214 BMT Pharmacists Conference: Debate - Haploidentical vs. Umbilical Cord Blood Transplant Claudio G Brunstein Associate Professor of Medicine University of Minnesota Minneapolis, MN Objectives Defend the selection of patients for umbilical cord blood (UCB) grafts. Review outcomes in patients who received reduced-intensity conditioning for UCB transplantation. Cord Blood is RelaOvely Recent Technology 2 th anniversary first cord blood transplant (28) Eliane Gluckman, MD MaEhew Farrow, Hopital St. Louis, Paris recipient First cord blood transplant Hal Broxmeyer, PhD ndiana University School of Medicine
Obtaining Cord Blood Courtesy of Dr. Mary Laughlin, University of Virginia Mismatched Cord Blood Advantages UCB units are rapidly available HLA matching is less frequently a barrier to finding a donor Risk of acute and chronic GVHD is low in the presence of HLA mismatch Low risk of infecoon transmission No risk for the donor LimitaOons RelaOvely limited repository No donor lymphocytes Delayed engrawment Fixed cell dose Cost Growing regulatory complexity Cryopreserved nucleated cell dose 2.5-3. x 1e7/kg Select the unit with highest cell dose regardless of the HLA- matching Cord Blood SelecOon Two Approaches HLA DRB1 at allele level HLA A and B at anogen level AWer a certain cell dose select the best HLA- matched unit
The Double Cord MN Style f no single graw is big enough then UCB 4/6 MSKCC 4/6 4/6 UCB HLA- match 6/6 3. x 1 7 /kg 5/6 4. x 1 7 /kg 4/6 5. x 1 7 /kg ndividual Boston unit combined cell dose cell 1.5 dose x 1 7 /kg 3.7 and allele HLA level A & B: A, Ag B level and DRB1 Combined cell dose 3. x 1 7 /kg HLA DRB1: Allele level Cryopreserved nucleated cell dose 2.5-3. x 1e7/kg Cord Blood SelecOon HLA DRB1 at allele level HLA A and B at anogen level Tie Breakers CD34 cell dose High resoluoon HLA matching Matching at HLA- C DirecOon of mismatch Mismatching Kir- ligand Non- inherited maternal allele AnO- HLA anobodies Experience with the cord blood bank Red cell depleted Licensed vs unlicensed cord blood How important is to use well HLA- matched cord blood units? Neutrophil recovery in Children awer Single UCBT UCB matched (n=35), 85% Probability, % 4 UCB MM high dose (n=362), 79% UCB MM low dose (n=97), 64% 2 2 4 Days Adapted from Eapen et. al. Lancet 27
AWer adjusong for disease status at transplantaoon, leukemia- free survival was BeEer for HLA- Matched UCB Adjusted Probability, % 4 2 12 24 36 48 Months UCB matched (n=35) % UCB 1- Ag MM high (n=157) 45% UCB 2- Ag MM (n=267) 33% UCB 1- Ag MM low (n=44) 35% Adapted from Eapen M et. al. Lancet 27 keep in mind: HLA- matching and cell dose are Oed to each other and the goal is to use a large, well matched, cord blood unit. n adults, it is easier said than done. f high resoluoon seems to have some influence in outcomes, should we be considering matching at HLA- C locus (like in unrelated adult volunteer donors) when selecong UCB Units? Tretment Related Mortality Zero, single, or mulople loci mismatches A, B, C, and DRB1 match 6/69 1.. One locus (A, B, C, or DRB1) mismatch Two loci (A, B, C, or DRB1) mismatch Three loci (A, B, C, or DRB1) mismatch Four loci (A, B, C, and DRB1) mismatch 27/147 2 2 ( 83 4 91) 12 75/259 3 27 (1 42 7 54) 6 83/253 3 34 (1 45 7 71) 5 28/75 3 51 (1 44 8 58) 6 Eapen et al. Lancet Oncology 211
f beeer convenoonal HLA- matching maeers, should we consider high resoluoon HLA- matching at A, B and DRB1 when selecong cord blood units? HLA- A and B anogen HLA- DRB1 allele HLA- A, B and DRB1 allele Kurtzberg et al Blood 28 HLA- A and B anogen HLA- DRB1 allele HLA- A, B and DRB1 allele Kurtzberg et al Blood 28 Effect of High Resolution HLA Matching on Outcomes of Single UCB Transplantation Eapen et al. Blood 214
Effect of High Resolution HLA Matching on Outcomes of Single UCB Transplantation Eapen et al. Blood 214 Effect of High Resolution HLA Matching on Outcomes of Single UCB Transplantation Relapse Eapen et al. Blood 214 Effect of High Resolution HLA Matching on Outcomes of Single UCB Transplantation Eapen et al. Blood 214
CumulaOve ncidence 1..8.6 Effect of High ResoluOon HLA Matching on Outcomes of Double UCB TransplantaOon All paoents Relapse P=.8 P=.3.4 9-1/1.4 9-1/1.2 6-8/1 6-8/1.2 2-5/1 2-5/1.. 1 2 3 4 5 1 2 3 4 5 Years Post Transplant Years Post- Transplant 1..8.6 Acute leukemia paoents Cumula>ve ncidence Effect of High ResoluOon HLA Matching on Outcomes of Double UCB TransplantaOon 1..8.6.4.2 Non- relapse mortality All paoents 9-1/1 P=.92 2-5/1 6-8/1. 6 12 18 24 Months Post- Transplant 1..8.6 Acute leukemia paoents P=.89.4 9-1/1.2 3-5/1 6-8/1. 6 12 18 24 Months Post- Transplant Cumula>ve Propor>on 1..8.6.4.2 Effect of High ResoluOon HLA Matching on Outcomes of Double UCB TransplantaOon All paoents Years Post- Transplant Disease- Free Survival P=.35 2-5/1 6-8/1 9-1/1. 1 2 3 4 5 1..8.6.4.2 Acute leukemia paoents 2-5/1 6-8/1 9-1/1 Years Post- Transplant P=.6. 1 2 3 4 5
Treatment Failure Acute Leukemia HLA- match long- term engrawing unit 2-5/1 1. 6-8/1 1.4 (.8-2.4).2 9-1/1 2.1 (1.1-4.2).3 Leukemia Status and CytogeneOcs CR1 non- poor risk cytogene>cs 1. CR1 poor risk cytogene>cs.8 (.5-1.5).57 CR2 with CR1 1 year 1.1 (.6-2.2).74 CR2 with CR1 > 1 year.8 (.4-1.6).56 CR3 2.3 (1.- 5.2).6 Not in remission 3.2 (1.4-7.3) <.1 Should donor specific ano- HLA anobodies be considered in the selecoon of cord blood units? 21 by American Society of Hematology Takanashi M et al. Blood 21;116:2839-2846 Adverse mpact of Donor Specific AnO- HLA AnObodies on Double UCBT is Less Clear MN Brunstein BMT 211 Boston Cutler Blood 211 MF >5 > No DSA 18 55 DSA 1 unit 12 11 DSA 2 units 6 7 GraY failure 14% 5.5% DSA 1 unit 25%(3 of 12) 18% (2 of 11) DSA 2 units 16% (1 of 6) 57% (3 of 7) rrelevant Aby 16% NA MF > > DSA 1 unit 4% (2 of 5) 18% (2 of 11) DSA 2 units 25% (1 of 4) 57% (3 of 7) > 4 of 16 (25%) 4 of 11 (36%)
Cord Blood SelecOon Cryopreserved nucleated cell dose 2.5-3. x 1e7/kg HLA DRB1 at allele level HLA A and B at anogen level Tie Breakers CD34 cell dose High resoluoon HLA matching Matching at HLA- C DirecOon of mismatch Mismatching Kir- ligand Non- inherited maternal allele AnO- HLA anobodies Experience with the cord blood bank Red cell depleted Licensed vs unlicensed cord blood PracOcal Example High resoluoon HLA- matching could be considered in paoents with mulople suitable 5/6 and 6/6 HLA- matched unit available Cryopreserved TNC x1e7 ConvenOonal HLA- match 3.5 6/6 4.5 5/6 5.5 5/6 High res HLA- match 5/6 5/6 3/6 PracOcal Example Similar concept may apply to HLA- C matching Cryopreserved TNC x1e7 ConvenOonal 6- loci HLA- match 3.5 6/6 4.5 5/6 5.5 5/6 ConvenOonal 6- loci + HLA- C match Mismatch or 6/8 Match or 7/8 Mismatch or 5/8
Fk1_49.ppt CTN4-11_7.ppt Overall, paoents who have a suitably dose single unit or double unit cord blood graws have outcomes similar to recipients of unrelated donor graws Probability, % 4 2 Single Double PBPC matched BM matched 4 MMUD PBPC mismatched BM mismatched 2 UCB 4 8 16 2 12 24 12 24 36 48 Months post- transplantaoon Months post- transplantaoon DUCB SB MUD Eapen et. al. Lancet Oncol 21 Brunstein et. al. Blood 211 Leukemia-Free Survival after URD vs double UCB Reduced ntensity Transplantation for Acute Leukemia Probability, % 9 7 5 4 3 2 P=.17 9 7 dcb, TCF: 26% 5 MUD: 31% 4 3 MMUD: 25% 2 1 dcb, other: 9% 1 6 12 18 24 3 36 Months Brunstein et al Blood 212 4 2 Cumulative ncidence, % BMT CTN 4: ducb Neutrophil Recovery 5/µL 94% (95%C, 87-%) Median 15 days (range 4-47) 4 2 2 4 Days Post-Transplantation Brunstein, Fuchs, Eapen, O Donnel Blood 211
CTN4-11_2.ppt CTN4-11_6.ppt BMT CTN 4: ducb Cumulative ncidence, % 4 2 Grade -V: 21% (95%C, 6-37%) 4% (95%C, 26-54%) 2 4 Days Post-Transplantation Brunstein, Fuchs, Eapen, O Donnel Blood 211 BMT CTN 4: ducb Progression-Free Survival Probability, % 4 65% (95%C, 5-77%) 46% (95%C, 31-%) 2 2 4 6 8 1 12 13 Months Post-Transplantation Brunstein, Fuchs, Eapen, O Donnel Blood 211 BMTCTN 4: Overall Survival Probability, % 4 2 Survival Estimate @ 2 years 46.% (95% C, 31.9%, 59.%) 4 8 12 16 2 24 28 32 36 4 Months Post Transplant Eapen et al. ms in prep
BMTCTN 4: Progression-free Survival Probability, % 4 2 Survival Estimate @ 2 years 38.% (95% C, 24.8%, 51.1%) 4 8 12 16 2 24 28 32 36 4 Months Post Transplant Eapen et al. ms in prep BMTCTN 4: Relapse Cumulative ncidence, % 4 2 Estimate @ 2 years 34. % (95% C, 2.7%, 47.3%) 4 8 12 16 2 24 28 32 36 4 42 Months Post Transplant Eapen et al. ms in prep BMTCTN 4: Treatment Related Mortality Cumulative ncidence, % 4 2 Estimate @ 2 years 28.% (95% C, 15.3%, 4.7%) 4 8 12 16 2 24 28 32 36 4 44 Months Post Transplant Eapen et al. ms in prep
BMTCTN 4: Chronic GVHD Cumulative ncidence, % 4 2 Estimate @ 2 years 28.% (95% C, 15.3%, 4.7%) 4 8 12 16 2 24 28 32 36 4 44 Months Post Transplant Eapen et al. ms in prep n summary UCB is a efficacious source of HSC for the treatment of children (more frequently single) and adults (more frequently double). RetrospecOve comparaove data suggests outcomes similar to adult donor types. mproved graw selecoon and novel strategies may further improved UCBT outcomes. Ongoing and future prospecove studies with help further define the role of UCB in HSC transplantaoon What are the two main criteria for the selection of UCB units? a. Viability and nucleated cell dose b. Matching at HLA C and date of cryopreservation c. NMA and blood type d. HLA matching at A, B and DRB1 and cell dose e. KR-matching and anti-hla antibodies
The NCORRECT statement is: a. Data suggest that DFS after UCB transplantation is similar to that of adult donor grafts b. Single and double UCB grafts are more frequently used for children and adults, respectively c. HLA-C may be used to refine UCB unit selection d. HLA antibodies are irrelevant in UCB selection e. Ongoing clinical trial is randomizing double UCB vs. Haplo donors