Double Cord Blood Transplantation Research Articles

Cord blood transplantation for adult mature lymphoid neoplasms in Europe and Japan

AbstractTo clarify the different characteristics and prognostic factors of cord blood transplantation (CBT) in adult patients with lymphoid neoplasms in Europe and Japan, we conducted a collaborative study. Patients aged 18-75 years receiving their first CBT (Europe: single CBT, n = 192; double CBT, n = 304; Japan: single CBT, n = 1150) in 2000-2017 were analyzed. Fewer patients with Hodgkin lymphoma (Europe vs Japan, 26% vs 5%), and older patients (≥50 years) (39% vs 59%) with a higher refined disease risk index (rDRI) (high-very high: 49% vs 14%) were included in the Japanese registry. High-very high rDRI was associated with inferior overall survival (OS) (vs low rDRI, Europe: hazard ratio [HR], 1.87; P = .001; Japan: HR, 2.34; P < .001) with higher progression/relapse risks. Total body irradiation (TBI)–containing conditioning contributed to superior OS both in Europe (vs TBI–reduced-intensity conditioning [RIC], non-TBI-RIC: HR, 1.93; P < .001; non-TBI–Myeloablative conditioning [MAC]: HR, 1.90; P = .003) and Japan (non–TBI-RIC: HR, 1.71; P < .001; non–TBI-MAC: HR 1.50, P = .007). The impact of HLA mismatches (≥2) on OS differed (Europe: HR, 1.52; P = .007; Japan: HR, 1.18; P = .107). CBT for lymphoid neoplasms, especially in those with high rDRI showed poor outcomes despite all the different characteristics in both registries. TBI should be considered in conditioning regimens to improve these outcomes. The different impacts of HLA mismatches call attention to the fundamental differences among these populations.

Mismatched Unrelated Donor Transplantation with Ptcy-Based Gvhd Prophylaxis Is Associated with Better Survival Than Double Unit Umbilical Cord Blood Transplantation in Patients with AML in First CR: A Study from the ALWP of the EBMT

Background: The best donor option for acute myeloid leukemia (AML) patients lacking an HLA-matched donor has remained unknown. The recently reported BNT CTN 1101 trial observed higher non-relapse mortality (NRM) and lower overall survival (OS) in patients randomized to double-unit unrelated umbilical cord blood transplantation (dCBT) in comparison to those randomized to HLA-haploidentical bone marrow transplantation with post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis 1. In addition, recent registry studies observed at least as good transplantation outcomes in AML patients given grafts from 9/10 HLA-matched unrelated donor (UD 9/10) with PTCy-based GVHD prophylaxis as those given grafts from HLA-haploidentical donors 2,3. These observations prompted us to perform a retrospective registry study comparing hematopoietic cell transplantation (HCT) outcomes between UD 9/10 and dCBT. Methods: Inclusion criteria consisted of adult patient, AML in CR1 at transplantation, either peripheral blood stem cells (PBSC) from UD 9/10 with PTCy as GVHD prophylaxis or dCBT, transplantation between 2013 and 2021, and no in vivo T-cell depletion. Results: A total of 208 dCBT patients and 270 UD 9/10 allo-HCT were included. The 180-day cumulative incidence of grade II-IV acute GVHD was 29% in UD 9/10 versus 44% in dCBT recipients (P=0.001). The 2-year cumulative incidences of relapse and of NRM were 23.5% and 12.5%, respectively, in UD 9/10 recipients versus 27% (P=0.39) and 18% (P=0.07), respectively in dCBT recipients. Two-year OS and LFS were 70% and 64%, respectively, in UD 9/10 recipients versus 60% (P=0.016) and 55% (P=0.028), respectively in dCBT recipients. In multivariate analyses, in comparison with UD 9/10 recipients, dCBT patients had a higher non-relapse mortality (HR=2.35, 95% CI: 1.23-4.48; P=0.01), comparable relapse incidence (HR=1.12, 95% CI: 0.67-1.86; P=0.66), lower leukemia-free survival (HR=1.5, 95% CI: 1.01-2.23; P=0.047), and lower overall survival (HR=1.66, 95% CI: 1.08-2.55; P=0.02). Conclusions: In summary, our results suggest that transplantation outcomes are better with UD 9/10 with PTCy-based GVHD prophylaxis than with dCBT for AML patients in CR1. These data might support the use of UD 9/10 with PTCy-based GVHD prophylaxis in AML patients lacking an HLA-matched donor. References Fuchs, E. J. et al. Double unrelated umbilical cord blood vs HLA-haploidentical bone marrow transplantation: the BMT CTN 1101 trial. Blood 137, 420-428 (2021).Baron, F. et al. Comparison of HLA-mismatched unrelated donor transplantation with post-transplant cyclophosphamide versus HLA-haploidentical transplantation in patients with active acute myeloid leukemia. Bone Marrow Transplant. 57, 1657-1663 (2022).Battipaglia, G. et al. Post-transplant cyclophosphamide in one-antigen mismatched unrelated donor transplantation versus haploidentical transplantation in acute myeloid leukemia: a study from the Acute Leukemia Working Party of the EBMT. Bone Marrow Transplant. 57, 562-571 (2022).

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.

Impact of Allele-Level HLA-Matching on Outcomes after Double Cord Blood Transplantation in Adults with Malignancies.

In single unrelated cord blood transplantation (UCBT), an increasing number of HLA allele mismatches (MM) has been associated with inferior overall survival (OS) attributed to higher transplant-related mortali-ty (TRM). Previous studies on the role of allele-level HLA matching following double UCBT (dUCBT) showed conflicting results. Herein we report the impact of allele-level HLA matching on outcomes of a large dUCBT cohort . We included 963 adults with hematologic malignancies, with available allele-level HLA matching at HLA-A, -B, -C and -DRB1, receiving dUCBT between 2006-2019. Assignment of donor-recipient HLA match was performed considering the unit with the highest disparity with the recipient. 392 patients received dUCBT with 0-3 and 571 with ≥4 allele MM. Day-100 and 4-year TRM were 10% and 23%, for recipients of dUCBT with 0-3 MM compared to 16% and 36% for those with ≥4 MM (HR 1.58, p=.002; and HR 1.54, p=.002), respectively. Higher degree of allele MM was also associated with worse neutrophil recovery and lower incidence of relapse; no significant effect on graft-versus-host disease was observed. Patients receiving units with 0-3 MM had a 4-year OS of 54% versus 43% for those with ≥4 MM (HR 1.40, p=.005). The inferior OS associated with higher HLA disparity was only partially mitigated by increased total nucleated cell doses. Our results confirm that allele-level HLA typing is a significant factor for OS following dUCBT and units with ≥4 MM (≤4/8 HLA-matched) should be avoided if possible.

Long-Term Persistence of Mixed Full Donor Chimerism after Double Cord Blood Transplantation. Example of Tolerance in Allogeneic Hematopoietic Cell Transplantation Setting

Background Double umbilical cord blood transplantation (UCBT) is recognized as an alternative source of hematopoietic donor cells for allogeneic haematopoietic cell transplantation (HCT), particularly in adult setting. Because of important infectious complications, UCBT are rarely utilized and more and more replaced by haplo-identical cell transplantation for adult patients. Nevertheless, some very good results were observed with a long-term follow-up. In most cases, after several weeks, one unit turns immuno-dominant and thus, the second one is no longer detected. Patients and Methods We reported three cases of long-term mixed full donor chimerism associated to documented complete remission of haematological malignancies after double UCBT. The indications of UCBT were acute myeloid leukaemia for 2 patients [1 AML MRC (female of 65 years) and 1 transformation of Fanconi disease (female of 20 years)] and acute lymphoid leukaemia for 1 patient (female of 22 years). AML received a reduced intensity and ALL a standard conditioning. The general characteristics of recipients and UCB are presented in Table 1. The chimerism follow-up were performed by STR and qPCR techniques with a sensitivity of 5 and 0.2% respectively. Early after transplantation, patient 1 developed a grade I graft-versus-host disease (GVHD), patient 3 a grade II GVHD treated by extracorporeal photopheresis, and patient 2 did not develop any GVHD. The follow-up of these patients were 14, 13 and 8 years respectively after UCBT without any episodes of relapse and at the last follow-up still a total donor mixed chimerism. Results Results of STR and qPCR after transplantation early revealed the presence of the two transplant units with a total donor chimerism (Table 1). Patient 1 presented a perfectly balanced chimerism with 54 % of the majority unit. The other two patients showed an imbalance in the proportions of their two UCB with 83% and 72% of their majority units respectively but a long-term persistence of 17% and 28% of their second UCB. The study of total blood chimerism during their follow-up revealed a stabilization of the proportions of the two units during the first year (Figure 1). A more in-depth study of circulating cell subsets (CD3+, CD15+ and CD19+) chimerism of patient 1 revealed a very strong initial imbalance of the two units, which ended up being balanced at two years after transplantation. In the other two patients, the respective study of CD3+ and CD33+ cells showed a stabilization of the two unit percentage around six months after transplantation. At five years after transplantation, patient 1 had an in-depth study of circulating cells sub-populations (CD4+ T lymphocytes, CD8+ T lymphocytes, B-lymphocytes, natural killer cells, regulatory T cells, monocytes, naive CD4+ and CD8+ T lymphocytes) by flow cytometry, after separation of the two units cells by specific monoclonal antibody directed against HLA mismatching antigen (HLA-A2). This analysis revealed an imbalance in the percentage of NK and monocytes. The immune-dominant unit had three times more NK cells than the other one and this imbalance ratio increased by twenty-two for monocytes. A co-culture study of the CD4+ lymphocytes demonstrated a lack of reactivity of both unit against the other one but a normal ability to react against an allogeneic third-part cell. Conclusions This expected tolerance, highlighted in co-culture experience, showed rare cases of naturally induced graft tolerance. A study of tolerance markers and underlying mechanisms in these special cases of persistent mixed full donor chimerism is necessary to acquire better knowledge and to define more investigations ways for the induction of tolerance in patients receiving hematopoietic cell transplantation or organ transplantations. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of Allele-Level HLA-Matching on Outcomes after Double Unrelated Cord Blood Transplantation in Adults with Malignant Diseases

Introduction: In single unrelated cord blood transplantation (sCBT), an increasing number of HLA-mismatches (MM) has been associated with inferior overall survival (OS) attributed to higher transplant-related mortality (TRM). These findings have prompted current guidelines to endorse high resolution HLA typing in the selection of CB (cord blood) units, including double CBT (dCBT). However, a comprehensive appraisal of the effect of allele-level HLA matching following dCBT was likely hindered by the relatively small sample sizes in previous studies. Herein we aimed to analyze the impact of allele-level HLA-matching on outcomes of a large cohort of dCBT recipients to improve CB unit selection and further explore the unique dCBT biology. Methods: We included patients ≥18 years-old receiving a dCBT between 2006-2019 with the availability of HLA typing minimally at HLA-A, -B, -C at the antigen-level and HLA-DRB1 at the allele-level for the recipient and both CB units. A validated high-resolution imputation tool, HaploStats, was used to adjudicate allele-level match status for a subset of cord and recipient pairs (n = 173) having only antigen-level typing at HLA-A, -B or -C. A sensitivity analysis for OS was performed excluding imputed cases, and results were unchanged. HLA matching was classified according to the CB unit with the greatest degree of HLA mismatch with the patient, meaning that only the most mismatched unit was considered and that the interunit matching was not considered. Continuous covariates were dichotomized to find an optimal cutoff value by using the Contal-O'Quigley method, except for cryopreserved CD34 and total nucleated cell (TNC) count, whose cutoffs were based on previous findings reported by our group. Pairwise comparisons of the numbers of allele MM showed that receiving units with ≥4 MM had the highest negative impact on OS. Cox and Fine-Gray regression models were built for the different outcomes using the backward elimination method (p<.05 to stay). Results: 963 patients met the eligibility criteria, of which 392 received at least one CB unit with 0-3 allele MM while 571 with ≥4 allele MM. Of those receiving at least one unit with ≥4 allele MM, 18% had a maximum HLA disparity of 5/6 at lower HLA-typing resolution, 69% of 4/6 and 13% of ≤3/6. Median age at dCBT was 49 years old. Acute leukemia and myelodysplastic syndrome (MDS) accounted for 70% of the cases. There was a larger proportion of patients receiving CB units with fewer allele MM after 2012. Other patient-, disease- and CB unit-related characteristics are summarized in Table 1. The day-42 cumulative incidence of neutrophil recovery was 83% (95%CI 81-85). The number of allele MM had no significant impact on neutrophil recovery (≥ 4 MM vs 0-3 MM, multivariate HR 0.94 [0.80-1.11], P=.46). The cumulative incidence of TRM at 4 years was 36% (95% CI 32-40) for patients receiving CB units with ≥4 MM vs. 23% (95% CI 19-28) for those with 0-3 MM (multivariate HR 1.58 [95%CI 1.18-2.11], P=.002] - Fig. 1A). Infectious complications were the most frequent cause of TRM in the group receiving dCBT with ≥ 4 allele MM (40%). Relapse, grade II-IV/III-IV acute and chronic GVHD were not significantly different between the two groups. Patients receiving CB units with 0-3 allele MM had a 4-year survival of 54% (95%CI 49-59) compared to 43% (95%CI 39-47) for those receiving units with ≥4 allele MM (multivariate HR 1.40 [1.11-1.78], P=.005 - Fig. 1B). The inferior OS associated with higher allele HLA disparity was only partially mitigated by increasing the TNC count in multivariate analysis (0-3 MM + TNC ≤ 3.9x10ˆ7/kg vs.0-3 MM + TNC > 3.9x10ˆ7/kg, HR 1.50 [0.97-2.32], P=.07; ≥4 MM + TNC > 4.9x10ˆ7/kg vs. 0-3 MM + TNC > 3.9x10ˆ7/kg, HR 1.42 [1.06-1.89], P=.02; ≥4 MM + TNC ≤ 4.9x10ˆ7/kg vs. 0-3 MM + TNC > 3.9x10ˆ7/kg, HR 1.66 [1.24-2.22], P=<.001 - Fig. 1C). Discussion: Our results confirm that allele-level HLA typing is a significant factor for OS following dCBT. The inferior OS associated with the increasing number of allele-level MM was driven by higher TRM. Selection of CB units with 0-3 allele-level MM is recommended. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Unrelated Cord Blood Transplantation in Children, Adolescents, and Young Adults with Acute Leukemia or Myelodysplastic Syndrome: A Retrospective Comparative Study from the French Society for Bone Marrow Transplantation and Cellular Therapy Between Real-World Data and Previously Reported Results of a Randomized Clinical Trial

We previously reported results of a French randomized clinical trial (RCT) comparing the risk of transplantation failure (including transplant-related mortality [TRM], engraftment failure, and autologous recovery) in single and double unrelated cord blood (UCB) transplantation in children and young adults with hematologic malignancies. We concluded that single-UCB transplantation with an adequate cell dose is the standard of care, leading to a 70% two-year overall survival (OS). It remains unclear, however, whether RCT participants have better outcomes than comparable patients not treated in the setting of a clinical trial. We compared the characteristics and outcomes of RCT participants (n=137) to a Francophone population-based registry of patients (real-world [RW] group) fulfilling the eligibility criteria used in our RCT and transplanted with 1 or 2 UCB units after a myeloablative conditioning (MAC) regimen between March 2015 (end of inclusion in the RCT) and February 2019 (n=141). The primary endpoint was the 2-year cumulative incidence (CI) of transplantation strategy failure as defined in our RCT. The 2 groups were comparable in terms of age, disease distribution, hematologic status at transplantation, follow-up, and HLA compatibility. Patients in the RW group were more likely to be transplanted with a single-unit UCB (87.9% versus 49.6%, P< .001) and to receive a radiation-free regimen (39.0% versus 60.6%, P< .001). The 2-year CI of transplantation strategy failure, TRM, and the 2-year probability of OS were similar between the 2 groups, although the relapse risk was higher in the RW group (31.2% ± 7.7% versus 20.4% ± 6.8%, P= .01), resulting in a significantly lower disease-free survival (DFS) (59.2% ± 8.4% versus 69.3% ± 8.0%, P= .047). This difference remained statistically significant only in the group of patients with acute lymphoid leukemia (ALL) who did not receive the conditioning regimen recommended by the RCT (fludarabine 75 mg/m2, total body irradiation 12 Gy, cyclophosphamide 120 mg/kg). The results of our RCT appear to be reproducible in real-world conditions, provided that the same cord blood selection criteria and conditioning regimen are used.

UM171 Expansion of Cord Blood Improves Donor Availability and HLA Matching For All Patients, Including Minorities

Cord blood (CB) stem cell transplantation offers a greater tolerance to HLA mismatches compared to adult-derived stem cell transplants (i.e., bone marrow or peripheral blood stem cells). Indeed, 4/6 or 5/8 HLA-matched CB transplantations are regularly performed for patients lacking a matched unrelated donor. Unfortunately, most banked CB units contain a stem cell dose that is too small to treat adult patients, resulting in only 4% to 5% of available CB units offering an adequate cell dose for prompt engraftment for adult patients. Ex vivo stem cell expansion appears to be an attractive strategy to circumvent this cell dose issue, while also enabling the selection of better HLA-matched CB units. In this study, we retrospectively performed HLA matching simulations to assess how the minimal cell content requirements associated with UM171 CB expansion may improve usability of existing CB unit inventories and donor availability for patients of different races and ethnicities. We analyzed a dataset of 58,971 adults for whom a donor search was initiated through the National Marrow Donor Program Be The Match registry against 142,942 CB units from major U.S. public CB banks listed on the Be The Match registry. Our results show that by enabling selection of smaller CB units, UM171-expanded CB transplantation increases donor availability from 72% to 84% for all patients compared to single unmanipulated CB transplantation. Furthermore, the low cell dose criteria for UM171-expanded CB also increases donor availability compared to double CB transplantation, while enabling better HLA matching between donor and recipient. UM171 expanded CB appears particularly beneficial for racial and ethnic minority patients as CB availability increases from 53% to 78% for African Americans, from 66% to 85% for Hispanics, and from 68% to 84% for Asians and Pacific Islanders, compared to single unmanipulated CB transplantation. In addition, UM171 expansion dramatically improves usability of CB units currently in inventories, as only 4.3% and 0.6% of banked CBs have sufficient cell doses for a 70 kg and 100 kg patient, respectively. UM171 raises this proportion to 53.8% and 20.2%, respectively, making CB banks potentially more cost effective. In conclusion, UM171 expansion allows the use of smaller CB units while also improving access to transplantation for racial and ethnic minorities.

Durable outcomes of double cord blood transplantation in adults with acute lymphoblastic leukemia: high-risk features for early and long-term mortality.

Background:Cord blood transplantation (CBT) has been reported as an acceptable option with comparable outcomes to conventional donors in adults with acute lymphoblastic leukemia (ALL). We aimed to analyze the long-term CBT outcomes and risk factors for early and long-term mortalities.Methods:Between 2006 and 2020, 112 patients (median age: 35 years; 62 Ph-negative ALL and 50 Ph-positive ALL) were treated with double CBT. Conditioning regimen consisted of total body irradiation (12 Gy) plus cytarabine (9.0 g/m2) plus fludarabine (150 mg/ m2), and graft-versus-host disease (GVHD) prophylaxis was attempted by administering tacrolimus plus mycophenolate mofetil.Results:The median time for neutrophil and platelet recovery was 25 days (range: 5–59 days) and 34 days (range: 7–185 days), respectively. The cumulative incidence of acute GVHD at 1 year was 43.8%, and the incidence of acute GVHD with grades III–IV was 8.9%. The overall cumulative incidence of chronic GVHD was 22.0%, and the incidence of moderate to severe chronic GVHD was 8.5%. After a median follow-up of 60.1 months (range: 5.7–181.3 months), the 5-year cumulative incidence of relapse (CIR) and nonrelapse mortality (NRM) were 15.9% and 28.5% (9.7% and 27.2% for CR1), respectively, and the 5-year overall survival (OS) was 57.9% (66.5% for CR1). In multivariate analysis of 88 patients receiving double CBT in CR1, delayed CR1 was related to high CIR, and age older than 40 years was associated with high NRM and early mortality. Unexpectedly, Ph-positive ALL with MRD had a higher NRM and early mortality than Ph-negative ALL and Ph-positive ALL without MRD subgroups, possibly due to delayed neutrophil and platelet recovery.Conclusion:Our data suggest that double CBT for adult ALL in CR1 has a greater benefit in younger patients and in patients with Ph-positive ALL without MRD or Ph-negative ALL.

Engraftment of Double Cord Blood Transplantation after Nonmyeloablative Conditioning with Escalated Total Body Irradiation Dosing to Facilitate Engraftment in Immunocompetent Patients

To improve accrual to a randomized clinical trial of double unrelated cord blood (dUCB) versus HLA-haploidentical bone marrow (haplo-BM) transplantation, patients with less previous therapy and potentially greater immunocompetence were enrolled. To reduce the risk of graft rejection, patients randomized to receive dUCB received a higher dose of total body irradiation (TBI) (300 cGy versus 200 cGy). In this study, we investigated whether the inclusion of recipients of 300 cGy TBI influenced the trial outcomes. This was a secondary analysis of dUCB recipients, 161 who received TBI 200 cGy and 18 who received TBI 300 cGy. Fine and Gray regression was used to evaluate the effect of TBI dose on relapse and nonrelapse mortality (NRM). Cox regression was used for evaluation of neutrophil engraftment and overall survival. Patient characteristics were similar in the 2 TBI dose subgroups. The probability of neutrophil engraftment was 100% for patients who received TBI 300 cGy versus 91% (95% confidence interval, 86% to 95%) for those who received TBI 200 cGy (P=.64), which was similar after regression analysis adjusting for age, total infused nucleated cell dose, HLA matching to the patient, and comorbidity score. We also investigated whether the lower survival probability and higher cumulative incidence of NRM observed in the dUCB arm of BMT CTN 1101 could be influenced by the TBI 300 cGy patient subset. There was no significant difference in the 1-year incidences of NRM and relapse or in 1-year survival, even after adjustment in multivariate analysis. Patients in BMT CTN 1101 who received TBI 300 cGy and 200 cGy had similar engraftment and early mortality. We conclude that inclusion of a modified regimen for dUCB transplantation had no demonstrable influence on this large randomized trial.

Haploidentical Hematopoietic Stem Cell Transplantation With Reduced Intensity Conditioning, T-Cell Replete Grafts and Post-Transplant Cyclophosphamide In Pediatrics

Hematopoietic stem cell transplants (HSCT) may be curative in the treatment of many hematological diseases. However, most patients do not have an HLA- matched sibling donor and an unrelated donor search may be a long process, during which the patients' disease may relapse or progress. Haploidentical transplants with in vitro T-cell depletion have been used in Pediatrics. However, it requires specialized laboratory infra-structure to manipulate the graft, increases the chances of graft failure and relapse. In vivo T-cell depletion can be achieved with the use of post-transplant cyclophosphamide, as reported by the Johns Hopkins and other groups. The results in adults are very promising and comparable to unrelated double cord blood transplants. Children, however, have not been included in any of the reported protocols. Our objective is to report the institutional experience with five consecutive children who received Haploidentical HSCT with reduced intensity conditioning, T-cell replete grafts and post transplant cyclophosphamide. MethodsChildren with clear indication to be treated with HSCT and no HLA-matched related or unrelated donor available were offered compassionate haploidentical transplants. Conditioning comprised cyclophosphamide 14.5 mg/kg/day on days -6 and -5, fludarabine 30 mg/m2/day for five consecutive days starting on day -6, and 2Gy total body irradiation given in a single fraction on day -1. Bone marrow was harvested from donors and infused into recipients on day 0. The target nucleated cell dose was 5 x10(8) mononuclear marrow cells/kg (i.e., peripheral blood count was substracted from the marrow cell count). There was no graft manipulation. GVHD prophylaxis consisted of cyclophosphamide 50 mg/kg IV on days +3 and +4 with 140% Mesna divided on hours 0, 4, 8 and 12 after each dose, Mycophenolate mofetil 15 mg/kg po every 8 hours (maximum 3 g/day) from day +5 to day +35, and tacrolimus from day + 5 to day +180 to keep levels between 5 and 10ng/ml. Prophylactic antimicrobial therapy was started on day +1 and included fluconazole and acyclovir. ResultsFive children with AML and T-ALL (three in CR2; one induction failure and one 4th relapse) were offered haploidentical transplants as the first HSCT. They had a median age of 10 years (4-16) and weight 41 kg (14-67), 2 girls. One graft was a peripheral blood stem cell collection per physician preference. The median total nucleated cell count was 12x10(8)/kg (10-27) with 10x10(6) CD34/kg (5-15). Mucositis was mild in three patients and none of them had sinusoidal obstruction syndrome. All patients engrafted after a median 14 days (13-17) but one of them, in 4th relapse of acute promyelocytic leukemia (APL), rejected the graft. Two of four evaluable patients had mild acute graft versus host disease (GVHD), and one mild chronic GVHD. The patient with APL died of two graft rejections on day+125, one T-ALL relapsed on day+180 and three children are disease-free with excellent clinical status one month to 1.7 years after transplant. We conclude that haploidentical HSCT with post-transplant cyclophosphamide is feasible to treat children without an available matched related or unrelated donor and should be prospectively studied. Disclosures:No relevant conflicts of interest to declare.

Impact of Donor Type on Long-Term Outcomes of Hematopoietic Cell Transplantation for Adult Acute Lymphoblastic Leukemia during First Remission

Background: Standard therapy for adult patients with high-risk acute lymphoblastic leukemia (ALL) consists of hematopoietic cell transplantation (HCT) including autologous-HCT (AUTO) and allogeneic-HCT from a matched-sibling donor (MSD) or matched unrelated donor (MUD). When a conventional donor is not available, HCT from a partially-mismatched unrelated donor (MMUD), cord blood transplantation (CBT) or a familial haploidentical donor (HID) is considered.Aim: Although HCT outcomes of those alternative strategies are advancing with optimization of pre-conditioning regimens with immunosuppressive agents, there are still subjects to debate. We tried to analyze the long-term HCT outcomes according to the donor types including MMUD, double CBT (DCBT) and AUTO as an alternative choice compared to the conventional donors.Methods: We enrolled 661 adult ALL patients who underwent transplantation from 1995 to 2015 in their first remission (CR1). Patients with acute undifferentiated leukemia (AUL, n=5) and mixed phenotype acute leukemia (MPAL, n=52) in the same department were also enrolled and median age was 33 years old (range, 15-65). Before 2010, our treatment strategy for ALL patients in CR1 was to offer allogeneic or autologous HCT according to the donor availability and the presence of high-risk features. After 2010, DCBT was mainly used for patients who were not available with conventional donors. For myeloablative regimen, we administered cyclophosphamide (120 mg/kg) combined with TBI (1320 cGy), and reduced intensity regimen was applied for elderly or patients with comorbid conditions which consisted of fludarabine (150 mg/m2 in total) and melphalan (140 mg/m2 in total). Conditioning regimen for AUTO was TBI (1200 cGy), ARA-C (9g/m2 in total) and melphalan (100mg/m2 in total), and fludarabine (150mg/m2 in total) was used for DCBT instead of melphalan. Graft-versus-host disease (GVHD) prophylaxis was attempted by administering calcineurin inhibitors (cyclosporine for MSD, tacrolimus for others) plus methotrexate or mycophnolate mofetil (for DCBT). Antithymocyte globulin (ATG) was administered to the patients who received grafts from MMUD.Results: Engraftment was successful in all donor types, but neutrophil and platelet recovery was significantly delayed only after DCBT (median recovery for neutrophil and platelet was 25 and 33.5 days respectively). After median follow-up of 80.4 months (range, 6.5-259.1), 7-year OS for the entire 661 patients was 57.0%. In detail, 7-year OS for MSD, MUD, MMUD, DCBT, and AUTO was 56.9%, 56.8%, 62.6%, 65.1% and 48.6% (p=0.423). MSD, MUD and MMUD showed similar relapse rate (27.5%) and non-relapse mortality (NRM) rate (20.6%), but DCBT showed significantly higher NRM rate (29.6%) and AUTO showed significantly higher relapse rate (41.6%). In contrast, DCBT showed lower relapse rate (7.2%) and AUTO showed lower NRM rate (9.7%). Interestingly, 7-year GVHD and relapse-free survival (GRFS) for MSD, MUD, MMUD, and DCBT was 34.1%, 15.0%, 40.9%, and 50.3%, respectively, which was related with higher incidence of severe chronic GVHD in MUD (27.6%) and MSD (14.1%) compared to DCBT (4.2%, p < 0.001). In high-risk subgroup (n=517) including 233 Philadelphia chromosome (Ph)-positive ALL, 7-year OS for MSD, MUD, MMUD, DCBT, and AUTO was 54.9%, 58.1%, 57.8%, 60.7%, and 33.3%, respectively. But the 7-year GRFS for MSD, MUD, MMUD, and DCBT was 30.7%, 14.5%, 35.3%, and 47.7%, respectively, which revealed lower relapse rate (8.7%) and low severe chronic GVHD (2.6%) of DCBT. Multivariate analysis showed that old age and AUTO was related with poor OS in high-risk ALL patients group, and old age and poor-risk karyotype and MUD transplant without ATG were related with poor GRFS.Conclusion: Our data showed similar transplant outcomes of alternative donors such as DCBT and ATG-applied MMUD compared to conventional donor transplants in ALL patients in CR1. In addition, GRFS was rather superior in patients treated with DCBT. Our long-term transplantation outcome results revealed that DCBT might be a good alternative choice for patients who are not available with conventional allogeneic donors, and AUTO may be considered for selected standard-risk patients with low NRM rate without a risk of GVHD. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Durable Outcomes of a Prospective Double Cord Blood Transplantation Trial in Adults with Acute Lymphoblastic Leukemia: Different Outcomes According to the Presence of Philadelphia Chromosome

▪Background: Alternative donor hematopoietic cell transplantation (HCT) is an emerging topic in acute leukemia for patients without matched sibling donors (MSD) or unrelated donors (MUD). Cord blood transplantation (CBT) has been tried for several years in adult acute lymphoblastic leukemia (ALL), and the long-term survival outcomes were comparable to those treated with conventional donor HCT.Aim : We have conducted double CBT (DCBT) in patients without both MSD and MUD for final step, and here, we report our phase 2 study results of clinical outcomes for adult ALL patients treated with DCBT.Methods: During the period between 2005 and 2016, 67 patients (median age, 37 years [range, 16-59 years]; 34 Ph-negative ALL and 33 Ph-positive ALL) were treated with DCBT in CR1 (n=48), CR2 (n=15), and in advanced status (n=4). The indications for DCBT were unavailability of MSD and MUD, agreement for conduction of the transplantation procedure, and proper performance status and organ function to undertake transplantation. The median time to transplant was 198 days (range, 97-1751 days). All patients received DCBT following total body irradiation (TBI) 12.0 Gy plus cytarabine 9.0 g/m2 plus fludarabine 150 mg/m2, and graft versus host disease (GVHD) prophylaxis was attempted by administering tacrolimus plus mycophenolate mofetil. If residual leukemia was detected in the absence of GVHD at 3 months after transplantation, calcineurin inhibitors were rapidly discontinued.Results: The median time for neutrophil and platelet recovery was 25 days (23 days [range, 12-109] for Ph-negative ALL and 26 days [range, 9-59] for Ph-positive ALL, P=0.336) and 34 days (27.5 days [range, 8-123] for Ph-negative ALL and 40 days [range, 9-185] for Ph-positive ALL, P=0.022), respectively. The median CD34+ cell count was 1.21 x 105/kg (range, 0.4-5.85) and TNC was 4.04 x 107/kg (range, 1.58-7.88). In our data, extramedullary involvements were more frequently observed in Ph-negative ALL, while hyperleukocytosis was frequently observed in Ph-positive ALL. Except for 5 patients who died in aplasia, 28 developed acute GVHD (grade II in 23 and grade III in 5), and the cumulative incidence of acute GVHD at 1-year was 41.8%, and the incidence was 9.0% for acute GVHD with grade III-IV. Except for 11 patients with early deaths within 100 days, 17 developed chronic GVHD (11 mild, 4 moderate, 2 severe), resulting in a 4-year cumulative incidence of 23.0% (3.0% for severe chronic GVHD). After a median follow-up duration of 43.7 months (range: 6.5 - 135.3), the 4-year cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 15.6% and 29.6% (7.2% and 29.2% for CR1), respectively, and the 4-year disease-free survival (DFS) and overall survival (OS) rates were 52.5% and 53.9% (62.9% and 65.6% for CR1), respectively. The 4-year CIR, NRM and DFS for Ph-negative and Ph-positive subgroup was 9.6% and 21.6% (P=0.140), 21.0% and 38.9% (P=0.107), and 66.5% and 37.7% (P=0.017). The results of Ph-negative and Ph-positive subgroup in CR1 were 4.8% and 9.9% (P=0.357), 19.1% and 43.0% (P=0.088), and 76.1% and 45.0% (P=0.029), respectively. In multivariate analysis, advanced disease status≥CR2 (HR, 5.61; 95% CI, 1.4-22.2; P=0.014) was related with higher CIR rate, and older age (HR, 3.75; 95% CI, 1.5-9.3; P=0.004) and lower CD34+ cell count (HR, 4.96; 95% CI, 1.1-22.3; P=0.037) were related with higher NRM rates. Overall, Ph-chromosome (HR, 2.65; 95% CI, 1.2-5.8; P=0.016), longer time to transplant (HR, 4.18; 95% CI, 1.9-8.9; P <0.001), lower CD34+ cell count (HR, 3.66; 95% CI, 1.4-9.5; P=0.008) and the absence of acute GVHD (HR, 3.19; 95% CI, 1.4-7.4; P=0.006) were related to poorer DFS.Conclusion: Our data showed that DCBT can be a good alternative choice for providing a long-term disease control for adult ALL patients especially in Ph-negative subgroup. Since Ph-positive subgroup was related with poorer DFS and higher NRM rate in our data, another alternative haploidentical HCT should be considered. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Pre-Transplant Transferrin Saturation Levels As a Predictive Marker for Invasive Fungal Disease Following Allogeneic Hematopoietic Stem Cell Transplantation

▪IntroductionInvasive fungal disease (IFD) following allogeneic hematopoietic stem cell transplantation (allo-HCT) is a well-known, potentially fatal complication. Previous multicenter, prospective observational studies (Girmenia et al., 2014; Sun et al., 2015) have showed that the incidence of IFD after allo-HCT was approximately 9.0%, and risk factors were disease status, development of IFD prior to allo-HCT, alternative donor source (cord blood donor and unrelated donor), diabetes mellitus, prophylaxis of IFD, and acute or chronic graft-versus-host disease (GVHD).Iron has a pivotal role in various types of fungal growth and iron overload impairs the host immune system, leading to IFD. Moreover, some retrospective studies have reported that elevated pre-transplant serum ferritin levels, as a marker of iron overload, might be associated with the development of IFD (Dadwal et al., 2015). Although use of ferritin and transferrin saturation (TSAT) to assess iron status is extremely common, whether pre-transplant TSAT levels might be related to the development of IFD after allo-HCT has not been fully examined.We therefore investigated risk factors of IFD, including iron overload markers such as ferritin and TSAT.Patients and MethodsWe retrospectively analyzed data from consecutive patients undergoing allo-HCT between 1 April 2007 and 31 December 2014. We excluded three patients with active IFD at initiation of the conditioning regimen and two patients undergoing double-cord blood transplantation. Proven or probable IFD cases were defined as IFD. According to our institution guidelines, we administered IFD prophylaxis in all patients. We used Cox proportional hazards models with time-dependent covariates to investigate risk factors for IFD.ResultsA total of 285 patients were eligible. Twenty-one patients developed IFD within 1 year after allo-HCT. Median time to onset was 77 days (range, 8-363 days). Pathogens included Aspergillus (n=12), Candida (n=2), and others (n=7).Notably, none of our participants from HLA-matched or one-antigen mismatched sibling donors developed IFD. The significant univariate risk factors were as follows: disease status (malignancies in complete remission, non-malignancies, and chronic myelogenous leukemia in chronic phase vs. others), donor type (cord blood vs. haploidentical peripheral blood with post-transplant cyclophosphamide (PT-CY) vs. others), GVHD prophylaxis (calcineurin inhibitor (CNI) plus methotrexate (MTX) vs. CNI plus mycophenolate mofetil (MMF) vs. PT-CY vs. others), use of antithymocyte globulin (ATG), TSAT, and hematologic relapse after transplant or refractory at transplant. However, development of IFD prior to allo-HCT, diabetes mellitus, and acute or chronic GVHD were not related to the development of IFD.In the multivariate model considering pre-transplant factors, although use of ATG (hazard ratio (HR) 2.68, 95% confidence interval (CI): 1.07-6.02, P=0.04) was significant, disease status (HR 2.04, 95% CI: 0.78-5.32, P=0.15) and TSAT (HR 1.02, 95% CI: 1.00-1.03, P=0.07) were marginally but significantly associated with development of IFD. Regarding post-transplant factors, in model 2, hematologic relapse after transplant or refractory at transplant (HR 9.63, 95% CI: 3.86-24.02, P<0.01), TSAT (HR 1.02, 95% CI: 1.00-1.04, P=0.03), CNI plus MMF (vs. CNI plus MTX) among GVHD prophylaxis (HR 3.48, 95% CI: 1.07-11.30, P=0.04) were significant. In model 3, hematologic relapse after transplant or refractory at transplant (HR 10.42, 95% CI: 4.21-25.79, P<0.01), TSAT (HR 1.02, 95% CI: 1.00-1.03, P=0.05), and use of ATG (HR 2.72, 95% CI: 1.08-6.82, P=0.03) were significant. Remarkably, 33 of 55 patients who underwent ATG received PT-CY (n=55) to prevent GVHD.ConclusionOur results suggest that pre-transplant TSAT value might be useful for predicting development of IFD. Further investigation might be warranted to validate the generalizability of this marker. DisclosuresHino:Novartis: Research Funding.

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.

Cord blood maternal microchimerism following unrelated cord blood transplantation.

Cord blood transplantation (CBT) is associated with low risk of leukemia relapse. Mechanisms underlying antileukemia benefit of CBT are not well understood, however a previous study strongly but indirectly implicated cells from the mother of the cord blood (CB) donor. A fetus acquires a small number of maternal cells referred to as maternal microchimerism (MMc) and MMc is sometimes detectable in CB. From a series of 95 patients who underwent double or single CBT at our center, we obtained or generated HLA-genotyping of CB mothers in 68. We employed a technique of highly sensitive HLA-specific quantitative-PCR assays targeting polymorphisms unique to the CB mother to assay CB-MMc in patients post-CBT. After additional exclusion criteria, CB-MMc was evaluated at multiple timepoints in 36 patients (529 specimens). CB-MMc was present in 7 (19.4%) patients in bone marrow, peripheral blood, innate and adaptive immune cell subsets, and was detected up to 1-year post-CBT. Statistical trends to lower relapse, mortality, and treatment failure were observed for patients with vs. without CB-MMc post-CBT. Our study provides proof-of-concept that maternal cells of the CB graft can be tracked in recipients post-CBT, and underscore the importance of further investigating CB-MMc in sustained remission from leukemia following CBT.

Impact of detectable measurable residual disease on umbilical cord blood transplantation.

The impact of measurable residual disease (MRD) on cord blood transplantation (CBT) outcomes has remained debated. To address this issue, we assessed the impact of measurable MRD at CBT on outcomes in large cohort of patients with acute leukemia. Inclusion criteria included adult patients with acute myeloid (AML) or acute lymphoblastic leukemia (ALL), CBT as first allo-HCT in first or second complete remission (CR) at transplantation, and known MRD status at the time of CBT. Data from 506 patients were included in the analysis. Among them, 317 patients had AML and 189 had ALL. Positive MRD was reported in 169 (33%) patients while the remaining 337 patients were MRD negative at CBT. At 2 years, relapse incidence was 18% in patients with MRD negativity vs 33% in those with MRD positivity at transplantation (P < .001). Two-year leukemia-free survival (LFS) and overall survival (OS) were 57% and 60%, respectively, in MRD negative patients, vs 38% (P < .001) and 48% (P = .004), respectively, in those with MRD positivity. There was no interaction between the impact of MRD on OS and LFS and diagnosis (ie, ALL vs AML), single or double CBT, and reduced-intensity or myeloablative conditioning. On multivariate analysis, MRD positivity was associated with a higher risk of relapse (HR = 1.8, P = .003), comparable non-relapse mortality (P = .44), worse LFS (HR = 1.4, P = .008) and a trend towards worse OS (HR = 1.3, P = .065). In conclusion, these data suggest that novel strategies that are aiming to achieve MRD negativity at CBT are needed for leukemic patients with positive MRD pre-CBT.

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.

Interrogating the impact of KIR ligand mismatch in engraftment following HLA-disparate stem cell transplantation

The effects of donor-derived natural killer (NK) cell alloreactivity on disease relapse and transplant-related mortality following allogeneic stem cell transplantation have been described while the impact of recipient-derived NK cell alloreactivity on donor engraftment is not well known. Epitopes of HLA Class I molecules act as ligands for NK cell killer immunoglobulin-like receptors (KIR) regulating their cytotoxicity. As such, NK cell alloreactivity is predictable from KIR ligand mismatches between donors and recipients. We analyzed the impact of KIR ligand mismatch (KIR-L-MM) on donor engraftment in 70 cord blood transplants (CBT) and 26 haploidentical transplants (HaploSCT). In CBT, host-versus-graft-directed KIR-L-MM predicted primary graft failure; an effect not mitigated by use of ATG. This trend was most significant with HLA-C KIR-L-MM. In addition, graft-versus-host-directed KIR-L-MM predicted the dominant cord blood unit in double CBT. In the limited HaploSCT cohort, host-versus-graft-directed KIR-L-MM did not predict graft failure. Time to neutrophil engraftment was unaffected by KIR-L-MM in either CBT or HaploSCT. The direction of KIR-L mismatch may be a parameter to consider when selecting CBT units to ensure successful engraftment. The role of KIR-L-MM in CBT and HaploSCT engraftment merits further exploration in a large transplant database.

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.