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Acquired Aplastic Anaemia – Trends in treatment and Bone Marrow Transplantation
Vikas Gupta, MDBlood and Marrow Transplant
ProgramPrincess Margaret Hospital
University of TorontoToronto
Objectives
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
Direct toxicity Iatrogenic causes
Radiation Chemotherapy
Benzene Intermediate
metabolites of some drugs
Immune-mediated causes
Idiopathic Hepatitis associated
disease Pregnancy Intermediate
metabolites of some drugs
Associated with autoimmune disorders
Management at Presentation
Review of morphology Define disease severity
(Camitta 1976; Bacigalupo 1988) Supportive care Management plan: BMT or IST
Assessment of Disease Severity Severe AA (Camitta et al, 1976)
BM cellularity <25% or 25-50% with <30% residual haemopoietic cells
Two of the three of the following: Neutrophils <0.5 x 109/l Platelets <20 x 109/l Reticulocytes <20 x 109/l
Very-severe AA (Bacigalupo et al, 1988) Same as for SAA but neutrophils <0.2 x 109/l
Non-severe AA
Management at presentation
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 :
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)
SAA WP March 2004
stratified by age at transplant (years)
0 730 1460 2190 2920 36500.00
0.25
0.50
0.75
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)
>30-<=40 years;n=138; 69,7% (61,4 - 78)
>40 years; n=124; 49,7% (39,4 - 60)
time after treatment (days)
Su
rviv
al
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 studyCSA vs. ATG + CSA (Marsh et al, Blood 1999)
Years after Start of Treatment
15129630
Cum
ulat
ive
Pro
port
ion
Sur
vivi
ng1,0
,8
,6
,4
,2
0,0
ATG + CsA
ATG
P = 0.6
German randomised study Frickhofen et al, Blood, 2003
Time to Treatment Failure (Years)
15129630
Pro
port
ion
surv
ivin
g Fa
ilure
-fre
e1,0
,8
,6
,4
,2
0,0
P = 0.04
ATG + CsA
ATG
German randomised study, Frickhofen et al, Blood, 2003
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
Japanese studies show increased risk Alarming high risk 45% in children
Small European randomized study did not show increased risk
EBMT observational study Incidence of AML/MDS
With G-CSF 10.9% Without G-CSF 5.8%
(Socie et al, Blood, 2006, available on line)
Current randomized study by EBMT will probably provide a final answer in the future
Immunosuppressive therapy (IST)
ATG + CSA is current standard of care of IST and is an effective treatment but 65-70% respond Delayed response One third of responders relapse secondary complications occur
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, 2005Re-produced by permission of Andre Tichelli, Basel, Switzerland
Refractory/Relapse after first course of IST
Treatment Options
BMT – Related or unrelated donor
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
1. Graft versus host disease 2. Graft rejection How can results be improved further ?
survival stratified by acute GvHD
0 730 1460 2190 2920 36500.00
0.25
0.50
0.75
1.00aGvHD 0-Io; n=768; 82,5% (79,6 - 85,4)
aGvHD IIo; n=112; 80,5% (72,5 - 88,4)
aGvHD III-IVo; n=66; 44% (31,4 - 56,6)
time after treatment (days)
su
rviv
al
WP AA Registry- HLA identical sibling donors -
SAA WP March 2004
survival stratified by extent ofchronic GvHD
0 730 1460 2190 2920 36500.00
0.25
0.50
0.75
1.00
Limited cGvHD; n=97; 96,6% (92,9 - 100)
Extensive cGvHD; n=60; 83,5% (73,6 - 93,4)
No cGvHD; n=488; 89,5% (86,6 - 92,4)
time after treatment (days)
Su
rviv
al
WP AA RegistryHLA identical sibling donors (1994 – 2003)
in patients surviving at least 100 days
SAA WP March 2004
Is GVHD necessary for AA? Unlike BMT for malignancies, GVL
is probably not necessary in AA With current protocols, 30-35%
develop chronic GVHD Adverse impact of GVHD on
Well-being Quality of life Fertility
Impact of GVHD on Fertility in AA (Deeg et al, Blood, 1997)
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
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 Gordon-Smith, J. Marsh(Biology of Blood and Marrow Transplant, 2004: 867-876)
GVHD
Days after BMT
Cu
mu
lativ
e in
cid
en
ce o
f a
cute
GV
HD
(%
)
0 20 40 60 80 100
05
10
15
20
25
11% (95%CI: 4-29%)
Years after BMT
Cu
mu
lativ
e in
cid
en
ce o
f ch
ron
ic G
VH
D (
%)
0 1 2 3 4 5 6
05
10
15
3% (95%CI: 0-20%)
Acute (11%) Chronic (3%)
Alemtuzumab for prevention of GVHD in AA The impact on acute and chronic
GVHD was favorable However, graft rejection was 24% Important Lesson
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 Therefore, timing and dose of anti-
CD52 MoAb is important At PMH, second generation
protocols for Campath antibodies were designed and initiated in October 2004 Day –8 10 mg Day –7 20 mg Day –6 30 mg
Traditional GVHD
prophylaxis (CSA+MTX)2000-2004
N=14
Campath based GVHD prophylaxis2005-2006
N=10
P value
Median age of patients (range)
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
AA patients receiving alemtuzumab based protocols at PMH
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
Infectious complications 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
Response at 4 months
Yes No
Response at 4 months
Yes No
MUD available
No Yes
Adequate performancestatus
Adequate performancestatus
Yes No Yes
MUD BMTSupportivetherapy
Options
1. 3rd ATG if previous response to ATG2. CRP using novel IST3. BMT using CRP with
UCB
HLA id sib BMT
ATG (horse)+CSA
2nd ATG (rabbit/horse)+CSA
MUD BMTSupportivetherapy
Options
Maintain on CSA while FBC rising, then very slow taper, often over one/more years
1. 3rd ATG if previous response to ATG2. CRP using novel IST3. BMT using CRP with UCB / haplotransplantation
Conclusions
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