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Aplastic Anemia- TransplantationPierre Noel MD

Mayo Arizona

Strategy by Age

< 40 > 40

1st Line Treatment

Identical sibling BMTATG+CSA if no donor

ATG + CSA

2nd Line Treatment

MUD BMTATG+CSA if no donor

Identical sibling BMTATG + CSA if no donor

3rd Line Treatment

Experimental ISTAlternative donor BMTSupportive Care

MUD BMTExperimental ISTSupportive Care

Passweg JR, Marsh JCW. ASH 2010 Education Book

Immunosuppression

ATG+ CSA

Response rate: 60-80%

5 year survival rate: 75%

Response rate (NIH)

Age

Reticulocyte count

Lymphocyte count

Complications

EFS 5 years: 30-50%

Relapse: 30%

Late complications

MDS/AML (8%)

PNH (10%)

Solid tumors (11%)

Pre –BMT IST is associated with a hazard ratio for mortality of 1.7 compared with upfront transplantation.

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IST-Relapse

30-35% when CSA is withdrawn at 6 months

13-16% when CSA is slowly tapered after 1 year

30% remain CSA dependent

Transplantation

Sources of Stem Cells

HLA matched family member

HLA matched unrelated donor

Umbilical cord

HLA related haploidentical donor

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Transplant basics

70% of patients do not have a suitable donor in their family

Each sibling has a 25% of matching

NMDP

9 million donors, 145,000 UCU

Global registries

16.5 million donors, 550,000 UCU

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HLA system

KIR

Minimum HLA matching requirements

HLA: A, B, DRB1

Unrelated stem cell donors

5/6 HLA markers

Cord blood units

4/6 HLA markers

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HLA-Identical Sibling Donor Transplantation.

Age 5 year survival

<20 82%

21-30 77%

31-40 71%

41-50 68%

>50 48%

EBMT, 1999-2009

HLA matched sibling BMT

HLA-Identical Sibling Donor Transplantation- Complications

Graft failure (4-14%)

Grade III-IV GVH (40%)

Chronic GVH (30-40%)

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Figure 1

Source: Biology of Blood and Marrow Transplantation 2009; 15:279-292 (DOI:10.1016/j.bbmt.2008.11.037 )

Copyright © 2009 American Society for Blood and Marrow Transplantation Terms and Conditions

Impact of age on matched-sibling allo-transplantation for AA

Stem cell source

Bone marrow is preferable to PBSCs (5 year-OS)

< 20 years: 85% to 73%

>20 years: 64% to 52%

Chronic GVHD (RR of 2.82)

Schrezenmeier H et al. Blood, 2007

Donor sex

Male recipients from female donors have a 33% increase in GVHD

Female recipients from male donors have a increased risk of graft rejection

Conditioning

Cy 50 mg/kg/day x 4 days + ATG for 3 days

The use of radiation was found to be a negative predictor for outcome in a recent EBMT analysis. Locasciulli A et al. Haematologica. 2007

Radiation-based preparative regimens reduce rejection, but increase GVHD, interstitial pneumonitis and malignancy.

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Conditioning

Champlin*, in a prospective randomized trial found no statistical difference in survival, graft failure, GVHD between Cy or Cy+ATG.

Champlin RE et al. Blood, 2007

Conditioning

Flu-Cy-ATG Cy-ATG

5 year OS 77% 60%

Maury S et al. Haematologica. 2009

Used in patients > 30 yo

GVHD prophylaxis

CSA and short course Methotrexate

CSA ≥ 12 months

Optimal duration of CSA?

Late graft failure may be associated with discontinuing CSA early.

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GVHD Prophylaxis

GVHD Survival

Grade 0-1 98%

Grade II-IV 70%

MTX+ CSA > MTX

Locatelli F et al. Blood, 2000

Engraftment, rejection, mixed chimerism

Cy 200 alone is not immunoablative

ATG reduces the incidence of graft failure (ChamplinRE, Blood, 2007)

Second grafts

Within 3 months, poor PS: 33% survival

After 3 months, good PS: 76% survival

Chimerism

Holland-Frei, Cancer Medicine, 6th edition, 2003.

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Chimerism

Complete donor chimerism : 45%

Transient mixed chimerism: 17%

Recipient cells of 1-5%, median time to reversion to donor (2 months)

Persistent mixed chimerism :37%

Stable mixed chimerism: 21%

Recipient cells <15%

Progressive mixed chimerism: 16%

Recipient cells >15%

Lawler M et al. Br J Haematol. 2009

Chimerism and clinical outcome

Graft failure GVHD

Donor chimerism 0/39 +

TMC 0/15

SMC 0/18

PMC 10/14

Lawler M et al. Br J Haematol. 2009

Unrelated Donor Transplantation

Probability of finding a matched donor

Caucasian 50-60%

Asian 20%

African American 17%

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MUD

Prospective trial of 52 pediatric patients comparing MUD to second course of IST

Response rate Failure-free survival (5 years)

IST 11% 9.5%

MUD 84%

Kosaka Y. Blood , 2008.

MUD

17-36% of patients undergoing IST will undergo HSCT salvage therapy (EBMT, Haematologica, 2007)

Higher chance of clonal evolution associated with second course of IST (Kosaka Y et al. Blood, 2008)

In patients < 40 yo who failed a first course of IST and do not have a matched sibling: MUD

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Unrelated donor transplant

OS is inversely related to the incidence of GVHD

GVHD appears is more frequent with cell dose>3.4 x 108 cells per Kg (Seattle Cancer Care Alliance)

Threshold CD34 cell dose for engraftment and prevention of graft failure: > 2 x 106/kg (Islam MS et al. BMT. 2010; 45:886-894

2 year OS: PBSC (55%), BM (76%) [CIBMTR]

Copyright ©2007 Ferrata Storti Foundation

Maury, S. et al. Haematologica 2007;92:589-596

Figure 1. Probability of survival after HSCT from unrelated donors for SAA according to the period of transplantation: 1989-1998 (n=37) or 1999-2004 (n=52)

Copyright ©2007 Ferrata Storti Foundation

Maury, S. et al. Haematologica 2007;92:589-596

Table 2. Outcome (probability {+/-} 95% confidence interval) of HSCT from unrelated donors for SAA between 1989 and 2004, by period of transplantation

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URD-HLA matching

Optimal donor:

2 year probability of survival [ 8/8=78%, 7/8= 60%)

HLA-A and HLA-DRB1 (most important)

HLA-B or HLA-C (better tolerated)

HLA-DQ mismatch (no adverse outcome)

HLA-DP mismatch (more GVHD, no change OS)

URD-Conditioning

CY-TBI: Historically the standard conditioning regimen

TBI dose of 2 GΥ

Increased TRM

Increased secondary malignancies

CY-ATG

Inadequate conditioning for URD

Unrelated Donor Transplantation

Conditioning regimen

TBI (200 cGy) + cyclophosphamide (200 mg/kg) + equine ATG (90 mg/kg)

Graft failure 5%

5 year OS [ <20 : 73%, >20: 46%]

Deeg et al. Blood, 2006

IBMTR and Japan Marrow Donor Program report highergraft failure rate (10%) and lower survival.

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URD-Conditioning

EBMT

<14: Fludarabine + CYT+ATG

18% graft failure, aGVHD 11%, cGVHD 27%,73% 2 year OS

Graft failure of 35% >14 yo

>14: Flu + CYT+ATG + TBI (200 cGy)

Graft failure of 10%

Blood and Bone Marrow Transplant Clinical Trials Network

Fludarabine +TBI (200 cGy) + ATG (90 mg/kg) + de-escalating dose of cyclophosphamide (100 mg/kg, 50 mg/kg)

Cord blood transplant/Umbilical cord transplant

UBC Haplo

Ease of finding donor +++ +++

GVHD Less More

Infection risk High (viral) High

2 year OS 40% (±) <40% (little data)

Umbilical Cord Blood Transplantation

10% of transplants for AA (CIBMTR)

Allows for a greater degree of donor-recipient HLA disparity

Delayed graft function (neutrophil recovery: D 20-30)

Long term immunodeficiency (viral infections)

CIBMTR data (45 patients, 1 single UCB unit)

70% mismatched at 2 loci

Median nucleated cell dose: 4 x 107/Kg

Graft failure: 35%

2 year OS: 40%

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Umbilical Cord Blood Transplantation

Conditioning regimens

TBI (200-500cGy) + fludarabine + cyclophosphamide(50-100 mg/kg)- Japan Cord Blood Network.

Fludarabine (175 mg/m2) + rabbit ATG (9mg/kg) + cyclophosphamide (120-150 mg/kg) + TBI (200 cGy)-Chan KW et al. BMT, 2008.

Optimal timing

Number of courses of IST?

Double UCB transplants in adults

Strategy by Age

< 40 > 40

1st Line Treatment

Identical sibling BMTATG+CSA if no donor

ATG + CSA

2nd Line Treatment

MUD BMTATG+CSA if no donor

Identical sibling BMTATG + CSA if no donor

3rd Line Treatment

Experimental ISTAlternative donor BMTSupportive Care

MUD BMTExperimental ISTSupportive Care

Passweg JR, Marsh JCW. ASH 2010 Education Book

Future

Develop better predictors of IST response.

Reticulocytes

Telomeres

Cytokine profile

Timing of transplantation

Improved survival for URD

Impact of iron overload

Impact of opportunitistic infections

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