Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010...

L’impiego del Rituximabnel LES

Gian Domenico Sebastiani

U.O.C. di ReumatologiaU.O.C. di Reumatologia

Azienda Ospedaliera San Camillo-Forlanini

Roma

13°Convegno Patologia Immune e Malattie Orfane 2010Torino, 21-23 gennaio 2010

obiettivi terapeutici nel LES

sviluppare terapie farmacologiche efficaci nel controllo della risposta autoimmune senza causare effetti autoimmune senza causare effetti

tossici inaccettabili

Linfocita BLinfocita B

•• produzione di anticorpiproduzione di anticorpi

•• produzione di citochineproduzione di citochine•• produzione di citochineproduzione di citochine

•• “secondary” antigen“secondary” antigen--presenting cellspresenting cells

Lipsky : Nat Immunol 2001;2:764

Mizoguchi: J Immunol 2006;176:705

Youinou : Ann NY Acad Sci 2005;1050:19

Linfocita B nel LES

•• linfopenia (cellule B nalinfopenia (cellule B naĩve)ĩve)

•• alti livelli di plasmacellule “early” e cellule prealti livelli di plasmacellule “early” e cellule pre--germinativegerminative

•• Espansione di sottopopolazioni cellule B autoreattiveEspansione di sottopopolazioni cellule B autoreattive•• Espansione di sottopopolazioni cellule B autoreattiveEspansione di sottopopolazioni cellule B autoreattive

Jacobi:J Exp Med 2005; 202: 341

Odendahl: Odendahl: J ImmunolJ Immunol 2000; 165: 59702000; 165: 5970

Yurasov: Yurasov: J Exp MedJ Exp Med 2005; 201: 703 2005; 201: 703

Rituximab ― la molecola

• Anticorpo monoclonale disegnato per colpire ed eliminare solo le B cellule CD20-positive

• Rituximab e’ una molecola • Rituximab e’ una molecola chimerica

– La regione costante, IgG-derivata ha origine umana

– La regione variable ha origine murina

B cell developmentB cell development

Stem cells

Pro-B cells

Pre-B cells

ImmatureB cells

ActivatedB cells

MemoryB cells

PlasmaB cells

CD10

CD19

Cell

su

rface

an

tig

en

s

Roitt et al. Immunology. London, UK: Mosby; 2002; Sell et al. Immunology, Immunopathology, and Immunity. Washington DC: ASM Press; 2001; Silverman et al. Arthritis Rheum 2003;48:1484–1492

CD19

CD20

CD24

CD38

CD39

Cell

su

rface

an

tig

en

s

CD22

Study population and clinical assessmentStudy population and clinical assessment

•• Patients populationPatients population

50 adult patients with SLE failing conventional immunosuppressive agents

Retrospective analysis of BCDT in SLE at University College London Hospital: the first 50 patients

•• Assessment of clinical outcomeAssessment of clinical outcome– Efficacy (improvement of BILAG score)– Safety (adverse events and laboratory assessments)

Lu TY et al. Athritis Rheum 2009;61:482-487

Treatment protocolTreatment protocol

•• 1000 mg Rituximab, 750 mg cyclophosphamide, 1001000 mg Rituximab, 750 mg cyclophosphamide, 100--250 250 mg methylprednisolone on 2 occasions 2 weeks apartmg methylprednisolone on 2 occasions 2 weeks apart


mg methylprednisolone on 2 occasions 2 weeks apartmg methylprednisolone on 2 occasions 2 weeks apart

35 (78%) patients followed for at least 1 year


RESULTSRESULTS

•• 19 (42.2%) total remission, 21 (46.7%) partial remission after 6 months19 (42.2%) total remission, 21 (46.7%) partial remission after 6 months

•• 5 non5 non--responderresponder

•• significant decrease of antisignificant decrease of anti--dsDNA antibody titer and increase of C3 leveldsDNA antibody titer and increase of C3 level

•• 20 patients no flare20 patients no flare


•• 20 patients no flare20 patients no flare

•• 20/25 patients with flare retreated20/25 patients with flare retreated

SAFETYSAFETY

•• 5 serious AE: 1 serum sickness5 serious AE: 1 serum sickness--like reaction after Rituximab, 1 death for active SLE, 1 pneumococcal like reaction after Rituximab, 1 death for active SLE, 1 pneumococcal pneumonia, 1 seizure secondary to hyponatremia, 1 death for ARDS secondary to cyclophosphamidepneumonia, 1 seizure secondary to hyponatremia, 1 death for ARDS secondary to cyclophosphamide


CONCLUSIONSCONCLUSIONS

Combination Rituximab therapy is an effective treatment for patients Combination Rituximab therapy is an effective treatment for patients with active SLE who are nonresponsive to standard with active SLE who are nonresponsive to standard immunosuppressive therapyimmunosuppressive therapy


1 12

immunosuppressive therapyimmunosuppressive therapy


il trial “EXPLORER”

EXPLORER EXPLORER Study population and objectivesStudy population and objectives


257 adult patients with moderate-to-severe* extrarenal SLE

Exploratory Phase II/III SLE Evaluation of Rituxima b

•• Primary objectivesPrimary objectives– Efficacy (achieving and maintaining a major or partial clinical response) vs

placebo infusion at week 52– Safety (adverse events and laboratory assessments)

** assessed by BILAGassessed by BILAG

Merrill JT et al. Athritis Rheum 2010;62:222–233

EXPLOREREXPLORERStudy design Study design –– multicenter, randomized, double blind, placebo multicenter, randomized, double blind, placebo controlledcontrolled

SCREENING -1W

Rituximab + Prednisone taper arm

open-label retreatment study

Study drug infusion (two 1000 mg infusions two weeks apart + 2 further infusions after 6 months)

added to prednisone and to baseline immunosuppressive regimen (AZA, MMF, MTX).

Prednisone tapered to 10 mg/day by week 10 and to 5 mg/day by week 52

Merrill JT et al. Arthritis Rheum 2010;62:222-233

Placebo + Prednisone taper arm

Weeks 1 and 3Days 1 and 15

Week 10Weeks 24 and 26 Week 52

EXPLORERResults

• 257 patients, 88 randomized to placebo and 169 to Rituximab• completed the study: 73% placebo and 71% Rituximab• placebo withdravals: 14.8% AE, 10.2% patient/physician • placebo withdravals: 14.8% AE, 10.2% patient/physician

decision, 2.2% lost, 0 deaths• Rituximab withdravals: 11.2% AE, 14.2% patient/physician

decision, 1.8% lost, 1.8% deaths

50

60

70

80

EXPLORER – CLINICAL RESPONSE AT WEEK 52

0

10

20

30

40

50

No clinicalresponse

Partial clinicalresponse

Major clinicalresponse

MCR+PCR

Placebo

Rituximab

Immunological parameters

EXPLORERSafety

• serious adverse events: 36.4% placebo, 37.9% Rituximab

• infusion reactions: 8% Placebo vs 13.6% Ritux I ciclo,4.5% Placebo vs 14.8% Ritux II ciclo

• infections: 83% Placebo vs 82.2% Rituximab• serious infections: 17% Placebo vs 9.5% Rituximab• 3 deaths Rituximab: 1 intestinal perforation, 1

multidrug toxicity, 1 unknown

EXPLORERConclusion

no difference in efficacy between Placebo andRituximabin patientswith activeSLE treatedforRituximabin patientswith activeSLE treatedfor52 weeks

Study population and objectivesStudy population and objectives


7 adult female patients with severe SLE and lupus nephritis failing conventional immunosuppressive agents including cyc

Rituximab treatment of cyclophosphamide-resistant proliferative Lupus Nephritis

•• ObjectivesObjectives– Efficacy (SLEDAI, renal response, histopathologic outcome)– Safety (adverse events and laboratory assessments)

Gunnarsson I et al. Athritis Rheum 2007;56:1263-1272

Treatment protocolTreatment protocol

• Day 0: methylprednisolone 250 mg + cyc 0.5 mg/m2

• Days 2, 9, 16: hydrocortisone100 mg + rituximab 375 mg/m2

• Day 23: methylprednisolone 250 mg + cyc 0.5 mg/m2 + rituximab 375 mg/m2

• oral prednisone 1 mg/kg starting from day 3 with tapering during the following


• oral prednisone 1 mg/kg starting from day 3 with tapering during the following weeks

Evaluation of renal rsponse

• GFR, urinary sediment, 24 h proteinuria, renal histology (biopsy repeated 3 – 12months after rituximab treatment)


RESULTS at 6 monthsRESULTS at 6 months

•• SLEDAI significantly decreased (mean score from 15 to 3)SLEDAI significantly decreased (mean score from 15 to 3)

•• mean oral prednisone decreased from 18.9 mg/day to 8.3 mg/daymean oral prednisone decreased from 18.9 mg/day to 8.3 mg/day

•• significant improvement of serum creatinine and serum albumin levelsignificant improvement of serum creatinine and serum albumin level

•• significant decrease of antisignificant decrease of anti--dsDNA and antidsDNA and anti--C1q antibodiesC1q antibodies

•• significant increase of C3 and C4 levelsignificant increase of C3 and C4 level


•• significant increase of C3 and C4 levelsignificant increase of C3 and C4 level

•• significant decrease of proteinuriasignificant decrease of proteinuria

•• improvement in the histopathologic type in 5/7 (from proliferative to mesangial) with reduction in the improvement in the histopathologic type in 5/7 (from proliferative to mesangial) with reduction in the renal activity indexrenal activity index

•• 3 patients complete remission and 1 partial remission3 patients complete remission and 1 partial remission

SAFETYSAFETY

•• 1 limited Herpes zoster, 1 photosensitive eruption, 1 neutropenic fever, 1 urinary tract infection1 limited Herpes zoster, 1 photosensitive eruption, 1 neutropenic fever, 1 urinary tract infection


CONCLUSIONSCONCLUSIONS

Treatment with Rituximab in combination with CYC was


Treatment with Rituximab in combination with CYC was effective and safe in 7 patients with therapy-resistant proliferative lupus nephritis


il trial “LUNAR”

ACR 2009 Annual Scientific MeetingOctober 16-21, Philadelphia

Efficacy and Safety of Rituximab in Subjectswith Active Proliferative Lupus Nephritis

Furie R, et al

LUNAR LUNAR Study population and objectivesStudy population and objectives


144 adult patients with class III/IV LN

Efficacy and Safety of Rituximab in Lupus Nephritis

•• Primary objectivesPrimary objectives– Efficacy (achieving and maintaining a complete or partial renal response) vs

placebo infusion at week 52– Safety (adverse events and laboratory assessments)

Furie R et al. Athritis Rheum 2009;60:S429

LUNARLUNARStudy design Study design –– multicenter, randomized, double blind, placebo multicenter, randomized, double blind, placebo controlledcontrolled

Furie R et al. Arthritis Rheum 2009;60:S429

72 patients Rituximab (Day 1, 15, 168, 182) + MMF + Prednisone72 patients Placebo (Day 1, 15, 168, 182) + MMF + Prednisone

LUNARResults

• 72 patients in each arm with similar baseline features• cumulative response 46% placebo vs 57% Rituximab (p ns)• Rituximab greater effect on anti-dsDNA (p<.01) and C3 (p<.03)• 11% placebo vs 1% Rituximab required another • 11% placebo vs 1% Rituximab required another

immunosuppressive add on drug• Serious adverse events in 35% placebo vs 30% Rituximab• Infections 16% in both groups – 2 deaths sepsis Rituximab

LUNARConclusion

Although there were more responders with Rituximab, nostatistically significant difference between Rituximab +MMFvsPlacebo+ MMF in patientswith activelupusnephritis.vsPlacebo+ MMF in patientswith activelupusnephritis.Rituximab decreased anti-dsDNA Abs and increased C3levels.

Ramos-Casals M et al. Arthritis Rheum 2009;61:1281-1282

Rituximab and Lupus: good in real life, bad in controlled trials

• patients with severe disease vs patients with milder disease• patients not responsive to other immunosuppressive therapies• high doses of corticosteroids in “Explorer” and “Lunar” (confounding factor)• ethnic factors may influence the clinical response to drugs• trials require demonstration of superiority of Rituximabover current first line therapy,thatis differentfrom clinical practicewhereRituximabis givento patientsrefractoryto

Ramos-Casals M et al. Arthritis Rheum 2009;61:1281-1282

thatis differentfrom clinical practicewhereRituximabis givento patientsrefractorytocommon immunosuppressors

Patients included in “Explorer” and “Lunar” seem to be completelydifferent from those who received Rituximab off-label since 2000

“Beliefs, evidence-based medicine and the real life”by Frederic Houssiau

• “As scientists, we mostly favour evidence-based therapies;therapies;

• as human beings, we sometimes favour beliefs;

• but as physicians, we always adopt patient-tailored therapies”.

Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010...

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Transcript of Sebastiani Gian Domenico Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010...