Total Nucleated Cell Dose Research Articles

Graft Failure Incidence, Risk Factors, and Outcomes in Patients Undergoing Non-Myeloablative Allogeneic Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide

Graft failure (GF) is a major complication of allogeneic hematopoietic cell transplantation (alloHCT) that results in significant morbidity and mortality. Post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis has emerged as an effective regimen across the spectrum of donor-match settings, but few studies have investigated the characteristics of GF in the setting of PTCy-based GVHD prophylaxis. The objective was to detail the incidence, clinical features, risk factors, and outcomes for patients with primary graft failure (PGF) and secondary graft failure (SGF). In this retrospective study at a single institution, 958 consecutive patients undergoing first nonmyeloablative (NMA) alloHCT with PTCy-based GVHD prophylaxis were analyzed. PGF was defined as a failure to achieve an ANC ≥ 500 cells/m3 by day 30 of transplant in the absence of residual disease. SGF was defined as complete loss of donor chimerism after initial engraftment. The incidences of PGF and SGF were 3.8% (n = 37) and 1.8% (n = 17), respectively. Neither PGF nor SGF were associated with HLA disparity. In a multivariate analysis, risk factors for PGF in this cohort included age ≥ 65 (OR 2.4, 95% CI 1.2 to 4.8, P = .0120), an underlying diagnosis of MDS, MPN, or MDS/MPN overlap (OR 2.8, 95% CI 1.4 to 5.7, P = .0050), post-transplant viremia with HHV-6 (OR 2.9, 95% CI 1.5 to 5.7, P = .0030), and low CD34+ dose (OR 0.7, 95% CI 0.5 to 0.9, P = .0080). Patients with PGF had poor overall survival, driven primarily by a high rate of nonrelapse mortality (59% at 36 months). SGF was associated with use of a bone marrow graft source and a diagnosis of Hodgkin lymphoma. Patients with SGF had excellent clinical outcomes with only one of seventeen patients experiencing relapse and relapse-related mortality. The incidence of PGF and SGF in patients receiving NMA conditioning and PTCy is low and is not impacted by HLA disparities between donors and recipients. PGF is more common in recipients with age ≥ 65, a diagnosis of MDS, MPN, or MDS/MPN-overlap, post-transplant HHV-6 viremia, and low CD34+ cell dose. Low total nucleated cell dose is also a risk factor for PGF in patients receiving a bone marrow graft source. Patients who experience PGF have poor outcomes due to high rates of nonrelapse mortality, whereas patients who experience SGF have excellent long-term outcomes.

Regimen Intensity and Age Affect Transplant-Related Outcomes after Matched Related Donor Hematopoietic Cell Transplantation for Sickle Cell Disease: A STAR Registry Study

Background: Serotherapies such as anti-thymocyte globulin (ATG) and alemtuzumab (AL) are added to conditioning chemotherapy for matched related donor (MRD) hematopoietic cell transplantation (HCT) for sickle cell disease (SCD) to facilitate engraftment and prevent graft-vs-host disease (GVHD). Most reports show ATG added to myeloablative (MA) conditioning; however, the use of AL has increased with investigation of different intensity regimens. The aim of this study was to compare HCT-related outcomes across common conditioning approaches to determine superiority. Methods: Retrospective data on baseline patient and HCT characteristics, and HCT outcomes were collected on 352 SCD patients >1 yr post-HCT at 14 Sickle cell Transplant Advocacy and Research (STAR) Alliance centers. Patients with a non-MRD (n=117) or without serotherapy (n=26) were excluded, leaving 209. MA included busulfan (BU) cumulative dose (CD) >8mg/kg or TBI ≥800 cGy; other regimens were termed non-MA (nMA). Summary statistics were presented as median (IQR) for continuous variables and count (%) for categorical variables. Comparisons were made using two-sample hypothesis tests, with p-value of < 0.05 as significant. Time-to-event analyses followed out to 3 years (censored after) and considered 4 outcomes. The first 3 were estimated via the Kaplan-Meier method: (1) overall survival (OS); (2) rejection-free survival (RFS); with death and rejection as events; (3) severe GVHD-free, RFS (GRFS), with death, RFS and severe GVHD as events; and (4) GVHD was estimated by Fine-Gray competing risk analyses, considering death as a competing event and censoring for rejection. Results: 209 patients received MRD HCT with MA+AL (66, 32%), nMA+AL (49, 23%), MA+horse (hATG) (71, 34%), or MA+rabbit (rATG) (23, 11%). Median recipient and donor age at HCT were 8.4yr (IQR: 5.1, 13.0) and 9.3 (5.1, 15.0) and similar across cohorts. MA+AL had a less severe clinical phenotype and nMA+AL had decreased pulmonary function; other baseline characteristics were similar (data not included). Conditioning for MA+AL included bu/cyclophosphamide (cy) (64%) or bu/fludarabine (flu) (36%), for MA+hATG bu/cy (68%) or bu/cy/flu (32%), for MA+rATG bu/cy (83%) or bu/flu (17%), and for nMA+AL melphalan/flu (92%) plus thiotepa (TT) (8%). GVHD prophylaxis was primarily calcineurin inhibitor and methotrexate or mycophenolate mofetil (91.4%). In MA, serotherapy was proximal timed with AL starting day -5 or -6 at a median (IQR) CD of 1.05mg/kg (0.8, 1.5), hATG starting day -3 at 90mg/kg (90), or rATG starting day -5 at 10mg/kg (9.6, 10.1); in nMA, AL was distal timed starting day -22 at a CD of 1.98mg/kg (1.0, 2.8). Stem cells were bone marrow in all, and GCSF primed in 15.4% of MA+AL and 4% of nMA+AL. Total nucleated and CD3 cell doses were similar across cohorts. nMA+AL had shorter median follow up at 2y (1, 4) vs 3y (2, 6) overall. nMA+AL had earliest time to neutrophil engraftment, required less platelet infusions, and had a shorter hospital stay at median 13d (12, 15), 8 infusions (4,13), and 21d (18, 26), respectively. Readmissions were highest for MA+AL at 77% (vs 64% overall). Graft rejection occurred only in nMA+AL (4, 8.2%) and MA+rATG (2, 8.7%). Table 3-yr CI of grade III/IV aGVHD was highest in nMA at 12% (CI: 0.05, 0.23) vs 0-7%, p=0.130 and for any cGVHD was significantly higher in nMA+AL at 33% (0.19, 0.46) vs 9-19%, p=0.001. 3-year OS was excellent at 94.4% (91.3, 97.7) and comparable per cohort. 3-year RFS was lowest though not significantly in nMA+AL at 87% (0.78, 0.97) vs 91-97%, p=0.260. 3-year GRFS was significantly lower in nMA+AL at 69% (0.57, 0.83) vs 83-94%, p=0.001. When age controlled GRFS in nMA+AL ≥13y was significantly lower at 59% (0.40, 0.88) vs 74-100%, p=0.007. Figure Conclusions: Despite small cohort sizes and retrospective nature, this study allowed for direct comparison of common approaches to MRD HCT for SCD. Outcomes were collectively excellent. nMA had earlier engraftment, less transfusion needs, and shorter hospital stay, although significantly more cGVHD and lower 3-yr GRFS influenced by older age. Current clinical trials in nMA+AL include TT and abatacept to mitigate this difference. We previously reported an association between MA and cardiac dysfunction (Stenger et al. Transplant Cell Ther 2023). Potential benefit of nMA must be balanced against risk of rejection and GVHD, thus providers should carefully consider such when selecting conditioning.

Impact of donor marrow cellularity on outcome of allogeneic stem cell transplantation

BackgroundOutcomes of allogeneic hematopoietic stem cell transplant (HSCT) are affected by a number of donor and patient related factors like extent of human leucocyte antigen mismatch, age, source of stem cells, female donor to male recipient and stem cell dose. All of these factors have been extensively investigated; however, effect of donor bone marrow cellularity on HSCT outcomes has not been evaluated. MethodsThis was a prospective study carried out at Armed forces bone marrow transplant center (AFBMTC/NIBMT) from January 2018 to December 2022. Bone marrow cellularity of donors was determined by separate assessment by two experienced Hematopathologists and classified as normocellular, hypocellular or hypercellular according to donor age. Total nucleated cells (TNC) were assessed by automated hematology analyzer and stem cell quantification was done by flowcytometric assay based on CD34, CD45 and 7-AAD immunophenotyping markers. Primary outcome measures were time to achieve neutrophil and platelet engraftment. Secondary outcome measures assessed were overall survival (OS), disease free survival (DFS) and graft versus host disease (GVHD). Frequency and percentage were calculated for categorical variables while Chi-square test was used for quantitative variables. Multivariate Cox regression analysis was used to determine significance of different variables and effect of cellularity on them. Kaplan Meier estimates with group differences were calculated using log rank tests for OS and DFS. A p value of 0.05 or less was considered statistically significant. ResultsCellularity of 95 donors was assessed, 39 (41.1 %) had normocellular marrow while 56 (58.9 %) were hypocellular for age. Median time from diagnosis to transplant was 13 months. In 38 (40 %) the indication for donation was for patients with bone marrow failure syndromes, 23 (24.2 %) for hematological malignancies, 21(22.1 %) for beta thalassemia major and 13 (13.6 %) for miscellaneous disorders including immune deficiencies. Median stem cell / CD 34 dose was 6 × 106/kg and median TNC dose was 5.09 × 108/kg. Median time of neutrophil engraftment was 13.6 days while that of platelet engraftment was 27.1 days. Mean OS was 84.2 %. OS for normocellular donors was 84.6 % and that for hypocellular donors was 83.9 % (p 0.995). DFS for normocellular donors was 84.6 % and for hypocellular donors was 83.9 % (p 0.96). No statistically significant association between the disease group and transplant type with donor marrow cellularity (p value 0.32 and 0.358 respectively) was determined. Multivariate logistic regression model and Backwald test showed no significant association between donor marrow cellularity and CD 34 dose (p 0.65), TNC (p 0.78), neutrophil engraftment (p 0.23), platelet engraftment (p 0.27), Acute GVHD (p 0.83), and chronic GVHD (p 0.44). ConclusionMajority of the donors had hypocellular bone marrow. Bone marrow cellularity had no statistically significant impact on the CD34 and TNC doses obtained; neither did it affect post-transplant neutrophil and platelet engraftment, OS, and DFS. Further population-based studies are required to confirm normal marrow cellularity in Pakistani population and the effects of various genetic and environment factors that make it hypocellular.

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.

Cytokine release syndrome in haploidentical stem cell transplant may impact T-cell recovery and relapse

AbstractCytokine release syndrome (CRS) following haploidentical hematopoietic cell transplantation (HCT) resembles CRS after chimeric antigen receptor-T therapy. We conducted this single-center retrospective study to evaluate the association of posthaploidentical HCT CRS with clinical outcomes and immune reconstitution. One hundred sixty-nine patients who underwent haploidentical HCT between 2011 and 2020 were identified. Of these, 98 patients (58%) developed CRS after HCT. CRS was diagnosed based on the presence of fever within the first 5 days after HCT without evidence of infection or infusion reaction and was graded according to established criteria. The development of posthaploidentical HCT CRS was associated with a lower incidence of disease relapse (P = .024) but with an increased risk of chronic graft-versus-host disease GVHD (P = .01). The association of CRS with a lower incidence of relapse was not confounded by graft source or disease diagnosis. Neither CD34 nor total nucleated cell dose was associated with CRS independently of graft type. In patients developing CRS, CD4+ Treg (P < .0005), CD4+ Tcon (P < .005), and CD8+ T cells (P < .005) increased 1 month after HCT compared with those who did not develop CRS, but not at later time points. The increase in CD4+ regulatory T cells 1 month after HCT was most notable among patients with CRS who received a bone marrow graft (P < .005). The development of posthaploidentical HCT CRS is associated with a reduced incidence of disease relapse and a transient effect on post-HCT immune reconstitution of T cells and their subsets. Therefore, the validation of these observations in a multicenter cohort is required.

Phase I study of intra-osseous co-transplantation of a single-unit cord blood and mesenchymal stromal cells with reduced intensity conditioning regimens.

Cord blood (CB) is a valuable graft source for patients undergoing allogeneic hematopoietic cell transplant (HCT) who lack human leukocyte antigen (HLA)-matched donors. However, single-unit CB-HCT is limited by the insufficient cell dose and slow engraftment. To overcome these limitations, we combined a single-unit CB with third-party healthy donors' bone marrow (BM) derived mesenchymal stromal cells (MSCs) to improve engraftment and injected intra-osseously (IO) to enhance homing. In this phase I clinical trial, six patients with high-risk hematologic malignancies were enrolled and received allogeneic HCT using reduced intensity conditioning regimens. The primary objective was to determine the engraftment rate at day 42. The median age of enrolled patients was 68 years, and only one patient was in complete remission at the time of HCT. The median CB total nucleated cell dose was 3.2x107/kg. No serious adverse events were reported. Two patients had early deaths due to persistent disease and multi-drug resistant bacterial infection, respectively. Of the remaining four evaluable patients, all had successful neutrophil engraftment in a median of 17.5 days. No grade 3 or higher acute graft-versus-host disease (GvHD) was observed, and only one patient developed moderate-extensive chronic GvHD. In conclusion, IO co-transplantation of a single-unit CB and MSCs was feasible and resulted in a reasonable engraftment rate in these very high-risk patients.

Effect of Autograft CD34+ Dose on Outcome in Pediatric Patients Undergoing Autologous Hematopoietic Stem Cell Transplant for Central Nervous System Tumors

Consolidation with autologous hematopoietic stem cell transplantation (HSCT) has improved survival for patients with central nervous system tumors (CNSTs). The impact of the autologous graft CD34+ dose on patient outcomes is unknown. We wanted to analyze the relationship between CD34+ dose, total nucleated cell (TNC) dose, and clinical outcomes, including overall survival (OS), progression-free survival (PFS), relapse, non-relapse mortality (NRM), endothelial-injury complications (EIC), and time to neutrophil engraftment in children undergoing autologous HSCT for CNSTs. A retrospective analysis of the CIBMTR database was performed. Children aged <10 years who underwent autologous HSCT between 2008 to 2018 for an indication of CNST were included. An optimal cut point was identified for patient age, CD34+ cell dose, and TNC, using the maximum likelihood method and PFS as an endpoint. Univariable analysis for PFS, OS, and relapse was described using the Kaplan-Meier estimator. Cox models were fitted for PFS and OS outcomes. Cause-specific hazards models were fitted for relapse and NRM. One hundred fifteen patients met the inclusion criteria. A statistically significant association was identified between autograft CD34+ content and clinical outcomes. Children receiving >3.6×106/kg CD34+ cells experienced superior PFS (p = .04) and OS (p = .04) compared to children receiving ≤3.6 × 106/kg. Relapse rates were lower in patients receiving >3.6 × 106/kg CD34+ cells (p = .05). Higher CD34+ doses were not associated with increased NRM (p = .59). Stratification of CD34+ dose by quartile did not reveal any statistically significant differences between quartiles for 3-year PFS (p = .66), OS (p = .29), risk of relapse (p = .57), or EIC (p = .87). There were no significant differences in patient outcomes based on TNC, and those receiving a TNC >4.4 × 108/kg did not experience superior PFS (p = .26), superior OS (p = .14), reduced risk of relapse (p = .37), or reduced NRM (p = .25). Children with medulloblastoma had superior PFS (p < .001), OS (p = .01), and relapse rates (p = .001) compared to those with other CNS tumor types. Median time to neutrophil engraftment was 10 days versus 12 days in the highest and lowest infused CD34+ quartiles, respectively. For children undergoing autologous HSCT for CNSTs, increasing CD34+ cell dose was associated with significantly improved OS and PFS, and lower relapse rates, without increased NRM or EICs.

A Single Center Analysis of Hematopoietic Recovery in Patients Undergoing Allogeneic BMT with Suboptimal CD34+ Doses

Background: Allogeneic stem cell transplant (allo-SCT) is the only curative treatment for many hematologic malignancies. Stem cells can be collected from bone marrow, peripheral blood, or cord blood. Peripheral blood is the most common utilized source due to its convenience and the ability to collect high numbers of stem cells, but studies suggest that bone marrow offers certain advantages over peripheral blood, especially lower rates of graft-vs-host disease (Holtick et. al. Cochrane 2014), leading to higher survival in patients with nonmalignant disorders . The ideal cell dose for SCT is 2 x 106 cells/kg CD34 cells. However, in cases of bone marrow graft, if a suboptimal cell dose is collected, it is often not feasible to repeat extraction. This is especially difficult for minority ethnic groups who already face systemic barriers to care. Our goal for this study was to assess the correlation of CD34 dose to hematopoietic recovery in a minority-rich population of fresh marrow allogeneic stem cell recipients. Prior studies have also suggested that the cell dosing for transplant should be calculated by ideal body weight (IBW) rather than the standard actual body weight (ABW) (Cilley et. al. Bone Marrow Transplantation 2004). We assessed the correlation of recovery for ABW vs IBW as well. Methods: From 2012-2022, eighteen patients were identified in the Montefiore health system who received a bone marrow graft for allo-SCT with suboptimal CD34 doses. Alongside CD34 dose, an additional predictor evaluated was total nucleated cell (TNC) dose. ABW-based and IBW-based doses were calculated for both CD34 and TNC doses. Several outcomes were tracked for the eighteen patients, including "Days to WBC 1000 cells/μL", "Days to ANC 500 cells/μL ", and "Days to Plt≥20,000 cells/μL." The relationship between cell doses (ABW and IBW-based) and outcomes were evaluated independently through calculation of Spearman's correlation. Analysis and modeling were performed in RStudio 4.1.2. Results: AML and NHL patients made up the largest proportion of the sample (7/18 and 5/18) (Table 1). The median ABW-based CD34 dose (0.530 x 106 CD34 cells/kg) was nearly four times smaller than the standard of 2 x 106 cells/kg CD34 cells. Fifteen of 18 patients achieved reconstitution goals. Of the three patients who did not, one had persistent disease at the time of transplant and developed multiorgan failure dying within 17 days prior to hematopoietic recovery. Another died at day 58 without any platelet recovery. A third maintained platelets above 20,000 cells/μL throughout transplant. Assessing ABW-based CD34 dosing and IBW-based CD34 dosing as independent predictors, none of the outcomes, were significantly correlated (P > 0.05) (Figure 2). However, the Spearman's correlation coefficients were consistently of larger magnitude for IBW-based CD34 dosing than for ABW-based CD34 dosing for all three outcomes. Assessing ABW-based TNC dosing and IBW-based TNC dosing as independent predictors yielded no significant correlation. Conclusion: Studies suggest that there are benefits to bone marrow grafts over that of peripheral stem cell grafts. However, bone marrow harvesting is a process that is not easily repeated in cases where doses are inadequate, especially if the recipient has already undergone conditioning. We reviewed 18 cases of allo-SCTs performed at a single center with suboptimal CD34+ doses. In most cases, hematopoietic reconstitution was achieved. In our cohort of patients with suboptimal CD34+ doses in allo-BM SCTs, we noted no significant correlation between the dosages and outcomes for hematopoietic reconstitution. These results suggest there may be utility in taking a more liberal approach to standards for bone marrow graft doses, but this requires further study, and a much larger sample size. Additionally, we looked at CD34 dosing based on ABW versus IBW and noted consistent increases in magnitude for the Spearman Correlation's. Given the small sample evaluated, it is worth looking at this further with larger samples to see if dosing for bone marrow harvest by IBW may be more correlated with hematopoietic reconstitution in allogeneic SCT than dosing by ABW. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Reducing Mortality of Single-Unit Unrelated Cord Blood Transplantation for Relapsed Acute Myeloid Leukemia after a Previous Allogeneic Transplantation: A Real-World Retrospective Study Over the Past 19 Years in Japan

Relapse is the most common cause of treatment failure after allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML). Second or subsequent allogeneic HCT using unrelated cord blood has been performed for adult patients with AML who have relapsed after a previous allogeneic HCT. Although outcomes after unrelated cord blood transplantation (CBT) as the first allogeneic HCT have significantly improved in recent years, it is unclear whether survival and engraftment improve after CBT as the second or subsequent allogeneic HCT for adult AML patients relapsing after a previous allogeneic HCT. The objective of this retrospective study was to evaluate trends of survival and other transplantation outcomes after single-unit unrelated CBT as a second or subsequent allogeneic HCT in adult patients with relapsed AML after a previous allogeneic HCT over the past 19 years in Japan. We retrospectively assessed survival trends and other outcomes of single-unit unrelated CBT as a second or subsequent allogeneic HCT in adult patients with relapsed AML after a previous allogeneic HCT according to the time period of CBT (2001-2007, 2008-2013, or 2014-2019) using a nationwide Japanese database. The median age was 45 years among 1109 CBTs, and 844 (78.6%) patients were not in complete remission at the time of CBT. Over the 3 time periods, there was a progressive increase in higher cryopreserved cord blood total nucleated cell dose and myeloablative conditioning regimens. The 2-year overall survival was 14.0% in 2001-2007, 19.9% in 2008-2013, and 24.4% in 2014-2019 (P <.001 by log-rank trend test). The 2-year relapse-related mortality was 54.0% in 2001-2007, 44.4% in 2008-2013, and 39.1% in 2014-2019 (P < 0.001 by Gray's test), but nonrelapse mortality was not significantly different across the time periods (P=0.557 by Gray's test). The 42-day neutrophil engraftment also significantly improved (62.9% in 2001-2007, 69.7% in 2008-2013, and 79.9% in 2014-2019; P < 0.001 by Gray's test). Our data demonstrate significant improvements in overall and relapse-related mortality, as well as neutrophil engraftment, after single-unit unrelated CBT as a second or subsequent allogeneic HCT for adult patients with AML relapsed after previous allogeneic HCT over the past 19 years.

Effect of Multiple HLA Locus Mismatches on Outcomes after Single Cord Blood Transplantation

The effect of single or multiple mismatches at each HLA locus on outcomes after cord blood transplantation (CBT) is controversial. We analyzed the effects of single or multiple HLA locus mismatches on the outcomes after single CBT using Japanese registry data from the Japan Society for Hematopoietic Cell Transplantation. Patients age ≥16 years with acute leukemia and myelodysplastic syndromes who underwent their first CBT between 2003 and 2017 (n=4074) were included. The effect of the number of HLA locus mismatches (0, 1, or 2 for the HLA-A, -B, -C, and -DRB1 loci) on outcomes was analyzed after adjusting for other significant variables. The patient cohort had a median age of 54 years. The median total nucleated and CD34 cell doses were 2.6×107/kg and .8×105/kg, respectively. The number of CBTs with single or double mismatches were 2099 and 292, respectively, for the HLA-A locus, 2699 and 341 for the HLA-B locus, 2555 and 609 for the HLA-C locus, and 2593 and 571 for the HLA-DRB1 locus. Single and double HLA-DRB1 mismatches were associated with a higher risk of grade II-IV acute graft-versus-host disease (GVHD; single: hazard ratio [HR], 1.29, P < .001; double: HR, 1.49, P < .001; P for trend <.001). Single and double mismatches at HLA-DRB1 as well as single mismatches at HLA-A and HLA-B also were associated with grade III-IV acute GVHD. Single and double HLA-B mismatches and double HLA-DRB1 mismatches were associated with a high risk of nonrelapse mortality (NRM). On the other hand, double mismatches at HLA-A or HLA-DRB1 and single mismatches at HLA-B were associated with a lower risk of relapse. HLA-DRB1 double mismatch was associated with high risk of grade II-IV and grade III-IV acute GVHD and NRM but lower risk of relapse. Not only the locus mismatch, but also the number of mismatches, should be considered in cord blood unit selection.

Post Transplantation Fludarabine and Cyclophosphamide Selected and Promoted Low Dose of Unrelated UCB Implanation in Combined Transplantation of Haploid and UCB Stem Cells in Childhood Leukemia: 40 Cases Report in Double Center

Background: For patients without HLA matched donor, Haploid stem cell transplantation with PTCY method has relatively higher risk of relapse and graft-versus-host disease (GVHD). Umbilical cord blood (UCB) is readily available and has helped expand the donor pool to almost all patients requiring a transplant. Meanwhile UCB transplant improves EFS in leukaemia with lower risk of relapse and GVHD. However, the clinical application of UCB is limited due to lower implantation rate because of its low dose of stem cells than other sources of hematopoietic stem cells (HSC).Aims: This study is to explore the feasibility and efficacy of post-transplantation fludarabine and cyclophosphamide to select and promote the unrelated UCB to engraft in combined transplantation of haploid and UCB stem cells for the treatment of childhood and adolescent leukemia.Methods: Total 40 children and adolescent patients with leukemia in Nanfang Hospital and Shenzhen Children's Hospital enrolled this study from Sept.2019 to Jun.2021. These patients were diagnosed as AML (20 HR, 5 IR, 2 relapsed AML), ALL (5 HR, 2 IR, 2 relapsed ALL), AL (1), JMML (2), MDS (1) and BPDCN (1) with a median age of 80 months (range 7 months -17 years). The biggest body weight reached to 77kg. The haploid stem cell was 5/10-9/10 mismatched and UCB was selected as 6/10-10/10 HLA matched or mismatched. The condition regimen was busulfan+fludarabine+CY+Ara-C. Haploid PBSC was infused in day0. All received PTCy 50 mg/kg and post-transplantation fludarabine 40mg/m 2 on days 3 and 4 along with tacrolimus or cyclosporine and mycophenolate mofetil for prophylaxis of acute GVHD. UCB was infused in day6. A median of haploid stem cells of 20.00×10 8/kg (13.00-32.10) of mononuclear cells was infused while a median of UCB cells of 4.32×10 7/kg (1.48-22.78) of total nucleated cells was infused. A median of CD34+ cells of haploid stem cells 13.00×10 6/kg (1.51-32.00) was infused while a median of CD34+ cells of UCB cells 1.74×10 5/kg (0.26-4.80) was infused. The survival rate, umbilical cord blood implantation rate, hematopoietic recovery and the rate of transplant-related complications were analyzed.Results: At a median follow-up of 8 months (range 1-21 months), there were 2/40（5%）cases of transplant-related death. All surviving patients were leukemia free, with one-year overall survival rate 92.8±5.0%. Among these patients, 37/40(92.5%, 95%CI: 84.0%~100.0%) of patients achieved complete chimerism of unrelated UCB cells and 3/40(7.5%, 95%CI: -1.0%~16.0%) of patients achieved mixed chimerism of unrelated UCB cells and haploid cells. In these transpltantation, the CD34+ cell dose of UCB less than 1.0×10 5/kg accounted for 10/40 (25.0%), and less than 2.0×10 5/kg accounted for 23/40 (57.5%).Two patients had primary poor graft function. Neutrophil reconstitution was achieved in 39/40 patients with a median time of 29 days (range 17 - 44 days) without G-CSF after transplantation. Platelet recovery was achieved in 37/40 patients with a median time of 37 days (range 8-92 days). There was a significant linear relationship between platelet recovery time and the dose of total nucleated cells and CD34+ cells in UCB（r=-0.368, P=0.025; r=-0.355, P=0.031）.The incidence of gradeⅠand gradeⅡGVHD was 32.5%（95%CI:17.3%-47.7%）and 42.5%（95%CI:26.5%-58.5%）, respectively. There was no grade Ⅲ-Ⅳ aGVHD and only 1/40(2.5%) case of extensive chronic GVHD. The incidence of chronic limited GVHD was 22.5% (95%CI: 9.0%-36.0%). Twenty-four of 40(60.0%, 95%CI:44.1%-75.9%) patients experienced clinically significant CMV reactivations or infections. One of 40（2.5%, 95%CI: -2.6%-7.6%）patients experienced EB virus reactivation. Two of 40（5.0%, 95%CI: -2.1%-12.1%）patients experienced human herpesvirus 6 infection. Thirteen of 40（32.5%, 95%CI: 17.3%-47.7%）patients presented with hemorrhagic cystitis.Conclusion: In our primary clinical study, post-transplantation fludarabine and cyclophosphamide could effectively select and promote the unrelated UCB to implant rather than haploid cells in combined transplantation of haploid and UCB stem cells even if the CD34+ cells of UCB less than 1.0×10 5/kg. Although acute GVHD was common but just milder degree and with lower incidence of EB virus reactivation. This new strategy has the potential to promote the wilder clinical use of unrelated UCB in the treatment of leukemia. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Review of Unrelated Donor Cord Blood Transplantation in Children over the Past 3 Decades

Review of Unrelated Donor Cord Blood Transplantation in Children over the Past 3 Decades

Long-term outcomes following the addition of granulocyte colony-stimulating factor-combined high-dose cytarabine to total body irradiation and cyclophosphamide conditioning in single-unit cord blood transplantation for myeloid malignancies.

An intensified myeloablative conditioning regimen, involving the addition of granulocyte colony-stimulating factor (G-CSF)-combined high-dose cytarabine (12g/m2) to standard total body irradiation and cyclophosphamide, has been performed for adult patients with myeloid malignancies in single-unit cord blood transplantation (CBT) since 1998 in our institute. We update the results of CBT, as the first allogeneic hematopoietic cell transplantation after this conditioning regimen, in 169 patients with a median long-term follow-up of 10.4years. The median age was 43years (range, 16 to 59years). Ninety-four patients (56%) were in non-remission at the time of CBT, and 124 patients (73%) were acute myeloid leukemia. The median cryopreserved cord blood total nucleated cell dose and CD34+ cell dose was 2.40 × 107/kg and 0.93 × 105/kg, respectively. The cumulative incidence of neutrophil recovery at 42days was 94.4% (95% confidence interval [CI]: 88.6-97.3%). Among the whole cohort, 105 patients were still alive at the end of the study period. The cumulative incidences of relapse and non-relapse mortality at 10years were 26.0% (95% CI: 19.5-33.0%) and 16.9% (95% CI: 11.4-23.4%), respectively. There was an overall survival probability of 62.5% (95% CI: 54.3-69.7%) at 10years. Higher disease risk index alone significantly affected higher overall mortality (hazard ratio 2.21, P = 0.003) in multivariate analysis. These outcomes demonstrate that G-CSF-combined myeloablative conditioning could have favorable long-term remission rates for adult patients with myeloid malignancies undergoing single-unit CBT.

Optimal umbilical cord blood collection, processing and cryopreservation methods for sustained public cord blood banking

Background aimsUmbilical cord blood is an established source of stem cells in patients with hematologic malignancies who do not have HLA-compatible matched related or unrelated donors. The success of an umbilical cord blood transplant depends on the dose of total nucleated and CD34+ cells infused. Therefore, collecting, banking and listing high-quality cord blood units with high total nucleated and CD34+ cell dose are essential. MethodsHere the authors describe their cord blood bank's novel collection technique, which involves both in utero and ex utero collection of a single cord blood unit. The authors also evaluated maternal, neonatal and collection parameters that may impact the cell dose. ResultsMaternal gestational age and race, and neonatal weight and sex correlated with the total nucleated cell dose. ConclusionsThe optimized collection of umbilical cord blood is critical for its use as a source of stem cells for transplantation.

Selecting Optimal Cord Blood Units: The Limitations of Cell Dose

BACKGROUNDHematopoietic stem cell transplantation (HCT) is a potentially lifesaving therapy for blood cancers and other diseases. For patients without a suitable related donor, unrelated-donor registries of adult volunteers and banked umbilical cord-blood units provide potential sources of donors. Umbilical cord transplantation has several advantages including lack of adverse effects on the donor, near-immediate availability and lower risks of acute and chronic graft-versus-host disease, even with donor-recipient HLA-disparity. The main disadvantage is the low absolute number of cells in each unit, often insufficient for engraftment and timely recovery of hematopoiesis in adults. Consequently, cell dose is often the prime driver of unit selection and HLA matching criteria are much less stringent than used for adult unrelated donor HCT. Most cord blood transplantations are mismatched for one or two HLA A, B and DRB1 loci, using only intermediate resolution typing for HLA A and B. HLA C is usually not considered. However, recent data from the CIBMTR suggest that outcomes are substantially better and transplant-related mortality rates very low (~5%) when cord blood units are matched with recipients for HLA-A, B, C and DRB1 (using high resolution typing for all loci) are selected.1,2 We sought to determine the likelihood of finding a suitable 6-8 of 8 HLA-matched cord blood unit for patients in the United States, given the current available inventory, and the potential impact of technologies that would allow smaller than currently acceptable units to be used successfully. METHODSUsing human HLA data from the NMDP cord-blood-unit registry, we built population-based genetic models for 21 U.S. racial and ethnic groups to predict the likelihood of identifying a cord-blood unit for patients in each group. The models incorporated the degree of HLA matching and cord-blood-unit pre-freeze total nucleated cell (TNC) dose. We also calculated models that assumed that cord-blood-unit TNC dose was not a limitation. RESULTSOur models indicated that currently, 81.8% of patients will identify a suitably-sized cord blood unit that is matched at high-resolution for 6-8 of 8 HLA A, B, C, DRB1 loci. This likelihood varies by patient race and ethnicity, from 49.4% to 87.4% patients as shown in Table 1. If cell dose were not an issue, these percentages increase with 97.4% of patients overall predicted to have a 6-8 of 8 HLA matched unit. Considering patient race/ethnicity, the likelihood is 98.9% for European Caucasians, 94.5% for Hispanics, 93.3% for Asian or Pacific Islanders and 87.1% for African Americans, for children and adults. The impact of TNC dose (and the potential impact of agents allowing cord blood units with smaller TNC doses to be used) is greatest for adults and people of color, particularly African Americans. CONCLUSIONStrategies to facilitate successful engraftment using lower cell dose units could increase the numbers of patients who could receive an optimally HLA-matched cord blood unit, with subsequent improvements in outcomes.

Poor Outcome of Domino Hematopoietic Stem Cell Transplantation in Humans - an International Case Series

BackgroundDomino hematopoietic stem cell transplantation (HSCT) refers to a situation where an HSCT recipient serves as the donor for another (HLA-identical) recipient. Several successful cases have been reported, suggesting that acquired tolerance to HLA-antigens in the first recipient allows for engraftment in the second recipient, with low risk of graft-versus-host disease (GvHD). However, no systematic analyses on the outcome of domino HSCT have been performed.MethodsA retrospective, questionnaire-based study was performed within the European Bone Marrow Transplant (EBMT) network and the Primary Immune Deficiency Treatment Consortium (PIDTC). Primary outcome measures were survival and re-transplantation; secondary outcome measures were incidence of GvHD and time to neutrophil and platelet engraftment.FindingsWe identified 11 domino-HSCTs performed in 9 different centers, between September, 1992 and March, 2016. Indications were immune deficiency (n=9), inborn errors of metabolism (n=1) and hereditary bone marrow failure (n=1). The outcome of domino recipients was poor and inferior to their donors and to published cases. Only five recipients (45%) survived with long-term donor engraftment, of whom one required repeated donor-lymphocyte infusions. Four recipients (36%) required re-transplantation and two (18%) engrafted but died from infectious complications. The time between domino-HSCT and re-transplantation ranged up to 190 months. No differences were found in CD34+ cell dose, total nucleated cell dose, nor in kinetics of engraftment between successful domino HSCTs and those resulting in re-transplantation. One domino recipient and six primary recipients developed GvHD.InterpretationThis study demonstrates the disappointing outcome of domino-HSCT. Alternative donor sources, if available, should be considered. Replicative stress on the transplanted stem cells, loss of “stem-ness”, and immune-mediated mechanisms may contribute to the limited engraftment upon serial transplantation. In addition, our results stress the importance of systematic evaluation of published and unpublished cases for unbiased clinical decision making. DisclosuresCowan:Homology Medicine: Consultancy.

Favorable Outcomes of Single-Unit Cord Blood Transplantation As Salvaged Treatment for Advanced Hematologic Malignancies

Treatments of advanced hematologic malignancies are limited, and the effects are very poor even after allogeneic hematopoietic stem cell transplantation. Recent study showed that cord blood transplantation was benefit for patients with pretransplantation minimal residual disease compared to both HLA-matched and HLA-mismatched unrelated donor transplantation. The relapse rate was lowest in cord blood transplantation group. But the effect of cord blood transplantation in advanced hematologic malignancies as salvaged treatment still remains unknown. We retrospectively analyzed 55 consecutive patients with advanced hematologic malignancies who received single-unit unrelated cord transplantation at our centre between December 2013 and December 2016. Among the patients, 42with acute leukemia, 8 with myelodysplastic syndrome (MDS with refractory anemia with excess blasts [RAEB]), 4 with CML-BC and 1 with plasma cell leukemia. All of them were in non-remission before transplantation. The median age was 10 years (range, 2-43 years), and the median weight was 31 kg (range, 9-82kg).All the patients received intensified conditioning regimen and a combination of CsA and MMF as GVHD prophylaxis. The infused total nucleated cell (TNC) dose was 4.99 (range 2.17-13.9) × 10⁷/kg and CD34⁺ cell dose was 2.53 (range 0.64-7.45) × 10⁵/kg. Neutrophil and platelet engraftment occurred in 49 (89.1%) and 42 (76.4%) patients, respectively. The median times to neutrophil recovery and platelet recovery were 16 days (range, 12-32 days) and 37.5 days (range, 18-83 days), respectively. Forty patients (72.7%) experienced pre-engraftment syndrome (PES). The cumulative incidence rates of II-IV acute GVHD and chronic GVHD were 25.5% (95% CI, 14.8-37.6%) and 18.8% (95% CI, 8.6-32.1%), respectively. The median follow-up period for the surviving patients was 654 days (range, 208 to 720 days). The probability of 2- year OS and LFS were 53.9% and 46.8%, respectively, whereas the cumulative incidence of 2-year NRM and relapse rate were 34.5% (95% CI, 21.6-47.8%) and 20.7% (95% CI, 10.9-32.7%), respectively. To further define the importance of matching at the HLA C locus on our special patient cohort outcomes, we analyzed the effect of HLA C disparity on patient outcomes. Results showed that although OS, LFS and NRM were not significantly different between the two groups, the relapse rate was significantly higher after transplantations with matched at HLA C(n=12) than mismatched at HLA C(n=42)(58.5% VS 27.9%,P=0.0426).Since the favorable outcomes, our results showed that single-unit cord blood transplantation might be a feasible choice as salvaged treatment for advanced hematologic malignancies, even in patients with a high leukemia burden. Choosing the cord blood with mismatch at HLA C locus might reduce the relapse rate without increasing the NRM in our special patient cohort, but this metric still requires further evaluation with a larger cohort. DisclosuresNo relevant conflicts of interest to declare.

Outcomes of Cord Blood Transplantation for Adult Patients with Hodgkin Lymphoma, a Eurocord and EBMT Lymphoma Working Party Study

Allogeneic stem cell transplantation represents an alternative for relapsed or refractory patients (pts) with Hodgkin Lymphoma (HL). In this setting, only limited data on unrelated umbilical cord blood transplantation (UCBT) are available. We analyzed 133 adult pts with HL who underwent UCBT in EBMT centers. Histological subtype was nodular sclerosis in 65% of the pts. Median age at UCBT was 29 (18-65) years. Median follow-up was 37 (2-119) months and median year of UCBT was 2010 (2003-2015). Ninety pts had received a previous autologous transplantation (ASCT), while 19 had received 2 ASCT before UCBT; median time from ASCT to UCBT was 15 (2-281) months. Disease status at UCBT was complete remission (CR) in 45%, partial remission (PR) in 28% and relapse or refractory disease in 27% of the pts. Sixty percent of pts were male and 54% had a positive cytomegalovirus serology. Fifty-one percent (n=68) received a single UCBT and 49% (n=65) a double UCBT; 58% of pts received a graft with 2 or more HLA mismatch. The majority of the pts (n=104, 77%) underwent a reduced intensity conditioning regimen, the most frequent conditioning regimen (n=69) being Cyclophosphamide + Fludarabine + Total Body Irradiation (TBI) (2 Gy). Forty percent (n=46) of pts received anti-thymocyte globulin and Cyclosporine A + mycophenolate mofetil prophylaxis was given to 60% (n=80) of the pts. Median total nucleated cell (TNC) dose at cryopreservation was 3.99 (1.5-12.2) x107/Kg.The cumulative incidence (CI) of neutrophil engraftment at 60 days was 87% (81%-93%). The 100-day CI of acute grade II-IV GVHD was 26% (19%-35%). At 3 years, chronic GVHD was 30% (21%-41%). Relapse incidence (RI) and non-relapse mortality (NRM) were 40% (32%-50%) and 30% (23%-40%) at 3 years, respectively. The overall survival (OS) was 48% (39%-57%) and progression free survival (PFS) was 28% (21%-37%) at 3 years. Sixty-nine patients died: 27 of relapse and 39 of transplant related causes (infections, n=13, GVHD, n=7, idiopathic pneumonia syndrome n=6, EBV-PTLD n=2, VOD n=2 and others causes, n=9). According to disease status at UCBT, OS at 3 years was 68% (55%-79%) for pts in CR, 31% (18%-50%) for pts in PR and 26% (14%-44%) for pts in relapsed or refractory disease.In multivariate analysis, adjusted for median year of UCBT, Cyclophosphamide + Fludarabine + low dose TBI conditioning regimen, disease status at UCBT, conditioning intensity and type of UCBT, none of these factors were found to be associated with acute or chronic GVHD. 3-year RI and NRM were higher for pts in relapse or refractory disease at UCBT compared to pts in CR (HR=2.62, 95%CI 1.12-6.11, p=0.03 and HR=3.66, 95%CI 1.52-8.80, p=0.004, respectively). The use of Cyclophosphamide + Fludarabine + low dose TBI conditioning regimen was associated with a lower risk of NRM (HR=0.38, 95%CI 0.15-0.95, p=0.04) and also with a better OS (HR=0.37, 95%CI 0.18-0.76, p=0.006). OS was significantly worse for pts who underwent UCBT in PR (HR=1.97, 95%CI 1.02-3.80, p=0.04) and for those in relapse or refractory disease at transplant (HR=2.86, 95%CI 1.41-5.81, p=0.004). Pts transplanted in relapse or refractory disease have also a lower PFS (HR=3.12, 95%CI 1.71-5.71, p<0.001).In conclusion, UCBT is feasible in heavily pretreated pts with HL, if there are no other alternative donors. Conditioning with Cyclophosphamide + Fludarabine + low dose TBI is associated with a better OS and NRM. However, outcomes are poor for patients not in CR at the time of UCBT and one might consider the use of new therapeutic agents earlier before UCBT in this setting. DisclosuresZuckerman:BioSight Ltd.: Consultancy. Snowden:Sanofi: Honoraria. Robinson:Gilead: Honoraria, Other: Travel Grants; Takeda: Consultancy, Honoraria, Other: Travel Grants; Roche: Honoraria, Other: Travel Grants; Riemser: Consultancy.

Adoptive Immunotherapy with Cord Blood (CB) Grafts Targeting Shared Inherited Paternal Antigens (IPA) and/or Non-Inherited Maternal Antigens (NIMA) during Induction Treatment for High Risk Myeloid Malignancies: Safety and Preliminary Results

BackgroundSeveral groups have reported use of haploidentical peripheral blood donor cells as adjunct to chemotherapy in remission induction of myeloid leukemia (Colvin et al, BBMT 2009, Gue et al, Blood 2011). Moreover, CB grafts have been associated with greater disease control and enhanced graft-versus-leukemia responses, as a consequence of the fetal-maternal interactions during pregnancy (van Rood et al, PNAS 2009 and PNAS 2012).We evaluated prospectively the feasibility and tolerability of infusing partially HLA matched cord blood units (CBUs) with specific alloreactive properties after salvage chemotherapy to patients (pts) with refractory myeloid leukemia.Patients and MethodsPts with confirmed diagnosis of AML or MDS, according to WHO classification (excluding acute promyelocytic leukemia) who had received two or more previous induction/re-induction regimens were eligible. All pts were treated at NYPH and all CBUs were obtained from the NCBP. The study was performed under FDA IND and was approved by the IRBs of both institutions. Pts received induction chemotherapy followed by CBU infusion (1-3 days later) without any immunosuppression.CBUs eligible for the study contained a pre-cryopreservation Total Nucleated Cell (TNC) dose of 0.5-2.5x107/kg. They were HLA matched at 4-6/6, HLA-A, -B intermediate resolution, -DRB1 high resolution. CBUs had undergone HLA typing of the mother, thus allowing determination of the paternal and maternal antigens. CBUs with shared IPA targets and/or NIMA match were selected for cell therapy.ResultsA total of 34 patients underwent CBU search. Mean CBU number per search was 134 (range: 7-250) with 58% potentially eligible CBUs per pt (range: 5-159). A total of 143 CBUs underwent testing including HLA confirmatory typing. At least one eligible CBU was identified for each pt. Higher HLA allele level match was preferred in the final selection.Of the 34 pts, 23 did not receive treatment because of progressive disease and death (n=8); other clinical trials/treatments (n=6); hematopoietic stem cell transplants (HSCT) (n=9); while one is currently undergoing evaluation. Ten pts have been treated (Table); 8 had AML, 7 with primary induction failure (PIF); one had myeloid blast phase CML and one with high risk MDS. Nine pts had poor risk karyotype and 4 had prior allografts. Median age was 52 years (range: 34-67); median number of prior treatments was 11 (2-15) and median HSCT-CI was 3 (0-7).Of the CBUs infused, six were 5/6 and four were 4/6 HLA matched. The allele level compatibility and presence of shared IPA targets and/or NIMA matches are shown in the Table. CBU median TNC was 90x107 (range: 63-151) and they tended to be “older” with a median cryopreservation time of 10 years. CBUs provided a mean cell dose of 1.66 x 107 TNC/kg (range: 1.1-2.4). Mean post-thaw CD34+ and CD3+ cell doses were 52x103/kg (range: 20-90) and 0.34x107/kg (range: 0.24-0.52; SD: 0.08), respectively, with excellent post-thaw CD34+ viability (93.5%-98.3%).No CBU infusion reactions or cytokine release syndrome were observed. One pt, recipient of a prior allograft with no history of GVHD, experienced skin rash 1 week after CBU infusion. The skin biopsy was consistent with GVHD. No GVHD was observed in the other 9 pts. One pt died of disseminated adenovirus infection early after treatment; viremia was present at the initiation of chemotherapy.Transient CBU chimerism was detected in 5 of the 10 pts as early as one week and as late as 6 months after CBU infusion. Four pts with median pre-treatment BM blast counts of 56% (range 13-94) had objective hematologic responses (Cheson B JCO 2003) with median post-treatment blast counts of 0% (range 0-12), 3 with morphologic leukemia free state and one with a partial response. One patient had aplastic marrow but with flow cytometry evidence of persistent leukemia; while 4 pts recovered with morphologic persistent leukemia. Six pts went on to receive HSCT. Two subsequently relapsed and one died of disseminated adenovirus, while 3 pts remain in remission.ConclusionUse of CBUs as adoptive immunotherapy for pts with refractory myeloid leukemia represents a safe, well tolerated treatment, in which the potential for alloreactivity can be enhanced through the selection of CBUs by targeting shared IPA and NIMA present in the patients. Further, smaller CBUs, unlikely to be adequate grafts for adult transplantation, can be utilized for cell therapy. [Display omitted] DisclosuresRoboz:Cellectis: Research Funding; AbbVie, Agios, Amgen, Amphivena, Array Biopharma Inc., Astex, AstraZeneca, Celator, Celgene, Clovis Oncology, CTI BioPharma, Genoptix, Immune Pharmaceuticals, Janssen Pharmaceuticals, Juno, MedImmune, MEI Pharma, Novartis, Onconova, Pfizer, Roche Pharmace: Consultancy. Ritchie:Celgene: Consultancy, Other: Travel, Speakers Bureau; Pfizer: Consultancy, Other: Research funding to my institution; Incyte: Consultancy, Speakers Bureau; Astellas Pharma: Other: Research funding to my institution; NS Pharma: Other: Research funding to my institution; Bristol-Myers Squibb: Other: Research funding to my institution; Novartis: Consultancy, Other: Research funding to my institution, and travel, Speakers Bureau. Lee:Amgen: Consultancy; Baxalta: Consultancy; Clinipace: Consultancy; Alexion Pharmaceuticals: Consultancy.

HHV-6 Prophylaxis with Foscanet Improves Hematopoietic Engraftment after Umbilical Cord Blood Transplantation

Delayed hematopoietic recovery is a major obstacle for successful use of umbilical cord blood (UCB) transplantation. In our recent report of patients receiving non-myeloablative (NMA) UCB transplantation with sirolimus/MMF as GVHD prophylaxis, we observed an association between early post-transplant HHV6 viral reactivation and delayed hematopoietic recovery. Therefore, in order to improve hematopoietic recovery, we added foscarnet (45 mg/kg twice daily) as antiviral prophylaxis for at least 10 days starting at day +7 until neutrophil engraftment. Here we report results in 19 consecutive patients treated with foscarnet and compared results in those treated with acyclovir (n=60, historical control) after NMA UCB transplant with sirolimus/MMF GVHD prophylaxis. The median age for the entire cohort was 63 years (range, 16-73 years). Acute leukemia was the principal indication for transplantation (45%). At the time of transplantation, 25% of the patients had many comorbidities (HCT-CI≥3), 21% had Karnofsky performance status (KPS) ≤80% and nearly 60% were CMV seropositive with 7 patients (9%) having had a prior allogeneic transplant (alloHCT). All patients received the same NMA conditioning regimen consisting of fludarabine (150 mg/m2), cytoxan (50mg/kg) and TBI (200 cGy) with 46% also receiving ATG if there was no recent chemotherapy. Median infused total nucleated cell dose for the entire cohort was 4.1 x107/kg (range, 2.7-9.6 x107/kg). Groups were similar except for prior alloHCT (21% vs. 5%, p=0.03) and lower KPS ≤80% (58% vs. 10%, p <0.01) in recipients of foscarnet as compared to the acyclovir cohort. Cumulative incidence of neutrophil engraftment by day 42 was 100% in the foscarnet group vs. 75% (64-85%) in those treated with acyclovir (p= 0.08). Cumulative incidence of platelet engraftment by 6 months was 95% (69-100%) for foscarnet group vs. 75% (60-90%) for acyclovir group (p=0.02). In multiple regression analysis (Table), after adjusting for CMV serostatus, neutrophil engraftment was 2-fold increased in recipients of prophylactic foscarnet as compared to acyclovir (HR=2.0, CI 95% 1.1-3.6; p= 0.02). Similarly, after adjusting for age and CMV serostatus platelet engraftment was 2.4-fold increased in recipients of foscarnet as compared to acyclovir (HR=2.4, 95% CI 1.3-4.0; p <0.01). In addition, positive recipient CMV serostatus was associated with poor hematopoietic engraftment. These data support the use of prophylactic foscarnet for prevention of HHV-6 reactivation which may delay or prevent successful engraftment after NMA UCB transplantation with sirolimus/MMF as GVHD prophylaxis. [Display omitted] DisclosuresBrunstein:Magenta Therapeutics: Research Funding; Novartis: Research Funding.