Transcript Slide 1

Aplastic Anemia: Current Thinking
on the Disease, Diagnosis, and
Non-Transplant Treatment
AA & MDS International Foundation
2014 Living with Aplastic Anemia, MDS, or PNH Patient and
Family Conferences
(Los Angeles California)
April 5, 2014
Ramon V. Tiu, MD
Cleveland Clinic Taussig Cancer
Institute
Dept. of Translational Hematology
and Oncology Research
Cleveland, Ohio USA
Objectives
• To give a brief historical overview of AA
• To provide a general overview of the diagnosis and pathogenesis of
aplastic anemia (AA)
• To discuss the treatment approach for newly diagnosed AA patients
• To discuss the treatment approach for relapsed/ refractory AA
patients
• To discuss the common side effects encountered with specific
pharmacologic therapies used in AA
Historical Perspective
Timeline
1888
Paul Ehrlich described the 1st case of Aplastic
Anemia
A young woman who died suddely after an abrupt
illness characterized by anemia, bleeding, fevers
and hypocellular BM
1899
Anti-lymphocyte activity of Anti-Lymphocyte
Serum (ALS) first described by Metchnikoff
1904
1972
Chauffard was the first to use the term Aplastic
Anemia
1st Allogeneic Bone Marrow Transplant Performed
It was performed on a patient with Aplastic Anemia
Overview
Natural History of Aplastic Anemia
PNH
32% at time
of dx of AA
PNH
Aplastic
Anemia
MDS/ AML
LGL
MDS
Leukemia
14% in 5 years
20% in 10 years
Disease Severity
sAA and vsAA
Moderate AA
0
1
2
3
4
5
6
7
8
9
10
Time from Diagnosis of AA (Years)
Maciejewski JP et al. BJH. 2001
Maciejewski JP et al. Leuk & Lymph. 2004
Overview
Epidemiology of AA
•
•
Diagnosis of AA
•
•
•
2-4 per 1 million individuals per year
(US)
2-3 fold higher in Asia
Hypocellular bone marrow (<30%)
cytopenias
normal karyotype by metaphase cytogenetics
(In general)
Decision to treat - Based on Disease Severity
Moderate AA
Severe AA
Very Severe AA
1) <30% BM cellularity
1) <30% BM cellularity
And depressed counts but did not
reach criteria for severe AA
And at least 2 of the ff:
And at least 2 of the ff:
Subset
Chronic moderate AA: >3 months
1)
2)
3)
1)
<30% BM cellularity
1) ANC <0.2 x 109/L
2) Plt count <20 x 109/L
3) Retic count <60 x 109/L
ANC <0.5 x 109/L
Plt count <20 x 109/L
Retic count <60 x 109/L
Needs Treatment
?
Needs Treatment
Natural Disease History by Disease Severity without treatment
sAA and vsAA
Moderate AA
0
1
2
3
4
Camitta B et al. Blood. 1976
Bacigalupo A et al. BJH 1988
5
6
7
Gluckman et al. BJH, 1982
8
9
10
Overview
Causes of Aplastic Anemia
Acquired Aplastic Anemia
1) Idiopathic Aplastic anemia
2) Secondary Aplastic Anemia
• Radiation
• Viruses
– EBV
– Hepatitis Virus
• Immune Disease
– Thymomas
– Eosinophilic fasciitis
– Hypogammaglobulinemia
• Pregnancy
• Drugs and Chemicals
– Idiosyncratic Reaction
• Chloramphenicol
• NSAIDs
• Gold
• Anti-epileptic medications
– Regular Effects
• Cytotoxic agents
• Benzene
Inherited Aplastic Anemia
•
•
•
•
•
•
•
•
Fanconi anemia
Dyskeratosis congenita
Schwachman-Diamond
syndrome
Reticular dysgenesis
Amegakaryocytic thrombocytopenia
Familial aplastic anemias
Preleukemia (monosomy 7, etc.)
Non-hematologic syndromes (Down,
Dubowitz, Seckel)
Maciejewski JP& Young N in Hoffman’s Texbook of hematology 2008
Pathogenesis
• Immune cause of AA was inferred based on:
– Response to immunosuppressive therapy
– Demonstration of immune activation
– Animal models
Overview
A Immune Pathogenesis
Stem cells
B
CD28
TCR
Stem cells
T cells
APC
Virus
Cell-Cell Contact
Unknown Antigens
Virus
Anergy
Inducers
•CTLA-4-Ig
•Anti-CD154
Calcineurin
Inhibitors
•Cyclosporine
•Tacrolimus
C
IL-2 receptor
Blockers
•Daclizumab
•Basiliximab
D
T cell
Activation
Stem cells
Effector Mechanisms
Cellular Damage
Cytostatics
•MMF
•AZA
•PUVA/ ECP
E
Depleting Agents
•ATG/ALG
•Alemtuzumab
•Visilizumab
Anti-cytokines
•Etanercept
•Infliximab
•Fontolizumab
F
IL-2, IL-4, IL-6
IL-1, IL-6
Naïve
T cells
MToR
Inhibitors
•Sirolimus
Cytokine Release
Activated
T cells
T cell
Effector
Differentiation T cells
T cell
Expansion
Expanded Effector
T cells
Overview
How to treat AA?
Severe AA or Very Severe AA
Age <40 years old
With Matched Sibling Donor
Bone Marrow Transplant
Age ≥40 years old
No Matched Sibling Donor
Immunosuppression
Non-Transplant
Pharmacologic Options
Non-Transplant Pharmacologic
Treatments (sAA)
Anti-Thymocyte Globulin/ Anti-Lymphocyte Globulin
•
Polyclonal purified IgG fraction of sera
from animals like rabbit, horse or
rarely goats that are immunized with
human thymocytes or T cell lines
•
Mainstay in the treatment of severe AA
or very severe AA
•
Combined with cyclosporine or
tacrolimus for the treatment of AA
•
Results in 70-80% overall response
rate in the frontline setting
•
Can be used in the salvage setting
•
Available as rabbit or horse
Thymus
T cell Lines
Polyclonal IgG
T cells
B cells
Monocytes
Dendritic
Cells/ APCs
Mohty M & Gaugler B. Leuk & Lymph 2008
ATG + Cyclosporine
G
A Mechanism of Action
B
Virus
Stem cells
CD28
TCR
Stem cells
T cells
Cell-Cell Contact
Unknown Antigens
Virus
Calcineurin
Inhibitors
•Cyclosporine
•Tacrolimus
Treatment Options
C
D
Stem cells
Effector Mechanisms
Cellular Damage
T cell
Activation
Depleting Agents
•ATG/ALG
E
F
IL-2, IL-4, IL-6
IL-1, IL-6
Naïve
T cells
Cytokine Release
APC
Virus
Activated
T cells
T cell
Effector
Differentiation T cells
T cell
Expansion
Expanded Effector
T cells
Non-Transplant Pharmacologic
Treatments (sAA)
How can we improve these results?
How
100can we improve these results?
Strategies Employed
100
75
ATG + CsA
70-80%
75
1)Use a different ATG
90%
50 CsA
ATG
% +
60-80%
ATG Alone
2)Add Additional Agents
25
40-50%
%
50
~35%
3)Use a completely different
~58%
Agent/ Pathway
~10-15%
0
Response
Rate
ATG Alone
Relapse
Rate
Clonal
Evolution
Overall
Survival
25
40-50%
~35%
~6-15%
0
4 Goals in sAA
Treatment
11 year follow-up
Response
Rate
Relapse
Rate
Clonal
Evolution
Overall
Survival
Frickhofen N et al. Blood. 2003
Non-Transplant Pharmacologic
Treatments (sAA)
Try a Different ATG
Non-Transplant Pharmacologic
Treatments (sAA)
Rabbit Anti-Thymocyte Globulin (rATG) – Relapsed/ Refractory setting
Study
Type of
AA
Median
Age (y)
Other Treatment
Dose
Response
Rate
Survival
% (mos)
Scheinberg P
et al. BJH.
2006. N=43
21 relapsed
22 refractory
Relapsed/
refractory
32 (8-75)
Refractory
31 (8-66)
Relapsed
42 (8-75)
Serum sickness Tx with
Prednisone
CsA (started D1) 10
mg/kg/D in two divided
doses
3.5 mg/ kg/
Dx5D
ORR=
65%relapsed
30%refractory
1000 d
survival
90% to
responders
vs 65% in
NR
Median
survival NR
in both
groups
Di Bona E. et
al. BJH. 1999
N=30
Refractory
1 prior Tx
with hALG
21 (2-67)
CsA 5 mg/kg PO D1180
G-CSF 5 ug/kg SC D190
3.5 mg/ kg/
Dx5D
ORR 23/30
(67%)
9/30 (30%)
93%
(~30 mos)
Non-Transplant Pharmacologic
Treatments (sAA)
Which ATG is better?
Horse ATG or Rabbit ATG ?
Non-Transplant Pharmacologic
Treatments (sAA)
Horse ATG vs Rabbit Anti-Thymocyte Globulin
Study
Type of
Study
Median
Age (y)
Treatment
Schema
Dose
Response
Rate
Survival
% (mos)
Atta EH et al.
2010. Ann
Hematol
N= 71 (42
Retrospective
-
-
-
ORR at 6
mos = 50%
(hATG) vs
35% (rATG)
p=0.05
OS at 2
years =
78.4 % vs
55.4%
p=0.03
Randomized
4 arms
34 (2-71)
Arm1=536
(6-63)
Arm2=35(871)
Arm3=36(568)
Arm4=29(266)
Arm 1=hATG
Arm2=hATG + CsA
Arm3=hATG+rhuGMCSF/rhu-EPO
Arm4=rATG+rhuGMCSF/rhu-EPO
Arm1=12
mg/kg/day x 5 D
Arm2=CsA 5
mg/kg/D x 6 mos
and maintenance
2.5 mg/kg/D x 6
mos
Arm3 †
Arm4 5 mg/kg/D
IV D1-5
ORR
Arm1=58%
Arm2=79%
Arm3=73%
Arm4=53%
5 yr act
survival
Arm1=58%
Arm2=81%
Arm3=80%
Arm4=66%
hATG; 29 rATG)
Frontline
Zheng Y et
al. 2006. Exp
Hematol.
N= 142
Frontline
All patients received
stanozolol/ testosterone
propionate
† rhuGM-CSF- 5μg/kd/D SC started on Day31 was administered 3 days a week for the first month, 2 days/ week for
2nd month, 1 day / week during the 3rd month
rhuEPO 100 units/kg/D IV x 3 days/ week x 1st month, 2 days/ week x 2nd month, 1 day/ week x 3rd month
Non-Transplant Pharmacologic
Treatments (sAA)
Horse ATG vs Rabbit Anti-Thymocyte Globulin
A. Comparison of Treatment Responses between 4 treatment arms
Zheng Y et al. Exp Hematol. 2006
Non-Transplant Pharmacologic
Treatments (sAA)
Horse ATG vs Rabbit Anti-Thymocyte Globulin
B. Overall Survival by Kaplan Meier Estimate of 4 treatment arms
12 months actuarial survival
Tx Arm
p value
Arm 1 = 70%
Arm 2 = 91%
Arm 3 = 83%
Arm 4 = 78%
0.01
0.2
0.4
( 1 vs 2)
(1 vs 3)
(1 vs 4)
60 months actuarial survival
Tx Arm
p value
Arm 1 = 58%
Arm 2 = 81%
Arm 3 = 80%
Arm 4 = 66%
<0.001 (1 vs 2)
0.002 (1 vs 3)
0.505 ( 1 vs 4)
Zheng Y et al. Exp Hematol. 2006
Non-Transplant Pharmacologic
Treatments (sAA)
Horse ATG vs Rabbit Anti-Thymocyte Globulin
Study
Type of
Study
Median
Age (y)
Treatment
Schema
Dose
Response
Rate
Survival
% (mos)
Afable M et
al. 2011.
Haematologi
ca
N= 87 (67
Phase 2
49 (hATG)
vs 55
(rATG)
rATG vs historical
cohort of hATG
treated patients
hATG 40 mg/kg/
day once daily for
4 days + CsA
ORR: hATG vs
rATG
3 mos: 40% vs
55% p=0.43
6 mos : 45% vs
58% p=0.44
12 mos : 50%
vs 58% p=0.61
No
difference in
OS
ORR: hATG vs
rATG
6 mos : 37% vs
68% p=<0.001
3 yr OS
96 % vs76%
p=0.04
rATG 3.5
mg/kg/day once
daily for 5 days +
CsA
hATG; 20 rATG)
Frontline
Scheinberg
P et al. 2011.
NEJM.
N= 60
Frontline
Randomized
2 arms
Mean
37 y vs 31 y
hATG vs rATG
hATG 40 mg/kg/ day
once daily for 4 days
+ CsA
hATG vs rATG
rATG 3.5 mg/kg/day
once daily for 5 days
+ CsA
(Time of
HSCT was
censored)
CsA is 10mg/kg in
twio divided doses
from D1 to at least 6
months
Afable M et al. Haematologica. 2011
Scheinberg et al. NEJM. 2011
Non-Transplant Pharmacologic
Treatments (sAA)
Horse ATG vs Rabbit Anti-Thymocyte Globulin
A. Comparison of Treatment Responses at 3 mos and 6 mos
Scheinberg P et al. NEJM. 2011
Non-Transplant Pharmacologic
Treatments (sAA)
Side Effects associated with ATG Therapy
• Decrease in Blood Counts (Blood Transfusions, bleeding and infections)
• Serum Sickness
• Abnormalities in liver enzymes
• Abnormalities in kidney function
Scheinberg P et al. NEJM. 2011
Non-Transplant Pharmacologic
Treatments (sAA)
Common Side Effects associated with Cyclosporine therapy
• High Blood Pressure
• Kidney Problems (Renal insufficiency)
• Thickening of the gums (gingival hyperplasia)
• Peripheral neuropathy
• Infections
• Headaches
• Tremors
Non-Transplant Pharmacologic
Treatments (sAA)
Add New Agents
Add New Agents
Mycophenolate Mofetil
• Blocks proliferation of activated T cells by inhibition of inosine
monophosphate Dehydrogenase (IMD)
• Has been used as a kidney sparing immunosuppresant as an
adjunct to CsA in renal and other solid organ transplantation
• May induce tolerance to allografts
• Dose tested in phase II single arm trial in the NIH is 600 mg /m2 PO
once daily starting on Day 1 for 18 months. This was given in
conjunction with hATG + CsA.
Scheinberg P. et al. BJH. 2005
Gregori S. et al. J immunol. 2001
Mycophenolate Mofetil
Mycophenolate Mofetil (MMF)
Cumulative incidence of
clonal evolution
Response Rate
60-80%
hATG + CsA
With
6-15%
9% in 4 years
MMF
Phase II Single
Arm Study
Cumulative incidence of relapse
35%
N=104
37% in 4 years
Survival at 3 years
58%
~80% in 4 years
Add New Agent
Sirolimus
• Inhibits the mammalian target of rapamycin (m-TOR) pathway
• May work through a non-calcium dependent calcineurin inhibitor
• Dose tested in phase III randomized trial in the NIH is 2 mg PO once
daily starting on Day 1 for 6 months.
• Associated with hypertriglyceridemia and hypercholesterolemia
Scheinberg P. et al. Haematologica. 2009
Sirolimus
Sirolimus
Response Rate
Clonal Evolution
hATG + CsA
Vs.
hATG + CsA
With
Sirolimus
Randomized
Prospective Study
N=120 planned
Superiority trial
Relapse Rate at 3 years
Survival at 3 years
Non-Transplant Pharmacologic
Treatments (sAA)
Try New Non- ATG based
Treatments
Non-Transplant Pharmacologic
Treatments (sAA)
Alemtuzumab
•
Selectively kills CD-52 bearing
cells via ADCC and complement
medeiated lysis
•
CD-52 is a GPI linked molecule
expressed in T, B , and Dendritic
cells but not on Langerhan cells
and not on dermal interstitial DC
•
Drug can be given subcutaneously
•
CMV reactivation is a concern
during therapy
ALEMTUZUMAB DOES NOT KILL
CD34+ CELLS IN VITRO
Risitano A. et al. Milano SIE Meeting. 2009
Non-Transplant Pharmacologic
Treatments
Alemtuzumab (Campath) – Frontline setting
Study
Study
Descrip
Median
Age (y)
Additional
Treatment
Dose
Response
Rate (%)
Survival
% (mos)
Risitano A et
al. 2010
N=15 (6 sAA,
8PRCA, 1
PWCA)
-
-
Low dose
Cyclosporine at 1
mg/kg starting on D7
3-10-30-30-(30)
x 4-5 days for
SAA
ORR 4/6 (66%)
CR 3/6 (50%)
PR 1/6 (17%)
80% (40
mos)
Total dose of 73-103
mg SC
Non-SAA – got
4 day Tx
GomezAlmaguer D et
al. Ann
Hematol. 2010
N=14
Median ff-up
20 mos
23
Cyclosporine 2 mg/kg
BID x 3 mos
10 mg SC daily
x 5 days
ORR 8/14 (57%)
CR 2/14 (14%)
PR 6/14 (43%)
71% (38
mos)
Kim H et al.
Leuk Res. 2009
N=19 (17 AA of
which 14 has
sAA)†
Dose
escalation
48 (16-74)
Cyclosporine x 6 mos
Dose Cohort 1
10 mg SC on
day 1, 20 mg
SC on day 2
and 30 mg SC
on day 3
Dose Cohort 2
30 mg Sc daily
for 3 days
ORR 6/17 (35%)
Dose 1 6/12
(50%)
Dose 2 0/5=0%
82% (24
mos)
†- Of note is that 3 patients with sAA were prev Tx with ATG+CsA and 1 previously received Danazol
Alemtuzumab
How can we improve these results?
100
Alemtuzumab
+ CsA
75
60-80%
ATG + CsA
%
82%
At
2yrs
66%
57%
50
37%
~58%
(at 10
years)
25
40-50%
ATG Alone
~35%
5%
~6-15%
0
4 Goals in sAA
Treatment
Response
Rate
Relapse
Rate
Clonal
Evolution
Overall
Survival
Kim H. et al. Leuk Res. 2009
Risitano A et al. Milano meeting. 2009
Non-Transplant Pharmacologic
Treatments (sAA)
Cyclophosphamide
• Commonly used alkylating agent for chemotherapy and
immunosuppression.
• used for AA in 10 patients in Johns Hopkins 45 mg/kg/ D x 4 days (3
of these received concomitant CsA)
• High mortality and morbidity rate particularly with invasive fungal
infection was seen in a randomized trial performed by the NIH
leading to premature closure of the study
• The most frequently used conditioning regimen before BMT for AA.
Cyclophosphamide
G
A Mechanism of Action
B
Virus
Stem cells
CD28
TCR
Stem cells
T cells
Cell-Cell Contact
Unknown Antigens
Virus
Stem cells
Effector Mechanisms
Cellular Damage
Depleting Agents
•ATG/ALG
•Alemtuzumab
•Visilizumab
•Cyclophosphamide
Treatment Options
C
D
T cell
Activation
E
F
IL-2, IL-4, IL-6
IL-1, IL-6
Naïve
T cells
Cytokine Release
APC
Virus
Activated
T cells
T cell
Effector
Differentiation T cells
T cell
Expansion
Expanded Effector
T cells
Cyclophosphamide
Cyclophosphamide (Cytoxan) – Frontline setting
Study
Type
Median
Age (y)
Additional
Treatment
Dose
Response
Rate
Survival
% (mos)
Brodsky R.
et al. Blood.
2010
Retrospec
(10 yr ff-up)
44 Tx naïve
and 23
refractory
-
All patients received GCSF (5 μg/kg/D) at D 10
until ANC is 1,000 for 2
consecutive days
Cy 50
mg/kg/D x
4 days +
Mesna
Actuarial RR in
newly dx pts
19/44 71%
Actuarial
Survival
rate os
88% at 10
yrs
Brodsky R.
et al. Ann of
Int Med. 2001
N=19
Maybe
Phase II
-
All patients received GCSF (5 μg/kg/D)
Cy 50
mg/kg/D x
4 days +
Mesna
Prob of
achieving CR at
50 mos is 65%
Survival
prob at 24
mos is 84%
Tisdale JF et
al. Lancet.
2000
N=31†
Phase III
Randomized
HD Cy +
CsA
vs hATG +
CsA
Cy 50
mg/kg/D x
4 days +
Mesna
46% HD Cy vs
75% ATG at 6
mos
N=67
No CsA
42 (18-67)
CsA 12 mg/kg/D and
adjusted to levels of
200-400 μg/L x 6 mos
excess
early
mortality (3
HD Cy 35
deaths
(18-67)
within first 3
Antimicrobial prophy:
mos in HD
(Norfloxacin,
hATG 40
Planned
ATG 47.5
Cy vs 0 in
Pentamidinde,
mg/kg/D x
sample size
(18-67)
ATG,
fluconazole, acyclovir)
4 days
was 91
p=0.101
† Median ff-up was21.9 mos (1-33). Excess morbidity (invasive fungal infections) in HD Cy Grp- 4 in HDCy vs 0 in ATG
(p=0.043). Primary endpoint of study is hematological response rate.
Cyclophosphamide
How can we improve these results?
100
Cyclophosphamide
88%
At
10yrs
75
71
60-80%
ATG + CsA
%
50
~58%
(at 10
years)
25
40-50%
ATG Alone
~35%
5
0
4 Goals in sAA
Treatment
At 10 year follow-up
Response
Rate
Relapse
Rate
~6-15%
Clonal
Evolution
5
Overall
Survival
Brodsky R. et al. Blood. 2010
Non-Transplant Pharmacologic
Treatments (sAA)
Relapsed/ Refractory
Setting
Relapsed/ Refractory AA
Rabbit Anti-Thymocyte Globulin (rATG) – Relapsed/ Refractory setting
Study
Type of
AA
Median
Age (y)
Other Treatment
Dose
Respons
e Rate
Survival
% (mos)
Scheinberg P
et al. BJH.
2006. N=43
21 relapsed
22 refractory
Relapsed/
refractory
32 (8-75)
Refractory
31 (8-66)
Relapsed
42 (8-75)
Serum sickness Tx with
Prednisone
CsA (started D1) 10
mg/kg/D in two divided
doses
3.5 mg/ kg/
Dx5D
ORR=
65%relapsed
30%refractory
1000 d
survival
90% to
responders
vs 65% in
NR
Di Bona E. et
al. BJH. 1999
N=30
Refractory
1 prior Tx
with hALG
21 (2-67)
CsA 5 mg/kg PO D1-180
G-CSF 5 ug/kg SC D190
3.5 mg/ kg/
Dx5D
ORR 23/30
(67%)
9/30 (30%)
93%
(~30 mos)
Cyclophosphamide (Cytoxan) Alone– Salvage setting
Study
Type
Median
Age (y)
Additional
Treatment
Dose
Response
Rate
Survival
% (mos)
Brodsky R.
et al. Exp
Hematology.
2004
N=17
-
31 (6-58)
All patients received GCSF (5 μg/kg/D) at D 10
until ANC is 1,000 for 2
consecutive days
No other IS therapy
Cy 50
mg/kg/D x
4 days +
Mesna
53% achieved a
drug free
remission. 24%
achieved a CR
Actuarial
Survival
rate os
52% at 5
yrs
Relapsed/ Refractory AA
Eltrombopag
• Thrombopoietin agonist that stimulates platelet production
• FDA approved for the treatment of Chronic ITP and hepatitis C
associated thrombocytopenia
Mechanism of Action
of TPO agonists
(AMG-531 and
Eltrombopag)
RV Tiu & MA Sekeres. Expert Opinion Biol Ther. 2008
Relapsed/ Refractory AA
Thrombopoietin Agonist (Mechanism of Action)
RV Tiu & MA Sekeres. Expert Opinion Biol Ther. 2008
Relapsed/ Refractory AA
Treatment Scheme
D1
If response achieved
0
1
E
E E E
2
3
E E
E
4
5
Months
E E E E E
6
E
Option to continue if
with response
8
9
10
E E E E
E E
E E
7
R
Eltrombopag Starting dose of 50 mg daily with provision to ↑ dose by 25 mg every
2 weeks if PLT count did not ↑ by 20 x 103/ul to a max dose of
150 mg daily
Response Assessment Hematologic response defined as uni or trilineage
responses (Primary Endpoint)
Olnes M. et al. NEJM. 2012
Non-Transplant Pharmacologic
Treatments (sAA)
Eltrombopag (Platelet Response)
Olnes M. et al. NEJM. 2012
Non-Transplant Pharmacologic
Treatments (sAA)
Eltrombopag (Hemoglobin Response)
Olnes M. et al. NEJM. 2012
Non-Transplant Pharmacologic
Treatments (sAA)
Eltrombopag (Neutrophil Response)
Olnes M. et al. NEJM. 2012
Non-Transplant Pharmacologic
Treatments (sAA)
Eltrombopag (Side Effect Profile)
Side Effects
N= (% of
patients)
Side Effects
N= (% of
patients)
URTI
3 (12)
Abdominal pain
1 (4)
Fever with (+) cultures
3 (12)
Nausea and vomiting
1 (4)
Fever w/o positive
culture
3 (12)
Viral hepatitis
1 (4)
Musculoskeletal pain
2 (8)
↑ liver enzymes
1 (4)
Orthostatic Hypotension
2 (8)
Gingival bleeding
1 (4)
Rash
2 (8)
Depression
1 (4)
Shingles
1 (4)
Weakness
1 (4)
C diff colitis
1 (4)
Myositis
1 (4)
Olnes M. et al. NEJM. 2012
Non-Transplant Pharmacologic
Treatments (sAA)
Follow-up study using Eltrombopag in Refractory/ Rel apsed AA
• Overall Response Rate = 40% (17/ 43 patients) at 3 to 4 months
• 82% (14/17) pts who went into an extension study continued to
show improvement with 7 eventually showing significant ↑ in RBC,
ANC and PLT
• 5 patients with robust near normalization of blood counts had drug
discontinued at a median of 28.5 months after entry (9 to 37 months)
and all maintained stable counts at median of 13 months (range 115 months) off eltrombopag
• 8 patients including 6 NR and 2 R developed new cytogenetic
abnormalities on Eltrombopag including 5 with chromosome 7 loss
or partial deletion but none evolved to AML as of time of publication.
Desmond R. et al. Blood. Oct 24, 2013
Non-Transplant Pharmacologic
Treatments (sAA)
Follow-up study using Eltrombopag in Refractory/ Rel apsed AA
Desmond R. et al. Blood. Oct 24, 2013
Special Considerations
•
Cyclosporine Taper
•
Addition of Growth factors
•
Moderate Aplastic Anemia
Supportive
Cyclosporine Taper (slowly taper CsA)
Cumulative incidence of relapse
By CsA Discontinuation
Cumulative probability of CsA
Discontinuation
Saracco P. et al (SAA-WP EBMT), BJH ,2007
Supportive
Growth Factors
•
Japanese study of 101 patients with sAA
•
Randomized study; median ff-up time of 52
mos
•
hATG + CsA vs hATG + CsA + G-CSF
•
Results:
–
–
–
–
–
Response Rate at 6 months is better in the
G-CSF + arm (77 vs 57 %) p=.03
No diff in infection or febrile episodes
No diff in survival
No diff in MDS/AML evolution (3 % (no GCSF) vs 5% (G-CSF + arm) p=0.63)
Decreased risk of relapse in G-CSF + arm
Prob of
survival
Prob of
Relapse
Teramura M et al. Blood. 2007
Moderate Aplastic Anemia
Daclizumab
•
Humanized monoclonal antibody
•
Recognizes 55-kDa α-chain of
heterotrimreic IL-2 receptor
•
Has been used in acute rejection in
kidney transplantation
•
Good toxicity profile.
•
Adverse events reported includes:
–
–
severe generalized erythema that can
sometimes be associated with arthralgia
(usually seen D20-70 after last dose of
daclizumab)
In two patients with thymoma s/p
thymectomy - myasthenia gravis in one
a rheumatoid arthritis and reactive
airway disease in a second patient .
Generalized erythematous pruritic rash
Sloand E. et al. Haematologica. 2010
Moderate Aplastic Anemia
Daclizumab (Zenapax)
Study
Median
ff-up
Median
Age (y)
Sloan EM et al.
Haematologica
2010 N=45
4.8 years
-
Maciejewski JP
et al. Blood.
2003 N=17
1.8 years
38
Additional
Treatment
Dose
Response
Rate
Survival
% (mos)
none
1 mg/kg
every
other
week x 5
ORR 19/45
(42%)
CR 6/45 (13%)
90%
(60 mos)
none
1 mg/kg
every
other
week x 5
ORR 6/16
(38%)
CR 2/16 (13%)
Unfortunately
As of January 2009, its marketing authorization has been withdrawn and the
product discontinued completely
Basiliximab: an anti-IL-2R mAb has been successfully used and reported in 1
case of AA who achieved only a PR after Tx with ATG plus MMA and achieved
a CR after treatment with basiliximab.
Berman JA et al. Am J Hematol. 2002
Conclusions
•
ATG remain the standard approach for the management of severe AA although
newer agents like Alemtuzumab are showing great promise
•
Horse ATG in combination with cyclosporine is superior to rabbit ATG in combination
with CsA in the management of newly diagnosed severe AA
•
Re-treatment with ATG can successfully salvage patients with Aplastic Anemia who
previously failed a prior course of ATG
•
Cyclophosphamide show promise as a therapeutic agent but has not gained
popularity because of the bad reputation (high mortality rate) it received in the past. It
is associated with prolonged cytopenia. Improvement in supportive care management
of AA including anti-fungals may allow for improvement in its safety profile
•
Eltrombopag is a thrombopoeitin agonist that can lead to improvements in
hemoglobin, platelet counts and neutrophil counts in AA patients who have previously
failed immunosuppressive agents
Thank You