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Rebranding Langerhans Cell Histiocytosis Rebranding Langerhans Cell Histiocytosis Disclosure of Relevant Financial Relationships 2017 USCAP/Society for Hematopathology USCAP requires that all planners (Education Committee) in a position to influence or control the content of CME disclose any relevant financial Carl Allen MD, PhD relationship WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which [email protected] relates to the content of this educational activity and creates a conflict of interest. Disclosures Histiocytoses • Histiocyte = “Tissue Cell” • Scientific Committee, NovImmune NI‐0501 (IFN‐g antibody) Clinical Trials. • “Classification” is dynamic with changing understanding of biology. • Consultant, Roche. • Classification based on presumed cell of origin. • There are no drugs approved for use in LCH. • Histiocytosis = Abnormal proliferation or function of a “histiocyte” Classification of Histiocytoses Neoplasms Derived from Histiocytes • DISORDERS OF VARIED BIOLOGICAL BEHAVIOR 2001 WHO 2008 WHO • Dendritic Cell Proliferation Histiocytic sarcoma Histiocytic sarcoma • Langerhans Cell Histiocytosis LCH Tumors derived from LC • Xanthogranulomas (LCH and LC sarcoma) LC sarcoma • Macrophage Proliferation • Rosai‐Dorfman Disease IDC sarcoma/tumor IDC sarcoma • Sinus histiocytosis with massive lymphadenopathy Follicular DC sarcoma/tumor Follicular DC sarcoma • Hemophagocytic Lymphohistiocytosis DC sarcoma, NOS NOS + Indeterminate DC • “HISTIOCYTIC” MALIGNANCIES • Malignant Histiocytosis Fibroblastic reticular • Histiocytic Sarcoma Disseminated JXG • AML (M7) Histiocyte Society Writing Group; Favara Med Ped Onc 1997 M Lim, J Hematopath 2009 1 ICD10 “Histiocytoses” Fernandes, Intl. Arch. Otorhinolaryngol 2009 North American Clinics in Hematology and Oncology, 1998 “…LCH treatment “strategy” is based Epidemiology more on a roulette wheel than on • Children: 5 cases/ 106 scientifically based logic. Certainly part • Adults: 2 cases/ 106 of the confusion and lack of consensus is derived from persisting ambivalence • ALL 34/ 106 as to whether LCH is primarily a • NHL 9/ 106 neoplastic disorder, an • AML 7/ 106 immunodysregulatory disorder, or a 6 disorder with characteristics of both.” • HD 5/ 10 • LCH 5/ 106 North American Clinics in Hematology and Oncology, 1998 “Langerhans Cell” Histiocytosis? WHAT IS LCH? 1868, On the Nerves of Human Skin 2 What is LCH? LCH: 1900‐2010 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 1953 3 What is LCH? Histiocytosis X 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 CD207+ CD11c+ CD207+ CD11c+ CD1a+ CD1a+ Epidermis Epidermis TNF TNF IFN IFN Draining LN IL1 IL1 IL2 IL2 IL6 IL6 Skin CCR6 Bone CCR7 CCR6 Liver Lung CCR7 E-Cad Lymph node Bone marrow E-Cad 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, 2008 4 Cell‐Specific Gene Expression Experiments PE ‐ Iso Ab LCH: 2010‐2015 CD207 Iso Ab CD1a‐FITC LCH CD207+ Transcriptome Suggests Myeloid Dendritic Cell Precursors Immature Myeloid Phenotype in LCH Increased lin‐CD11c+ in LCH Myeloid DC‐Associated Genes Increased M‐CSF and Flt3L CD300LF Epidermis ITGAX (CD11c) ITGAM (CD11b) ICAM1 (CD54) CD33 CD1d Dermis ITGA4 (CD49d) Draining LN ANPEP (CD13) CD207 is promiscuous ‐Dermis, Lung, Kidney, Spleen Epidermal LC LCH CD207+ Rolland et al., JI 2005 Ginhoux et al., JEM 2007; Merad, Ginhoux, Collin, Nat Rev Imm 2008 Allen et al., JI, 2010 Shifting Focus: BRAFV600E: The Myeloid Dendritic Cell in LCH 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 BRAFV600E: Clinical Correlations BRAFV600E in Texas: Clinical Correlations •63% of patients with BRAFV600E •No significant correlation: V600E • high risk vs low risk WT • age (<2, 2-8, >8 years) • gender Probability of RecurrenceProbability of • single vs multifocal (Weeks) • overall survival Hazard Ratio: V600E Increased Risk of Recurrence 2.05 (95% CI: 0.99-4.25) Berres et al., JEM 2014 Berres et al., JEM 2014 Circulating Cells with BRAF‐ BRAF Bar‐Code: V600E in High Risk LCH BRAFV600E in CD11c and CD14 cells MB0037 8 6 4 2 0 % Circulating Cells with BRAF-V600E Allele BRAF-V600E with Cells % Circulating 0% 13% 100% CD11c CD14 BDCA2 NF (0/26) (5/38) (12/12) Berres et al., JEM 2014 Berres et al., JEM 2014 BRAF Bar‐Code: **50% of “normal” bone marrows BRAF‐V600E in CD34+ cells had BRAF‐V600E+ CD34/precursors 16 16 14 14 12 12 10 10 8 8 6 6 4 4 2 2 % Cells with BRAF-V600E Allele % withCells BRAF-V600E Allele % withCells BRAF-V600E 0 0 CD34 CD14 CD34 CD14 Berres et al., JEM 2014 Berres et al., JEM 2014 6 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 CD1a+/CD207+ N CD34+ stem/progenitor precursors precursors LCH Cells Somatic mutation rate (Per MB x 10 ) (bone marrow) (BM-blood) (tissue) Inflammation Inflammation Inflammation High-risk LCH (multisystem) Median of ONE somatic mutation per LCH sample Low-risk LCH 0.03 muts/MB (multifocal) Low-risk LCH (single lesion) Pediatric cancers Collin and Allen, HO Clinic NA 2015 Chakraborty Blood 2014 7 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 65% BRAFV600E RAF 6% BRAF indel *BRAF Fusion *ARAF 11% Unknown MEK 15% MAP2K1 ERK + Fusions: BRAF, ALK, NTRK1 in JXG/ECD LCH 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 Front‐Line Randomized Trial Front‐Line Randomized Trial LCH-IV (Histiocyte Society) Pilot Trial (N=16) Front-line Cyatarabine: -100% EFS Open Now… -93% 1 Year PFS LCH REASON Phase III: Pred/Vbl (6MP) 1 vs 2 years 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 3% (6 month) RO+: 56% Minimal Weitzman (5mg/m2 x 5 day) RO- : 90% 2009 2-CdA/Ara-C 70% (3 year) RO+: 70% (7/10) Universal Bernard (9mg/m2; 1g/m2 x 5 day) 2005 CML Ara-C 60% (1 year) RO+: 100% (6/6) Minimal Simko >75% (100-125 mg/m2 x 5 days) RO-: 100% 2015 Clofarabine 75% (1 year) RO+: 67% (2/3) Minimal Simko (25mg/m2/day x 5 day) RO- : 100% 2014b Ware, R. Blood. 2010. Example of Response to HU Salvage – BRAFV600E Inhibition Prior Treatment: • Ara-C • Clofarabine Vemurafenib in Adult ECD (Haroche JCO 2015) •6MP/MTX Left 9th rib Right T8 Vertebra Objective: Retrospective review of outcomes of patients with Right iliac crest BRAF-V600E+ ECD Splenic uptake Needle biopsy = LCH 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 2016 9 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… NACHO-Clo: (Open) Clofarabine salvage for LR and HR LR Salvage: Pred/VCR/Ara-C with 6MP/MTX + Indomethacin NCI COG MATCH: vs Vemurafenib (BRAF-V600E Inhibitor) Pred/VCR/Ara-C with 6MP/MTX Selumetinib (MEK Inhibitor) HR Salvage: BASKET: Response after 2 courses Ara-C/2-CDA Multiple novel agents 2nd 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 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 Peripheral Blood Progenitors in Peripheral Blood Progenitors in LCH‐ND? LCH‐ND? Response to BRAFi in LCH‐ND Model: LCH‐ND is LCH Pt 1 Pt2 Pt3 Circulating Tissue-restricted CD1a+/CD207+ CD34+ HSC mDC precursor mDC LCH Lesion DC ND of High-risk LCH Onset (multisystem) 2 years 4 years 10 years Low-risk LCH (multifocal) BRAFi ‐ Low-risk LCH Pre (single lesion) 15 mo 8 mo 2 mo Neurodegeneration BRAFi On Implications: 1. Treat LCH to eradicate clone. 2. Look for LCH-ND in some systematic fashion (MRI/blood). PR PR NR 3. Treat early unpublished Lung LCH: A Case of Surgical Cure Lung Cytarabine x 12 months 12 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 2016 13 Coffee Break Question Bonus Case • LCH: (Inflammatory) Myeloid Neoplasia? 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.
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