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Transcript of Emoglobinuria Parossistica Notturna: principi di terapia e ... · PDF fileEmoglobinuria...

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

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

Glicosil-Fosfatidil-Inositolo (GPI)

il glicosil-fosfatidil-inositolo (GPI) svolge un ruolo importante nellancoraggio di proteine che non possono entrare nella membrana lipidica per la mancanza di un segmento idrofobo sufficientemente esteso.

EPN

4

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.

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

EPN: rilievi laboratoristici

Anemia, reticolocitosi, 40% pts Aumento parametri di flogosi (infezioni) Ipertensione polmonare Insufficenza renale

EPN: Emoglobinuria

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

Granulocyte Lymphocyte

Monocyte Erythrocyte

CD66b

CD24

CD59 CD14

CD48

T

B

NK

Panel for cytometric analysis in patients with suspected PNH

Studio midollare in corso di EPN: procedura errata a fini diagnostici

FLAER Alexa-488

ERITROCITI

13.3%

FSC e SSC log

EPN: Monociti 3 popolazioni

CD33 CD45

CD14 CD14

I II III

CD64

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

14

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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

REFERTAZIONE CASO I

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.

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

20

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

Suppor9ve Care Op9ons Do Not Impact Progression and Risk for Severe Morbidi9es and Mortality1

21

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

Bone Marrow Transplant (BMT) Is Associated With Significant Morbidi9es and Mortality2,3

22

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.

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

23

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.

24

25

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. Soci G et al. 49th Annual Mee%ng of the American Society of Hematology; December 8-11, 2007; Atlanta, GA. Poster 891-III