Perspective historique

30 derniéres années

83 93 04/96 LCH II 07/01 01/02 LCH III 11/07

91 LCHI 95

VP16 Arac

Bolus

stéroide

BMT 4/98 2 Cda Arac

Etat des lieux 1983 - 1993

Survie des patients – années 1983 -1993

Séquelles 1983-1993

Années 2000-2007

• Protocoles thérapeutiques ouverts

– LCH II � 07/01

– LCH III 01/02---11/07

– LCH S 2005 04�

– Atra LCH 99�03

• Etudes épidémiologiques / RNHE Registre

• 55 patients/ an age < 15 ans attendus

• 440 patients attendus entre 1/00 et 31/12/07

Etudes des patients 2000-2007

Age < 15 ans 358 patients

020

40

60

80

Fre

quency

2000 2002 2004 2006 2008année

Nb de patients par année

Age au diagnostic

Médiane 3,1 ans (0-14.7 ans)

% de Garçon: 53%

0,3%1Neuro Deg

3%12Neuro Tumoral

12%44DI hypophyse

8%27Foie

11%41Poumon

9%32Hemato

16%57ORL

34%122Peau

80%288Os

%N

Suivi: médian: 2.29 ans

Min 0- max 8.6 ans

Classification des patients selon les

groupes de la société histiocytaire

Groupes

unisystémique

57%

Groupes

multisystémiques

Non OV

23%

Groupe Organes

vitaux

20%

Classification des patients selon les

groupes de la société histiocytaire

Groupes

unisystémique

57%

Groupes

multisystémiques

Non OV

23%

Groupe Organes

vitaux

20%

Groupes

unisystémique

67%

Groupes

multisystémiques

Non OV

18%

Groupe Organes

vitaux

15%

Au diagnostic Fin de suivi

0,6%2Radiothérapie

49,7%178Chimiothérapie

50,3%180Abstention - TT local

au diagnostic Thérapeutique

0,6%2Radiothérapie

59,8%214Chimiothérapie

40,2%144Abstention - TT local

Ensemble evolutionThérapeutique

Thérapeutique

98,5%

82,9%

40,5%

0,0%

10,0%

20,0%

30,0%

40,0%

50,0%

60,0%

70,0%

80,0%

90,0%

100,0%

Multivisceral Org Vitaux Mutlivisceral non vital Unifocal

Proportion de patients sous chimio

0,6%2Radiothérapie

59,8%214Chimiothérapie

40,2%144Abstention - TT local

Ensemble evolutionThérapeutique

0,0%0Glivec

0,0%0Thalidomide

0,0%0Diphosphonate

1,4%3Anti TNFalpha

7,5%16Indocid

1,9%4Atra

0,9%2HSCT

7,9%172cda Arac

6,5%142cda seul

5,6%12VP16

11,7%25Mtx

22,9%496MP

97,7%209Stéroide

94,9%203Vinblastine

Résultats

• Survie

• Rechute

• Séquelles

Survie

0.2

5.5

.75

1

0 2 4 6 8analysis time

335 195 91 23 0 Number at risk

95% CI Survivor function

Kaplan-Meier survival es timate

2 décés

2001 Sepsis

après 2 cda

arac

2003 Décés

avant tt

d’un

nouveau né

Rechute

0.0

00

.25

0.5

00

.75

1.0

0

358 121 44 8 0 Number a t risk

0 2 4 6 8analysis time

Kaplan-Meier failure estimate

0.0

00

.25

0.5

00

.75

1.0

0

72 23 11 2 0MV _tout = 281 28 10 4 1MV _tout = 1

205 70 23 2 0MV _tout = 0Number a t ri sk

0 2 4 6 8analysis time

MV_tout = 0 MV_tout = 1

MV_tout = 2

Kaplan-Meier failure estimates

Rechutes par groupes

Séquelles

• En partie trop prématuré pour évaluation et

pas assez de data collecté

Déjà

44 DI

3 cholangite scélorasante

1 atteinte neuro

dégénérative

Clinique (et + de 20 avec

lésions IRM)

Informations données par des

essais thérapeutiques

• VP16 sans intérêt

• MTX sans intérêt

• 12 mois >> 6 mois sur les réactivations

• 2 cda arac Sauvent des vies !

Informations données par essais

thérapeutiques

• Essai randomisé LCH II: VP16 sans intérêt

Essai LCH III

• Question 1: intérêt du MTX dans les

formes sévéres: NON: aucun intérêt !

RISK PATIENTS

PRIMARY ENDPOINT:

Non-Response in Risk Organs at Week 6/12

Group Sequential Design according to O‘Brien Fleming

3rd interims analysis Last Evaluation Current Analyses

139 evaluable patients 177 204

Arm A: 20/70 (29%) 25/92 (27%) 31/102 (30%)

Arm B: 21/69 (30%) 25/89 (28%) 29/102 (28%)

INNER BOUNDARY CROSSED

next interim originally planned after 182 pts. Maximum Sample size 228

-6

-4

-2

0

2

4

6

0% 20% 40% 60% 80% 100%

no

min

al cri

tica

l p

oin

t

accept H0

accept alternative hypotheses

accept alternative hypotheses

%Nb DcN

11,9%32269

22,2%29Spain

22,2%29Brazil

26,9%1452Argentine

0,0%028France

9,2%776GPHO

0,0%04Scandinavie

20,8%524Italy

3,4%258USA

0,0%09UK

Patients haut risque inclus dans le LCH III et Décés par pays

Question 2: durée du traitement pour

les formes intermediaires

• 12 mois > 6 mois

Group Sequential Design

according to O‘Brien Fleming

-5

-4

-3

-2

-1

0

1

2

3

4

5

0% 20% 40% 60% 80% 100%

no

min

al

cri

tical

po

int

accept H0

accept alternative hypotheses

accept alternative hypotheses

LOW RISK Reactivations after

NAD/ADB

2-yrs 3-yrs after Tx-Start

6 months n=34/74 0.43±0.08 0.50±0.0812 months n=18/64 0.26±0.06 0.35±0.08 p=0.019

0.0

00

.25

0.5

00

.75

1.0

0

0 1 2 3 4 5analysis time

RANDO2_tout = 6 RANDO2_tout = 12

Kaplan-Meier survival estimates, by RANDO2_tout

La comparaison sur les 24 patients français montre une différence

NON significative

3 ème apport : Une association

thérapeutique 2cda Arac permet

de guérir les atteintes

hématologiques réfractaires

Expérience française: 22 patients traités depuis 1998

Essai thérapeutique international LCH S 2005

The rationale

• Patients with risk organs refractory to standard approach: universally a very poorprognosis for all group

• 2 cda alone: not enough

• 2 cda and AraC: a synergy

• A pilot study with 10 patients withhematological dysfunction refractory to standard approach: 7 good long termoutcome

Inclusion criteria• The objective: to select patients with a very clear bad outcome

• Inclusion criteria:

• All the 5 following criteria must be present:

• � a biopsy-proven definitive diagnosis of LCH

• � Risk organ involvement

• � Failure to initial therapy defined by disease progression

• � Performance Status: Karnofsky ≥ 40 for patients >10 years of age and Lansky Play-Performance Scale ≥ 40 for children ≤ 10 years of age (Appendix 5)

• � Informed consent.

Exclusion criteria

Exclusion criteria:

�Isolated sclerosing cholangitis,

�Isolated lung involvement

�Inadequate renal function as defined by serum

creatinine > 3x normal for age.

� Pregnancy or breast-feeding.

The core of the study=

Initial therapy

Aracytine 500 mg/m² IV 2 hours/ twice a day

D1-D5

2 Cda 9 mg/m² IV 2 hours D1-D5

At least two courses recommended

Second course D28-D35

Major endpointMajor endpoint:

The major endpoint is the response rateafter two courses of therapy, evaluated at 9-10 weeks from the initiation of the therapy.

Response rate = LCH III scale AD/ NAD B – S – W(but we will collect information to evaluate the diseaseactivity score)

The response is considered as favorable if the status of the patient is Active Disease Better or Non Active Disease. Any early death, whatever the cause, is considered as an unfavorable response.

Secondary endpoints

• The early and late mortality.

• The number of courses and the time period taken

to obtain Non Active Disease.

• The time period taken to obtain hematological

recovery.

• Maintenance therapy utilized.

• Early and late toxicity.

Supportive care

• Without intensive supportive care, this therapy is

100% letal

• Supportive care:

– Positive air pression room

– Large Antibiotics

– Albumin infusion almost daily

– IV immunoglobulin at least weekly

– Transfusion at the demand

– Parenteral nutrition

….. For 2 to 4 months

Statistical consideration

• NOT A RANDOMISED STUDY

• OPEN LABELLED PHASE II Study

Method: 2 steps « Simon »Plan

ONE Interim analysis after 13 pts

Final analysis after a total of 30 Patients

• Expected Enrollement: 6 to 10 /years

• Interim analysis: May be done within 2 years

• Final analysis: May be done within 4 years

Additional interest

• To collect prospectively enough

information to evaluate a disease activity

scale

Preliminary results

• 8 patients – 5 from France

– 3 from Netherlands

• Age at diagnosis: median 0.7 y (0.4 -0.97 y)

• Median follow up: 0.9 years (0.1 – 1.6 years)

• Occurrence:

First occurrence: 6Second occurrence: 1

Third occurrence: 1

• All are Active Disease worse after one or two vinblastine steroid course(s)• After 1 induction 4

• After 2 inductions 3

• After 3 inductions 1

• All have hematological dysfunction at the time of inclusion in the trial

Primary endpoints

situation after 2 courses

• 7 patients are assessable

– None AD worse

– 4 AD stable -� Third courses

– 3 AD better

Disease score activity - Evolution with therapy

0

2

4

6

8

10

12

14

16

18

20

Diagnosis end VLB Ster Pre therapeutic End course 1 End course 2 Endcourse 3

JMC

LIL

Pb

LEL

DRF

AD s

ADb

ADs

ADbADb

Secondary endpoints: Toxicity

information n=5

• All WHO grad 4 for anemia – neutropenia-thrombocytopenia

• All had fever > 2 days

• 2 episodes of hyperbilirubinemia – one disease related –one transient and unknown origin

• 3 sepsis defined by Positive blood culture and fever (Gram – 2 / Cocci + 1)

• One patient treated just after Candida Septicemia

• No transfert in ICU !

• Hospitalization duration: 80 to 160 days almost in air positive pression room.

Secondary endpoints efficacy

• 8 patients

• All alive at the last update

• 2 Follow- up < 6 months

• 6 evaluable for disease activity

– 5 NAD: NAD not before Month 5—month 9

– 1 severe sclerosing cholangitis – no systemic activity

French group

• Now 22 patients (including one from belgia, and one from algeria) (including the 5 protocol patients)– First patient 1996 � all eligible since 2001

• Data recorded through a national register � exhaustivity of the cases in France – external control with death certifications system

• 3 deaths - already described in the initial paper. • 2 toxic at D14 / D38

• 1 After BMT

• One patient – major violation of the protocol– 2 cda Overdose – then more than 2 months between two courses

• Two courses response– Among 22 evaluable patients:

• 3 ‘no response»– late response after addition of retinoic acid in one

– Very good response to mini HSCT in one

– Slow response in one after HSCT (after violation of the protocol)

• 19 AD better ---> NAD about 5 to 9 months after onset

Mortality by Langerhans cell histiocytosis < 15 years in France

Data from national death certification data base

0

1

2

3

4

5

6

1978_1982 1983_1987 1988_1992 1993_1997 1998_2002

Each bar: mean number of death/year for 5 years period

Conclusion

• 40% des histiocytoses ne nécessitent pas d’un traitement par voie générale

• 60% vont avoir recours à un schéma thérapeutique comportant VLB et corticoide qui contrôle la maladie MAIS qui reste associé à un taux de ré activation globalement de 30 %

• 12 mois de traitement limite ce risque mais n’est pas connue pour limiter les séquelles

• Un traitement très agressif pour 5% des patients permet de limiter la mortalité de la maladie