Sindromes de Falência Medular

Aplastic Anemia in Developing Countries
Phillip Scheinberg, MD
Head, Clinical Hematology
Antônio Ermírio de Moraes Cancer Center
Hospital São José and Beneficência Portuguesa
São Paulo, Brazil
A Randomized Trial of H-ATG vs. R-ATG in SAA
Hematologic Responses at 3 and 6 months
Horse ATG
Rabbit ATG
P-value
3 months
37/60 (62%)
20/60 (33%)
0.002
6 months
41/60 (68%)
22/60 (37%)
< 0.001
Scheinberg et al. New Engl J Med 365: 430, 2011
A Randomized Trial of H-ATG vs. R-ATG in SAA
Overall Survival
Censored for stem cell transplantation
Not censored for stem cell transplantation
Horse ATG
100
100
80
Rabbit ATG
Survival, %
Survival, %
80
Horse ATG
60
40
P = 0.04
20
Rabbit ATG
60
40
P = 0.008
20
0
0
Days 0
Horse ATG 60
Rabbit ATG 60
500
1000
1500
39
34
23
12
10
1
2000
Days
0
500
1000
1500
Horse ATG
Rabbit ATG
60
60
44
41
27
22
12
6
2000
Median follow-up,
all patients
= 839
days
(range,
– 1852)
Median
follow-up
of all
patients
472(0.1
– 83) months
follow-up
of =surviving
patients
(20– –1852)
83) months
Median follow-up,Median
surviving
patients
891 days
(range,51
185
Studies comparing horse and rabbit ATG
as first therapy in SAA
Study
(Year)
H-ATG
(N)
R-ATG
(N)
H-ATG
Resp
R-ATG
Resp
Design
Zheng
(2006)
47 (LG)
32 (Fr)
79%
53%
Prospective,
randomized
Atta
(2010)
42 (LG)
60%
35%
Retrospective
Afable
(2011)
67
(ATGAM)
20 (Thymo)
58%
45%
Retrospective
Scheinberg
(2011)
60
(ATGAM)
60 (Thymo)
68%
37%
Prospective,
randomized
Marsh
(2012)
105 (LG)
67%
40%
Shin (2013)
46 (LG)
53 (Thymo)
39%
45%
Yoshimii (2013)
96 (LG)
32 (Thymo)
65%
34%
Retrospective
Vallejo (2015)
62 (LG)
162 (Thymo)
66%
63%
Retrospective
29 (Thymo)
35 (Thymo)
Prospective
Retrospective
* Only complete manuscripts shown that include a comparative analysis between the 2 ATG formulations are
shown. Abstracts are not included.
Exp Hematol. 2006;34(7):826-Ann Hematol. 2010;89(9):851-859
831
Blood 119: 5391, 2012
N Engl J Med. 2011;365(5):430-438
Blood 121: 860, 2013
Haematologica 96:1269, 2011
Ann Hematol 92: 817, 2013
Ann Hematol 2015 epub
IMMUNOSUPPRESSIVE THERAPY FOR ACQUIRED
APLASTIC ANEMIA
Response to Immunosuppression with ATG + CsA, by ATG type
Rabbit
(n=170)
P
(Chisquare)
3 Months
37 (44%)
28 (17%)
<0.001
6 Months
50 (59%)
53 (31%)
<0.001
0.50
0.75
1.00
Horse
(n=85)
0.25
HORSE ATG
RABBIT ATG
0.00
N = 255
Logrank Test < 0.05
0
Number at risk
HORSE 85
RABBIT 170
500
1000
time(days)
1500
2000
75
107
73
75
68
39
60
21
Diego V. Cle, manuscript in preparation
Hematologic response at 3 and 6 months to
second course rabbit ATG plus cyclosporine
Response at 3 months
no. (%)
Response at 6 months
no. (%)
Refractory to
first r-ATG/CsA
(n=32)
5 (16%)
7 (22%)
95% CI
Relapsed to first
r-ATG/CsA
(n=5)
95% CI
3-28%
3 (60%)
17-100%
8-36%
3 (60%)
17-100%
Diego V. Clé et al. Haematologica 2015;100:e345-e347
Overall survival curves.
©2015 by Ferrata Storti Foundation
Diego V. Clé et al. Haematologica 2015;100:e345-e347
SALVAGE RATE AFTER INITIAL RABBIT ATG
FAILURE IS LOW
Salvage therapy
Overall response
Horse ATG (N=19)
4 (21%)
Alemtuzumab (N=13)
1 (8%)
Rabbit ATG (N=32)
7 (22%)
Scheinberg et al. Blood 119: 345, 2012
Scheinberg et al. Am J Hematol 2014
Diego V. Clé et al. Haematologica 2015;100:e345-e347
Brazilian MarrOw Failure Network (BONE)
Brazilian MarrOw Failure Network
(BONE)
ELTROMBOPAG AND CYCLOSPORINE AS FIRST LINE THERAPY IN
SEVERE ACQUIRED APLASTIC ANEMIA
ATG Pros and Cons
Pros
Track record
High response rate
Cons
US
Infusional
Expertise
Catheter
Serum sickness
Older
Developing (US +)
Access (cost, h-ATG)
Beds
Hospitalization duration
CsA, androgens available
Cyclophosphamide remains too toxic in the era of modern antimicrobials
YEAR 2000
ATG/CSA
Cy (200)/CsA
N=16
N=15
Overall response
13 (81%)
8 (53%)
CR
10 (63%)
6 (40%)
Relapse
6 (46%)
2 (25%)
Cytogenetic evolution
2 (14%)
1 (8%)
Fungal infection or death (first 6mo)
0 (0%)
6 (40%)
YEAR 2012
Cy (120)/CSA (N=22)
Overall response
9 (41%)
CR
4 (18%)
Cytogenetic evolution
4 (18%)
Fungal infection or death (first 6mo)
5 (23%)
Scheinberg et al.Blood 124: 2820, 2014
Horse ATG unavailable
Studies comparing horse and rabbit ATG
as first therapy in SAA
Study
(Year)
H-ATG
(N)
R-ATG
(N)
H-ATG
Resp
R-ATG
Resp
Design
Zheng
(2006)
47 (LG)
32 (Fr)
79%
53%
Prospective,
randomized
Atta
(2010)
42 (LG)
60%
35%
Retrospective
Afable
(2011)
67
(ATGAM)
20 (Thymo)
58%
45%
Retrospective
Scheinberg
(2011)
60
(ATGAM)
60 (Thymo)
Marsh
(2012)
105 (LG)
Shin (2013)
46 (LG)
Yoshimii (2013)
Vallejo (2015)
29 (Thymo)
Prospective,
randomized
35- 40%
68%
37%
67%
40%
53 (Thymo)
39%
45%
96 (LG)
32 (Thymo)
65%
34%
Retrospective
62 (LG)
162 (Thymo)
66%
63%
Retrospective
35 (Thymo)
Prospective
Retrospective
* Only complete manuscripts shown that include a comparative analysis between the 2 ATG formulations are
shown. Abstracts are not included.
Exp Hematol. 2006;34(7):826-Ann Hematol. 2010;89(9):851-859
831
Blood 119: 5391, 2012
N Engl J Med. 2011;365(5):430-438
Blood 121: 860, 2013
Haematologica 96:1269, 2011
Ann Hematol 92: 817, 2013
Ann Hematol 2015 epub
Probability
of response
Probability
of response
according to age
according to age
Scheinberg P et al. J Pediatrics 2008
ELTROMBOPAG AND CYCLOSPORINE AS FIRST LINE
THERAPY IN SEVERE ACQUIRED APLASTIC ANEMIA
Original design
• 2- stage Simon design
• alpha 0.05 and beta 0.80
• 18 + 20
• OR (CR + PR) primary
ELTROMBOPAG ADDED TO IST
Cohort 1 Cohort 2 Cohort 3
N=30
N=31
N=31
N (%)
N (%)
HISTORIC IST RATES
3
months
6
months
OR
57-62%
6268%
CR
7-10%
1015%
N (%)
3 months
OR
23 (77)
24 (77)
23/25 (92)
CR
5 (17)
8 (26)
11/25 (44)
OR = 84% (51/61)
6 months
OR
24 (80)
27 (87)
19/20 (95)
CR
10 (33)
8 (26)
12/20 (60)
P=0.013*
(95% CI, 71-91%)
OR = overall response (blood counts no longer meeting criteria for SAA)
CR = complete response, (ANC ≥1,000/µl, hemoglobin ≥10 gm/dL, and platelets ≥100,000/µl)
*null probabability 68%, 1-sample proportions test with continuity correction
With permission from Danielle Townsley
Eltrombopag added to IST (CSA) as first-line treatment for SAA
Hematologic response
FPFV
09/2016
3 months
6 months
12 months
CSA × 24 months
Eltrombopag 150 mg
Day 0 to 6 months
5 year
follow-up
Phase II, open label, single-arm trial to assess efficacy and safety of
eltrombopag combined with CSA as first-line therapy in patients with SAA
Primary endpoints: OR rate at 6 months
Secondary endpoints: OR rate at 3 and 12 months, survival and safety
Overall hematologic response (OR) = complete response (CR) plus partial response (PR)
CSA, cyclosporine; FPFV, first patient first visit
CETB115 2403
Translational Hematology Lab
Larissa Medeiros - UFPR
Michel Oliveira - UFPR
Marco Salvino - UFBA
Elias Atta - INCA
Sara Saad - UNICAMP
Translational Hematology Lab
Diego Clé
Raquel Alves Paiva
Gustavo Borges
Flávia Donaires
Lilian Figueiredo
Fernanda Gutierrez Rodrigues
Barbara Santana
André Santos
João Paulo Silva
Florencia Tellechea
Leonardo Zanelatto
Neal Young
Danielle Townsley
Hospital Beneficência Portuguesa
São Paulo, Brazil
Bogdan Dumitriu