YES Antonio M. Risitano, M.D., Ph.D. Hematology Department of - - PowerPoint PPT Presentation
The 1st World Congress on Controversies in Hematology Rome, September 4th Do the benefits of complement blockade extend to all patients with PNH clone? YES Antonio M. Risitano, M.D., Ph.D. Hematology Department of Biochemistry and Medical
Antonio M. Risitano, M.D., Ph.D.
Hematology Department of Biochemistry and Medical Biotechnologies Federico II University of Naples
The 1st World Congress on Controversies in Hematology Rome, September 4th
Without the complement inhibitors CD55 and CD59 PNH RBC are susceptible to complement attack
PNH
Hemolysis of PNH RBC
Complement activation
CLINICAL CONSEQUENCES OF HEMOLYSIS IN PNH
Renal Failure Pulmonary Hypertension
Anemia Thrombosis
Hemoglobinuria Smooth Muscle Dystonias including Dysphagia, Abdominal Pain, and Male Erectile Dysfunction Fatigue
Eculizumab (h5G1.1mAb)
Anti-C5 Humanized mAb
hinge Variable heavy chain Variable light chain Human constant light chain Ck Human constant heavy chain IgG4 CH2 and CH3 Human constant heavy chain IgG2 CH1 and hinge Human framework regions Murine complementarity determining regions C H 1 C k CH2 CH3
Lectin Pathway Activation (MBL)
Targeting Complement Inhibitors
C5
C5b-9
C5b C6 C7 C8 C9
Classical Pathway Activation Antibody/Antigen Complexes Alternative Pathway Activation Microbiological membranes Bacterial LPS Immune Complexes Mammalian Cell Membranes
C3b
C3
C1q Activated C1 C4+C2 C4b2a C4b2a3b
C3 Convertase C5 Convertase
C5a
C3 Convertase C5 Convertase
C3bBb3b C3bBb C3a C3b Factor B+D C3, C3H2O
Weak Anaphylatoxin Immune Complexes and Microbial Opsonization
Cell Activation Lysis
Potent Anaphylatoxin Chemotaxis Cell Activation
EFFECT OF ECULIZUMAB ON HEMOLYSIS
Lactate dehydrogenase (LDH)
Time, Weeks Lactate Dehydrogenase (U/L) 500 1000 1500 2000 2500 3000 10 20 30 40 50 TRIUMPH – Placebo/extension TRIUMPH – SOLIRIS/extension SHEPHERD – SOLIRIS
Study Week
2 4 6 8 10 12 14 16 18 20 22 24 26
Patients Avoiding Transfusion (%)
10 20 30 40 50 60 70 80 90 100
P < 0.000001 Eculizumab Placebo 51% 0% 44% reduction in PRBC units transfused
EFFECT OF ECULIZUMAB ON TRANSFUSIONS
Time to first transfusion
SHEPHERD study: a non randomized trial for broader PNH population
– patients with thrombocytopenia and minimal transfusional need
Transfusion Requirements (12 Months Prior to Treatment)
51% of patients treated with eculizumab were transfusion independent (12 m) Efficacy demonstrated in all patient cohort
(n = 97) (n = 21) (n = 47) (n = 15) (n = 14)
8 2 8 17 33,5 4 7,5 5 10 15 20 25 30 35 40 Overall < 4 Units 4 - 14 Units 15 - 25 Units > 25 Units Median Units Packed RBCs 1 Year Pre-Treatment 1 Year Post-Treatment
Patient Age Years from diagnosis Treatment duration (months) LDH before Ecu LDH during Ecu Hb before Ecu Hb during Ecu Hb gain PNH RBC before Ecu (%) PNH RBC during Ecu (%) 1 41 15 17 680 225 10 12,8 +2,8 n.a. 48 2 25 2 18 1216 356 7,5 10 +2,5 23 60 3 51 10 16 727 250 9,3 10,5 +1,2 40 89 4 16 1 1 1425 342 7,3 9 +1,7 10 24 5 50 7 39 3968 860 8 10 +2 19 89 6 59 17 4 3100 290 7 11,6 +4,6 50 n.a. 7 39 10 5 2190 250 10,7 11,5 +0,8 46 48 8 38 3 18 1500 360 9 10,7 +1,7 12 45 9 16 1 9 2100 250 9 11,7 +2,7 13 52 Mean 37 6,1 14,1 1878 353 8 10 +2,2 26,6 58,1 Median 39 5 16 1500 290 9 10,7 +2 21 52
ECULIZUMAB IN NON TRANSFUSED PATIENTS
An Italian pilot experience (Risitano et al, EHA 2009) Terminal complement inhibition by eculizumab in non transfused PNH patients leads to improvement of most clinical manifestations, including symptoms of intravascular hemolysis and anemia
2 4 6 8 10 12 14 16
Pre-Eculizumab Treatment Eculizumab Treatment Thrombosis Event Rate (TE per 100 pt-years)
92% reduction in event rate with eculizumab
(n=195) (n=195)
39 events 3 events P = 0.0001
Hillmen et al., Blood 2007
Normalized by time of
(pre and post)
Hill et al., ASH 2009
Blocking C5 Activity Lead to An Increase in Platelet Counts in Thrombocytopenic Patients
30 40 50 60 70 80 90 100
26 52
Eculizumab Treatment (Weeks) Mean Platelet Counts (x109/L)
5 10 15 20 25 26 52 Eculizumab Treatment (Weeks)
Mean Change in Platelets (x109/L) <100,000 >100,000
Complement-mediated platelet consumption? Possible relation with thrombophilia?
Platelet count in thrombocytopenic patients Platelet count change in thrombocytopenic vs non- thrombocytopenic patients
Markers of thrombin generation and fibrinolisis decrease during eculizumab treatment Markers of endothelial activation decrease during eculizumab treatment
Evaluation of hemostasis and endothelial function in patients with paroxysmal nocturnal hemoglobinuria receiving eculizumab. Helley D, de Latour RP, Porcher R, Rodrigues CA, Galy-Fauroux I, Matheron J, Duval A, Schved JF, Fischer AM, Socié G; French Society of Hematology.
NATURAL HISTORY OF PNH
De Latour et al, Blood 2008
Increased mortality due to:
– Thromboembolism – Severe marrow failure – (Clonal evolution to MDS/leukemia?)
Overall survival by subcategory
NATURAL HISTORY OF PNH
Cumulative incidence of complications
De Latour et al, Blood 2008 Cytopenia Thrombosis MDS/AML
Am J Hematol. 2010 Aug;85(8):553-9. Long-term effect of the complement inhibitor eculizumab on kidney function in patients with paroxysmal nocturnal hemoglobinuria. Hillmen P, Elebute M, Kelly R, Urbano-Ispizua A, Hill A, Rother RP, Khursigara G, Fu CL, Omine M, Browne P, Rosse W. Br J Haematol. 2010 May;149(3):414-25. Epub 2010 Mar 8. Effect of eculizumab on haemolysis-associated nitric oxide depletion, dyspnoea, and measures of pulmonary hypertension in patients with paroxysmal nocturnal haemoglobinuria. Hill A, Rother RP, Wang X, Morris SM Jr, Quinn-Senger K, Kelly R, Richards SJ, Bessler M, Bell L, Hillmen P, Gladwin MT.
SolirisTM is the first and only approved therapy for the treatment of hemolysis of transfusion-dependent PNH (USA March 2007, Europe June 2007) In Italy, extended access program (law #648) for all PNH patients (even not transfusion dependent) with either:
Severe symptomatic intravascular hemolysis (frequent paroxisms, invalidating symptoms) Overt life-threatening thromboembolism
ECULIZUMAB AND PNH
Indication to the treatment Caveat: Caveat:
unlikely to respond
CLINICAL OVERLAP BETWEEN PNH AND BMF
AA Florid PNH AA/PNH Hypoplastic PNH Subclinical PNH MDS? IMF?
PNH in the context of other hematological disorders
In almost all patients, optimal control of intravascular hemolysis, with:
Reduced transfusion requirement, improvement of anemia Improved hemolysis-related symptoms and QoL
Marked reduction in thromboembolic risk Improvement of markers of pulmonary hypertension and chronic kidney failure (clinically relevant?) Possible effect on survival No major safety concerns
ANTI-COMPLEMENT THERAPY AND PNH
Reasons to treat all PNH patients (but not patients with PNH clone)
However: However:
1. Elevated cost 2. Life-long supportive treatment, without expected cure 3. No effect on underlying bone marrow failure 4. Minor hematological benefit (as Hb level) in many patients
Hematological response Hgb ≥ ≥ ≥ ≥11
36.6%
8 ≤ ≤ ≤ ≤ Hgb < 11
43.9%
≤ ≤ ≤ ≤50%
12.2%
>50%
7.3%
THE CLINICAL RESPONSE TO ECULIZUMAB
The Italian experience
n= 41
Risitano et al, Blood 2009
Untreated PNH
Anti C3d FITC Anti CD59 PE
C3 coating on RBCs from PNH patients on eculizumab
Double color flow cytometry
PNH on eculizumab
Risitano et al, Blood 2009
THE COMPLEMENT CASCADE REGULATION IN PNH
C3b C3
+
C5b C5 C3b
C5 convertase
PNH RBCs
Classical pathway Lectin pathway Alternative pathway
C6 MAC
Physiological C3 tick-over
C7 C8 C9
CD55 CD55 CD59
Amplification loop
C3b
MAC-mediated intravascular hemolysis
THE COMPLEMENT CASCADE REGULATION IN PNH
C3b C3
+
C5 C3b
C5 convertase
PNH RBCs
Classical pathway Lectin pathway Alternative pathway
Physiological C3 tick-over
CD55 CD55
Amplification loop
Eculizumab
C3b,iC3b,C3d
C3-mediated extravascular hemolysis Risitano et al, Blood 2009
C3
RES macrophages Liver Spleen
C3 C3
In vivo RBC survival
51Cr hepato-splenic uptake after RBC labeling
Risitano et al, Blood 2009
3000 2000 1000
96 192 288 384 480
Spleen Liver
Excess count Hours
PNH #2 PNH #3
control Hemolytic anemia
SPLENECTOMY: THE PROOF OF PRINCIPLE
Overcoming extravascolar hemolysis in PNH on eculizumab
LDH IU/L
0,0 2,0 4,0 6,0 8,0 10,0 12,0
1 3 5 7 9 13
Weeks from splenectomy
500 1000 1500 2000 2500 3000 3500 4000
Hb g/dL
Transfusions
Splenectomy % PNH RBC Eculizumab Placebo
100 80 60 40 20
Risitano et al, Blood 2008
Lectin Pathway Activation (MBL)
Targeted Complement Inhibitors
C5
C5b-9
C5b C6 C7 C8 C9
Classical Pathway Activation Antibody/Antigen Complexes Alternative Pathway Activation Microbiological membranes Bacterial LPS Immune Complexes Mammalian Cell Membranes
C3b
C3
C1q Activated C1 C4+C2 C4b2a C4b2a3b
C3 Convertase C5 Convertase
C5a
C3 Convertase C5 Convertase
C3bBb3b C3bBb C3a C3b Factor B+D C3, C3H2O
Weak Anaphylatoxin Immune Complexes and Microbial Opsonization
Cell Activation Lysis
Potent Anaphylatoxin Chemotaxis Cell Activation
Anti-C3 mAb as candidate agents for PNH
Preclinical data (Lindorfer et al, Blood 2010)
3E7 and its chimeric deimmunized derivative H17 are anti-C3 mAb which inhibit the C3 convertase
THE COMPLEMENT CASCADE REGULATION IN PNH
C3b C3
+
C5 C3b
C5 convertase
Classical pathway Lectin pathway Alternative pathway
Physiological C3 tick-over
C5b
C6 MAC C7 C8 C9
CD55 CD55
Amplification loop
Factor H
CD59
TARGETING THE COMPLEMENT INHIBITION
Combining a targeting protein (CR2) with a complement regulator (fH)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
CR2 Factor H (fH)
1 2 3 4 5 1 2 3 4
1 2 3 4 5 1 2 3 4
SCR 1-4 of CR2 (targeting module) fused to SCR 1-5 of fH (complement inhibitor module)
TT30
fH CR2
ECULIZUMAB FOR THE TREATMENT OF PNH PATIENTS
An evidence-based medicine assessment
Classical PNH
AA/PNH
Clinically relevant hemolysis
Life-threatening thrombosis
Recommendation Clinical features Diagnosis Elevated thrombotic risk
Standard thrombotic risk
Not clinically relevant PNH
Clinically relevant PNH