UNRELATED DONOR TRANSPLANTSA Bacigalupo,

Ospedale San Martino, Genova, Italy

Donor Safety

deathBM 277701PB 232544

5/36317 RELATED

0/14706 UNRELATED

One additional death in Unrelated Donor

Age =Gender=Cause = repiratory insufficiency after attempted insertion of CVC , and bilateral pneumothorax

SAEBM 2777012PB 2325425

DONOR SAFETY

1.HSC donations carries a small, but proven hazard: we must be cautious (VERY) in selecting HSC donor

2. PB donations are not safer than BM Higher death rate and signficantly higher SAE rate for PB vs BM donations. Informed consent should say so

3. Accurate donor screening will reduce risk of lethal complicationsLower death risk occurred in UNRELATED donations

Donor Safety Graft versus Host Disease

Preventing acute GvHD II-IVBlood 2000 BBMT 2008;BJH 201196:2062 14:920 Lancet Onc 2009:10march 8

Reduction of GvHD in alternative donor TX for 402 Myeloid Leukemias: Genova San MartinoP

Preventing Chronic GvHDBlood 2000 BBMT 2008;BJH 201196:2062 14:920 march 8

Biol Blood Marrow Transpl ; 2006 ; 12: 560Lancet Oncol 2009; 10:855Same results withATG Thymo OrATG FreseniusChronic GvHDP

Day -7-6-5-4-3-2-10+3+4BU 3.2 mg/kgx4CY 50 mg/kgx2UD or SIBBM Tx CY 50 mg/kgCY 50 mg/kg

GvHD

1.Prophylaxis with 2 drugs (C+M, T+M) is associated with significant acute+chronic GvHD

2. A third agent (ATG or CAMPATH or SIROLIMUS) signifanctly REDUCES acute +GvHD

3. ATG significantly reduces chronic GvHD

4. High dose CY post-Transplant may be a promising new option with or without C+M

Donor Safety Graft versus Host DiseaseDoes reduction of GvHD translate in better OS?

GITMO trial (Thymo)BBMT 2006; 12:560German trial (Thymo)Lancet Onc ; 2009OS not significantly different (not inferior) with ATG vs no ATG

Very long follow up (over 10 years) , may allow for late complications of chronic GvHD (in particular lung complications) to become clinically relevant

Donor Safety Graft versus Host DiseaseDoes eduction of GvHD translate in better OS?HLA matching criteria

Worse outcomes with

Any single locus mismatch

A single mismatch is associated with worse survival, DFS, TRM, acute GVHD

Early Stage Disease: Adverse impact of HLA mismatchHLA-A ,B, C, DRLee et al, 2007Each mm yield 10-11% worse survival

Advanced Disease: Limited impact of HLA mismatch HLA-A ,B, C, DRLee et al, 2007Delay had worse consequences than MM

StudyReferenceN.patientsDiagnosisSurvival disadvantage in mismatched pairsType of mismatchOne should avoidSeattllePetersdorf Blood 2004; 104: 29761249LeukemiaEarly disC locusNMDP CIBMTR Lee Blood 20073860AML ALL MDS CMLEarly disA or DRB1JMDP Takakazu Blood 2007 110; 22355210Malignant and non malignantAll patientsC locus Non permissive mismatches positions 9,77,80,99,116,156Seattle PetersdorfPlos Med 2007; 4: 59246LeukemiaAll patientsHaplotypeMismatchedGITMOCrocchiolo, Blood 2009, 114:1437537LeukemiaAll patientsDP non permissive mismacthCIBMTRCooley, Blood 2010, 116:24111409LeukemiaAMLDonor B gene content

KIR genes on Chromosome 19Segregate indep. From HLA

A group (inhibitory receptors)B group (activating receptors)

A/A= homozygous for AB/x (at least one B)

Lancet February 15, 2012

HLA 10/10 match

DP permiss mm# same TRM as DP=# lower TRM as DP non perm mm# lower Relapse as DP=

VV

Faster Registration on International Donor Registries and Shorter Time to Allogeneic Hematopoietic Stem Cell Transplantation After Having Found a Donor Confers Better Outcome In Acute Leukemia PatientsMauricette Michallet1, Lyon Abstract 2371 ASH 2010;

Patients = 251 with acute leukemia and active donor search 2000-2008

The 3years OS for SD allo-HSCT59%UD allo-HSCT early registration: 47%UD allo-HSCT late registration: 29%

Donor selection

EARLY DISEASE1.Choose 8/8 = A,B,C,DRB1 donors

2. permissive DP mm should be preferred of non permissive mm

3.In AML patients , if possible, with a NK -B cent haplotype

ADVANCED DISEASEThe earlier, the better

Donor RegistriesDonor Safety Graft versus Host DiseaseDoes eduction of GvHD translate in better OS?HLA matching criteriaStem cell source

Patient SelectionTransplants in 2000-2003PB = 451BM = 781Age, 18-60 yrsALL, AML, MDS and CML Excluded:T-cell depleted graftsReduced Intensity ConditioningMedian follow-up: PB, 34 monthsBM, 38 monthsPBG05_3.pptEapen et al, Biol Blood Marrow Transplant, 2007

Transplant-Related MortalityEapen et al, Biol Blood Marrow Transplant, 2007

MonthsCumulative Incidence, %1000204060800361224BM (N=777; 40%)PB (N=447; 54%)Chronic GVHD

RelapseEapen et al, Biol Blood Marrow Transplant, 2007

Leukemia-free SurvivalEapen et al, Biol Blood Marrow Transplant, 2007

Randomized CTN trial (Anasetti et al ASH 2011)Median follow up 36 months

Peripheral BLOODMARROWP273278

Overall survival51%46%0.3OS transplanted52%48%0.3DFS transplanted47%44%0.6

Relapse28%28%0.8NRM26%27%0,6ANC 500 day 10095%86%0.09

aGvHD II-IV47%46%0.8aGvHD III-IV16%14%0.3

cGvHD53%40%0.02Ext cGvHD46%31%0.01

Stem cell source

1.Same TRM /relapse / LFS

2.More chronic GvHD

Both in retrospective and prospective trials

PERIPHERAL BLOOD TRANSPLANTS

DONORS# more SAE for PB donations (significant)# more deaths (ns) # should be stated in the informed consent

PATIENTS# no protection against relapse# same TRM; same LFS # more chronic GvHD

Should we continue to use PB grafts routinely? ??

Donor RegistriesDonor Safety Graft versus Host DiseaseHLA matching criteriaStem cell sourceOutcome

ACUTE LEUKAEMIA REGISTRYADULTS TRANSPLANTED FROM 2000 TO 2010 MATCHED UNRELATED DONOR / OS at 5 yearsAML n=2901ALL n=165550%140%221%246%228%213%2CR1 (n=1117)CR2 (n=879)ADV (n=905)CR1 (n=804)CR2 (n=510)ADV (n=341)

Matched Unrelated Transplants for SAAEffect of transplant era 10 year OS >2000 (752)67%>1990 (230)44%>1980 (27)29%1971-80 (1)0%P=0.1P20001991-001971-801981-90 days from transplant

Conclusions

1.Caution required for donor harvest (BM and especially PB)2.Several options for HLA /non HLA donor selection3.Three agents (C+M+other) for appropriate GvHD prophylaxis4.Time to transplant= crucial factor5. Should we continue to use PB??

Donor Registries

2009 2010Activations 44201 46919BMT Tx 3445 (8%) 3574 (8%)PB Tx 8162 (18%) 9248 (20%)CB 3792 (9%) 4036 (9%)TOTtranspl 15399 (35%) 16858 (37%)WMDA 2012

REGISTRIES:

Large Donor poolSearches Activated : UD Transplants=44201 : 12822=

We are transplanting 1/3 of patients who activate a donor search (optimistically 50%)

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