma SPORE (Heslop, PI) HistioCure Foundation National Cancer Institute (5R01CA154489) St. Baldrick s Consortium Award (NACHO) ASH Scholar Award Histiocytosis Association Baylor COM Seed Grant Texas Children s Hospital Pilot Award Thrasher Research Fund 15