Acquired Aplastic Anaemia

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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
• vikas.gupta_at_uhn.on.ca

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Objectives

• Management at Presentation
• Treatment strategies Immunosuppressive therapy
  (IST) or Bone Marrow Transplant (BMT)

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Aplastic anaemia bone marrow aspirate
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Severe aplastic anaemia
Normal
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Aplastic anaemia
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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

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Management at Presentation

• Review of morphology
• Define disease severity
• (Camitta 1976 Bacigalupo 1988)
• Supportive care
• Management plan BMT or IST

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Assessment of Disease Severity

• Severe AA (Camitta et al, 1976)
• BM cellularity lt25 or 25-50 with lt30 residual
  haemopoietic cells
• Two of the three of the following
• Neutrophils lt0.5 x 109/l
• Platelets lt20 x 109/l
• Reticulocytes lt20 x 109/l
• Very-severe AA (Bacigalupo et al, 1988)
• Same as for SAA but neutrophils lt0.2 x 109/l
• Non-severe AA

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Management at presentation

• Review of morphology
• Define disease severity
• (Camitta 1976 Bacigalupo 1988)
• Supportive care
• Treatment options BMT or IST

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HLA identical sibling BMT

• Initial treatment of choice if
• severe or very severe aplastic anaemia
• HLA identical sibling
• age lt40 yr
• Controversy over upper age limit

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WP AA Registry Survival for aplastic anaemia
HLA identical sibling donors (1994 2003)
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Indications for immunosuppressive therapy (IST)

• Severe or very severe AA gt40y of age
• Non-severe AA and transfusion dependent
• Severe or very severe AA lt40 y with no compatible
  sibling donor

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What is the Optimum IST?
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EBMT randomized study CSA vs. ATG CSA
(Marsh et al, Blood 1999)

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German randomised study Frickhofen et al,
Blood, 2003
ATG CsA
ATG
P 0.6
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German randomised study, Frickhofen et al, Blood,
2003
ATG CsA
ATG
P 0.04
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Is there a role for combining long term G-CSF
with ATG and CSA?
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Randomised study of ATG, CSA G-CSF, Gluckman
2002
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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

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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

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IST vs. BMT Q-TwiST Study Viollier et al, Ann
Haematol, 2005Re-produced by permission of Andre
Tichelli, Basel, Switzerland
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Refractory/Relapse after first course of IST

• Treatment Options
• BMT Related or unrelated donor
• Repeated course of ATG

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Response to second course of ATG (Di Bona et
al, BJH, 1999)
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Response to third course of ATG (Gupta et al,
BJH, 2005)
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HLA identical sibling BMT - current issues

• 1. Graft versus host disease
• 2. Graft rejection
• How can results be improved further ?

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WP AA Registry
- HLA identical sibling donors -
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WP AA Registry
HLA identical sibling donors (1994 2003)
in patients surviving at least 100 days
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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

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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
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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

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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)
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GVHD
Chronic (3)
Acute (11)
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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)

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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

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AA patients receiving alemtuzumab based protocols
at PMH
Traditional GVHD prophylaxis (CSAMTX) 2000-2004 N14 Campath based GVHD prophylaxis 2005-2006 N10 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
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AA patients receiving alemtuzumab based protocols
at PMH
Outcomes Traditional GVHD prophylaxis (CSAMTX) N14 Campath based GVHD prophylaxis N10 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
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AA patients receiving alemtuzumab based protocols
at PMH

• Infectious complications
• Increased CMV reactivation in the campath
  patients (p0.008)
• Other infections do not appear to be increased

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What is the current role of unrelated donor BMT ?
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International BMT Registry (IBMTR)
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Unrelated donor tx for AA (Deeg et al. Blood
2006)
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Low-Dose Cyclophosphamide, Fludarabine and ATG as
preparative regimen for aplastic anaemia from
alternative donors (Bacigalupo et al, BMT,
2005)
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Treatment strategies for newly diagnosed patient
with Severe Aplastic Anaemia (Gupta and Marsh, In
Press, 2007)
Age of patient
? 40yr
gt 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
No
Yes
Adequate performance status
Adequate performance status
Yes
No
Yes
1. 3rd ATG if previous response to ATG 2. CRP
using novel IST 3. BMT using CRP with UCB
1. 3rd ATG if previous response to ATG 2. CRP
using novel IST 3. BMT using CRP with UCB /
haplotransplantation
Supportive therapy
Options
MUD BMT
Supportive therapy
Options
MUD BMT
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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