7 High rates of sustained donor engraftment. Neutrophil Engraftment after DCBT (n = 108)Median 41 yrs (range 6-69), high risk heme malignancies102030400.00.20.40.60.81.0Days Post-TransplantCumulative IncidenceAblative: 94%@ 25 daysNMA*: 10 days* Early auto recovery –switched to sustaineddonor engraftmentHigh rates of sustained donor engraftment.Dahi, P., ASBMT 2012
8 MSK Allo Tx for Heme Malignancies 2005-2009: Months Post-TransplantProgression-Free Survival12243648600.00.20.40.60.81.0P = 0.573MSK Allo Tx for Heme Malignancies :2 Year PFS After Double-Unit CB vs RD vs URD TransplantPonce, BBMT 20112 Yr PFS after CBT: comparable to RD or URD transplant.CB (n = 75)RD (n = 108)URD (n = 184)Up-front TRMcompensated by reducedlate mortality
9 Comparison of Donor-Recipient HLA-Match: CB (n = 75, 150 units) vs URD (n = 184)P < 0.001Ponce,BBMT2011CB grafts: marked HLA-disparity.CD34+ cell dose also much lower:RD 7.9, URD 6.0, CB 0.09 ( p < 0.001).
10 DCBT if Acute Leukemia & MDS/MPD: 2-yr DFS Children* (n = 23, median 9 yrs, range ): 78%Low incidenceof relapse(9% children,6% adults)translatesto relativelyhigh survivalrates.Adults** (n = 52, median 41 yrs, range 16-69): 64%Disease-Free SurvivalInf. TNC:***Time Post-Transplant (Months)Barker et al, ASH 2011
13 Best Matched URD & Best CB if Combined Search by Patient Ancestry (n = 525)Best DonorsEuropeans(n = 341)Non-Europeans(n = 184)pBest URD10/10 (n = 218)180 (53%)38 (21%)<0.0019/10 (n = 148)99 (29%)49 (27%)<8/10 (n = 159)62 (18%)97 (53%)Best CB5-6/6 (n = 401)270 (79%)131 (71%)4/6 (n = 90)56 (16%)34 (18%)No CB (n = 34)15 (4%)19 (10%)Volunteer unrelated donors: poor HSC source for non-Europeans.Barker et al 2010, BBMT
14 CB Extends Transplant Access to “Minorities”: URD vs CB vs No Graft by Ancestry (n = 385)Barker et al 2010, BBMT
15 Greater than 50% of CBTs had non-European ancestry Updated Data, MSKCC 2012 (n = 597)URD (n=426)CB (n=137)No Graft (n=34)25% % %NW EuropeAsianEastern EuropeAfricanSouthern EuropeWhite HispanicEurope MixMiddle EasternNon-Europe MixGreater than 50% of CBTs had non-European ancestry
16 Variables that Determine Outcome Transplant Related FactorsCB: Dose, match, qualityConditioning:High, Midi , Mini-7+28+100+180+1 yearImmunosuppression: rejection/ GVHDSupportive care: infection, bleeding,nutritionPatient Related FactorsBiology of Malignancy: determines need for hi dose prep vs reliance on GVLPatient Characteristics: age, extent of prior Rx, co-morbidities.
18 TRM by Combined TNC Dose & A,B Antigen, DRB1 Allele-Match 1061 NYBC Single Unit Myeloablative CBTCI of Transplant-Related MortalityYears Post-Transplant4/6 & TNC <2.54/6 & TNC ≥5.04/6 & TNC5/6 & TNC5/6 & TNC <2.55/6 & TNC ≥5.0801002040606/6 & all doses (mean TNC 4.4)Very high TRM if mismatch& low TNCLowest TRM: 6/6 matchLowest TRM: best HLA-match, not highest dose.Barker et al, Blood 2010
19 Implications for Unit Selection (applies to single unit CBT, may also apply to double)Biggest cell dose not necessarily the best.6/6 units highly attractive (?cell dose threshold).Sliding scale: more mismatch, greater requiredcell dose. Converse also true: match can compensatefor low dose.Implies:Above a cell dose threshold best matched unit the best.New measures needed if best unit is mismatched.Barker, Blood 2010
20 Additional factors to consider revealed in investigation in unit selection -revealed in investigationof double unit biology
21 Engraftment in 44 Double Unit CBTs Engrafting with a Single Unit. % CD34+ CellViabilityEngraftingUnit(N=44)Non-Engrafting<75%(N=16)115≥75%(N=72)4329Using CD34+ viability threshold of 75% (mean-2SD), all but one(43/44) engrafting units had CD34+ viability >75% (p=0.0006)OR Only 1/16 poor viability units engrafted.Poor CD34+ viability correlated with lower CFUs (p=0.02).Scaradavou, BBMT 2010
22 BAD UNIT GOOD UNIT Unit Quality: Schema of CD34+s of 2 CB Units GOOD Total CD34+ Cellsin 2 UnitsBADUNIT GOODGOODUNIT50%viable90%viableUnit # Unit #2Units similar infused viable CD34+ doses-but very different.In part, double unit CBT effective as increases chance of transplanting at least one good quality unit.Scaradavou, BBMT 2010
23 Implications Unit quality varies from unit to unit, & bank to bank. Not all banks are the same.Factors that dictate unit quality need to be determinedeg collection standards, processing methodology, redcell content, cryo volume, age.Methods to test unit quality prior to thaw shouldbe priority eg testing the segment.
24 Do the principles of single unit CBT also apply to double unit CBT?
25 Sustained Neutrophil Engraftment After Myeloablative DCBT by CD34+ Cell Dose of Engrafting Unit (n = 61)(n=13): 100%@ 20 days>2.0 (n=10):100%@ 16.5 days<1.0 (n=38):89%@ 27.5 daysP < 0.001High rate sustained engraftment directly dependent on infused CD34+ of winner; if low can be very slow.Avery, Blood 2011
26 Total Graft Cell Dose & DCB Engraftment (n = 61) 1.01.0>4.3 x107/kg:100%>1.8 x105/kg:97%0.80.8<4.3 x107/kg:87%<1.8 x105/kg:90%0.60.60.40.40.2TNC0.2CD34+p =p = 0.10Sustained Neutrophil Engraftment0.00.0p = 0.020.00.20.40.60.81.00.00.20.40.60.81.0p = 0.001>6.2 x104/kg:97%>7.8 x106/kg:97%<6.2 x104/kg:90%<7.8 x106/kg:90%CD3+CFUTime Post Transplant (Days)Total TNC & CD3+ dose of graft also have an effect.Avery, Blood 2011
27 Grade III-IV aGVHD by Engrafting Unit-Recipient 10 Allele HLA-Match (n = 115)100Recipient-Unit Match HR P2-7/10 (n = 88) Reference8-9/10 (n = 27)8060C.I. Grade III-IV aGVHD402-7/10 HLA Match208-9/10 HLA MatchMonths Post-TransplantP = 0.07 on multivariate: HLA-match likely critically importantPonce, D., ASBMT 2012
28 Evaluate search for units 4-6/6 & > 2.0 x 107/kg. Review info & bank for each unit.Obtain missing info, CT units of interest.Prepare CB Search Summary Report.Review CTs, update Search SummaryRank units by A,-B antigen, -DRB1 allele match*Hi to low TNC within each match grade (correct for RBC).1st2nd3rd6/6 units:Choose largest.5/6 units:Choose largest.4/6 units:Choose largest.Make final selection of unit(s) (1a & 1b if double).Prepare domestic back-up unit(s).Plan shipment(s)* Ignore unit-unit match in double unit CBT
29 Require att. segment for identity testing & complete IDMs. Select on bank, dose, match, other (RBC content).
31 COBLT Single CBT: OS in Pediatric Malignancies A, B, DRB1allele match:< 5/6 allele matchassociated withhigher severeaGVHD.Trend towardimproved OSwith bettermatch.Kurtzberg, J.et al,Blood 2008
32 Effect of C: A,B,C Antigen, DRB1 Allele N = 803, median 10 yrs (<1 – 62), leukemia/ MDSInferior neut engraftment with hi degree MM (< 5/8).Worse GVHD if < 5/8 including HLA-A MM.Relapse lower if any MM vs match (but no advantage tomultiple mismatches.TRM significantly worse if < 6/8 (trend for 7/8).3 year TRM: 8/8 9%; 7/8 (non-C) 19%; 7/8 (C) 26%;6/8 (C + other) 31%.Significance lost in overall mortality except for 6/8 (C +other). Contributed to by rel. high TNC of group?C is important-but how to trade off against cell dose?What is new lower limit of acceptable match?Eapen, M. et al, Lancet, 2011
34 Incorporating Vector of HLA-Match: CI of Neutrophil Engraftment 1202 Single Unit CBT, NYBCCI of Neutrophil EngraftmentSignificant advantage to both 0 & GVHD vector only mismatchesStevens C E et al. Blood 2011
35 HLA-Match Vector: 1202 Single Unit CBT CI of 3 Year TRMIn heme maligs: GVH only mismatch equal to 0 mismatch.Stevens C E et al. Blood 2011;118:3969
36 But More Difficult to Implement New………But More Difficult to Implement
37 NIMA-Match: 1121 Single Unit CBT, NYBC 3 Year TRM in Patients> 10 Years OldIf 1 MM,advantage ifthis is a NIMAmatch(predom. due tobetter neutrophilengraftment).van Rood J et al. PNAS 2009
38 Relapse by Shared IPA: 845 Singles (AML/ALL) 1.01-3 HLA MM, No Shared IPA Reference1-3 HLA MM, Shared IPA <0.0010 HLA MM0.80.6Cox Regression: MultivariateNo Shared IPA (n=49)C.I. of Relapse0.40 HLA Mismatch (n=45)0.2Shared IPA (n=751)0.0Years Post-TransplantPatient shares IPA = reduced relapse. ??Indirect evidencethat maternal T-cells mediate GVL?
39 Implications for Unit Selection CB banks should report maternal HLA type.Should:Select for NIMA match – expands no. of “well matched” units.Avoid “No Shared IPA” grafts in leukemics.
40 MSKCC Strategy for Unit Selection 1) TNC/ HLA-match: Above 2.0 x 107/kg prioritize match Within match grade choose largest. Consider vector & C.2) Also consider bank of origin (speed, reliability, quality).3) For malignancy use 2: Increase chance of transplanting at least one unit of good quality PLUS unit vs unit effects may augment engraftment & reduce relapse.4) For doubles same rules apply to selecting units 1 & 2. Ignore unit-unit HLA-match.5) Consider hi res match if possible-esp in children.6) Unresolved issues: selecting based on CD34+ dose, red cell content, testing of segment, high res match vs dose, incorporation of NIMA & IPA.Barker, Blood How I Treat