Origin of Histiocytes Dendritic Cells - Cure4Kids

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Current Concepts in the Diagnosis and Treatment of Langerhans Cell

Histiocytosis

Carlos Rodriguez-Galindo, MD St Jude Children’s Research Hospital

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Origin of HistiocytesPPSC

CFU-GM

MonocytesHistiocytes Granulocytes

Professional Ag-presenting cells:

• Langerhans cells

• Dendritic cells

Mononuclear Phagocytes:

• Blood monocytes

•Tissue macrophages

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Dendritic Cells

• Critical Ag-presenting cells that initiate and coordinate the host immune response

• Originate in bone marrow

Migration to tissues

First line of defense4

Epidermis Lungs Orobuccal and vaginal epithelia

Regional LNs

Interdigitating dendritic cells

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Classification of Histiocytic Disorders

Class I

Class II

Class III

Cell

Dendritic cells

Macrophages

Monocytes Histiocytes

Disorders • Langerhans cell histiocytosis

• Juvenile Xanthogranuloma

• Hemophagocytic syndromes: • FEL • IAH

• Rosai-Dorfman

• Leukemias: • M4, M5 • CMML

• Lymphomas

Favara et al, Med Pediatr Oncol 1997

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•Uncontrolled clonal proliferation of DC

•DC arrested in an immature, partially activated stage

•Deviant regulation of cell division

•Aberrant interactions with the lesional microenvironment

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Pathogenesis

• Dendritic Cells: Critical role in immune system

• Langerhans Cell Histiocytosis:– LC with early activation: IL-1, TNF-a, GM-

CSF, IL-2 Activation of local T lymphocytes

– Demonstration of clonalityNeoplasia?

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Pathogenesis

Benign histological appearance of lesionsSpontaneous remisionsResponse to immunomodulation

Suggest reactive disease

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Models of Pathogenesis

Immune Dysregulation

Clonal Proliferation of Dendritic Cells


Uncontrolled ImmuneDysregulation

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Histopathology

• Uniform regardless of clinical severity:– Collections of pathologic

LC, interdigitating cells, macrophages, T lymphs, multinucleated giant histiocytes, eosinophils

– Diagnosis:• CD1a• EM: Birbeck granules

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Organ system involvement in LCH

Site % of casesinvolved

BoneSkinLiver, spleen, LNBone marrow

80603330

LungsOrbitOrodental

252520

OtologicalDiabetes insipidusGI tract

2015<5

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3

13

T10:Vertebra Plana

L4:Compr. fracture

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15 16

17 18

4

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Langerhans Cell Histiocytosis

Eosinophilic Granuloma Skin DiseasePoliostotic Bone DiseaseHand-Schuler-ChristianMulti-systemic DiseaseLetterer-Siwe

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Neuro-Endocrine Involvement

• DI:– Before, during, after (median 10-12 months)– Skull lesions and extraosseous disease– MRI: absent post pituitary bright signal, thickened

infundibulum– CT/RT: do not revert DI

• Other deficits:– GH deficiency > ACTH def > alt puberty

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CNS Involvement

• Hipothalamic-Pituitary system– Hypothalamus:

• Dist. Social behavior, appetite, temp regulation, sleep pattern

– Posterior Pituitary:• DI, growth failure, precocious/delayed puberty

• Neurologic dysfunction– Cerebellar-pontine pathway:

• Ataxia, tremor, intellectual impairment, severe CNS deterioration

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Pulmonary LCH

• Incidence and prevalence unknown– “15 LCH vs 274 Sarcoidosis”

• Mainly among whites• 90-95% adults• 90-95% smokers

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Histopathologic Features

• Proliferation of LC along small airways• Nodules 1-5 mm (equivalent to E.G.)• Progression + Fibrosis Honeycomb• LC may be identified in other processes• Histopathol. landmarks:

– CD1a+ stain– Birbeck granules

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Clinical Features

• Presenting symptoms: Cough, dyspnea• 25% asymptomatic• 30% systemic symptoms• Other sites of involvement:

– >85% isolated lung– 5-15% multi-system

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Radiologic Features

• Micronodular, reticulonodular cystic• Middle and upper lobes >> lower lobes• HR-CT:

– Reticulonodular changes– Combination of diffuse cystic changes with small

peribronchial nodular opacities

• D.D.: Emphysema, lymphangioleiomyomatosis

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LCH-Treatment

• LCH-I• DAL HX 83/90• LCH-II• LCH-III• Salvage Therapies

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LCH-I Study

A

B

MP 30 mg/kg VBL 6 mg/m2 q wk

VP-16 150 mg/m2/d x 3 q 3 wk

24 wks

24 wks

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LCH-I Study1991-1995 N= 143 pts

23%22%DI

55%61%Disease react.

80%76%Survival

69%58%Resp 24 wks

48%57%Resp 6 wks

VP-16VBL

H. Gadner J Pediatr 2001

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LCH-I

• Rapid response as a prognostic factor:– Good responders: 91% survival – Poor responders: 34% survival

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• DAL HX 83/90 (1983-1990)– Risk adapted protocols

• Induction: PRD + VBL +/- ETO• Continuation: PRD + VBL

PRD + VBL + ETOPRD + VBL + ETO + MTX

• Better results than LCH-I: response, reactivation rates

• No diffs in survival

Treatment DAL HX studies

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DAL-HX 83 and 90 Studies

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TreatmentDAL HX-83

Group N. Compl. Rem. Recurrences Mortality

Poliostotic 28 89% 12% 0%

Inv. soft tissues 57 91% 23% 4%

Organ Dysfunction 21 67% 42% 38%

H. Gadner, 1994

35Minkov et al Med Pediatr Oncol 2002

Response to Initial Treatment in Multisystem LCH

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IHS StratificationSingle-systemdisease

Single site • Single bone lesion

• Isolated skin disease

• Solitary lymph nodeinvolvement

Multiple site • Multiple bone lesions

• Multiple lymph nodeinvolvement

Multi-system disease Low risk • Without involvement ofliver, lungs, BM, spleen

High risk • With inv. of liver, lungs,BM, spleen

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Protocol LCH-II for multi-system LCH

• Low Risk:– > 2 years– Without involvement of hemop. system,

liver, spleen, lungs

• High Risk:– < 2 years or– > 2 years with involvement of risk organs

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• LCH-II protocol (1996-2000)– Randomized study for multi-system disease

• Low Risk: – Induction: [PRD + VBL] x 6 wks – Continuation: [PRD + VBL] q 3wk x 6 mo

• Risk:– Arm A: [PRD+VBL]x6 wks + [PRD+VBL+6-MP] x 6 mo– Arm B: + ETO + ETO

Treatment IHS Studies

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Protocol LCH-II for multi-system LCH

Induction x 6 wks. Maintenance x 6 mos.

Low Risk

High Risk

PRD

VBL

6-MP

VP-16

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Protocol LCH-II H. Gadner, Amsterdam, October 2000

• Multi-system disease: 321 patients– Low Risk: 87 (27%) Age 4 y.– High Risk: 233 (73%) Age 12 m.

• 69% > 2 yrs with organ inv.• 31% < 2 yrs

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Response Frequency Mortality

Good Response 66% 8%

Intermediate 16% 27%

No response 17% 38%

High Risk, response to induction

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Risk Group EFS S

Low Risk 84% 100%

< 2 yrs without O.D. 75% 95%

+ Organ Dysfunction 49% 62%

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• Remission induction:– Low Risk: 84%– Risk: 57%

• Reactivation of Disease:– LCH I, LCH-II >> DAL-HX-83/90

• No benefit of addition of etoposide• Most important prognostic factors:

– Risk organ involvement– Poor response to induction

• < 2 yrs without risk-organ inv: not associated with poor outcome

LCH-II ProtocolConclusions

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• Conclusions:– Results are worse than DAL-HX-83/90– No differences arms A vs B – Response to induction: most important

prognostic factor – Patients < 2 yrs without O.D.don’t have

worse prognosis

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Stratification LCH-III H. Gadner, Amsterdam, October 2000

• High Risk:– Patients with O.D.

• Low Risk:– Multi-system without O.D.– Poliostotic disease– Skull involvement with intracraneal

extension

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LCH-IIIRisk Definition

• Involvement of “Risk Organs”:– Hematopoietic:

• Hb < 10 g/dl, WBC < 4,000, Plat < 100,000

– Spleen:• Palpable > 2 cm

– Liver:• Palpable > 3 cm• Liver dysfunction

– Lung:• Interstitial disease

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LCH-IIIStratification

• Group 1: Risk Group– Multi-system disease with 1+ RO involv.

• Group 2: Low-Risk Group– Multi-system disease without RO involv.

• Group 3:– Multifocal Bone Disease and Special Sites

(CNS-risk lesions, vertebral)

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LCH IIITreatment

• Group 1: Risk patients– Randomization PRD+VBL+6-MP +/- MTX– Duration: 12 months

• Group 2: Low-risk patients– PRD+VBL– Randomization: 6 vs 12 months

• Group 3: MFB and CNS-risk patients– PRD+VBL x 6 months

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Arm A

12 months

No Active Disease

Intermediate Response or Worse

12 months

No Active Disease


Arm B

LCH-III Protocol: Group 1 – Multisystem “Risk” Patients

VBL 6 mg/m2

PRD 40 mg/m2/d x 3

PRD 40 mg/m2/d x 5

6-MP 50 mg/m2/d

MTX 500 mg/m2

MTX 20 mg/m2 qwk

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LCH-III Protocol: Group 2 – Low Risk Patients

6 monthsNo Active Disease


12 months

VBL 6 mg/m2

PRD 40 mg/m2/d x 3

PRD 40 mg/m2/d x 5

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CNS-Risk LesionsFacial bones or Anterior or Medial Cranial Fossa:

Temporal Sphenoidal Ethmoidal Cygomatic bone Orbits

With intracranial extension

3 x risk of CNS disease52

6 months

No Active Disease

Intermediate Response or Worse VBL 6 mg/m2

PRD 40 mg/m2/d x 3

PRD 40 mg/m2/d x 5

LCH-III Protocol: Group 3 – Multifocal Bone Disease and Special Sites

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Accumulation of abnormal LCs

Recruitment of normal MN cells, lymphocytes, eos

Secretion of proinflammatory chemokines and cytokines

Late consequences:•Endocrine abnormalities•Lung and liver fibrosis•CNS abnormalities•Bone and dental problems•Learning difficulties

Late Effects

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Future Challenges

• Endocrinologic Sequelae:– Diabetes Insipidus– Multiple Endocrinopathies

• Neurologic Sequelae:– Neuro-degenerative disease– Intelectual deficits

Low Quality of Life

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LCH-Treatment

• LCH-I• DAL HX 83/90• LCH-II• LCH-III• Salvage Therapies

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•Uncontrolled clonal proliferation of DC

•DC arrested in an immature, partially activated stage

•Deviant regulation of cell division

•Aberrant interactions with the lesional microenvironment

57Henter et al. NEJM 2001

Anti-TNF-α Therapy

• 5 mo girl with MS-LCH• Failure to induction

therapy (PRD+VBL)• SD to HD-PRD + MTX +

6MP +VBL• Etanercept 0.4 mg/kg

sc twice/week

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Pathogenesis of Bone Lesions

Langerhans Cells

IL-1 PGE-2

•Osteoclast-activation

• Inhibition of bone formation

•Bone resorption

Bone Lysis

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Langerhans Cells

IL-1 PGE-2



•Bone resorption

Bone Lysis

Indomethacin

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Indomethacin

• 10 pts with bone LCH– 6 single system– 4 MS

• IDM: 1-2.5 mg/kg/d• CR in 8 pts

Munn et al MPO 1999

Brown, MPO 2000

Cox-2 expression

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Langerhans Cells

IL-1 PGE-2



•Bone resorption

Bone Lysis

IndomethacinBisphosphonates

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Bisphosphonates

• Osteoclast inhibitors– Improve bone structure– Decrease inflammatory substances

• Experience:– Pamidronate90 mg iv x 3d q 3 mo– Pamidronate 90 mg iv q month– Etidronate 200 mg/m2/d x 14d po q 3 mo

Farran, JPHO 2001; Kamizono JBMR 2002; Arzoo NEJM 2001

63Kamizono et al, JBMR 2002

Etidronate 200 mg/m2/d x 14d po q 3 mo

Dx 3 courses 6 courses

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2-chloro-deoxyadenosine

ADA

d-Adenosine

dAMP, dADP, dATP Detoxification

d-Adenosine

dAMP, dADP, dATP Toxicity

Lymphopenia

ADA

Normal Cell

SCIDS

dCK

dCK

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2-CdA

Cl-dAMP, Cl-dADP, Cl-dATP DetoxificationADA

Cl-dAMP, Cl-dADP, Cl-dATPCl-dAMP, Cl-dADP, Cl-dATP Cell death

dCK

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2-CdA


Cl-dAMP, Cl-dADP, Cl-dATPCl-dAMP, Cl-dADP, Cl-dATPCl-dAMP, Cl-dADP, Cl-dATPCl-dAMP, Cl-dADP, Cl-dATP

Cell death

dCK

12

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2-CdA in Malignant Hemopathies

• Adults:– Hairy Cell Leukemia 90%– CLL 50-80%– NHL 50-60%– T-cell lymphomas 30-40%

• Children:– AML 60%

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2-CdA


Cl-dAMP, Cl-dADP, Cl-dATPCl-dAMP, Cl-dADP, Cl-dATPCl-dAMP, Cl-dADP, Cl-dATPCl-dAMP, Cl-dADP, Cl-dATP

Cell death

dCKMature lymphocytesMature Monocytes

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Models of Pathogenesis

Uncontrolled Immune Dysregulation



Uncontrolled Immune Dysregulation

2-CdA

Cyclosporine A

Cyclosporine A

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2-CdA in LCH

Author N. Involvement Dose Responses

Saven, 1999

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Multi-system

0.14 mg/kg/d x 5 d.

82%

Stine, 1997

3

Multi-system

5-8 mg/m2/d x 5 d

100%

Weitzman, 1999

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Multi-system

5-13 mg/m2/d

60%

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2-CdA in LCHSt. Jude Experience

Age Inv. Previus tx Dose Response F-U

5 y.

Bones

PRD, VBL

[6 mg/m2 x 5] x 6

CR

12 mos.

6 y.

Bones

PRD, VBL ETO, 6-MP

[5 mg/m2 x 5] x 6

CR

3 mos.

6 y.

Skin

PRD, VBL

[5 mg/m2 x 5] x 6

CR

10 mos.

10 y.

Skin,

subcut., LN

PRD, VBL

[5 mg/m2 x 5] x 6

CR

9 mos.

Patients with recurrent low risk disease

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2-CdA in LCHSt. Jude Experience

Age Previous tx. Inv. Treatment Response F-U

8 y.

PRD, VBL, ETO, CsA

Skin, LN, Lung, Liver, Spleen

2-CdA x 7

CR

Rec. 13

m. 2nd CR

4 m.

-

Skin, LN, Bone,

Lung, Heart, Liver, Spleen, GI

2-CdA +

VBL, ETO, CsA

CR

10 mos.

9 m.

-

Skin, Liver,

Spleen, BM, GI

2-CdA + PRD, VBL

CR

10 mos.

Patients with multi-system disease

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73 74

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Other Salvage Therapies

• Immunosuppression:– CsA, ATG Not effective

• Hematopoietic Stem Cell Transplant• AML-type therapy

– DAV/DAE– 2-CdA + Ara-C

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2-CdA + Ara-C

Ara-C Ara-CTP

2-CdA 2-CdATP

dCK dCTP

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2-CdA + Ara-C

Ara-C Ara-CTP

2-CdA 2-CdATP

dCK dCTP

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2-CdA + Ara-C

Ara-C Ara-CTP

2-CdA 2-CdATP

dCK dCTP

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Current Concepts in the Diagnosis and Treatment of Langerhans Cell

Histiocytosis

Carlos Rodriguez-Galindo, MD

St Jude Children’s Research Hospital

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Origin of Histiocytes Dendritic Cells - Cure4Kids

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