Transcript Document

Acquired Aplastic Anaemia –
Trends in treatment and Bone
Marrow Transplantation
Vikas Gupta, MD
Blood and Marrow Transplant Program
Princess Margaret Hospital
University of Toronto
Toronto
[email protected]
Objectives
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Management at Presentation
Treatment strategies:
Immunosuppressive therapy (IST) or
Bone Marrow Transplant (BMT)
Aplastic anaemia bone marrow aspirate
Normal
Severe aplastic anaemia
Aplastic anaemia
Etiologic classification
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Direct toxicity
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Iatrogenic causes
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Radiation
Chemotherapy
Benzene
Intermediate
metabolites of some
drugs
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Immune-mediated
causes
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Idiopathic
Hepatitis associated
disease
Pregnancy
Intermediate metabolites
of some drugs
Associated with
autoimmune disorders
Management at Presentation
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Review of morphology
Define disease severity
(Camitta 1976; Bacigalupo 1988)
Supportive care
Management plan: BMT or IST
Assessment of Disease Severity
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Severe AA (Camitta et al, 1976)
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BM cellularity <25% or 25-50% with <30% residual
haemopoietic cells
Two of the three of the following:
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Very-severe AA (Bacigalupo et al, 1988)
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Neutrophils <0.5 x 109/l
Platelets <20 x 109/l
Reticulocytes <20 x 109/l
Same as for SAA but neutrophils <0.2 x 109/l
Non-severe AA
Management at presentation
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Review of morphology
Define disease severity
(Camitta 1976; Bacigalupo 1988)
Supportive care
Treatment options: BMT or IST
HLA identical sibling BMT
Initial treatment of choice if :
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severe or very severe aplastic anaemia
HLA identical sibling
age <40 yr
Controversy over upper age limit
WP AA Registry: Survival for aplastic anaemia
HLA identical sibling donors (1994 – 2003)
stratified by age at transplant (years)
1.00
<= 10 years;n=172; 89,7% (84,7 - 94,7)
10-<=20 years; n=389; 86,3% (82,7 - 89,9)
>20-<=30 years; n=296; 76% (70,6 - 81,4)
Survival
0.75
>30-<=40 years;n=138; 69,7% (61,4 - 78)
0.50
>40 years; n=124; 49,7% (39,4 - 60)
0.25
0.00
0
730
1460
2190
2920
time after treatment (days)
3650
SAA WP March 2004
Indications for immunosuppressive
therapy (IST)
Severe or very severe AA >40y of age
Non-severe AA and transfusion
dependent
Severe or very severe AA <40 y with no
compatible sibling donor
What is the Optimum IST?
EBMT randomized study
CSA vs. ATG + CSA
(Marsh et al, Blood 1999)
German randomised study
Frickhofen et al, Blood, 2003
1,0
,8
ATG + CsA
,6
ATG
,4
P = 0.6
,2
0,0
0
3
6
Years after Start of Treatment
9
12
15
German randomised study, Frickhofen et al, Blood, 2003
1,0
,8
,6
ATG + CsA
,4
ATG
,2
P = 0.04
0,0
0
3
6
Time to Treatment Failure (Years)
9
12
15
Is there a role for combining
long term G-CSF with ATG
and CSA?
Randomised study of ATG, CSA
± G-CSF, Gluckman 2002
G-CSF and risk of malignancy
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Japanese studies show increased risk
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Alarming high risk 45% in children
Small European randomized study did not
show increased risk
EBMT observational study
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Incidence of AML/MDS
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With G-CSF
Without G-CSF
10.9%
5.8%
(Socie et al, Blood, 2006, available on line)
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Current randomized study by EBMT will
probably provide a final answer in the future
Immunosuppressive therapy (IST)
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ATG + CSA is current standard of care of IST
and is an effective treatment but
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65-70% respond
Delayed response
One third of responders relapse
secondary complications occur
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Risk of clonal disorders such as MDS/AML,PNH
Cytogenetic evolution
Solid tumors
Time favours BMT over IST
IST vs. BMT – Q-TwiST Study
Viollier et al, Ann Haematol, 2005
Re-produced by permission of Andre Tichelli, Basel,
Switzerland
Refractory/Relapse after first course of
IST
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Treatment Options
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BMT – Related or unrelated donor
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Repeated course of ATG
Response to second course of ATG
(Di Bona et al, BJH, 1999)
Response to third course of ATG
(Gupta et al, BJH, 2005)
HLA identical sibling BMT
- current issues
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1. Graft versus host disease
2. Graft rejection
How can results be improved further ?
WP AA Registry
- HLA identical sibling donors surv iv al stratifie d by acute Gv HD
1.00
aGvHD 0-Io; n=768; 82,5% (79,6 - 85,4)
survival
0.75
aGvHD IIo; n=112; 80,5% (72,5 - 88,4)
0.50
aGvHD III-IV o; n=66; 44% (31,4 - 56,6)
0.25
0.00
0
730
1460
2190
2920
3650
time afte r tre atme nt (days)
SAA WP March 2004
WP AA Registry
HLA identical sibling donors (1994 – 2003)
in patients surviving at least 100 days
surv iv al stratifie d by e xte nt of
chronic Gv HD
1.00
Survival
0.75
0.50
Limited cGvHD; n=97; 96,6% (92,9 - 100)
No cGvHD; n=488; 89,5% (86,6 - 92,4)
0.25
Extensive cGvHD; n=60; 83,5% (73,6 - 93,4)
0.00
0
730
1460
2190
2920
3650
time afte r tre atme nt (days)
SAA WP March 2004
Is GVHD necessary for AA?
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Unlike BMT for malignancies, GVL is
probably not necessary in AA
With current protocols, 30-35% develop
chronic GVHD
Adverse impact of GVHD on
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Well-being
Quality of life
Fertility
Impact of GVHD on Fertility in AA
(Deeg et al, Blood, 1997)
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Chances of becoming pregnant /
fathered a child in long term BMT
survivors of AA
Gender
With GVHD
No GVHD
Female
26%
61%
Male
29%
62%
An ideal protocol for BMT for AA
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Durable Engraftment
Minimal Regimen-related toxicity
Minimal risk of acute and chronic GVHD
Preserves Fertility
Applicable to a wider group of patients
especially relatively older patients and
those with co-morbidities
Favorable effect on acute and chronic GVHD
with cyclophosphamide and in vivo Anti-CD52
Monoclonal antibodies for marrow
transplantation from HLA-identical sibling
donors for acquired aplastic anaemia
V. Gupta, S.Ball, Q-L Yi, D. Sage, S. McCann, M
Lawler, M. Ortin, G Hale, H Waldmann, EC GordonSmith, J. Marsh
(Biology of Blood and Marrow Transplant, 2004:
867-876)
GVHD
Chronic (3%)
10
5
Cumulative incidence of chronic GVHD (%)
20
15
3% (95%CI: 0-20%)
0
5
10
11% (95%CI: 4-29%)
0
Cumulative incidence of acute GVHD (%)
25
15
Acute (11%)
0
20
40
60
Days after BMT
80
100
0
1
2
3
Years after BMT
4
5
6
Alemtuzumab for prevention
of GVHD in AA
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The impact on acute and chronic GVHD
was favorable
However, graft rejection was 24%
Important Lesson
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Graft rejection was higher in patients who
received campath both prior and after stem
cell infusion (36%) compared to those who
received campath only prior to stem cell
infusion (16%)
Alemtuzumab for prevention
of GVHD in AA
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Therefore, timing and dose of antiCD52 MoAb is important
At PMH, second generation protocols for
Campath antibodies were designed and
initiated in October 2004
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Day –8
Day –7
Day –6
10 mg
20 mg
30 mg
AA patients receiving alemtuzumab
based protocols at PMH
Traditional GVHD
prophylaxis
(CSA+MTX)
2000-2004
N=14
Campath based
GVHD
prophylaxis
2005-2006
N=10
P value
38 (20-59)
40 (25-56)
NS
Stage of disease
New Diagnosis
Relapsed/Ref.
11(79%)
3(21%)
5(50%)
5(50%)
NS
Type of donor
MSD/MFD
AD
12 (86%)
2 (14%)
8(80%)
2(20%)
NS
Median age of
patients (range)
AA patients receiving alemtuzumab based
protocols at PMH
Outcomes
Traditional GVHD
prophylaxis
(CSA+MTX)
N=14
Campath based
GVHD
prophylaxis
N=10
P value
Graft Failure
3(21%)
1(10%)
NS
Had 2nd BMT
2(14%)
0
NS
Acute GVHD (II-IV)
9/14(64%)
1/9(11%)
0.03
Chronic GVHD
7/9(78%)
0
0.002
Serious GVHD
8/14(66%)
0
0.007
AA patients receiving alemtuzumab based
protocols at PMH
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Infectious complications
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Increased CMV reactivation in the campath
patients (p=0.008)
Other infections do not appear to be
increased
What is the current role of
unrelated donor BMT ?
International BMT Registry (IBMTR)
Unrelated donor tx for AA (Deeg et al. Blood 2006)
Low-Dose Cyclophosphamide, Fludarabine and ATG as
preparative regimen for aplastic anaemia from alternative
donors
(Bacigalupo et al, BMT, 2005)
Treatment strategies for newly diagnosed patient with Severe
Aplastic Anaemia (Gupta and Marsh, In Press, 2007)
Age of patient
 40yr
> 40 yr
HLA identical sibling
Yes
No
ATG (horse)+CSA
Response at 4 months
HLA id sib BMT
Yes
No
2nd ATG (rabbit/horse)
+CSA
Maintain on CSA while FBC
rising, then very slow taper,
often over one/more years
Response at 4 months
Yes
No
MUD available
Yes
No
Adequate performance
status
3rdATG
ATGif ifprevious
previous
1.1.3rd
responsetotoATG
ATG
response
CRPusing
usingnovel
novelIST
IST
2.2.CRP
BMTusing
usingCRP
CRPwith
with
3.3.BMT
UCB
/ haplotransplantation
UCB
Yes
Options
No
Supportive
Supportive
therapy
therapy
Adequate performance
status
Yes
MUD BMT
BMT
MUD
Conclusions
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Survival has improved in young patients with
AA treated with BMT and immunosuppressive
therapy (IST)
Improvements in supportive care such as
new antimicrobials, anti-fungals and better
transfusion practices have contributed to
better outcome
Quality of recovery is different between BMT
and IST, need for prospective QOL studies