emoglobinuria parossistica notturna: principi di terapia e ... · emoglobinuria parossistica...
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Emoglobinuria Parossistica Notturna: principi di terapia e ruolo della rete
regionale
LANZA FRANCESCO
UOC EMATOLOGIA Lab. Specialistico
di Citometria e Cellule Staminali
Az Ospedaliera CREMONA
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EPN
Malattia clonale di natura acquisita delle cellule staminali emopoietiche che
provoca:
1. Anemia dovuta ad emolisi intravascolare cronica e acuta;
2. Diatesi tromboembolica; 3. Leuco-piastrinopenia 4. Distonia della muscolatura liscia
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Glicosil-Fosfatidil-Inositolo (GPI)
il glicosil-fosfatidil-inositolo (GPI) svolge un ruolo importante nell’ancoraggio di proteine che non possono entrare nella membrana lipidica per la mancanza di un segmento idrofobo sufficientemente esteso.
EPN
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In PNH, GPI-Deficient Cells Are Positively Selected in Pathologic Bone Marrow
Inoue N et al. Int J Hematol. 2003;77:107:107-112.
RBCs
Monocytes
Platelets
Granulocytes
Lymphocytes
Step 1 Step 2
Hematopoie9c Stem Cells
RBCs = red blood cells
GPI-‐Deficient Cell
Selected Cells*
GPI = glycerophosphatidylinositol.
Somatic Mutation in PIG-A
Immunologic Attack
Clonal Expansion by
Immuno-selection
Benign Tumor-Like Expansion
*Clones presumed to have a conferred growth advantage, in addition to the PIG-A mutation, resulting in GPI deficiency.
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CLASSIFICATION OF HAEMOLYTIC ANAEMIAS
• Malaria • Auto-immune • Drug-induced • Micro-angiopathic • Other
Paroxysmal Nocturnal
Haemoglobinuria (PNH)
Acquired
Familial HUS (due to defective
C regulatory protein)
• emoglobinopathies • Enzimopathies • Membranopathies • Other
Hereditary
Extracorpuscolar causes
Intracorpuscolar causes
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EPN: rilievi laboratoristici
• Anemia, reticolocitosi, <aptoglobina • Aumento del valore serico LDH (800-3000) • Citopenia: neutropenia, trombocitopenia • Emoglobinuria a poussee • “Perpetual Hemosiderinuria” • Segni di trombosi (dimero D) >40% pts • Aumento parametri di flogosi (infezioni) • Ipertensione polmonare • Insufficenza renale
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EPN: Emoglobinuria
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CD59, CD90, CD109
CD55 CD58 CD59 CD48 CD52 PrPc CD16
CD24 CD55
CD58 CD59 CD48 PrPC CD73 CD108
CD55 CD58 CD59 CD109 PrPC GP500 Gova/b
CD55 CD58 CD59 PrPC AChE JMH Ag Dombroch HG Ag
CD55 CD58 CD59 CD14 CD16 CD24 CD48 CD66b CD66c CD87 CD109 CD157 LAPNB1 PrPC p50-80 GPI-80 ADP-RT NA1/NA2
CD14 CD55 CD58 CD59 CD48 CD52 CD87 CD109 CD157 Group 8 PrPC GPI-80 CD16*
CD55 CD58 CD59 CD48 CD52 CD87 CD108 PrPc ADP-RT CD73 CD90 CD109 CD16
Haematopoietic Stem Cell
Platelets
RBC
Granulocytes
B cells
Monocytes
T cells
NK cells
Proteins deficient on PNH blood cells
Courtesy L. Del Vecchio
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Granulocyte Lymphocyte
Monocyte Erythrocyte
CD66b
CD24
CD59 CD14
CD48
T
B
NK
Panel for cytometric analysis in patients with suspected PNH
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Studio midollare in corso di EPN: procedura errata a fini diagnostici
FLAER Alexa-488
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ERITROCITI
13.3%
FSC e SSC log
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EPN: Monociti 3 popolazioni
CD33 CD45
CD14 CD14
I II III
CD64
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The gold standard diagnos9c test for PNH is high sensi9vity flow cytometry performed on peripheral blood
• Tes%ng for PNH Iden%fies 3 Popula%ons of PNH Cells Type I: Cells with normal expression of CD59 Type II: PNH cells with par%al CD59 deficiency Type III: PNH cells with complete CD59 deficiency
• Granulocytes provide more accurate representa%on of PNH clone size
Percentages of PNH RBCs may be affected by hemolysis or blood transfusions
• Evaluate granulocytes and at least 1 addi%onal cell line: RBCs and/or monocytes
Borowitz MJ et al; Clinical Cytometry Society. Cytom B Clin Cytom. 2010;78:211-‐230
Standard Diagnostic Testing for PNH
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Routine Testing Is Recommended for High-Risk Patient Populations
Two independent, interna9onal groups recommend tes9ng of high-‐risk pa9ents for PNH
Interna9onal Clinical Cytometry Society (ICCS) – provides laboratory tes%ng guidelines for rou%ne diagnosis of PNH
Interna9onal PNH Interest Group (I-‐PIG) – provides guidelines on diagnosis and management of PNH
1. Borowitz MJ et al; Clinical Cytometry Society. Cytometry B Clin Cytom. 2010;78:211-230.
2. Parker C et al; International PNH Interest Group. Blood. 2005;106:3699-3709.
Advancements in treatment op9ons warrant early diagnosis and interven9on Early diagnosis is essen9al for improved pa9ent prognosis1-‐2
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REFERTAZIONE CASO I
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Rule PNH In or Out Using High Sensitivity Flow Cytometry
and Clinical Assessment
Early Diagnosis Is Essen9al for Improved Pa9ent Management and Prognosis1-‐2
1. Borowitz MJ et al; Clinical Cytometry Society. Cytometry B Clin Cytom. 2010;78:211-230.
2. Parker C et al; International PNH Interest Group. Blood. 2005;106:3699-3709. 19
Unexplained Thrombosis
(venous or arterial)
Unexplained Cytopenia
RA-MDS (RCUD)
Aplastic Anemia Hemoglobinuria
Coombs-Negative Hemolytic
Anemia
RA-MDS= refractory anemia-myelodysplastic syndrome.
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• PNH cells detected in 57% to 70% of AA1, 2, 3
• PNH cells detected in 20-‐50% of MDS pa9ents2,3
• PNH cells detected in 50% in other bone marrow
failure3
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1. Sugimori C et al. BJH. 2009; 147: 102-12;
2. 2. Sugimori C et al. Blood. 2006 (107):1308-14; 3. 3. Galili N et al. JCO. 2009; Abstract 7082.
Co-‐evolu9on of PNH and BMF in a Hypoplas9c Marrow
Mutation of the PIG-A
AA / MDS
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Suppor9ve Care Op9ons Do Not Impact Progression and Risk for Severe Morbidi9es and Mortality1
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Historical care op9ons for PNH
• Transfusions1 – risk of iron overload • An%coagulants1 – ineffec%ve in many pa%ents
• Red cell supplements1 – may expand clone and elevate hemolysis
• Steroids/androgen hormones1 – adverse events
1. Parker C et al; Interna%onal PNH Interest Group. Blood. 2005;106:3699-‐3709.
THERAPY OF PNH
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Bone Marrow Transplant (BMT) Is Associated With Significant Morbidi9es and Mortality2,3
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Although it is the only poten9ally cura9ve therapy for PNH, BMT is associated with significant morbidi9es and mortality2,3
• In a study examining PNH pa%ents (n=23)2:
– 50% chronic grad-‐versus-‐host-‐disease (GVHD); 42% acute GVHD3
– 42% transplant-‐related mortality2 – \
• BMT has a significant impact on quality of life post-‐transplant4,5
1. Parker C et al; International PNH Interest Group. Blood. 2005;106:3699-3709. 2. Santaraone S et al. Haematologica. 2010;95:983-988. 3. de Latour PF et al. EBMT 2009:Abstract 316. 4. Bieri S et al. Bone Marrow Transplant. 2008;42:819-827. 5. Fraser CJ et al. Blood. 2006;108:2867-2873.
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• Eculizumab binds with high affinity to C51,2
• Terminal complement - C5a and C5b-9 formation is blocked1,2
• Proximal functions of complement remain intact1,2 – Weak anaphylatoxin2,4
– Immune complex clearance2
– Microbial opsonization2
1. Soliris® (eculizumab) Summary of Product Characteris%cs. Cheshire, CT: Alexion Europe SAS. 2. Rother RP et al. Nature Biotechnol. 2007;25:1256-‐1264. 3. Walport MJ. N Engl J Med. 2001;344:1058-‐1066. 4. Figueroa JE, Densen P. Clin Microbiol Rev. 1991;4:359-‐395
Eculizumab is an An9-‐C5 An9body That Blocks Complement-‐Mediated Hemolysis
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Eculizumab Clinical Development Program
Eculizumab (n = 11)
Eculizumab (n = 43)
Placebo (n = 44)
Eculizumab (n = 97)
Entered long-term extension (up to 3 years;
n = 10)
Entered long-term extension (up to 3 years;
n = 41)
Entered long-term extension (up to 3 years;
n = 44)
Entered long-term extension (up to 3 years;
n = 92)
Phase II pilot study NEJM 20041
(12 weeks) + 2 extension studies (52 and 104 weeks) 11 patients
Phase III study Blood 20083
SHEPHERD
(52 weeks) 97 patients
187 patients entered long-term extension trial4
Investigation: Measure clinical and biochemical indicators of hemolysis
Primary end points: stabilization of hemoglobin levels and the number of units of packed red blood cells
transfused
Primary efficacy end point: hemolysis as assessed by LDH
AEGIS study
Int J Hematol 20115
(12 weeks) 29 patients
Eculizumab (n = 29)
Primary end point: reduction of hemolysis
Entered long-term extension (up to 2
years; n = 27)
Phase III study NEJM 20062 TRIUMPH (26 weeks) 87 patients
Overview of the Eculizumab Clinical Development Program: Pilot Study, TRIUMPH, SHEPHERD, and AEGIS
1. Hillmen P et al. N Engl J Med. 2004;350:552-559. 2. Hillmen P et al. N Engl J Med. 2006;355:1233-1243. 3. Brodsky RA et al. Blood. 2008;111:1840-1847. 4. Hillmen P et al. Br J Haematol. 2013;162:62-73. 5. Kanakura Y et al. Int J Hematol. 2011;93:36-46.
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1. Hillmen P et al. N Engl J Med. 2006;355:1233-‐1243. 2. Hillmen P et al. Blood. 2007;110:4123-‐4128. 3. Brodsky RA et al. Blood. 2008;111:1840-‐1847. 4. Hillmen P et al. Br J Haematol. 2013;162:62-‐73. 5. Socié G et al. 49th Annual Mee%ng of the American Society of Hematology; December 8-‐11, 2007; Atlanta, GA. Poster 891-‐III [Blood.007;110:3672.)
TRIUMPH1,2
• Patients not on Soliris (n = 44) • Soliris (n = 43) • Patients not on Soliris transitioned • to Soliris (n = 44)
SHEPHERD2
• Soliris (n = 97) EXTENSION studies • Hillmen 2013 (n = 189 and 87 at 72 and 144 weeks, respec%vely)4 • Socié 2007 (n = 10)5
Reduc9on in Hemolysis as Measured by LDH Was Sustained With Long-‐Term Soliris Treatment
Patients being treated with Soliris maintained an 86% reduction in hemolysis as measured by LDH over a 36-month treatment period4
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Blood transfusion requirements in the 12 months before eculizumab therapy and the most recent 12 months on eculizumab treatment in 64 patients.
Kelly R J et al. Blood 2011;117:6786-6792 ©2011 by American Society of Hematology
Transfusion independence: 40 of 61 patients (66%)
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Eculizumab Riduce l’Incidenza di Trombosi in Pazienti Trattati con Anticoagulanti1
! 94% di riduzione di incidenza di trombosi con SOLIRIS
(n=91)
P<0.001
*excludes patients on antiplatelet agents
1. Hillmen P, et al. Blood. 2007;110:4123-4128.
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Soliris Treatment Resulted in Significant Improvements in Survival for Pa9ents With PNH
Years A[er Diagnosis
Pa9e
nts S
urviving (%
)
Actuarial Survival From the Time of Diagnosis in 80 Patients With PNH1
100
80
60
40
20
0 0 5 10 15 20 25
Age- and Gender- Matched Controls
Patients With PNH
Pa9ents With PNH on Soliris Compared With Age-‐ and Gender-‐Matched Controls2*
Time, (Years) Pa
9ents S
urviving, (%)
*Survival after 10-years is slightly inferior to controls with causes of
death related to bone marrow failure and not hemolysis or thrombosis
1. Hillmen P et al. N Engl J Med. 1995;333:1253-1258 2. Hill A et al. Presented at: 54th Annual Meeting of the American Society of Hematology (ASH); December 8-11, 2012; Atlanta, GA. Abstract 3472
Results from a 10-‐year mul9center observa9onal cohort study
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• Treatment with Eculizumab resulted in a 92% reduc9on in thrombo9c events1
• Pa%ents being treated with Eculizumab reported significant improvement in evidence of pulmonary hypertension and dyspnea3,4
• 82% of pa%ents being treated with Eculizumab achieved transfusion independence at 36 months2
• Treatment with Eculizumab resulted in clinically meaningful improvements in quality of life, including reduced fa%gue and pain5
1. Hillmen P et al. Blood. 2007;110:4123-4128. 2. Hillmen P et al. Br J Haematol. 2013;162:62-73. 3. Hill A et al. Br J Haematol. 2012;158:409-414.
4. Hill A et al. Br J Haematol. 2010;149:414-425. 5. Hillmen P et al. N Engl J Med. 2006;355:1233-1243.
Clinical Efficacy of Eculizumab in Pa9ents With PNH
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1. Hillmen P et al. N Engl J Med. 2006;355:1233-1243. 2. Brodsky RA et al. Blood. 2008;111:1840-1847. 3. Hillmen PD et al. Blood. 2007;110:4123-4128
4. Hill A et al. Br J Haematol. 2010;149:414-425. 5. Hillmen P et al. Am J Hematol. 2010;85:553-559. 6. Richards SJ et al. Blood. 2005;106:Abstract 1047.
7. Hillmen P et al. Br J Haematol. 2013;162:62-73. 8. Soliris® (eculizumab) summary of product characteristics. Cheshire, CT: Alexion Europe SAS. 9. Kelly RJ et al. Blood. 2011;117:6786-6792
Soliris Treatment Expecta9ons
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REGIONE LOMBARDIA
PRESIDI REGIONALI DI RIFERIMENTO PER L’EPN:
CREMONA
MILANO
BERGAMO
BRESCIA
PAVIA
MONZA
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Percorso Diagnos?co, Terapeu?co e Assistenziale (PDTA) rela?vo a: EMOGLOBINURIA PAROSSISTICA
NOTTURNA Codice esenzione RD0020
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12,5 6,1 8,3 9,3
79,2 100,0 84,6
0
10
20
30
40
50
60
70
80
90
100
LOMBARDIA EMILIA-‐ROMAGNA ITALIA
%
Distribuzione della dimensione del clone
<1%
1-‐5%
>5%