Double-unit Cord Blood Grafts Research Articles

Engraftment kinetics after transplantation of double unit cord blood grafts combined with haplo-identical CD34+ cells without antithymocyte globulin.

Double unit cord blood (dCB) transplantation (dCBT) is associated with high engraftment rates but delayed myeloid recovery. We investigated adding haplo-identical CD34+ cells to dCB grafts to facilitate early haplo-identical donor-derived neutrophil recovery (optimal bridging) prior to CB engraftment. Seventy-eight adults underwent myeloablation with cyclosporine-A/mycophenolate mofetil immunoprophylaxis (no anti-thymocyte globulin, ATG). CB units (median CD34+ dose 1.1 × 105/kg/unit) had a median 5/8 unit-recipient HLA-match. Haplo-identical grafts had a median CD34+ dose of 5.2 × 106/kg. Of 77 evaluable patients, 75 had sustained CB engraftment that was mediated by a dominant unit and heralded by dominant unit-derived T-cells. Optimal haplo-identical donor-derived myeloid bridging was observed in 34/77 (44%) patients (median recovery 12 days). Other engrafting patients had transient bridging with second nadir preceding CB engraftment [20/77 (26%), median first recovery 12 and second 26.5 days] or no bridge [21/77 (27%), median recovery 25 days]. The 2 (3%) remaining patients had graft failure. Higher haplo-CD34+ dose and better dominant unit-haplo-CD34+ HLA-match significantly improved the likelihood of optimal bridging. Optimally bridged patients were discharged earlier [median 28 versus 36 days]. ATG-free haplo-dCBT can speed neutrophil recovery but successful bridging is not guaranteed due to rapid haplo-identical graft rejection.

Double-Unit Cord Blood (CB) Transplantation with Haplo-Identical CD34+ Cells (haplo-dCBT) May Speed Neutrophil Recovery Although Successful Bridging Is Contingent on Close Haplo-Winning CB Unit HLA-Match

Background: While dCBT is associated with high rates of sustained donor engraftment, delayed neutrophil recovery in adults is frequent and can contribute to extended hospitalization and early transplant-related mortality.Methods: We investigated engraftment after myeloablative dCBT supplemented with CD34+ selected haploidentical PBSC (haploCD34+) in patients (pts) with high risk hematologic malignancies or aplastic anemia in a phase II clinical trial. The aim was to abrogate neutropenia (ANC >/= 500 within 14 days) with a haplo myeloid bridge prior to CB engraftment. Pts did not receive ATG due to the increased mortality risk reported in adult CBT. Double unit CB grafts allowed comparison to dCBT controls without haploidentical graft supplementation.Results: 78 adult pts [median age 48.5 years (range 21-68), median weight 82 kgs (range 48-138), 44 (56%) CMV+, 3 with prior allografts] underwent haplo-dCBT between 9/2012-12/2017. Diagnoses included 54 (69%) acute leukemias, 10 (13%) MDS/ MPN (all ≤ 10% blasts at work-up), 10 (17%) NHL/ HD and 1 aplastic anemia. Conditioning was myeloablative (1 Cy 120/ Flu 75/ TBI 1375, 77 intermediate intensity Cy 50/ Flu 150/ Thio 5-10/ TBI 400) with CSA/ MMF. CB units had a median infused TNC of 2.3 (range 1-5.7) x 107/kg/unit & median infused viable CD34+ cell dose of 1.1 (range 0.1-3.1) x 105/kg/unit with a median 5/8 (range 2-7) unit-recipient HLA-allele match. Haplo CD34+ grafts [procured from children (46%), siblings (31%), parents (13%) or extended family (10%)] had a median infused CD34+ dose of 5.2 x 106/kg (range 1.1-16.8) and a median infused CD3+ dose of 1.6 x 103/kg (range 0.3-13.7). Sixty-one (78%) haplos were 4/8 and 17 (22%) were 5-7/8 HLA-matched to the pt. In 77 evaluable pts (1 pt died on day 14), 4 engraftment patterns were observed (Table 1). All but 2 pts had sustained CB engraftment with either an optimal haplo-bridge (Gp. 1, 34/77, 44%), a transient bridge with a second nadir preceding CB engraftment (Gp. 2, 20/77, 26%), or no bridge (Gp. 3, 21/77, 27%). The 2 remaining pts had CB/ haplo graft failure (Gp. 4, 2/77, 3%); both were successfully re-transplanted with single CB units. While there was no difference in the day 100 TRM in the 34 optimal bridge pts vs pts with transient or no bridge [9% (95%CI 2-21) vs 15% (95%CI 6-27), p = 0.388], optimal bridge pts had faster platelet recovery [19 (range 14-41) vs 44.5 days (range 14-67)] and earlier hospital discharge [28.5 (range 20-60) vs 36 days (range 28-98)]. Similar to dCBT alone, chimerism analysis revealed sustained engraftment in haplo-dCBT is mediated by a “winning” CB unit. This was heralded by winning unit-derived T-cells seen as early as day +28. Although universal, the speed of haplo rejection varied, and a high haplo chimerism percentage early post-transplant did not guarantee successful bridging. Analysis of factors potentially predicting an optimal bridge is shown in Table 2. The median winning CB unit-haplo 8-allele HLA-match was 3/8 (range 1-7/8). In univariate analysis, higher haplo CD34+ dose/kg, > 4/8 haplo-recipient HLA-match and ≥ 3/8 winning unit-haplo HLA-match were associated with a higher likelihood of bridging. Haplo CD34+ dose and winning unit-haplo HLA-match remained significant in multivariate analysis.Conclusions: While haplo-dCBT can be associated with enhanced neutrophil recovery, this platform does not guarantee a successful myeloid bridge due to early haplo rejection by the winning CB unit. This universal haplo rejection highlights the importance of the CB graft dose and quality with this ATG-free strategy as the CB will mediate sustained engraftment. Our findings have significance for strategies that combine unmanipulated CB with any third-party or ex vivo expanded T-cell depleted product given higher product CD34+ cell dose and better HLA-match to the unmanipulated CB unit could improve the likelihood of successful myeloid bridging. The data also support alternative approaches to improve myeloid recovery after CBT such as optimized unit selection and vivo expansion. [Display omitted] DisclosuresO'Reilly:Atara Biotherapeutics: Consultancy, Patents & Royalties, Research Funding. Perales:Takeda: Other: Personal fees; Novartis: Other: Personal fees; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Merck: Other: Personal fees; Abbvie: Other: Personal fees. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy. Shah:Janssen: Research Funding; Amgen: Research Funding.

A Prospective Study of Allogeneic Hematopoietic Stem Cell Transplantation in Relapsed/ Refractory Hodgkin Lymphoma

INTRODUCTION: Patients with Hodgkin Lymphoma (HL) relapsing post autologous transplant (ASCT) are not cured with standard chemotherapy. In addition, a subset of patients with relapsed or primary-refractory HL fare poorly with ASCT. Such patients may benefit from allogeneic transplantation (allo-HCT) with its graft-versus-lymphoma (GVL) effect. METHODS: We performed a phase II study of salvage therapy (ST) followed by allo-HCT in adult patients with relapsed/refractory (rel/ref) HL (NCT00574496, Fig. 1a). Conditioning was dictated by PET status after ST, with NMA flu/cy/TBI 200 cGy for patients in CR and RIC mel/flu for those with PR/SD. Patients in the intent-to-treat (ITT) cohort were enrolled prior to ST and proceeded to allo-HCT if in CR, PR, or SD after 1 line of ST. The primary endpoint was successful allo-HCT and PFS at 1 year after allo-HCT (estimated as a proportion as all patients had at least 1 year of followup). Landmark analysis (from end of ST) with Kaplan-Meier curves and log-rank test were used to compare OS and PFS in the ITT cohort. A second cohort of patients referred with CR, PR, or SD after ST received HCT on protocol, but was not included in the ITT analysis. No differences in OS or PFS after HCT were seen between ITT and non-ITT cohorts, and patients were combined for further analysis. OS and PFS from time of HCT were estimated using all HCT patients, and PFS was compared based on baseline covariates. Cumulative incidence of GVHD, relapse/POD and nonrelapse mortality (NRM) were estimated using competing risks methodology. P-values less than 0.05 were considered significant. RESULTS: From 6/2008 to 6/2014, 25 patients were consented, 15 on the ITT analysis and 10 on the post-ST arm (Table 1). All had relapse after ASCT, primary refractory or high-risk HL relapsed within 1 year of 1st-line therapy. Allografts (n = 18) were PBSC from matched or single-allele mismatched related (n = 8) or unrelated (n = 3) donor, or double unit cord blood grafts (n = 7). Eleven were in PET CR before HCT and 7 in PR. ITT analysis (n=15) : 5 patients had POD on ST and were ineligible for allo-HCT. Of the remaining 9, 1 withdrew during conditioning. 1-year and 3-year OS were 50% (95% CI 22.5, 100) and 16.7% (95% CI 2.8, 99.7), respectively, in patients with POD after ST, and 100% at both time points if no POD after ST (Fig 1b). At median 5.6 years of follow-up, 5 patients survive. The percent of patients successfully meeting the primary endpoint was 33% (95% CI 13, 61). Allo-HCT analysis (n=18): Cumulative incidence (CI) of grade 2-4 and 3-4 aGVHD at d+100 were 23.3% (95% CI 13.1, 55.3) and 11.1% (95% CI 1.70, 30.4), respectively. CI of cGVHD at 1 year and 3 years was 11.1% (95% CI 1.7, 30.7) and 35.6% (95% CI 13.2-59.0), respectively, and of mild severity in all but 1 patient. 3-year CI of relapse/POD was 34.3% (95% CI 13.2-56.7), and NRM 23.6% (95% CI 6.8, 46.1). Estimated 3-year PFS was 42.1% (95% CI 24.1, 73.6) and OS 70.3% (95% CI 51.5, 96.1) (Fig 1c). There was no significant association between PFS and disease stage or status (CR vs. PR). There was a trend toward poorer PFS in the 5 patients without prior ASCT (3 year PFS 20.0% vs. 50.8%, p = 0.088), 3 of whom had primary refractory HL. CONCLUSION: We demonstrate that allo-HCT provides long-term survival for a substantial portion of patients with rel/ref HL. Though limited by small sample size, the ITT analysis showed more than 1/3 of patients never attained sufficient disease control for allo-HCT, and have a dismal prognosis. Of note, none had received brentuximab or a checkpoint inhibitor, and the long-term impact of these agents in those patients remains to be seen. In patients undergoing allo-HCT with chemosensitive disease, proceeding to allo-HCT in PET PR vs. CR had no significant negative impact on PFS in this limited sample. The trend toward poor outcomes in patients who had not previously undergone ASCT likely reflects poor prognosis in patients with primary refractory disease. Factors informing prognosis after allo-HCT, and interventions to attenuate risk, remain an important area for further investigation. Disclosures Perales: BeTheMatch/ National Marrow Donor Program: Membership on an entity9s Board of Directors or advisory committees; Takeda: Honoraria; Astellas: Honoraria; Merck: Honoraria; Amgen: Honoraria. Giralt: TAKEDA: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding. Straus: Millenium Pharmaceuticals: Research Funding. Moskowitz: GSK: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding.

Successful Salvage of High-Risk B-Cell Non-Hodgkin and Hodgkin Lymphoma with Double-Unit Cord Blood Transplantation Provides a Platform for Further Optimization

Introduction: Allogeneic transplantation using double-unit cord blood grafts (DCBT) is an alternative therapy for adult patients with high-risk lymphomas without a HLA-matched sibling or volunteer donor but the efficacy of DCBT in this setting is not established.Methods: We analyzed overall survival (OS) and progression-free survival (PFS) after 4-6/6 HLA-matched DCBT in adults with B-cell non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma (HL) who were transplanted 2/2006-5/2013.Results: Patient characteristics by diagnosis are shown in the Table. Overall, the 47 patients (median age 46 years, range 20-70) had a median number of prior treatment regimens of 4 (range 1-13), 22/47 (47%) patients had had a prior autologous transplant, and the median pre-transplant HCT-CI score was 2 (range 0-6). Twenty-eight (60%) were in complete remission (CR). Conditioning was reduced intensity (RI) but functionally myeloablative in 16 patients (8 Cy/Flu/Thio/TBI400, 8 Mel/Flu) and 31 patients received non-myeloablative conditioning (NMA, Cy/Flu/TBI200). CB units had a median infused TNC dose x 107/kg of 2.7 (range 1.5-4.3) for the larger unit and 1.9 (range 0.9-3.4) for the smaller unit and a median donor-recipient HLA-allele match of 5/8 (range 1-7). The cumulative incidence of donor-derived engraftment was 98% (95%CI:77-99) with a median 22 day (range 13-37) and 10 day (range 7-46) neutrophil recovery after RI and NMA conditioning, respectively. Day 100 grade II-IV acute GVHD (20 grade II, 7 grade III, 1 grade IV) and 1-year chronic GVHD were 61% (95%CI:45-74) and 17% (95%CI:8-29), respectively. Day 180 transplant-related mortality (TRM) was 17% (95%CI:8-29). To date, 11 patients have progressive disease (median 3.4 months, range 2.8-58.0). The 3-year cumulative incidence of progression was 22% (95%CI:11-34). With a median 60 month (range 15-101) follow-up of survivors, the 3-year KM estimate of OS and PFS are 56% (95%CI:44-73) and 44% (95%CI:31-61), respectively (Figure). Of 23 patients who have died, 7 died of progressive disease whereas 16 died of transplant complications (2 organ failure, 10 GVHD, 2 infection, 1 encephalopathy of unknown cause, and 1 donor leukemia). Best PFS was observed in patients with follicular NHL (3-year PFS 62%) followed by HL (3-year PFS 47%) whereas those with diffuse large B-cell lymphoma, for example, did poorly (Table). There was no differences in 3-year PFS according to recipient age, HCT-CI, or number of prior regimens (each split above versus below the median), or receipt of a prior autologous transplant (all p = NS). Similarly, patients in CR pre-CBT (n = 28) had a 3-year PFS of 42% as compared to a 46% PFS in the non-CR patients (n = 19), p = 0.568. Four of 11 patients who relapsed survive to date (range 29-81 months) after treatment with chemotherapy (n = 3) or subsequent CB-derived mobilized peripheral blood stem cell (PBSC) transplant (n = 1).Conclusions: PFS after DCBT in patients with follicular NHL and HL is similar to that of adult donor allograft series and warrants further investigation. However, DCBT in other histologies is not as favorable. The high TRM rates may be influenced by the extent/intensities of prior therapy. Future clinical trials with DCBT should focus on strategies to reduce TRM, especially related to GVHD. Post-transplant maintenance to prevent disease progression could also be beneficial. Finally,chemotherapy to treat post-CBT relapse and CB-derived PBSC transplant are potential therapeutic options in selected patients.TableDiseaseType(N)Median(range) ageMedian(range)HCT-CIRemission statusMedian (range) prior regimens /N prior autoRegimenintensityPFSFollicular(n = 13)52 yrs (29-63) 1 (0-4)5 CR, 5 PR, 3 SD4 (2-8) / 3/13 (23%)3 MA 10 NMA3-yr: 62% (95%CI: 40-95)Diffuse large cell(n = 13)53 yrs (35-64) 2 (0-6)8 CR, 4 PR, 1 SD4 (1-7) / 3/13 (23%)4 MA 9 NMA3-yr: 23% (95%CI: 9-62)Mantle cell(n = 5)57 yrs (37-71)2 (1-6)5 CR3 (2-4) / 4/5 (80%)5 NMA2 disease-free at 29-70 monthsHodgkins(n = 15)35 yrs (20-50)3 (0-5)10 CR, 3 PR, 1 SD, 1 PD4 (2-13) / 12/15 (80%)8 MA 7 NMA3-yr: 47% (95%CI: 27-80)T-cellrich B-cell NHL (n = 1)38 yrs2PR7 / No auto1 MADied at 1.5 months [Display omitted] DisclosuresMoskowitz:Merck: Research Funding; Genentech: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding.

Comparable 3-Year Disease-Free Survival Regardless of Anti-Thymocyte Globulin Inclusion in Pediatric Myeloablative Cord Blood Transplantation for Acute Lymphoblastic Leukemia

Background: Cord blood (CB) is routinely used as an alternative stem cell source for the treatment of children with acute leukemia and has been associated with high rates of disease-free survival (DFS). However, one controversial issue in pediatric CB transplantation is the role of anti-thymocyte globulin (ATG) as immunoprophylaxis. While inclusion of ATG in the conditioning may decrease the risk of graft-versus-host disease (GVHD), it could potentially abrogate graft-versus-leukemia effects and increase the risk of opportunistic infections. Thus, we compared outcomes in a uniform group of pediatric patients with acute lymphoblastic leukemia (ALL) who underwent myeloablative CB transplantation with or without ATG.Methods: Patients with ALL in morphologic remission (CR1 n=106, CR2 n=146, CR3 n=45) aged ≤ 20 years transplanted between 01/2007-12/2011 with high-dose total body irradiation-based conditioning and single or double unit CB grafts were eligible for analysis. CB units were 4-6/6 HLA-A,-B at the antigen-level, -DRB1 allele matched to the recipient and had CB unit with cryopreserved total nucleated cell dose of ≥ 2.5 x107/kg/unit. Cox regression models were built to evaluate potential differences in outcome in ATG versus non-ATG CB transplant recipients. The primary endpoint was 3-year DFS.Results: Of 297 patients, 92 received ATG and 205 did not. Age and disease status were similar in each group whereas ATG recipients were less likely to be CMV seropositive and more likely to receive single unit CB grafts. While neutrophil engraftment was similar in each group, the risk of day 100 grade II-IV acute GVHD [30% (95%CI: 21-40) versus 54% (95%CI: 47-61), p = 0.0002] and 3-year chronic GVHD [22% (95% CI: 14-31) versus 43% (95% CI: 36-50), p = 0.0008] were decreased in ATG recipients. However, day 100 grade III-IV aGVHD was comparable: 11% (95%CI: 5-18) in ATG versus 17% (95%CI: 12-23) in non-ATG recipients, p = 0.15]. The 3-year TRM was similar in both groups: 16% (95%CI: 10-25) in ATG versus 17% (95%CI: 13-23) in non-ATG recipients (p = 0.98). Relapse was also similar in ATG and non-ATG recipients: 17% (95%CI: 10-23) versus 27% (95%CI: 21-34, p = 0.12), respectively. In multivariate analysis, negative CMV serostatus was associated with reduced TRM risk [HR 0.55 (95%CI: 0.30-0.98), p = 0.004] whereas remission status CR2 or CR3 significantly increased relapse risk [HR 2.18 (95%CI: 1.22-3.89), p = 0.008], but inclusion of ATG had no effect on either outcome. With a median follow-up of survivors of 36 months (range 5-72), the 3-year DFS was 66% (95%CI: 56-76) and 55% (95%CI: 48-62) in ATG and non-ATG recipients, respectively (p = 0.23, Figure 1). The distribution of causes of death was similar in each group. In multivariate analysis, treatment failure risk was increased in patients transplanted in CR2 or CR3, but the inclusion of ATG had no effect (p = 0.24) (Table 1).Conclusion: Inclusion of ATG in pediatric myeloablative CB transplant for ALL is associated with a decreased risk of grade II-IV acute GVHD and chronic GVHD but not severe grade III-IV acute GVHD. There was no difference in 3-year DFS in each group and multivariate analysis revealed ATG inclusion had no impact upon treatment failure risk. These results indicate that optimization of both ATG and non-ATG conditioning platforms are needed in order to further improve CB transplantation survival in children with ALL. Unanswered questions include the impact of the formulation, dose and timing of ATG administration. These findings cannot be extrapolated for other diagnoses, reduced intensity conditioning, or adults.Table 1Hazard ratio(95% confidence interval)p-valueATG useConditioning without ATG Conditioning with ATG1.00 0.78 (0.52 – 1.18)0.24 Disease statusCR1 CR2, CR31.00 2.01 (1.31 – 3.08)0.001 [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Prospective Evaluation Of Alternative Donor Availability In 708 Patients: Improved Allograft Access With Enlarging CB Inventory For All Patients Including Racial and Ethnic Minorities

BackgroundAvailability of suitably HLA-matched adult donors is a major barrier to allogeneic transplantation. Cord blood (CB) extends transplant access to many patients including minorities. However, some patients have no suitable unrelated donors (URDs) or CB grafts. Moreover, HLA-match is a critical determinant of URD & CB transplantation (CBT) outcome, & some patients will only have access to mismatched URDs &/or highly HLA-mismatched CB units. We evaluated if URD/ CB access has improved with increased size of URD registries & global CB inventories. MethodsWe prospectively collected ancestry data on patients undergoing searches between 10/2005-6/2013, & analyzed the availability of 9-10/10 HLA-matched URDs or 4-6/6 HLA-A,-B antigen, -DRB1 allele matched CB units by recipient ancestry in patients with hematologic malignancies. 10 HLA-allele matched URDs were given priority if available; otherwise HLA-mismatched URDs or double-unit CB grafts were chosen. Given our minimum CB total nucleated cell (TNC) dose criteria was increased from 1.5 to 2.0 x 107/kg/unit in 2010, this analysis was restricted to units with a cryo. TNC dose ≥ 2.0. Also, as high-resolution typing was performed in all CB units & considered in unit selection since 2012, availability of CB units by 10-allele match was evaluated. Finally, given the global public CB inventory reached 500,000 units in 2011, URD/CB availability was compared between early (10/2005-12/2010) & recent (1/2011-6/2013) periods. Results708 patients were evaluated including 223 (31%) of non-European origins. 511 (72%) patients received an URD transplant, 159 (22%) received a CBT, & 38 (5%) had no graft. URD recipients were predominantly of European ancestry (n = 400, 78%) whereas only 77 (48%) of CBT recipients had European origins. 30/38 (79%) patients without any graft were non-European with over half (n = 20) being of African ancestry. “No graft” patients had a higher weight (median 93 kg, range 50-151) than CBT recipients (median 68 kg, range 8-133), p < 0.001. The availability of grafts for Europeans & non-Europeans during the early versus recent time periods is shown (Table). Patient ancestry distribution was equal during the periods. The majority of Europeans received a 10/10 URD transplant in both periods & very few had no graft (< 1% recently). However, only approximately half of non-Europeans undergoing URD transplant received a 10/10 match. Moreover, of non-Europeans overall, only 29/129 (22%) had a 10/10 URD in the early period, & this has not improved recently [28/94 (30%), p = 0.28]. The percentage of non-Europeans receiving CB units with a ≥ 5/6 donor-recipient HLA-match has not improved (data not shown). However, while only 28% of non-Europeans received a CB graft consisting of ≥ 6/10 HLA-matched units in the early period, this donor-recipient HLA-match rate improved to 69% recently (p < 0.001), a rate similar to that of European patients. The percentage of non-Europeans with no graft has decreased from 17% to 8.5% (p = 0.08). Furthermore, while African patients were the largest group among no graft patients (68% in early period & 63% recently), of African patients without an URD, 16/31 (52%) had a CB graft in the early period versus 15/20 (75%) recently, p = 0.14.TableN in Early Time PeriodN in Recent Time Period(n = 424, 60% of total patients)(n = 284, 40% of total patients)Europeans (n = 485)N = 295N = 190URD: 246 [175/246 (71%) received 10/10]URD: 154 [117/154 (76%) received 10/10]CB: 42 [20/42 (48%) ≥ 6/10]CB: 35 [19/35 (54%) ≥ 6/10]No graft: 7 [7/295 (2%) of Europeans]No graft: 1 [1/190 (0.5%) of Europeans]Non-Europeans (n = 223)N = 129N = 94URD: 61 [29/61 (48%) 10/10]URD: 50 [28/50 (56%) 10/10]CB: 46 [13/46 (28%) ≥ 6/10]CB: 36 [25/36 (69%) ≥ 6/10]No graft: 22 [22/129 (17%) non-Europeans]No graft: 8 [8/94 (8.5%) of non-Europeans] ConclusionVery few Europeans do not have an URD &/or CB graft. However, URDs are a poor donor source for patients with non-European ancestry. By contrast, CB is a critically important stem cell source for minorities, & transplantation of units with higher rates of 10 HLA-allele match is now frequently possible likely due to a bigger inventory & the use of high-resolution matching. Our analysis suggests CB availability in non-Europeans has improved. However, additional measures are required to extend graft access for African ancestry patients. Disclosures:No relevant conflicts of interest to declare.

Graft-Specific HLA-Antibodies Do Not Influence Unit Dominance and Do Not Prevent High Rates of Sustained Donor Engraftment in Recipients of Double-Unit Cord Blood Transplantation

AbstractAbstract 960 Background:Pre-transplant human leukocyte antigen (HLA)-antibodies have an established role in failed engraftment after single-unit cord blood (CB) transplantation (CBT). Their role in double-unit CBT (DCBT) engraftment, however, is more controversial. Some transplant centers advocate pre-transplant screening of the recipient for HLA-antibodies, and avoidance of units with the corresponding antigens if antibodies are detected. Methods:We evaluated the influence of pre-transplant HLA-antibodies on sustained donor neutrophil engraftment and unit dominance in 82 recipients (median 48 years, range 2–69) of 4–6/6 HLA-A, B antigen, DRB1 allele matched double-unit CB grafts, and transplanted for hematologic malignancies at MSKCC from July 2008 to July 2012. HLA-antibodies were measured by the HLA Laboratory of the American Red Cross Blood Service using Single Antigen Luminex beads and analyzed by HLA Fusion software. The cut-off for positive results was a normalized mean fluorescence intensity value > 1000. Results:Overall, 28/82 (34%) patients were positive for HLA-antibodies [16 (19.5%) had antibodies without graft specificity, and 12 (14.5%) had antibodies with graft specificity]. These patients were more likely to be female with acute leukemia and cytomegalovirus seropositive. All patients with graft-specific antibodies received myeloablative conditioning; 5 had antibodies against class I HLA, 6 against class II, and one patient had antibodies to both Class I/II. Moreover, of these 12 patients, 6 had antibodies against one unit, and 6 had antibodies against both units. Neutrophil engraftment according to antibody presence is summarized in the Table. 64 of 66 (97%) evaluable myeloablative DCBT recipients (Table 1A) engrafted at a median of 24 days (range 12–40); one patient without antibodies and one with antibodies against both units had primary graft failure, both in the setting of early onset multi-organ failure. Both patients were 100% donor with one unit but did not recover counts. Of the 6 patients with antibodies to one unit, 3 engrafted with that unit and 3 with the opposite unit. Of the 6 patients with antibodies against both units, one had clinical graft failure as described above, and the 5 others had sustained donor engraftment (4 with one unit and one with both). In engrafting myeloablative recipients, the median time to neutrophil recovery was 8 days slower in patients with graft-specific antibodies, but the engrafting unit in these patients also had the lowest infused dose: median CD34+ cell dose/kg if no antibodies 0.83 × 105/kg, non-specific antibodies 1.09 × 105/kg, and antibodies specific to graft 0.65 × 105/kg. In non-myeloablative recipients, 15/16 (94%) engrafted (Table 1B). The single patient with graft rejection and autologous recovery had HLA-antibodies that were not graft specific. Conclusions:11 of 12 double-unit CBT recipients with graft-specific antibodies engrafted successfully. While myeloablative recipients with graft-specific antibodies engrafted more slowly, this may be explained by a lower infused CD34+ cell dose of their engrafting units. Multivariate analysis of larger patient numbers will be required to further evaluate the effect of graft-specific antibodies on engraftment speed. At this time, however, the presence of graft-specific antibodies should not preclude DCBT, and whether their presence should influence graft selection is not clear. Furthermore, there is no suggestion that the presence of HLA-antibodies influences unit dominance after DCBT.TableSustained Donor Neutrophil Engraftment According to HLA-antibodies1A) Myeloablative Conditioning (n=67)Median (Range) Time to Neutrophil Recovery (> 0.5)N (%) Sustained EngraftmentNo antibodies (n=41)23 days (range 12–38)39/40 (1 non-evaluable)Antibodies: not graft-specific (n=14)23 days (range 12–37)14/14Antibodies: graft-specific (n=12)31 days (range 13–40)11/12Against engrafting unit (n=3)28 days (range 24–31)3/3Against non-engrafting unit (n=3)31 days (range 25–32)3/3Antibodies against both units (n=6)33 days (range 13–40)5/61B) Non-Myeloablative Conditioning (n=15)Median (Range) Time to Neutrophil Recovery (> 0.5)N (%) Sustained EngraftmentNo antibodies (n=13)10 days (range 8–20)13/13Antibodies: not graft specific (n=2)19 days in 1 patient (other had graft failure/autologous recovery)1/2Antibodies: graft specific (n=0)-- Disclosures:Giralt:Celgene: Honoraria, Research Funding.

Donor-Recipient HLA-Matching of Unrelated Cord Blood Units At High-Resolution Reveals High Degrees of HLA-Mismatch and Alters Graft Selection

AbstractAbstract 957 Background:Optimal criteria for cord blood (CB) unit selection are unknown. Traditionally, units are matched to the recipient only at human leukocyte antigen (HLA)-A, B antigens, and DRB1 alleles with up to 2 mismatches permitted. Recently, however, a significant association between intermediate resolution HLA-C matching and transplant-related mortality has been reported in single unit CB transplantation (CBT) (Eapen, M., Lancet Oncol, 2011). Moreover, we have recently demonstrated a decreased day 180 grade III-IV acute graft-versus-host disease incidence if the engrafting unit of a double-unit pair is ≥ 4/6 HLA-A, B, DRB1 allele matched to the recipient (Ponce, D., unpublished, 2012). This suggests that CB donor-recipient match criteria should be upgraded to 6 HLA-alleles or higher. However, how to clinically implement higher resolution HLA-matching and how it could affect CB unit selection are not known. Methods:To examine the extent of HLA-mismatch, we analyzed the HLA-match grade of 96 double-unit CB grafts (units 1a and 1b) and the 1–2 back-up units chosen for each transplant at various HLA-match grades. 362 CB units were selected for 95 patients (one patient was transplanted twice) who underwent CBT from 1/1/2009-6/30/2012 for hematologic malignancies. Units were selected based on cryopreserved total nucleated cell (TNC) dose (initially ≥ 1.5, later increased to ’ 2.0 × 107/kg), donor-recipient 4–6/6 HLA-A, B antigen, DRB1 allele match, and CB bank. Unit-unit HLA-match was not considered. High-resolution typing for 10 alleles was obtained prospectively, although usually did not influence unit selection. Results:The median age was 41 years (range 1–69) and the median weight was 65 kilograms (range 10–125). The median cryopreserved TNC/kg × 107 of units 1a and 1b (n = 192) was 2.89 (range 1.53–17.78), and their median donor-recipient HLA-match was 4/6 (range 1–6/6), 5/8 (range 2–8/8), and 6/10 (range 2–9/10) at 6, 8 and 10 HLA-alleles, respectively. The median (range) of 6/6 HLA-A, B antigen, DRB1 allele matched units (n = 9) was 6/6 (3-6/6), 7/8 (5-8/8) and 9/10 (7-9/10) at 6, 8, and 10 allele resolution, respectively. However, 5/6 HLA-A, B antigen, DRB1 allele matched units (n = 90) were a median (range) of 5/6 (2-5/6), 6/8 (3-7/8) and 7/10 (3-9/10) at allele resolution. Moreover, 4/6 HLA-A, B antigen, DRB1 allele matched units (n = 93) were a median (range) of 3/6 (1-4/6), 4/8 (2-6/8) and 5/10 (2-8/10) at allele resolution. We then evaluated how often the use of higher resolution HLA-match criteria would change graft selection to substitute one or both back-up units over units 1a and/or 1b, and the effect on the graft TNC dose (Table). If a cryopreserved TNC/kg ≥ 2.0 × 107 and a better HLA-match were required for either units 1a or 1b to be substituted, the frequency that graft selection would change was up to 38/96 (40%) of transplants for 10 allele HLA-match. The effect on TNC was minimal (≤ 12% reduction in the total graft TNC dose). Conclusions:Recent data suggest the criteria for CB match should be re-evaluated. However, units currently chosen based on HLA-A, B antigen, DRB1 allele match have a very high degree of mismatch when typed at higher resolution (as low as 3/10 for 5/6 units, and 2/10 for 4/6 units). Adoption of higher match grade criteria will frequently change the selection of the “optimal” graft in both adult and pediatric patients. While both the new lower limit of acceptable HLA-match and how to “trade off” higher resolution HLA-match against TNC dose are unknown, our data suggest that higher resolution HLA-match is possible without significant compromise in graft dose. Ultimately, large studies will be required to understand the impact of higher resolution HLA-match on disease-free survival to further guide clinical practice.TableMatchN (%) Grafts That Would ChangeFor Grafts That Would ChangeGradeMedian (Range) Cryo. TNC: Original Choice for Graft (Larger/Smaller)Median (Range) Cryo. TNC: New Choice Based on Higher Match Grade(Larger/Smaller)6 allele:26/96 (27%)3.7 (2.1-12.0)/2.7 (1.9-6.6)3.0 (2.0-8.0)/2.6 (2.0-6.6)A, B, DRB18 allele:33/96 (34%)3.6 (1.9-10.5)/2.7 (1.9-6.4)3.2 (2.0-7.6)/2.5 (1.9-6.8)A, B, C, DRB110 allele:38/96 (40%)3.6 (2.1-10.5)/2.6 (1.6-6.4)3.1 (2.0-8.7)/2.5 (1.6-7.6)A, B, C, DRB1, DQ Disclosures:Giralt:Celgene: Honoraria, Research Funding.