Malattie oncoematologiche

ed emofilia acquisita

Francesco Baudo – SC di Ematologia Ospedale Niguarda – Milano

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Milano, 29 aprile 2011

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•L’emofilia acquisita è una sindrome emorragica caratterizzatada:

– carenza di fattori della coagulazione (FVIII in oltre il 98% deicasi)

– secondaria ad auto-anticorpi contro epitopi specifici conneutralizzazione e/o accelerata “clearance” dal plasma

Emofilia acquisita (EA): definizione

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Eziopatogenesi

• Condizioni cliniche associate

Nessuna 48.7 - 63.3% Malattie autoimmuni 16.4 - 6.6%

Neoplasie 11.1 - 14.6%

Gravidanza 2.0 - 10.5%

Farmaci 1.0 - 3.3%

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EA e neoplasie

• Inhibitors against FVIII in patients with cancer (Sallah S, Cancer 2001;91:1067-74).

• Analisi della letteratura con lavori (16) che includono almeno 10pazienti pubblicati nelle ultime due decadi (Baudo F. Acquired haemophilia inthe elderly. In: Balducci L, Ershler W, de Gaetano G, eds. Blood Disorders in the Elderly. Cambridge:Cambridge University Press; 2007:389-407).

• Acquired hemophilia A in United Kingdom: a 2-year surveillancestudy. (Collins P. Blood 2007;109:1870-77)

• EACH registry (Knoebl P. Blood 2010)

– registro multicentrico, internazionale, web-based, in 11 paesi europei– periodo di arruolamento: gennaio 2003 - gennaio 2009– numero pazienti 501

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EA e incidenza di neoplasie

Baudo Collins EACH

Numero pazienti 633 150 501

Neoplasie 70 (11%) 22 (14,6%) 59 (11,8%)

- solide 52 (8,2%) 13 (8,6%) 40 (7,9%)

- ematologiche 18 (2,8%) 9 (6%) 19 (3,8%)

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EA e tipo di neoplasie

Sallah Baudo Collins

Neoplasie 41 70 22

Solide 25 52 13- polmone 6 14 5- app gastrointestinale 2 14 8- prostata 6 8 3- altro 11 16 9Ematologiche 16 18 9- LNH, LLC 9 13 n.a.- mieloma 1 4 n.a.- mielofibrosi 2 1 n.a.- altro 4 --- ---

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•Epidemiologia ben definita

– incidenza ~ 1.5 casi per milione/anno

– età mediana >70 anni

– elevata mortalità per emorragia, variabile da 7,9 al 22%

– nessuna correlazione tra quadro clinico, FVIII e titolo inibitore

• Controversa la terapia ottimale per il controllo dell’emorragia el’eradicazione dell’inibitore

Emofilia acquisita: epidemiologia

Collins P. Blood, 2007;109:1870. Baudo F. Blood Disorders in the Elderly In: Balducci L, et al. Cambridge University Press;2007:389. European Acquired Hemophilia Registry, 2010

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Raccomandazioni•Prioritario il controllo dell’emorragia acuta

– consenso sull’uso degli agenti by-passanti come terapia di primalinea

•Iniziare la terapia immunosoppressiva alla diagnosi; elevato rischiodi emorragie fatali finché l’inibitore è presente

– non ancora definita la terapia ottimale; nelle ultime due decadi iregimi terapeutici con maggiore successo includono steroidi da soli oin combinazione con ciclofosfamide

EA: principi del trattamento

Huth-Kühne A, Baudo F, et al. International recommendations on the diagnosis and treatment ofpatients with acquired hemophilia A. Haematologica 2009;4:566-575

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•Dati derivati da studi osservazionali e retrospettivi•Numero limitato di pazienti

•Differenti condizioni cliniche associate

•Decisioni terapeutiche spesso basate su dati ottenuti neltrattamento dei pazienti con emofilia congenita•Studi controllati non disponibili e molto difficili da condurre; ilregistro come solo mezzo per identificare il trattamento ottimale diquesti pazienti

Trattamento dell’EA: limiti degli studi disponibili

• Primary end-point: control of the 1st episode of bleeding treated withthe 1°-line hemostatic therapy to avoid any potential indication bias(i.e. low enrollement, management of the patients judged by eachinvestigator)

• Groups comparison: A – bypassing agents (rFVIIa or aPCC) vs. FVIII or DDAVP

• B – rFVIIa vs aPCC

• Type of analysis: 1 – Pre-matching comparison with Pearson’s χ2

• or Mann-Whitney U-test• 2 – Unbiased comparison with propensity score• (PS)

• Balancing Baseline Covariates for PS models: age, gender, FVIII, inhibitor titer,Hb, bleeding site, cause, severity, delay of therapy start.

Anti hemorrhagic therapy: statistical analysis

EACH2 registry flow chart

501 patients

19 patients without bleeding

482 patients with at least 1 bleed

144 patients had no hemostatic therapy

338 patients started hemostatic therapy

31 patients received other therap ies

307 patients treated with rFVIIa, APCC,

FVII I, DDAVP

19 patients without endpoint available

288 patients with endpoint available

No difference in age, weight, Hb, delay between diagnosis and treatment, cause ofbleeding

Unmatched baseline characteristics: bypassingagents vs FVIII or DDAVP

Variable Category rFVIIa, aPCC FVIII, DDAVP pPatients number 219 69Gender Female 109 (49.7) 26 (37.7) 0.079

Male 110 (50.3) 43 (62.3)FVIII (%) 1.0 (1.0-4.0) 3.0 (1.0-8.0) 0.039

Inhibitor titre (BU/mL) 15.4 (0.1-2765.0) 8.0 (0.3-200.0) 0.0003

Bleeding site CNS 5 (2.2) 0 (0.0) 0.044Deep 139 (63.4) 32 (46.3)Hemarthroses 6 (2.7) 3 (4.3)Mucosa 34 (15.7) 21 (30.4)Skin 34 (15.5) 13 (18.8)Multiple sites 1 (0.4) 0 (0.0)

Severity of bleeding Unknown 1 (.) 0 (.) 0.032

Severe 193 (88.5) 54 (78.3)Non-severe 25 (11.5) 15 (21.7)

Data are reported as n (%) as median (IQR) for categorical and continuous variables respectively.P-values refer to Pearson chi-square or Mann-Whitney U-test.

Matched baseline characteristics: bypassingagents vs FVIII or DDAVP

Variable Category rFVIIa, aPCC FVIII,DDAVP p

Patients number 60 60Gender Female 25 (41.7) 23 (38.3) 0.69

Male 35 (58.3) 37 (61.7)FVIII (%) 2.0 (0.0-40.0) 3.0 (0.0-34.0) 0.61Inhibitor (BU/mL) 9.3 (1.0-2765) 8.0 (0.3-200) 0.52Bleeding Site Deep 30 (50.0) 30 (50.0) 0.99

Hemarthroses 3 (5.0) 2 (3.3)Mucosa 15 (25.0) 16 (26.7)Skin 12 (20.0) 12 (20.0)

Severity of bleeding Severe 47 (78.3) 49 (81.7) 0.63Non-severe 13 (21.7) 11 (18.3)

Data are reported as n (%) and median (IQR) for categorical and continuous variables respectively.P-values refer to McNemar chi-square or Wilcoxon signed-rank test.

Proportion of patients with bleeding control:bypassing agents vs FVIII or DDAVP

* p<0.0001

Bypassing agents are significantly more effective than FVIII or DDAVP

Unmatched samples Matched samples

rFVIIa,aPCC

FVIII,DDAVP

rFVIIa,aPCC

FVIII,DDAVP

Patients number 219 69 60 60

Bleeding Resolved No 18 (8.2) 21 (30.4) 4 (6.7) 19 (31.7)

Yes 201 (91.8)* 48 (69.6) 50 (93.3)* 41 (68.3)

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Unmatched baseline characteristics: rFVIIa vs aPCC

Data are reported as n (%) and median (IQR) for categorical and continuous variables respectively.P-values refer to Pearson chi-square or Mann-Whitney U-test.

No difference in gender, weight, FVIII, inhibitor, Hb, delay between diagnosis andtreatment, cause and severity of bleeding

Variable Category rFVIIa aPCC p

Patients number 184 70Age (years) 73.0 (15.0-92.0) 77.0 (24.0-92.0) 0.005Bleeding site CNS 7 (3.8) 0 (0.0) 0.034

Deep 107 (58.1) 51 (72.8)Hemarthroses 6 (3.2) 2 (2.8)Mucosa 36 (19.5) 4 (5.7)Skin 26 (14.1) 13 (18.6)Multiple Sites 2 (1.1) 0 (0.0)

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Matched baseline characteristics: rFVIIa vs aPCC

Data are reported as n (%) or median (IQR) for categorical and continuous variables respectively.P-values refer to McNemar chi-square or Wilcoxon signed-rank test.

Variable Category rFVII aPCC p

Patients number 64 64

Age (years) 71.7 (12.3) 72.2 (16.2) 0.29

74.0 (24.0-92.0) 76.0 (24.0-92.0)

Bleeding site Deep 46 (71.9) 48 (75.0) 0.88

Haemarthroses 1 (1.5) 2 (3.1)

Mucosa 7 (10.9) 4 (6.2)

Skin 10 (15.6) 10 (15.6)

Proportion of patients with bleeding control:rFVIIa vs aPCC

*p = 0.6; **p = 1

No difference in efficacy between rFVIIa and aPCC

Unmatched samples Matched samples

rFVIIa aPCC rFVIIa aPCC

Patients number 159 60 57 57

Bleeding Resolved No 14 (8.8) 4 (6.7) 4 (7.1) 4 (7.0)

Yes 145 (91.2)* 56 (93.3) 53 (92.9)** 53 (93.0)

Deaths due to bleeding 3.0 %

Myocardial infarction 1.4 %

Stroke 0.2 %

Venous thromboembolism 1.0 %

no significant association of death or severe adverseevents with a specific hemostatic therapy

Hemostatic therapy: adverse events

• Terapia di prima linea– Steroide da solo o in combinazione con la ciclofosfamide

• Terapia di seconda linea:– Se non risposta dopo 4-6 settimane, rituximab (meglio associato a

steroide)

• Terapie alternative– Azatioprina, vincristina, micofenolato o ciclosporina

• Non raccomandate le immunoglobuline endovena

Raccommandazioni per l’eradicazione dell’inibitore (1)

1. Huth-Kühne A, Baudo F, et al. International recommendations on the diagnosis and treatment of patientswith acquired hemophilia A. Haematologica 2009;4:566-575

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Immunosuppression: EACH evaluationcriteria

• CR: complete remission

– FVIII >70IU/dL

– Inhibitor undetectable

– Immunosuppression stopped

• NR: no remission

• The study was reviewed by the ethical committees in each country but

– in 2 countries no informed consent (IC) was required,

– in 6 required only for patients who were alive,

– in 5 required for all patients; therefore died patients were not recruited witha possible exclusion of more severely affected cases.

• In this analysis only individuals from countries that could enter allpatients have been included.

• The outcome of first line immunosuppressive therapy was analysed indetail in three groups: steroids alone, steroids + cyclophosphamideand rituximab based regimens

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EACH Registry: inhibitor eradication

Patients included in analysis of immunosuppression

EACH2 cohortn=501

Countries that could enterall patients

n=331

Countries that could notenter patients who have died

n=270

Excluded

No outcome data recordedn=37

outcome data for IS recordedn=294

Excluded

Treated withsteroid alone: 142

steroid + cyclophos: 83Rituximab regimens: 51

N=276

Other regimensFVIII based ITI (n=7)cyclosporine (n=5)

cytotoxic alone (n=6)n=18

Excluded

Outcome of first-line IS

S = steroid; Cytotox = cytotoxic; Ritux = Rituximab

RegimensCR

n (%)Time to CR

(days)Relapse

n (%)

Time torelapse(days)

Stable CRn (%)

Steroidsn=142

83 (58) 34 (17-76) 15 (18) 134 (36-317) 68 (48)

S + cytotoxicn=83

66 (80) 32 (12-77) 8 (12) 139 (14-135) 58 (70)

Rituximabn=51

31 (61) 65 (29-144) 1 (3) 44 30 (59)

CR rate and time to CR of PS matched groups

Higher rate of stable CR with steroid and cyclophosphamidethan with steroids alone confirmed using patients matched byPS for age, sex, weight, FVIII level, inhibitor titre and aetiology

P<0.001

Outcome of 2 lines IST

S = steroid; Cyclo = cyclophosphamide

1st line IST 1st linestable CR

2nd linestable CR

Overallstable CR

Steroid alonen=142 68 31 99 (69.7)

S + cyclon=83 58 11 69 (83.1)

RituximabN=51 30 7 37 (72.5)

Patients not achieving a stable CR after 1st line IST were treated with a varietyof 2nd line therapies.•1st line S 2nd line mainly combination containing cyclophosphamide orrituximab•1st line S + cyclo rituximab regimens

IST adverse events

Regimen

Adverse events

Any AE n (%) Infection Neutropenia Diabetes Psychiatric

disorder

Steroids alone n=142

36/142 (25)

23 (16)

2 (1)

11 (8)

6 (4)

Steroids + cyclo n=83

34/83 (41)

22 (27)

12 (14)

5 (6)

3 (4)

Rituximab N=51

19/51 (37)

6 (12)

9 (18)

11 (22)

1 (2)

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• Prima scelta: agenti “by-passanti” (aPCC, rFVIIa)– azione rapida

– elevata efficacia

– rischio trombotico non significativo

• rFVIIa e aPCC egualmente efficaci

• RC stabile maggiore con steroidi + ciclofosfamide

Commenti (1)

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• Da tener presenti il rischio cardio-vascolare per l’età, leco-morbidità e i farmaci impiegati

• Cautela in pazienti con espressione di fattore tessutale(e.g. malattia aterosclerotica avanzata, traumi, setticemia,CID)

• I rischi, i benefici e i costi del trattamento devonoaccuratamente valutati su base individuale

Commenti (2)