Double-unit Cord Blood Transplantation Research Articles

High Progression-Free Survival with Low Relapse Rates after Double-Unit Cord Blood Transplantation in Patients with High-Risk AML

High Progression-Free Survival with Low Relapse Rates after Double-Unit Cord Blood Transplantation in Patients with High-Risk AML

High Progression-Free Survival with Low Relapse Rates after Double-Unit Cord Blood Transplantation in Patients with High-Risk AML

Background : Double-unit cord blood transplantation (dCBT) is standard therapy for patients with acute myelogenous leukemia (AML) who do not have suitable adult donors. We & others have reported low relapse rates & high progression free survival (PFS) in dCBT recipients suggesting robust CB-derived graft-versus-leukemia effects. However, the efficacy of dCBT in high-risk AML as determined by ELN genetic risk & pre-transplant minimal residual disease (MRD) status has not been performed to date. Methods : All consecutive adult patients with AML who received first dCBT with intermediate intensity conditioning (Cy50/ Flu150/ Thio10/ TBI400) between 2014-2022 were analyzed. GVHD prophylaxis was with either Cyclosporine-A (CSA)/ Mycophenolate Mofetil (MMF) or CSA/MMF/Tocilizumab on an institutional protocol. Results : 63 patients (pts) (median age 49 years, range 23-63) were eligible for analysis (Table); 42 (67%) were CMV seropositive, 31 (49%) had non-European ancestry, & median HCT-CI was 2 (range 0-6). Most (n = 55, 87%) were in CR1, 5 (8%) in CR2, & 3 were relapsed or primary refractory at transplant (5-9% blasts). By ELN2022 genetic risk criteria, 8 pts had favorable, 29 intermediate, & 20 adverse risk AML (6 were missing ELN status). Of the 60 pts in CR, 36 were MRD- & 18 MRD+ by multicolor flow cytometry (6 had unknown/ indeterminate MRD status). Sixty-one of 63 pts engrafted for a 60-day cumulative incidence of 98% (95%CI:81-100). The median follow-up of survivors was 58 months (range 8-104 months). The 1- & 3-yr incidences of transplant-related mortality (TRM) were 13% (95%CI: 5.9-22) & 18% (95%CI: 9.6-29), respectively. The 1- & 3-year relapse incidences were 3.2% (95%CI: 0.6-9.9) & 8.6% (95%CI: 3.1-18), respectively. The 1- & 3-year OS were 87% (95%CI: 79-96) & 82% (95%CI:72-92) respectively, whereas the 1- & 3-year PFS were 84% (95%CI: 76-94) & 73% (95%CI: 63-85), respectively. When stratified by ELN2022 genetic risk, the 3-year relapse incidence was 0% in favorable, 10% (95%CI: 2.5-25) in intermediate & 13% (95%CI: 2-36%) in adverse risk AML patients. Pts with favorable risk AML had a 3-year PFS of 88% (95%CI: 67-100); the 3-year PFS was similar in patients with intermediate [68% (95%CI: 53-88)] or adverse [67% (95%CI: 48-93)] risk AML (Figure 1A). When stratified by MRD status, the 3-year relapse incidence was 8.4% (95%CI:2.1-20) in MRD- & 13% (95%CI: 1.9-34) in MRD+ patients. The 3-year PFS was similar in patients with AML in CR who were MRD- 80% (95%CI: 68-94) or MRD+ 76% (95%CI: 57-100), whereas all 3 relapsed/ refractory patients died of TRM (Figure 1B). Of 4 TP53-mutated AML patients, one relapsed, one died of TRM, & two are alive in remission. Conclusions: While retrospective, our findings highlight the low relapse rates & promising PFS in adult AML patients, including those with high risk features such as adverse-risk ELN genetic risk &/ or MRD positivity supporting robust CB-derived graft-versus-leukemia (GVL) effects. This observation, together with the mitigation of TRM in recent years due to the optimized transplant practices in adult dCBT (see Politikos et al, ASH 2023), makes intermediate intensity dCBT an attractive strategy for AML patients with a suitable dCB graft & high-risk disease. Our findings warrant prospective multi-center investigation with correlative studies to elucidate the biology of CB-derived GVL.

Optimized Double-Unit Cord Blood Transplantation Mitigates Transplant-Related Mortality Resulting in High Progression-Free Survival in Adults with Hematologic Malignancies

Background : Double-unit cord blood transplantation (dCBT) with intermediate intensity conditioning (Cy50/ Flu150/ Thio10/ TBI400cGy) and cyclosporine-A (CSA)/ mycophenolate mofetil (MMF) graft-versus-host disease (GVHD) prophylaxis has been associated with high progression-free survival (PFS) in adult patients (pts) with hematologic malignancies ( Barker JN et al, Blood Advances 2020). Now, our Center has investigated multiple refinements to further mitigate transplant-related mortality (TRM). Herein, we have analyzed transplant outcomes in these adult dCBT pts to establish an optimized dCBT platform. Methods : Consecutive adult first allograft pts with high-risk hematologic malignancies who underwent first allografts with intermediate intensity dCBT between 3/2018-8/2022 were analyzed. Optimizations involved further refined unit selection placing highest priority on unit quality (i.e. optimized banking practices) & CD34+ cell dose over HLA-match, ensuring therapeutic (CSA) levels (> 250 ng/mL) by day 0, prompt treatment of pre-engraftment syndrome (PES) & letermovir prophylaxis in CMV seropositive pts from day +7. Also, we have investigated 2 strategies to mitigate acute graft-versus-host disease (aGVHD): pts early in the study period received CSA, MMF & tocilizumab (8 mg/kg on day -1) prophylaxis ( Toci Group), whereas recent pts ( Recent Group) received CSA/ MMF with prompt therapy of clinically diagnosed aGVHD. Results : Of 74 patients (Table), 49 were in the Toci Group, & 25 in the Recent Group. Most pts were transplanted for acute leukemia (n = 55, 74%) & over half (n = 39, 53%) had non-European ancestry. Distribution of diagnoses, CMV serostatus, HCT-CI & graft characteristics were similar between the groups but Recent Group pts tended to be younger (38 vs. 47 years, p = 0.071). Toci Group pts had delayed neutrophil recovery [engraftment incidence 94% (95%CI: 87-99) at a median of 25 days (range 16-40), one graft failure], but low rates of PES (n = 19, 39%). The day-100 incidence of grade II-IV & III-IV aGVHD were 69% (95%CI: 56-82) & 10% (95%CI: 2-19), respectively. One pt (false negative CMV-serostatus) who did not receive letermovir had CMV infection. One-year TRM was 16% (95%CI: 6-27) with a 1-year relapse rate of 6% (95%CI: 3-13). TRM was due to infection (n = 3), aGVHD (n = 3, 1 with concurrent COVID-19 infection), multiorgan failure (n = 2) & graft failure (n = 1). With a median follow-up of 47 months (range 28-62), the 1-year OS was 84% (95%CI: 73-94) & 1-year PFS was 78% (95%CI: 66-89). By contrast, the engraftment incidence in Recent Group pts was 100% with a faster median neutrophil recovery of 19 days (range 11-36, p = 0.002) & all engrafted platelets at a median of 36 days (range 24-92). However, most Recent group pts developed PES [n = 20 (80%), p < 0.001] although this responded promptly to short course corticosteroids. Day 100 grade II-IV aGVHD was also higher [92% (95%CI: 81-99), p = 0.009], although grade III-IV aGVHD was low [8% (95%CI: <1-19)] & similar to tocilizumab pts. Day 100 incidence of CMV was 0%. With a median follow-up of 17 months (range 6-50), the 1-year TRM in Recent Group pts is 0% with a 1-year relapse incidence of 13% (95%CI: 7-27). Consequently, the 1-year OS & PFS are high at 96% (95%: 89-99) & 87% (95%CI: 74-99), respectively (Figure). Conclusions: Optimized dCBT with intermediate intensity conditioning, graft selection that prioritizes unit quality & CD34+ dose, CSA/ MMF prophylaxis with prompt therapy of PES & aGVHD, & letermovir CMV prophylaxis mitigates TRM in young & middle-aged adults. Thus, combined with relatively low relapse rates, the PFS & OS are high. Tocilizumab has been abandoned due to its notable association with delayed neutrophil engraftment & lack of survival advantage. Letermovir is highly effective completely preventing CMV infections & may contribute to the reduced aGVHD-related mortality recently (as compared to the pre-tocilizumab era), since avoidance of CMV antiviral therapy toxicities greatly facilitates aGVHD prevention & therapy. Given the rapid availability of cryopreserved unmanipulated CB grafts & frequent limitations of URD availability for minority populations, optimized dCBT is a highly attractive curative therapy for acute leukemias & other high-risk myeloid malignancies warranting prospective multi-center investigation.

Cord blood transplantation for AML: Comparable LFS in patients with de novo versus secondary AML in CR1, an ALWP/EBMT study.

We investigated whether secondary versus de novo acute myeloid leukaemia (AML) would be associated with poor outcomes in adult acute AML patients in first complete remission (CR1) receiving unrelated cord blood transplantation (CBT). This is a retrospective study from the acute leukaemia working party of the European Society for Blood and Marrow Transplantation. Inclusion criteria included adult at first allogeneic haematopoietic cell transplantation between 2000 and 2021, unrelated single or double unit CBT, AML in CR1, no ex vivo T-cell depletion and no post-transplant cyclophosphamide. The primary end-point of the study was leukaemia-free survival (LFS). A total of 879 patients with de novo (n = 696) or secondary (n = 183) AML met the inclusion criteria. In multivariable analyses, sAML patients had non-significantly different LFS (HR = 0.98, p = 0.86), overall survival (HR = 1.07, p = 0.58), relapse incidence (HR = 0.74, p = 0.09) and non-relapse mortality (HR = 1.26, p = 0.13) than those with de novo AML. Our results demonstrate non-significantly different LFS following CBT in adult patients with secondary versus de novo AML.

Umbilical cord blood: an undervalued and underutilized resource in allogeneic hematopoietic stem cell transplant and novel cell therapy applications.

The purpose of this review is to primarily discuss the unwarranted decline in the use of umbilical cord blood (UCB) as a source of donor hematopoietic stem cells (HSC) for hematopoietic cell transplantation (HCT) and the resulting important implications in addressing healthcare inequities, and secondly to highlight the incredible potential of UCB and related birthing tissues for the development of a broad range of therapies to treat human disease including but not limited to oncology, neurologic, cardiac, orthopedic and immunologic conditions. When current best practices are followed, unrelated donor umbilical cord blood transplant (CBT) can provide superior quality of life-related survival compared to other allogeneic HSC donor sources (sibling, matched or mismatched unrelated, and haploidentical) through decreased risks of relapse and chronic graft vs. host disease. Current best practices include improved UCB donor selection criteria with consideration of higher resolution human leukocyte antigen (HLA) typing and CD34+ cell dose, availability of newer myeloablative but reduced toxicity conditioning regimens, and rigorous supportive care in the early posttransplant period with monitoring for known complications, especially related to viral and other infections that may require intervention. Emerging best practice may include the use of ex vivo expanded single-unit CBT rather than double-unit CBT (dCBT) or 'haplo-cord' transplant, and the incorporation of posttransplant cyclophosphamide as with haploidentical transplant and/or incorporation of novel posttransplant therapies to reduce the risk of relapse, such as NK cell adoptive transfer. Novel, non-HCT uses of UCB and birthing tissue include the production of UCB-derived immune effector cell therapies such as unmodified NK cells, chimeric antigen receptor-natural killer cells and immune T-cell populations, the isolation of mesenchymal stem cells for immune modulatory treatments and derivation of induced pluripotent stem cells haplobanks for regenerative medicine development and population studies to facilitate exploration of drug development through functional genomics. The potential of allogeneic UCB for HCT and novel cell-based therapies is undervalued and underutilized. The inventory of high-quality UCB units available from public cord blood banks (CBB) should be expanding rather than contracting in order to address ongoing healthcare inequities and to maintain a valuable source of cellular starting material for cell and gene therapies and regenerative medicine approaches. The expertise in Good Manufacturing Practice-grade manufacturing provided by CBB should be supported to effectively partner with groups developing UCB for novel cell-based therapies.

Comparison of Outcomes after Unrelated Double-Unit Cord Blood and Haploidentical Peripheral Blood Stem Cell Transplantation in Adults with Acute Myelogenous Leukemia: A Study on Behalf of Eurocord and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

Unmanipulated haploidentical hematopoietic stem cell transplantation (HCT) with post-transplantation cyclophosphamide as graft-versus-host disease (GVHD) prophylaxis (haplo-PTCY) and unrelated double-unit umbilical cord blood transplantation (dUCBT) are feasible options for treating patients with high-risk acute myelogenous leukemia (AML). This study compared outcomes after dUCBT and haplo-HCT using peripheral blood stem cells (PBSCs) in adult patients with AML in complete remission (CR) who underwent transplantation in European Society for Blood and Marrow Transplantation (EBMT)-affiliated centers. In a population of adults with de novo AML in first or second CR, we compared outcomes after dUCBT (n = 165) and after haplo-PTCY PBSC (n = 544) performed between January 2013 and December 2018. Patients receiving in vivo antithymocyte globulin, Campath, or ex vivo T cell depletion were excluded. The median follow-up was 33 months for the haplo-PTCY arm and 52 months for the dUCBT arm. No statistically significant differences were observed between the 2 arms in the rates of grade II-IV acute graft-versus-host disease (GVHD) (hazard ratio [HR], 1.31; P = .18), grade III-IV acute GVHD (HR, 1.17; P = .56), chronic GVHD (HR, .86; P = .48), relapse (HR, 1.07; P = .77), nonrelapse mortality (NRM) (HR, .94; P = .77), leukemia-free survival (LFS) (HR, .99; P = .95), or overall survival (OS) (HR, .99; P = .97). Favorable cytogenetic risk was the sole factor predictive of lower relapse incidence (RI). Younger age at transplantation was associated with lower NRM and higher LFS and OS. Both dUCBT and haplo-PTCY with PBSCs can be considered valid approaches for adult AML patients in CR. New strategies should be investigated in both settings to define the most appropriate conditioning regimen and potentially decrease RI and NRM through better immune reconstitution and optimal supportive care.

44 - Double Unit Cord Blood Transplantation Compares Favorably to T-Cell Depleted Matched Adult Donor Transplantation for the Treatment of Acute Leukemia Due to a Robust Protection Against Relapse

44 - Double Unit Cord Blood Transplantation Compares Favorably to T-Cell Depleted Matched Adult Donor Transplantation for the Treatment of Acute Leukemia Due to a Robust Protection Against Relapse

Donor-Derived Leukemia in a Recipient of Double-Unit Cord Blood Transplantation for Acute Myeloid Leukemia: A Case Study and Literature Review.

We report a case of donor-derived leukemia (DDL) occurring 34 months after double-unit cord blood transplantation (CBT). Molecular analysis using short tandem repeat (STR) sequences proved the acute myeloid leukemia (AML) to be of dominant cord blood origin. Karyotype was normal and molecular analysis showed WT1 and EVI1 overexpression. Cytological and molecular remission were achieved with only induction and consolidation chemotherapy. Relapse occurred after 6 years of remission from one clone with only WT1 overexpression. Potential etiologies for donor cell leukemogenesis in the recipient are discussed, including occult leukemia in the donor or genetic predisposition to hematologic malignancies, impaired immune surveillance, induced or inherited stromal abnormalities, transformation of donor cells during engraftment via altered signals of the host tissues, and fusion of donor cells with residual leukemic cells leading to acquisition of oncogenes. Although cases of DDL occurring after umbilical CBT have already been reported, very few cases have been described arising after double-unit CBT. DDL cases following CBT previously described in the literature have been reviewed.

First-Line Unrelated Double-Unit Umbilical Cord Blood Transplantation for Acquired Severe Aplastic Anemia

We analyzed the outcomes of 14 patients with severe aplastic anemia (SAA) who received first-line double-unit cord blood transplantation (dUCBT). Patients' median age was 24.5 years (range, 10-44 years). The median numbers of infused nucleated and CD34+ cells were 5.48×107/kg (range, 3.33-7.96×107/kg) and 2.30×105/kg (range, 0.86-3.97×105/kg), respectively. One patient died 5 days after transplantation. Three of the 13 patients acquired autologous myeloid recovery. Neutrophil engraftment was observed in 10 patients (76.29%), and the median time of neutrophil recovery was 19 days (range, 15-40 days). Platelet engraftment was observed in 7 cases (53.8%), and 3 patients experienced platelet graft failure. The median time of platelet recovery was 32 days (range, 22-80 days). The cumulative incidence of grade II-IV acute graft-vs-host disease (GVHD) was 38.5%. One patient demonstrated mild chronic GVHD. After a median follow-up of 61 months (range, 18-102 months), 6 patients were alive. The predicted 5-year overall survival and GVHD-free, failure-free survival rates were 42.9% ± 13.2% and 14.3% ± 9.4%, respectively. The first-line dUCBT for SAA is still primarily evaluated through multicenter prospective clinical trials by an optimal conditioning regimen, cell dose, and other graft and transplantation-related factors.

Long-Term Follow-up of Adult Double Unit Cord Blood (CB) Transplantation (dCBT) Recipients Reveals High Rates of Progression-Free Survival after a Novel Cy/ Flu/ Thio/ TBI 400 Intermediate Intensity Conditioning Regimen

Background: CB transplantation (CBT) can be associated with the advantages of low rates of chronic GVHD & relapse. These benefits, however, can be offset by early post-transplant transplant-related mortality (TRM). Therefore, we have investigated CBT after a novel intermediate intensity, reduced toxicity myeloablative cyclophosphamide 50 mg/kg, fludarabine 150 mg/m2, thiotepa 5-10 mg/kg, 400 cGy TBI regimen in an effort to reduce early organ toxicity while also maximizing engraftment & disease control.Methods: We analyzed CBT outcomes, including patient (pt) & graft characteristics associated with TRM, relapse and progression-free survival (PFS), in adult CBT recipients transplanted with this approach. Eligible pts were first allograft recipients </= 65 yrs transplanted for acute leukemia/ MDS/ MPD (</= 10% blasts pre-CBT), B-cell NHL or Hodgkin lymphoma. Graft-versus-host disease (GVHD) prophylaxis was with cyclosporine-A/ mycophenolate mofetil (no ATG).Results: 139 consecutive pts [74 (53%) non-European, 84 (60%) CMV seropositive, median age 51 yrs (range 23-65), median weight 83 kg (range 49-136)] were transplanted 10/2007-12/2016. Diagnoses included 102 acute leukemia, 22 MDS/ MPD, 15 B-cell NHL/ HL. All received double unit grafts [median donor recipient 8-allele HLA-match 5/8 (range 2-8), median infused CD34+ dose 1.0 x 105/kg/unit (range 0.2-8.6)]. 54 (39%) CB grafts were supplemented with haplo-identical CD34+ cells as a myeloid bridge. The incidence of CB engraftment was 96% (95%CI: 91-99). Day 180 incidence of grades II-IV & III-IV aGVHD was 78% (95%CI: 70-84) & 21% (95%CI: 15-28), respectively. 1-yr cGVHD was 8% (95%CI: 4-14). Cumulative incidence of day 180 TRM was 12% (95%CI: 7-17) & 21% (95%CI: 14-29) at 3 yrs. 11% (95%CI: 6-18) of pts relapsed by 3 yrs post-CBT. With a median survivor follow-up of 2.7 yrs (range 6.5 months-9.5 yrs), the 3-yr overall survival is 71% (95%CI: 63-80) & PFS is 67% (95%CI: 59-76). 3-yr PFS in 75 acute leukemia CR1 pts is 66% versus 74% in 27 other disease status pts (p = 0.574). 3-yr PFS in 23 FLT-3 mutated AML pts is 83%. The 3-yr PFS is 62% in 22 MDS/ MPD pts & 67% in 15 NHL/ HD pts. The revised disease risk index (rDRI) was not associated with TRM, relapse or PFS (Figure, Table). By contrast, pts with an age adjusted hematopoietic cell transplant-comorbidity index (aaHCT-CI) 0-2 (n = 54) had very low day 180 TRM [4% (95%CI: 1-11)] & high PFS [81% (95%CI: 71-94)] whereas the 85 pts with high aaHCT-CI (median 4, range 3-9) had a day 180 TRM of 17% (95%CI: 10-25) & 3-yr PFS of 58% (95%CI: 48-71). In multivariate analysis of TRM, aaHCT-CI had a HR of 4 (95%CI: 1.4-11.6, p = 0.01) whereas age alone was not significant [HR 1.9 (95%CI: 0.8-4.5), p = 0.12]. In multivariate analysis of PFS, aaHCT-CI HR was 2.4 (95%CI: 1.2-4.7, p = 0.01) whereas for recent pts (CBT 2014-2016) HR was 0.6 (95%CI: 0.3-1.2) although this was not significant (p = 0.17)Conclusions: The 3-yr PFS in this older (median 51 yrs) intermediate intensity dCBT population is very promising. The incidences of cGVHD & relapse are low & DRI was not associated with TRM, relapse or PFS. Notably, addition of haplo-identical cells & better CB HLA-match was not associated with better PFS, & older age (51-65 yrs), CMV sero-positivity & non-European ancestry did not adversely affect PFS. Notably, day 180 TRM in recent pts is 9%. While high aaHCT-CI pts require additional strategies to reduce early post-CBT complications, given PFS is excellent in low aaHCT-CI CBT recipients (39% of pts in this analysis), survival comparisons of intermediate intensity dCBT in this population versus all other HSC sources is warranted. CB can also be attractive in pts with high risk disease given its rapid availability. [Display omitted] Disclosuresvan den Brink:Seres: Research Funding; Therakos Institute: Other: Speaking engagement; PureTech Health: Consultancy; Jazz Pharmaceuticals: Consultancy.

High progression-free survival after intermediate intensity double unit cord blood transplantation in adults

AbstractCord blood transplantation (CBT) after high intensity or nonmyeloablative conditioning has limitations. We investigated cyclosporine-A/mycophenolate mofetil–based intermediate intensity (cyclophosphamide 50 mg/kg, fludarabine 150 mg/m2, thiotepa 10 mg/kg, total body irradiation 400 cGy) unmanipulated double-unit CBT (dCBT) with prioritization of unit quality and CD34+ cell dose in graft selection. Ninety adults (median age, 47 years [range, 21-63]; median hematopoietic cell transplantation comorbidity index, 2 [range, 0-8]; 61 [68%] acute leukemia) received double-unit grafts (median CD34+ cell dose, 1.3 × 105/kg per unit [range, 0.2-8.3]; median donor-recipient human leukocyte antigen (HLA) match, 5/8 [range 3-7/8]). The cumulative incidences of sustained CB engraftment, day 180 grade III-IV acute, and 3-year chronic graft-versus-host disease were 99%, 24%, and 7%, respectively. Three-year transplant-related mortality (TRM) and relapse incidences were 15% and 9%, respectively. Three-year overall survival (OS) is 82%, and progression-free survival (PFS) is 76%. Younger age and higher engrafting unit CD34+ cell dose both improved TRM and OS, although neither impacted PFS. Engrafting unit-recipient HLA match was not associated with any outcome with a 3-year PFS of 79% in 39 patients engrafting with 3-4/8 HLA-matched units. In 52 remission acute leukemia patients, there was no association between minimal residual disease (MRD) and 3-year PFS: MRD negative of 88% vs MRD positive of 77% (P = .375). Intermediate intensity dCBT is associated with high PFS. Use of highly HLA mismatched and unmanipulated grafts permits wide application of this therapy, and the low relapse rates support robust graft-versus-leukemia effects even in patients with MRD.

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.

Research Advances on Clinical Application of Umbilical Cord Blood Transplantation in the Treatment of Hematological Diseases--Review

Abstract Umbilical cord blood (UCB) is an alternative source of hematopoietic stem cells (HSCs) for patients who were lack of HLA match related or unrelated donors. Compared with bone marrow and mobilized peripheral blood, UCB has the advantages of easy availability, safety for donors, and low requirement for HLA match between donors and recipients. However, the cell amount in UCB is relatively less, which was associated with increased graft failure, delayed hematologic recovery, immune reconstitution, and higher transplant related mortality after UCB transplantation (UCBT). Double-unit UCB is a straightforward method to augment cell amount in UCB. Compared with single-unit UCBT, double-unit CBT associated with less risk of primary disease relapse and increased incidence rate of graft-versus-host disease (GVHD), but the hematologic recovery and overall survival of recipients were no significantly difference between single and double-unit UCBT. Novel strategies for UCB expansion significantly increased the cell amount in UCB, single-unit expanded UCBT not only increased the sources of UCB, but also decreased the high cost of double-unit UCB. ATG can decrease the risk of graft failure and GVHD rate, but the role of ATG in UCBT is still controversial. Herein, the recent clinical advances on UCBT in the treatment of hematologic diseases are systematically reviewed.

Adult cord blood transplant results in comparable overall survival and improved GRFS vs matched related transplant

AbstractWe compared outcomes among adult matched related donor (MRD) patients undergoing peripheral blood stem cell transplantation and adult patients undergoing double unit cord blood transplantation (CBT) at our center between 2010 and 2017. A total of 190 CBT patients were compared with 123 MRD patients. Median follow-up was 896 days (range, 169-3350) among surviving CBT patients and 1262 days (range, 249-3327) among surviving MRD patients. Comparing all CBT with all MRD patients, overall survival (OS) was comparable (P = .61) and graft-versus-host disease (GVHD) relapse-free survival (GRFS) was significantly improved among CBT patients (P = .0056), primarily because of decreased moderate to severe chronic GVHD following CBT (P < .0001; hazard ratio [HR], 3.99; 95% confidence interval [CI], 2.26-7.04). Among patients undergoing our most commonly used MRD and umbilical cord blood (CB) myeloablative regimens, OS was comparable (P = .136) and GRFS was significantly improved among CBT patients (P = .006). Cumulative incidence of relapse trended toward decreased in the CBT group (P = .075; HR, 1.85; CI 0.94-3.67), whereas transplant-related mortality (TRM) was comparable (P = .55; HR, 0.75; CI, 0.29-1.95). Among patients undergoing our most commonly used nonmyeloablative regimens, OS and GRFS were comparable (P = .158 and P = .697). Cumulative incidence of both relapse and TRM were comparable (P = .32; HR, 1.35; CI, 0.75-2.5 for relapse and P = .14; HR, 0.482; CI, 0.18-1.23 for TRM). Our outcomes support the efficacy of CBT and suggest that among patients able to tolerate more intensive conditioning regimens at high risk for relapse, CB may be the preferred donor source.

Addition of Tocilizumab to Cyclosporine-a/ Mycophenolate Mofetil (CSA/ MMF) Graft-Vs-Host Disease (GVHD) Prophylaxis Significantly Abrogates Pre-Engraftment Syndrome (PES) &amp; Severe Acute Gvhd after Adult Double Unit Cord Blood Transplantation (dCBT)

Background Anti-thymocyte globulin-free dCBT is associated with high rates of acute GVHD (aGVHD) especially involving the GI tract. Investigation of augmented aGVHD prophylaxis is indicated. Methods We are investigating the addition of a single dose of tocilizumab 8 mg/kg (day -1) to CSA/ MMF (starting day -3) aGVHD prophylaxis in adult patients (pts) with hematologic malignancies undergoing dCBT with intermediate intensity Cy 50/ Flu 150/ Thio 10/ TBI 400 conditioning (NCT03434730). Outcomes of the first 26 patients (with survivor follow-up of at least 100 days) were analyzed & compared to 54 dCBT historic controls transplanted with identical conditioning & only CSA/ MMF. All patients received letermovir if CMV seropositive. Results 26 pts [median age 47 years (range 26-60), median weight 82 kg (range 59-125), 11 AML, 8 ALL, 2 MPAL, 3 MDS/ CML, 2 NHL, median age-adjusted HCT-CI 2.5 (range 0-6)] received dCB grafts with a median CD34+ cell dose of 1.5 × 105/kg/unit (range 0.23-5.94) & median unit-recipient 8-allele HLA-match of 5/8 (range 3-6). One patient had graft failure in the setting of low graft viability/ disseminated adenovirus & a second pt had early transplant-related mortality (TRM) with incomplete count recovery. The remaining 24 patients engrafted at a median of 24 days (range 18-40) for a cumulative incidence of 92% (95%CI:67-98). 88% (95%CI:59-97) of pts engrafted platelets at a median of 43 days (range 32-78). Of evaluable pts, 68% & 83% had 100% single-unit donor chimerism in the blood at days 30 & 100, respectively; single-unit dominance was observed in the remaining cases. Six of 26 pts (23%) developed pre-engraftment syndrome (PES) at a median of 12.5 days, & only 3 of these (12%) required systemic corticosteroids. Additionally, 16 pts (62%) had no neutropenic fever prior to engraftment. The day 100 cumulative incidence of grade II-III & grade III aGVHD was 62% (95%CI:39-78) & 4% (95%CI: Conclusions Tocilizumab-based dCBT appears safe with reduced PES & grade III-IV aGVHD. While many pts developed upper GI aGVHD, the marked reduction in lower GI aGVHD supports preferential reduction of T-cell homing to the lower gut. Investigation of this approach including aGVHD treatment responses, immune recovery & correlative biomarker/ microbiota studies are ongoing.

Incidence of Pulmonary GVHD Is Increased and Incidence of Late Infection and Pulmonary Embolism Is Comparable Comparing Adult MRD Versus Cord Transplant Patients

Pulmonary GVHD (bronchiolitis obliterans organizing pneumonia (BOOP) and bronchiolitis obliterans (BO)), infection, and pulmonary embolism (PE) are the most common late pulmonary complications of allogeneic stem cell transplantation. We compared outcomes of these pulmonary complications among adult patients undergoing first double unit cord blood transplant (CBT) or matched related donor transplant (MRD) at our center between July 2013 and July 2018. Patients experiencing death or relapse before 100 days post-transplant were excluded; 153 CBT and 77 MRD patients were included. Only events occurring after day 100 were included. Patient details are summarized in Table 1. Incidence of complications were described using the Kaplan-Meier method and comparisons were made using a log-rank test. Incidence of BOOP and BO were higher in the MRD group versus the CBT group (for BOOP p=0.004, 2 yr incidence 15% for MRD and 3% for CBT; for BO P=0.015 2 yr incidence 9% for MRD and 1% for CBT.) Incidence of first infection and PE were comparable for each group (for first infection p=0.65, 2 yr incidence 16% for MRD and 20% for CBT; for PE 0=0.74 2 yr incidence 3% for MRD and 7% for CBT.) 10 CBT (7%) and 6 MRD patients (8%) had more than one infection. During the period reviewed, 9 CBT (6%) and 6 MRD (8%) patients died of issues related directly to these pulmonary complications. MRD patients have a higher rate of BO and BOOP than CBT patients and a comparable rate of late infections and PE. Comprehensive review all pulmonary outcomes for MRD and CBT patients undergoing transplant at our center, including early complications, is ongoing.

Addition of Tocilizumab to Cyclosporine/ MMF for Acute Graft-Vs-Host Disease (aGVHD) Prophylaxis in Adult Double Unit Cord Blood Transplant (dCBT) Recipients: Promising Preliminary Results of a Phase II Clinical Trial.

Background Adult dCBT recipients are at significant risk for aGVHD especially involving the GI tract. Investigation of augmented prophylaxis is indicated. Methods Based on adult donor allograft data (Kennedy et al, Lancet 2015; Drobyski et al Haematologica 2018), we are investigating the addition of a single dose of tocilizumab 8 mg/kg (cap 800mg) on day -1 to standard cyclosporine/ MMF starting day -3 in adult patients (pts) with hematologic malignancies undergoing intermediate intensity Cy 50/ Flu 150/ Thio 10/ TBI 400 dCBT. We report an interim analysis of the first 16 pts of a 27 pt phase II trial (NCT03434730). All pts received standard bacterial/ fungal prophylaxis & Letermovir if CMV seropositive. Results 16 pts [median 50 years (range 27-59), median 85 kg (range 59-125), 6 AML, 5 ALL, 2 MPAL, 2 MDS, 1 CML, median aaHCT-CI of 3 (range 0-6)] received double-unit CB grafts with a median CD34+ cell dose of 1.33 × 105/kg/unit (range 0.24-3.83) & median unit-recipient 8-allele HLA-match of 5/8 (range 3-6). Pt outcomes are shown (Table). All (100%) pts engrafted with a median neutrophil recovery of 26 days (range 19-40). 94% of pts engrafted platelets (median 44 days, range 32-59). All pts had single unit dominance (median day 28 blood winning unit chimerism 100% (range 58-100). Prior to engraftment, 11/16 (69%) had no neutropenic fever, 3/16 (19%) pts had fever with bacteremia, 1 pt (6%) had febrile neutropenia (duration 2 days) responding to antibiotics, & 1 pt (6%) had initial fever due to bacteremia followed by fever/ rash attributed to pre-engraftment syndrome (PES). An additional 2 pts developed rash without fever prior to engraftment attributed to PES. Thus, a total of 3/16 (19%) pts had PES (onset ranging 12-14 days). Ten pts developed grade II aGVHD (median onset 45 days, range 26-81) for a cumulative incidence of 63% (95%CI: 33-82). This was limited primarily to skin &/or the upper gut with one pt having stage I lower GI. No pt has developed grade III-IV aGVHD & no pt has had stage II-IV lower GI aGVHD to date (Figure). With a median follow-up of 147 days (range 74-214), 15 pts are alive & disease-free (1 death due to HHV-6 pneumonitis). Conclusions Preliminary data suggests tocilizumab is safe with no adverse effects upon engraftment or unit dominance. Tocilizumab mitigates PES (expected incidence 65% in dCBT controls, Bhatt et al, ASBMT 2019). Expected days of febrile neutropenia were also reduced especially given the prolonged neutrophil recovery. Notably, lower gut aGVHD appears markedly reduced with no cases of grade III-IV aGVHD or aGVHD mortality to date. Our findings appear consistent with the published adult donor data. Overall, one tocilizumab dose has improved the early post-dCBT morbidity & investigation of this promising & potentially cost-effective approach is ongoing.

Pre-Engraftment Syndrome (PES) Is Frequent in Double Unit Cord Blood Transplantation (dCBT) Recipients and Is Potentiated By the Addition of Haplo-Identical CD34+ Cells

Introduction PES is common after dCBT. Manifestations have been described but severity & risk factors are not fully established. Methods We analyzed the incidence, manifestations, severity & risk factors of PES in adult dCBT recipients transplanted 8/2012-12/2017 for hematologic malignancies/ severe aplastic anemia with Cy 50/ Flu 150/ Thio 5-10/ TBI 400 & CSA/ MMF. Standard PES therapy was IV methylprednisolone (IV MP) 1 mg/kg/day x 3 days. Results 133 1st allograft dCBT recipients (median 49 years, range 21-65) were analyzed. Patients (pts) most commonly had acute leukemia (n = 98, 74%). The median TNC cell doses were 2.4 × 107/kg/unit (range 1.2-6.0). The median unit-recipient HLA-match was 5/8 (range 3-7); the median unit-unit HLA-match was 4/8 (range 0-8). 71 (53%) pts also received haploidentical CD34+ cells. 96% of pts engrafted with CB. Overall, 98 pts developed non-infectious sustained fevers ≥ 38.5°C consistent with PES for a cumulative incidence of 74% (95%CI: 65-80) by 21 days post-dCBT (Table). The median onset was 10 days (range 6-21) post-dCBT with a median temperature at onset of 38.9°C degrees (range 38-39.8). Nearly all (94, 95%) of PES pts required IV MP therapy. PES associated rash within the 1st 72 hrs only occurred in a minority of pts (incidence 24%; 95%CI: 17-32). Weight gain > 5% from the baseline 24 hrs prior to PES onset (incidence 18%; 95%CI: 12-25) was correlated with the development of hypoxia requiring oxygen (incidence 20%; 95%CI: 14-28). Incidence of PES associated renal impairment (gr 2-3 AKI) was low overall at 2% (95%CI: 0-8). No pt had hypotension. Concurrent bacteremias were treated in 2 pts but clinical manifestations/ therapy response was consistent with PES. Median time to MP therapy was 1 day (range 0-12). Therapy response was rapid (median 1 day, range 1-9). The median MP duration was 3 days (range 3-14). 7/94 (7%) PES pts [7/133, 5% of entire cohort) required ICU care; this correlated with delayed therapy [median MP start 4 days (range 0-5)]. 30 (32%) pts required a 2nd MP course. Addition of haploidentical cells was associated with a higher PES incidence & severity as measured by weight gain & hypoxia (Table). There was no association with age, disease (acute leukemia vs other), dominant unit-recipient or unit-unit HLA-match or total TNC infused dose (split at median). Conclusions PES is common after dCBT. It should be promptly treated with IV MP without waiting for results of infectious work-up as delay can be associated with severe capillary leak syndrome & multi-organ failure. The worse manifestations in haplo-dCBT recipients supports PES being mediated by GVG/ GVH reactions & an associated cytokine storm. This is highly relevant to CBT platforms that involve infusion of multiple donors including 3rd-party products. We are now investigating day -1 tocilizumab 8 mg/kg in dCBT recipients with the aim to abrogate PES & acute GVHD (Politikos et al, ASBMT 2019).

Engrafting Unit-Recipient HLA-Allele Mismatch Is Not Associated with an Increased Risk of Transplant-Related Mortality (TRM) or Inferior Progression-Free Survival (PFS) after Double Unit Cord Blood (CB) Transplantation (dCBT) in Adults with Hematologic Malignancies

Background The less stringent CB HLA-match requirement extends allograft access. The extent to which HLA-mismatch can adversely affect CBT outcomes & the maximum permitted HLA-mismatch, however, are not established. Methods We analyzed TRM, relapse & PFS after cyclophosphamide 50 mg/kg, fludarabine 150 mg/m2, thiotepa 5-10 mg/kg, 400 cGy TBI dCBT in adults with hematologic malignancies. Eligible patients (pts) were 1st allograft recipients ≤ 65 years transplanted 1/2014 - 12/2017. TNC & CD34+ dose were typically given priority over HLA-match in unit selection. Results 102 pts [51 (50%) non-European, median 50 years (range 21-65), median 80 kg (range 36-137), 71 acute leukemias & 17 CML/ MPD/ MDS (all ≤ 10% blasts pre-CBT), 14 NHLs] received double unit grafts. The majority of units [181 (89%)] were 4/6 matched. At high resolution the unit-recipient 8-allele HLA-match was a median of 5/8 (range 3-7). The median infused viable CD34+ dose was 1.3 × 105/kg/unit (range 0.2-8.6). 48 (47%) pts also received haplo-identical CD34+ cells as a myeloid bridge. 97% (95%CI 90-99) engrafted with CB. All pts had a dominant unit (1 early death excluded). Day 180 grade II-IV & III-IV aGVHD were 89% (95%CI 81-94) & 23% (95%CI 15-31), respectively. 1-yr cGVHD was 4% (95%CI 1-9). Day 180 TRM was 9% (95%CI 4-15) & 14% (95%CI 8-22) at 2 yrs. 11% (95%CI 6-19) of pts relapsed by 2 yrs. With a median survivor follow-up of 2 yrs 3 months (range 6 - 51), 2-yr OS is 82% (95%CI 75-90) & PFS is 74% (95%CI 66-84). Causes of death were transplant-related in 16 pts [6 aGVHD, 4 infection (2 viral, 1 bacterial, 1 fungal), 4 organ failure, 1 graft failure, 1 unknown] & relapse in 4 pts. By 2-yrs, engrafting unit-recipient HLA-allele match had no association with TRM or PFS ( Figure ). Analysis of the association between recipient/ graft variables & TRM/ relapse/ PFS are shown ( Table ). Pts In multivariate analysis, aaHCT-CI was associated with worse PFS [HR 2.82 (1.28-6.25) if score 4-9 vs 0-3, p = 0.01]; neither rDRI [HR 1.21 (0.54-2.69) if high-very high vs low-intermediate, p = 0.64] nor engrafting unit-recipient HLA-match [HR 2.06 (0.89-4.74) if 5-7/8 vs 3-4/8 matched (p = 0.09] were significant. Conclusions dCBT with mismatched units facilitates allograft access extension & has a high PFS. While further investigation of the CD34+ dose – HLA-mismatch interaction is required, this supports unit selection prioritizing quality & dose in adults to optimize engraftment. Finally, this data supports CBT in younger pts, those with low 0-3 aaHCT-CI, or high rDRI given the high 2-yr PFS in such pts.

Double-Unit Cord Blood (CB) Transplantation (dCBT) Supplemented with Haplo-Identical CD34+ Cells May be Associated with Enhanced Neutrophil Recovery but Successful Myeloid Bridging Is Strongly Influenced By Haplo CD34+ Cell Dose and Haplo-Winning CB Unit HLA-Match

Background While dCBT is associated with high rates of sustained donor engraftment, delayed neutrophil recovery is frequent. Methods We investigated the addition of CD34+ selected haplo-identical PBSC to double unit CB grafts (haplo-dCBT) in patients (pts) undergoing ablative dCBT with the aim to provide a myeloid bridge prior to CB engraftment. ATG was not used due to its adverse effects on immune recovery & potential to increase relapse risk. Results 78 adult pts [median 48.5 years (range 21-68), median 82 kgs (range 48-138), 3 with prior allografts, 54 (69%) acute leukemias or 10 (13%) MDS/ MPN (all 4/8 haplo-recipient HLA-match & ≥ 3/8 winning unit-haplo HLA-match were associated with higher likelihood of bridging (Table 2). Haplo CD34+ dose & winning unit-haplo HLA-match remained significant in multivariate analysis. While there was no difference in the day 100 TRM in the 34 optimal bridge pts vs others [9% (95%CI 2-21) vs 15% (95%CI 6-27), p = 0.388], optimal bridge pts had earlier hospital discharge [28.5 (range 20-60) vs 36 days (range 28-98)]. Conclusions ATG-free haplo-dCBT can speed neutrophil recovery but this benefit is highly variable, and a successful myeloid bridge is not guaranteed due to early haplo rejection. For these reasons our data does not support pursuit of haplo-dCBT. It is likely that similar limitations will also apply to ATG-free single CB unit-haplo transplants. Our findings also have significance for strategies that combine unmanipulated CB with third-party or ex vivo expanded T-cell depleted products given higher CD34+ cell dose & better HLA-match to the unmanipulated CB unit could improve successful bridging.