Acquired Aplastic Anaemia – Trends in treatment and Bone Marrow Transplantation

Vikas Gupta, MDBlood and Marrow Transplant

ProgramPrincess Margaret Hospital

University of TorontoToronto

vikas.gupta@uhn.on.ca

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