E.SIENI RICCIONE 13€¦ · Non-risk LCH STRATUM III : n=30 Salvage Therapy for Risk LCH STRATUM...

GdL IstiocitosiRiccione, 12.11.2013

LCH IV Registry & Stratification

STRATUM II: n=4002nd-line Therapy for

Non-risk LCH

STRATUM III: n=30Salvage Therapy for

Risk LCH

STRATUM VII:Long-term Follow up

STRATUM IV: n=25

LCH-HSCT

Lack of response, Progression,in risk organs

STRATUM I: n=1200 (800 rand.)1st-line Therapy (Group 1 & 2)

Progression, Reactivation,

in non-risk organs

Other single system LCH

Multisystem, multifocal bone, and special single system LCH

STRATUM VI: n=450 Natural history and

Management of “other” SS-LCH

NAD

Lack of response, Progression,in risk organs

Progression, Reactivation

STRATUM V: n=50 Monitoring & Treatment of

CNS-LCH

Isolated tumorous LCH of the brain

3

Group 1: All patients with MS-LCH (+/- RO)

Group 2: Patients with MFB or special SS-LCH

Stratum II: Second-Line Initial Therapy for Non-Ris k LCH

Stratum II: Second-Line Continuation therapy for Non-R isk LCH

STRATO III: Salvage Therapy for Risk-LCH

8

-8Fludarabin 5 x 30 mg/m2

Melphalan 1 x 140 mg/m2

MabCampath 5 x 0.2 mg/kg

CSAMMF

-7 -6 -5 -4 -3 -2 -1 0

Prophylaxis of GvHD/ Rejection from day -3 if indicated

Conditioning regimen

STRATO IV: RIC-HSCT for Risk-LCH

STRATO V: Treatment and Monitoring of Isolated Tumorous and Neurodegenerative

CNS-LCH

Primary Objectives:

1. To study the course of ND-CNS-LCH 2. To study the impact of 2-CdA on the

response of isolated tumorous CNS lesions

3. To study whether systemic therapy (Ara-C or IVIG) could be beneficial in ND-CNS-LCH

Treatment and Monitoring of Isolated Tumorous CNS-LCH

2-CdA 5 mg/m2/day for 5 days

Repeat every 4 weeks to max 6 courses

Treatment of ND-CNS-LCH

1. ARA-C Mono 150mg/m2 daily for 5 days, repeat monthly for 1 year.

OR

2. Intravenous Immunoglobulines0.5 g/kg/dose repeat monthly for 1 year

STATO DI APPROVAZIONE

Aperto all’arruolamento:• Austria Vienna• USA: Boston (MA), Little Roc (AR)• Italia: Firenze Meyer, Napoli Pausilipon

In collaboration with: •Pediatric Radiology, AOU A. Meyer : M.Mortilla, S.Savelli, C.Fonda•Pediatric Neurology, AOU A.Meyer : C.Barba, R. Guerrini•Department of Statistics, University of Florence: L. Grisotto, A. Biggeri

Neurodegenerative complication of LCH. Proposal of a multidisciplinary approach for

screening of presymptomatic disease

ND-LCH• Rare, challenging and enigmatic

permanent consequence of LCH. • Patients may undergo progressive

deterioration, refractory to LCH-directed therapies used in the past.

• Unmet needs: – natural history– standardized diagnostic approach– effective therapy.

Aims

To define a multidisciplinary, diagnostic work-up aimed at:•early identification of patients who will develop ND-LCH;•definition of a follow-up strategy;•identification of the preclinical stage in which patients committed to ND-LCH may benefit of a therapeutic intervention.

Inclusion criteria

• histologically proven LCH• either ND-LCH verified by MRI or risk

factors for ND-LCH: craniofacial bone lesions and/or DI

• informed consent

Diagnostic protocol

• Clinical history• Neurological evaluation• Neurophysiological study (VEPS, SEPs,

BAEPs, EEG) • Neuropsychology evaluation• Neuro-imaging (including 3T structural and

spectroscopic MRI)

Study population (n=27) April 2010 - February 2012

Gender 16 M, 11 FMedian age at study entry 8.7 years

(range, 1.4 - 27.5 years)

Median age at dx of LCH 2.9 years (range, 4 m - 18 years)

MS vs. SS 19 vs. 8Reactivating or chronic active LCH 21Risk lesions for ND-LCH: DI/CFBL 17/11Previous CT (ongoing) 24 (11)

Results: neuroimaging

Pt MRI abnormalities/grading MR Spectr

1 Cerebellum/1 N

2 Cerebellum, sWM, brainstem/2 N

3 Cerebellum, Brainstem/3 N

4 Cerebellum, sWM/2 N

5 Cerebellum, sWM, brainstem/3 A

6 Cerebellum/1 N

7 Cerebellum, sWM,BG, Brainstem/4 A

8 Cerebellum/4 A

9 Cerebellum, sWM, Brainstem/3 A

10 Cerebellum, sWM/1 A

11 Cerebellum/1 N



14 Cerebellum, sWM, BG, Brainstem/2 N

15 Cerebellum, Brainstem/4 A

16 Cerebellum, sWM/2 N

17 Cerebellum/1 A

• 17/27 patients had

MRI abnormalities

• 10/17 1st abnormal

• 6/17 grading 1

3/17 grading 4

• 9/17 pts had

abnormal MRS

Results

• NE was abnormal in 10/27 (37%) patients • SEPs were abnormal in 11/27 (40%)

patients• BAEPs were abnormal in 6/27 (22%) • VEPs were normal in all patients. • EEG was normal in all patients but one • NPI was normal in 18/18 patients

Data analysis

On the basis of MRI findings two groups of patients were identified: •Group 1 , patients with evidence of ND-LCH at MRI;•Group 2 , patients with risk factors (craniofacial bone lesions and/or DI) for ND-LCH.

Clinical features Group 1 N=17 Group 2 N=10 α

Gender 9 M, 8 F 7 M, 3 FMedian age at study entry (range) 8.2 y

(1.7 - 27.5 y)10.2 y

(3.7 -16.4 y)p=0.670

The time elapsed between the clinical onset of LCH and the first MRI evaluation

3.8 y 4.7 y p=0.688

Median time between the clinical onset of LCH and the first observation of ND-LCH at MRI(quartiles)

4.2 y

(0.8; 2.5; 4.2; 6.5; 14.5 y)

-

Median age at dx of LCH 2 y(4 m -18 y)

5.5 y(18 m -15 y)

p=0.024

MS vs. SS 13 (76%) vs. 4 6 (60%) vs. 4 p=0.023Reactivating or chronic active LCH 15 (88%) 6 (60%) p=0.000

Risk lesions for ND-LCH: DI/ CFBL 11 / 6 6 / 5

Previous CT/ ongoing 15 (88%)/ 7 (41%) 9 (90%)/ 4 (40%) p=0.821/p=1.000

Neurological, neurophysiological, MR-spectroscopy findings

Abnormal findings Group 1 Group 2

NE 9/17 (52%) 1/10

SEPs 11/17 (67%) 0/10

BAEPs 6/17 (35%) 1/10

MRS 9/17 (52%) 0/10

Statistical analysis Sensitivity Specificity ROC area PPV NPV N° patients

MRI

NE 52.9% (27.8%-77.0%)

90.0% (55.5%-99.7%)

0.71 (0.50- 0.86)

90.0% (55.5%-99.7%)

52.9% (27.8%-77.0%)

27

BAEP s 29.4% (10.3%-56.0%)

90.0% (55.5%-99.7%)

0.60 (0.39-0.78)

83.3% (35.9%-99.6%)

42.9% (21.8%-66.0%)

27

SEP s 70.6% (44.0%-89.7%)

100.0% (69.2%-100%)*

0.85 (0.66-0.96)

100.0% (73.5%-100%)*

66.7% (38.4%-88.2%)

27

MRS 52.9% (27.8%-77.0%)

90.0% (55.5%-99.7%)

0.71 (0.50-0.86)

90.0% (55.5%-99.7%)

52.9% (27.8%-77.0%)

27

NP S 22.2% (2.8%-60.0%)

71.4% (29.0%-96.3%)

0.47 (0.20-0.70)

50.0% (6.8%-93.2%)

41.7% (15.2%-72.3%)

16

Grading of MRI

NE 80.0% (44.4%-97.5%)

88.2% (63.6%-98.5%)

0.84 (0.66-0.96)

80.0% (44.4%-97.5%)

88.2% (63.6%-98.5%)

27

BAEP s 30.0% (6.7%-65.2%)

82.5% (56.6%-96.2%)

0.56 (0.35-0.75)

50.0% (11.8%-88.2%)

66.7% (43.0%-85.4%)

27

SEP s 90.0% (55.5%-99.7%)

82.4% (56.6%-96.2%)

0.86 (0.66-0.96)

75.0% (42.8%-94.5%)

93.3% (68.1%-99.8%)

27

MRS 50.0% (18.7%-81.3%)

70.6% (44.0%-89.7%)

0.60 (0.39-0.78)

50.0% (18.7%-81.3%)

70.6% (44.0%-89.7%)

27

NP S 14.3% (0.4%-57.9%)

66.7% (29.9%-92.5%)

0.40 (0.15-0.65)

25.0% (0.6%-80.6%)

50.0% (21.1%-78.9%)

16

MRI

normal abnormal

normal abnormal

normal abnormal

normal abnormal

Group 1Patients with abnormal MRI

11%


50%

Neurological exam


66.7%


100%

BAEPs

MRS Group 5Patients with abnormal MRI

100%

SEPs

Grading of MRI

normal abnormal

normal abnormal normal abnormal

normal

normal abnormal

normal abnormal

normal abnormal


0%


50%

Neurlogical exam


0%


66.7%

MRS


100%


0%


100%

MRS

BAEPs

Neurlogical exam

SEPs

Regression tree analysis

If we consider positive the patient with at least one positive test between SEPs and NE ROC area was 0.86 (0.66-0.96)

ROC curves for SEPs and NE for ND-LCH

Conclusions

• High frequency of abnormalities , likely reflects the diagnostic accuracy.

• The combined use of SEPs and accurate NE may represent a valuable, low-cost and widely-available approach to select candidates to MRI studies.

• Spectroscopy may usefully complement anatomic MRI.

Conclusions (2)

• These data may help to determine which patients deserve, in the pre-clinical phase, a treatment aimed at prevention of neurological damage.

• Patients with ND-LCH have a younger age at the diagnosis of LCH: undefined predisposing factor(s)?

Aggiornamento casistica:

Registro HLH

Numero dei casi afferiti al Registro HLH 2006-2013 (1.10.2013)

Numero dei casi con marcatore genetico2006-2013 (1.10.2013)

HLH Registry in 2013

Secondary HLH;

537; 60%Genetic HLH;

266; 29%

No HLH;97; 11%

N=900

HLH Registry in 2013: distribution of genetic defec ts

M.Aricò, unpublished

FHL NO MARKER

• Tempistica dell’analisi• Costi• Tecnica diversa

EXOME SEQUENCING

Enorme quantità di informazioni!!!

FHL, LCH…….? Are we sure enough?

36

V:5ROSA II

IV:6CARLO

IV:7ANNA MARIA

III:7Enrico

III:8Elvira

IV:8 IV:9 IV:10 IV:11 IV:12

III:5Armando

III:6Rosa

IV:3 IV:4 IV:5

V:4ROSA I

V:6ARMANDO

V:7ANDREA

II:9Salvatore

Vila di Briano

II:10Teresa

Villa di Briano

II:7Antonio

II:8Barbara

II:11Salvatore

Villa di Briano

II:12Antonietta

Villa di Briano

III:4Attilio

III:3Rosa

IV:2Giuseppe

IV:1Antonietta

V:1Rosa Maria Ingrid

V:3Attilio Graziano

V:2Marco

II:6Giuseppe

Villa di Briano

II:5Angela

S.Marcellino(CE)

III:2Maria

II:3Luigi

Frignano

II:4BenedettaFrignano

CantileAnna Maria

PuotiCarlo

In collaboration with:• Pediatric Hem/Onc, University of Padova

Monoallelic mutations of the perforin gene may represent a predisposing factor to childhood anaplastic large cell lymphoma

(J Pediatr Hematol Oncol 2013;00:000–000)

In collaboration with:• Pediatric Rheumatology, IRCCS O.P.Bambino Gesù, Roma• Pediatric Hem/Onc, Pausilipon, Napoli• Hematology, IRCCS I.G.Gaslini, Genova

Monoallelic mutations of the FHL-related genes predispose to macrophage

activation symdrome (MAS)

Methods

• Patient selection from HLH National Registry• Data collection and update follow-up• Functional screening of perforin expression

and degranulation by flow-cytometry. • Mutation analysis by Sanger (PRF1, STX11)

or massive (STXBP2, UNC13d, Rab27a) sequencing

HLH RegistryPatients with MAS

MAS

n=46

5.9 %

n = 779

Ethnic origin: • Caucasian, n=36; Indian, n=10

Sex:• M: 18, F: 28

Age at onset:• Median: 7.7 years• Range: 36 months - 59 years• Quartiles: 3; 8; 11 years

HLH RegistryPatients with MAS (n=46)

Rheumatologic disease N

sJ IA 32

SLE 43

Kawasaki D. 1

Dermatomyositis 1

Connectivitis 1

Other, undefined yet 8

Italian HLH RegistryPatients with MAS (n=46)

Clinical features N/total * (%)

Fever 41/41 (100)

Splenomegaly 27/41(66)

CNS manifestations 14/40 (35)

Anemia 24/39 (61)

Neutropenia 8/38 (21)

Thrombocytopenia 21/39 (54)

Hypofibrinogenemia 8/35 (23)

Hypertriglyceridemia 22/35 (63)

Hyperferritinemia (quartiles: 205; 3.601, 11.839, 22.893; 207.000 ng/ml)

36/37 (97)

Hemophagocytosis 16/39 (41)

Dead of progressive disease 4/46(9)

HLH RegistryPatients with MAS (n=46)

*evaluable patients

UPN Age(months)

PRF expression GRA Mutation Gene

238 6 Normal ND c.272T (p.A91V) PRF1

431 53 ND ND c.272T (p.A91V) PRF1493 7 Normal Normal c.418C>G (p.Q140E)

c. 1289C>T, p.A433VRAB27ASTXBP2

527 120 Normal Normal c.799G>A (p.V267M) STX 11

579 95 Reduced Reduced c.1034C>T (p.T345M) STXBP2

660 ND Normal Reduced c.272T (p.A91V) PRF1

661 6 Reduced Reduced ��

Normalc.272T (p.A91V) PRF1

717 106 Reduced ND c.1357G>A (p.V453M) PRF1

738 40 ND ND c.1681T>C (p.W561R) STXBP2

787 115 Reduced Normal c.755A>G, p.N252S PRF1799 0 Reduced Normal c.272T (p.A91V)

c.811C>T (p.P271S)PRF1

UNC13D895 144 ND Normal c.272T (p.A91V)

c.3G>A (p.M1I)(monoallelic)

PRF1

896 132 ND ND c.589G>A, p.V197M STX11

13/46 (28%) patients with MAS harbor monoallelic mutations of the FHL-related genes

Conclusion

• MAS is a life-threatening complication of rheumatologic

diseases in children

• Heterozygous mutation in one FHL-related gene was

observed in 28% of patients: moderate reduction of

cellular cytotoxicity machinery appears as a frequent

predisposing factor in patients who develop MAS as

part of a rheumatologic disease

Conclusion (2)

• At least one functional test was defective in 13/29 (44.8%)

� Of the 8 patients with reduced perforin expression, 4 had monoallelic PRF mutation.

� Of the 8 patients with reduced GRA, only one had a mutation (in STXBP2).

� In two patients the functional study restored at repetition during the follow-up

• Whether further regulatory mechanisms for the FHL-related proteins are involved in these patients remains to

be clarified.

Risk of hemophagocytic syndrome, neoplasm, and autoimmune disorders in subjects with monoallelic mutation of the

FHL related genes

Background

The HLH Registry provides the opportunity to evaluate an unselected series of “healthy subjects” identified as with monoallelic mutation, during the genetic study of patients with FHL (parents, relatives)

Methods

• Analysis of HLH Registry to identify families with FHL

• Selection of subjects with documented monoallelic mutation

• Assessment of their vital status (collection of available data; personal or telephone interview for update)

• Comparison of the cumulative incidences of neoplasm and autoimmune diseases in our cohort to that of the general population in our country.

• Study approved by A.O.Meyer IRB

Study population

Cancer (n) Autoimmune disease Other

Prostate (2) J RA Aplastic anemia

Breast (2) ITP S. Williams

Uterus (3) Hypothyroidism Heavy Chain Dis.

ALL Recurrent enthesitis Keratoconus bilat.

NHL Fibromyalgia

Colon «Glucose intolerance»

Thyroid NF1

Liver Cerebral vasculopathy

Melanoma HCV Hepatitis

Undefined Liver cyrrhosis

• 130 «healthy» heterozygous subjects enrolled (update 30.6.13)

• 28/130 (21.5 %) report a relevant clinical condition

Open questions

• Preliminary data apparently do not suggest an excess of cancer (14/130, 11%) or autoimmune disease;

• cumulative risk to be assessed

• Data collection still incomplete; hopefully to be extended to the grandparents’ generation, with longer follow-up time

EURO-HIT-HLH

0 1 2 3 4 5 6 7Week

CSA

IT MTX/HC(CNS+ only)

Update, October 2013

PARTICIPATING COUNTRIES AND NATIONAL COORDINATORS

ITALY Maurizio Aricò, Study PIIstituto Toscano Tumori, Florence; [email protected] Sieni, Study CoordinatorAO.U. Meyer, Florence; [email protected]

GERMANY Gritta JankaUniversitätskrankenhaus Eppendorf, Hamburg; [email protected]

SPAIN Itziar AstigarragaHospital de Cruces Barakaldo, Vizcaya; [email protected]

AUSTRIA Milen Minkov MD, St. Anna Kinderspital, Wien; [email protected]

CZECH REPUBLIC

Jan Stary,University Prague and University Hospital MotolV Uvalu; [email protected]

PARTICIPATING COUNTRIES AND STUDY STATUSITALY Open to accrual

GERMANY Expected to be open to accrual by December 2013

SPAIN On hold due to administrative reasons

AUSTRIA Approval ongoing, November 2013

CZECH REPUBLIC

Open to accrual

�

� Firenze, Oncoematologia, AOU Meyer� Cosenza, Unità Operativa Pediatria Azienda Ospedali era Annunziata� Ancona, Centro Regionale Oncoematologia Pediatrica Ospedale dei Bambini “G. Salesi” � Padova, Oncoematologia Pediatrica; � Napoli, Dipartimento di Oncologia A.O. Santobono – Pausilipon,• Monza, Clinica Pediatrica dell’Università Milano – Bicocca A.O. San Gerardo – Fondazione MBBM• Genova, Ematologia Pediatrica Istituto “ G. Gaslini”. • Pavia, Oncoematologia Pediatrica Fondazione IRCCS, Policlinico San Matteo• Bergamo, U.O. Pediatrica – OO.RR Bergamo• Brescia, Clinica Pediatrica Oncoematologia pediatrica e TMO Ospedale dei Bambini• Verona, U.O.C Oncoematologia Pediatrica Policlinico “G.B: Rossi”; • Trieste, U.O. Emato-Oncologia Pediatrica Università, Ospedale Infantile Burlo Garofolo• Parma, U.O. di Pediatria e Oncoematologia Pediatrica Az. Osp. Di Parma• Modena, U.O. di Ematologia, oncologia e trapianto Azienda Policlinico• Bologna, Oncologia ed Ematologia “Lalla Seràgnoli” Clinica Pediatrica Policlinico Sant’Orsola Malpighi; • Pisa, Oncoematologia Pediatrica e Trapianto Midollo Osseo A.O.U. Pisana Ospedale S. Chiara;• Perugia, S.C. di Oncoematologia Pediatrica con Trapianto di CSE, Ospedale “S.M. della Misericordia”; • Roma, Sezione Ematologia Dipart. di biotecnologie Cellulari ed Ematologia Università “La Sapienza”• Roma, Divisione Oncologia Pediatrica Università Cattolica• Roma, Oncoematologia pediatrica Ospedale ‘Bambino Gesù’• San Giovanni Rotondo (FG) U.O. Oncoematologia Pediatrica Ospedale "Casa Sollievo della Sofferenza• Bari, Dipartimento Biomedicina Età Evolutiva U.O Pediatrica I Policlinico, • Palermo, Oncoematologia Pediatrica Ospedale dei Bambini G. di Cristina• Catania, Divisione Ematologia - Oncologia Pediatrica Clinica Pediatrica• Cagliari, Oncoematologia Pediatrica

Patients accrualUPN Insert Date Centre Status Final

Dx

906 11-10-2013 S.C. Oncoematologia Pediatria e Centro Trapianti

Ospedale Infantile Regina Margherita

valid XIAP

880 09-07-2013 U.O. Pediatria A.O. Annunziata Cosenza valid FHL3

878 04-07-2013 S.C. Oncoematologia Pediatria e Centro Trapianti

Ospedale Infantile Regina Margherita

valid FHL2

- 29-05-2013 Department Pediatric Hematology-Oncology

Charles University Prague and University Hospital

Motol

valid HLH

860 14-05-2013 Department Pediatric Hematology-Oncology

Charles University Prague and University Hospital

Motol

valid FHL no

marker

Messages• Accrual very slow• Insurance had to be paied by a charity• By law IRBs in Italy have been «institutional»;

since September 2013 they have been partly centralized (one IRB per «region»)

• QC of centers and monitoring/auditing performed by AIEOP

• Activation of studies is increasingly difficult!

• More and more patients treated off-protocol!

Plasma levels of IFN- γγγγ in hemophagocytic syndrome

HLH and IFN -γγγγ: background

• Data from the literature show that patients with HLH have high plasma levels of several cytokines.

• Mouse model of FHL shows that blockade of IFN-γγγγ, but not other cytokines, interferes with the pathogenesis of FHL (Jordan 2004)

“FIGHT HLH”An FP7 grant awarded to NovImmune, July 1, 2012. 6 M Euros

Creation of

a drug to

fight HLH

Pivotal trial Pilot trial

New animal

models of

secondary HLH

Gene

analysis

NI-0501

manufacturin

g

July 2012October 2015

NovImmun

e

Meyer

Childrens’

Hospital

Bambino Gesu’

Childrens’ Hospital

Lonza

Novimmu

ne

NovImmun

e

The threshold for the development of HLH can be reached by variable combinations of:

�severe genetic defects in the granule exocytic pathway (e.g. perforin defects)

�“strength” of the infectious triggers (e.g. H5N1, leishmania)

�overt inflammation (e.g. JIA, LES)

A model of HLH pathogenesisDifferent contribution of genetics, “strength“ of infectious agent, inflammatory status

Courtesy of F De BenedettiCourtesy of F De Benedetti

68

Cytokine blockade in prf KO miceNo impact on survival

Days after LCMV

infection

J ordan et al, Blood 2004

69

IFNγ blockade leads to survival of prf KO mice

Days after LCMV

infection

J ordan et al, Blood 2004

70

High serum IFN γ levels characterize HLH

� All HLH patients had IFNγ levels above ULN (53.5 % of HLH patients had levels above 1000 pg/mL) (ULN: 17.3 pg/mL)

� IFNγ levels rise early and quickly and can fall from > 5000 pg/mL to normal in 48 hrs of effective treatment of HLH

Xu et al, J Pediat 2011

71

NovImmune prf KO miceDose response study

Day 0

LCMV200 pfu

Day 6 Day 10

Euthanized

Anti-mouse IFNγ mAb (3, 10, 30, 100 mg/kg XMG1.2

i.p.)

• NI-0501 does not cross-react with mouse IFNγ and is, therefore, unsuitable to be used in mouse models of disease

• XMG1.2 is a rat anti-mouse IFNγ mAb with similar affinity and potency to NI-0501 and therefore is a functional surrogate to study in vivo PK/PD relationships

Data on file at NovImmune in collaboration with Pinschewer

72

NI-0501 pilot study designStudy PI: M. Aricò

At any time during the study, if the patient’s condition is worsening, s/he will be withdrawn (rescue therapy)

Diagnosis of HLH

reactivation

SD3 SD6

2 weeks

Clinical Assessment (worsening or response): on study day 3, 6, 15, 18, 27, 36, 45, 54 as well as at week 9, 11, 12 and on unscheduled visits (if any)

Week 8Study Day

(SD) 0

SD9 Week 4

Dose adjustment periodInitial Dose

TREATMENT PERIOD (NI-0501 Infusions every 3 days)8 WEEKS

FU PERIOD

4 WEEKS

Week 9 10 11 12 Study

Completion Visit

SCREENIN

G(within 1 week

of NI-0501 administration)

73

NI-0501 dosing regimen• NI-0501 is administered at the initial dose of 1 mg/kg every 3 days

• After the first dose of 1 mg/kg, the NI-0501 dose can be adapted for the following 3 consecutive administrations, based on PK data and/or clinical and laboratory response (Initial dose adjustment)

• Subsequently, dose or frequency of administration may be adapted depending on NI-0501 PK profile

• A background of 10 mg/m2 daily dexamethasone is also administered, starting the day before the 1st NI-0501 infusion and can be tapered when Partial Response is achieved

Safety endpoints• Incidence, severity, causality and outcomes of Adverse Events

(AEs) (serious and non-serious), with particular attention being paid to infections

• Evolution of laboratory parameters such as complete blood cell count (CBC), with focus on red cells (haemoglobin), neutrophils and platelets, liver tests, renal function tests and coagulation

• Withdrawals for safety issues

• Level (if any) of circulating antibodies against NI-0501 to determine immunogenicity ; i.e. the development of anti-drug antibodies (ADA)

Efficacy endpointsAll endpoints in the Pilot Study are considered as

exploratory

• Non-active Disease by week 8 (SD60)

• Partial or Complete Response by Week 2 (SD15), Week 4 (SD27) or Week 8 (SD60)

• Time to achievement of Non-active Disease, Complete Response, Partial Response

• Time to reactivation

• Survival at week 8 (SD60) and at the end of the follow-up period

• No Response at any time

Pharmacokinetic & pharmacodynamic endpoints

– Free NI-0501 concentrations

– Levels of circulating free IFNγ at screening and pre-dose

– Total IFNγ (free + bound) at subsequent time-points

– Markers of disease activity or predictors of response, e.g., sCD25, CXCL-9, CXCL-10, CXCL-11, IL-10

Clinical development of an anti-IFN γ mAb (NI-0501) in HLH

� The clinical program for the development of NI-0501 in HLH has been reviewed in the context of the Scientific Advice/Protocol Assistance procedure at European Medicines Agency (EMA), receiving positive feedback from Committee for Medicinal Products for Human Use (CHMP)

� As part of this program, a pilot study in HLH patients in whom the disease has reactivated will be conducted

� This study has been submitted to Competent Authorities and Ethical Committees in Europe and is awaiting for approval

� The objectives of the pilot study are to determine safety and tolerability and to assess preliminary efficacy and benefit/risk profile of NI-0501

Pilot study recruitment sites and study status

• 10 HLH patients in whom the disease has reactivated to be recruited world wide

• 12 sites opened in Europe (Italy, Spain, Germany, Austria, Czech Republic)

• 4 sites to be opened in the US in the coming weeks (IND approved)

• One patient was recruited on July 26, completed the study, went through conditioning and transplantation on October 9

Componenti GdL Istiocitosi

Laboratorio Istiocitosi (Firenze)

Valentina Cetica (responsabile)

Benedetta Ciambotti

Maria Luisa Coniglio

Martina Da Ros

Collaborazioni esterne

Genova CBA/Gaslini: D.Pende, L.Moretta

Cambridge: G.M.Griffiths

Reum. Roma O.P. B. Gesù: F. De Benedetti

Cincinnati: M.Jo rdan, L.Filipovich

Boston: L.D . Notarangelo

E.SIENI RICCIONE 13€¦ · Non-risk LCH STRATUM III : n=30 Salvage Therapy for Risk LCH STRATUM...

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