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