Busulfan-based Myeloablative Conditioning Research Articles

Comparing haploidentical transplantation with post-transplantation cyclophosphamide and umbilical cord blood transplantation using targeted busulfan in children and adolescents with hematologic malignancies

PurposeThis study compared the outcomes of haploidentical-related donor (HRD) and umbilical cord blood (UCB) hematopoietic stem cell transplantation (HSCT) in pediatric patients with hematologic malignancies.MethodsData on patients who underwent HRD HSCT with post-transplant cyclophosphamide (n = 41) and UCB HSCT (n = 24) after targeted busulfan-based myeloablative conditioning with intensive pharmacokinetic monitoring between 2009 and 2018 were retrospectively analyzed.ResultsThe median follow-up durations in the HRD and UCB groups were 7.0 and 10.9 years, respectively. The cumulative incidence of acute graft-versus-host disease (GVHD) grades II–IV and moderate-to-severe chronic GVHD did not differ significantly between the groups. However, the HRD group demonstrated significantly lower rates of acute GVHD grades III–IV (4.9% vs. 29.2%, p = 0.009) and non-relapse mortality (2.6% vs. 34.2%, p < 0.001) but a higher relapse incidence (32.1% vs. 8.8%, p = 0.004) than the UCB group. The 5-year event-free and overall survival rates were 65.8% and 54.2% (p = 0.204) and 78.0% and 65.7% (p = 0.142) for the HRD and UCB groups, respectively. Multivariate analysis identified disease status as a significant risk factor for overall survival (hazard ratio, 3.24; p = 0.016). Additionally, UCB HSCT exhibited a trend toward worse event-free survival compared to HRD HSCT (hazard ratio, 2.63; p = 0.05).ConclusionsThese findings indicate that HRD HSCT with post-transplant cyclophosphamide provides promising outcomes compared to UCB HSCT in pediatric patients, with a trend toward improved survival over a long-term follow-up period exceeding a median of 7 years. Thus, HRD HSCT may be a valuable option for pediatric patients without human leukocyte antigen-matched donors.

Comparable outcomes of allogeneic peripheral blood versus bone marrow hematopoietic stem cell transplantation from a sibling donor for pediatric patients.

Traditionally, bone marrow (BM) has been preferred as a source of stem cells (SCs) in pediatric hematopoietic SC transplantation (HSCT); however, the use of peripheral blood SCs (PBSC) has recently increased. With advancing graft-versus-host disease (GVHD) prophylaxis, whether the BM is still a better SC source than PB in sibling donor HSCT remains controversial. Here, we compared the results of BM transplantation (BMT) and PBSC transplantation (PBSCT) in pediatric patients with malignant or non-malignant diseases receiving sibling HSCT using a total of 7.5mg/kg of anti-thymocyte globulin (ATG). We retrospectively reviewed children who received HSCT from a sibling donor between 2005 and 2020 at Seoul National University Children's Hospital. Of the 86 patients, 40 underwent BMT, and 46 underwent PBSCT. Fifty- six patients had malignant diseases, whereas thirty patients had non-malignant diseases. All conditioning regimens comprised ATG. Busulfan-based myeloablative conditioning regimens were administered to patients with malignant diseases and approximately half of those with non-malignant diseases. The remaining half of the patients with non-malignant diseases were administered cyclophosphamide-based reduced- intensity conditioning regimens. According to studies conducted at our center, all BM donors received G-CSF before harvest to achieve early engraftment. In all 86 patients (47 males and 39 females), the median age at the time of HSCT was 11.4 (range, 0.7 - 24.6) years. The median follow-up period was 57.9 (range, 0.9-228.6) months, and the corresponding values for those with BM and PBSC were 77 (range, 2.4-228.6) months and 48.7 (range, 0.9-213.2) months, respectively. Engraftment failure occurred in one patient with BM and no patient with PBSC. The cumulative incidence of acute GVHD with grades II-IV was higher in PBSC (BM 2.5%, PBSC 26.1%, p = 0.002), but there was no significant difference in those with grades III-IV acute GVHD (BM 0%, PBSC 6.5%, p = 0.3703) and extensive chronic GVHD (BM 2.5%, PBSC 11.6%, p = 0.1004). There were no significant differences in treatment-related mortality (TRM) (BM 14.2%, PBSC 6.8%, p = 0.453), 5-year event-free survival (EFS) (BM 71.5%, PBSC 76.2%, p = 0.874), and overall survival (OS) rates (BM 80.8%, PBSC 80.3%, p = 0.867) between BM and PBSC in the univariate analysis. In the multivariate analysis, which included all factors with p < 0.50 in the univariate analysis, there was no significant prognostic factor for EFS or OS. There was no significant difference in the relapse incidence between BM and PBSC among patients with malignant diseases (BM 14.2%, PBSC 6.8%, p = 0.453). Additionally, there were no significant differences in the TRM, 5-year EFS, and OS rates between malignant and non-malignant diseases nor between the busulfan-based myeloablative regimen and reduced-intensity chemotherapy using cyclophosphamide. In this study, we showed no significant differences in EFS, OS, TRM, and GVHD, except for acute GVHD grades II-IV, between BMT and PBSCT from sibling donors, using ATG (a total of 7.5mg/kg). Therefore, PB collection, which is less invasive for donors and less labor-intensive for doctors, could also be considered an acceptable SC source for sibling donor HSCT in children.

Comparison of Pulmonary Toxicity after Total Body Irradiation- and Busulfan-Based Myeloablative Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Patients

Pulmonary toxicity after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for childhood leukemia and myelodysplastic syndrome (MDS), along with the impact of different myeloablative conditioning regimens, remain incompletely described. Here we compared the acute and long-term incidence of pulmonary toxicity (PT) after total body irradiation (TBI)- and busulfan-based myeloablative conditioning. We conducted this retrospective cohort study of 311 consecutive pediatric patients with leukemia or MDS who underwent allo-HSCT at Dana-Farber Cancer Institute/Boston Children's Hospital between 2008 and 2018. PT was graded using Common Terminology Criteria for Adverse Events version 5.0. The primary objective was to compare the cumulative incidence of grade ≥3 and grade 5 PT after TBI-based and busulfan-based myeloablative conditioning using Gray's test. Secondary objectives were to determine factors associated with PT and overall survival (OS) using competing risk analysis and Cox regression analyses, respectively. There was no significant difference between the TBI-conditioned group (n=227) and the busulfan-conditioned group (n=84) in the incidence of grade ≥3 PT (29.2% versus 34.7% at 2 years; P=.26) or grade 5 pulmonary toxicity (6.2% versus 6.1% at 2 years; P=.47). Age (hazard ratio [HR], 1.70, 95% confidence interval [CI], 1.11 to 2.59; P=.01), grade ≥2 PT prior to allo-HSCT or preexisting pulmonary conditions (HR, 1.84, 95% CI, 1.24 to 2.72; P < .01), acute graft-versus-host disease (GVHD) (HR, 2.50; 95% CI, 1.51 to 4.14; P < .01), and chronic GVHD (HR, 2.61; 95% CI, 1.26 to 5.42; P=.01) were associated with grade ≥3 PT on multivariable analysis. Grade ≥3 PT was associated with worse OS (81.1% versus 61.5% at 2 years; P < .01). In pediatric allo-HSCT recipients, rates of PT were similar in recipients of TBI-based and recipients of busulfan-based myeloablative conditioning regimens. Age, the presence of PT or preexisting pulmonary conditions prior to transplantation, and the development of either acute or chronic GVHD were associated with grade ≥3 PT post-transplantation. Furthermore, the occurrence of grade 3-4 PT post-transplantation was associated with inferior OS.

Post-Transplantation Cyclophosphamide-Based Haploidentical versus Matched Unrelated Donor Peripheral Blood Hematopoietic Stem Cell Transplantation Using Myeloablative Targeted Busulfan-Based Conditioning for Pediatric Acute Leukemia

The use of haploidentical related donors (HRDs) is a common alternative donor strategy used when matched sibling or unrelated donors are not available for hematopoietic stem cell transplantation (HSCT). However, there have been no studies comparing HRD HSCT with post-transplantation cyclophosphamide (PTCy) and matched unrelated donor (MUD) HSCT with antithymocyte globulin using similar busulfan-based myeloablative conditioning regimens in pediatric acute leukemia. Here we compared the outcomes in children and adolescents with high-risk acute leukemia who underwent HRD HSCT with PTCy (n=35) or MUD HSCT (n=45) after targeted busulfan-based myeloablative conditioning using intensive pharmacokinetic monitoring. The median duration of follow-up was 3.7 years in the HRD group and 4.6 years in the MUD group. No engraftment failure was observed in either group. There were no significant between-group differences in the cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) (34.3% versus 48.9%; P=.142), grade III-IV acute GVHD (2.9% versus 8.9%; P=.272), moderate to severe chronic GVHD (11.4% versus 18.3%; P=.417), relapse (25.6% versus 28.0%; P=.832), and nonrelapse mortality (0% versus 2.2%; P=.420). The 3-year severe chronic GVHD-free/relapse-free survival (GRFS), leukemia-free survival (LFS), and overall survival (OS) rates in the HRD and MUD groups were 62.9% (95% confidence interval [CI], 45.8% to 80.0%) versus 49.8% (95% CI, 34.9% to 64.7%; P=.318), 74.4% (95% CI, 58.7% to 90.1%) versus 67.5% (95% CI, 53.4% to 81.6%; P=.585), and 88.6% (95% CI, 78.0% to 99.2%) versus 83.7% (95% CI, 72.5% to 94.9%; P=.968), respectively. In a subgroup analysis of patients with acute lymphoblastic leukemia (HRD, n=17; MUD, n=26), the 3-year GRFS, LFS, and OS rates in the HRD and MUD groups were 49.4% (95% CI, 24.3% to 74.5%) versus 39.5% (95% CI, 19.7% to 59.3%; P=.601), 61.8% (95% CI, 37.5% to 86.1%) versus 63.6% (95% CI, 44.4% to 82.8%; P=.872), and 82.4% (95% CI, 64.4%, 100%) versus 84.2% (95% CI, 70.1% to 98.3%; P=.445), respectively. In patients with acute myelogenous leukemia (AML) (HRD, n=16; MUD, n=16), the 3-year GRFS, LFS, and OS rates in the HRD and MUD groups were 80.8% (95% CI, 61.2% to 100%) versus 61.9% (95% CI, 37.8% to 86.0%; P=.326), 87.1% (95% CI, 70.2% to 100%) versus 73.9% (95% CI, 51.8% to 96.0%; P=.478), and 93.8% (95% CI, 81.8% to 100%) versus 85.6% (95% CI, 67.0% to 100%; P=.628), respectively. Although the difference was not statistically significant and the number of patients was small, the promising outcomes of HRD HSCT in AML patients were encouraging. Our results demonstrate that HRD HSCT with PTCy using a targeted busulfan-based myeloablative conditioning regimen has outcomes similar to those of MUD HSCT with antithymocyte globulin. HRD HSCT with PTCy could be a feasible option for pediatric high-risk acute leukemia patients who lack an HLA-matched related or unrelated donor.

Total body irradiation-based versus busulfan-based myeloablative conditioning for single-unit cord blood transplantation in adults

Comparative studies between total body irradiation (TBI)-based and busulfan-based myeloablative conditioning (MAC) regimens for cord blood transplantation (CBT) have been limited. We retrospectively analyzed the results of single-unit CBT in 333 adult patients who received either TBI-based (n = 258) or busulfan-based (n = 75) MAC regimens at our institute. After adjusting for significant variables in the univariate analysis, there were no significant differences in neutrophil recovery (hazard ratio (HR), 0.88; p = .460), grade III–IV acute graft-versus-host disease (GVHD) (HR: 1.40, p = .410), extensive chronic GVHD (HR: 0.73, p = .380), relapse (HR: 0.61, p = .270), non-relapse mortality (HR: 1.38, p = .420), overall survival (HR: 1.18, p = .637), or event-free survival (HR: 1.08, p = .773), although platelet recovery was lower with marginal significance for the busulfan-based regimen (HR: 0.67, p = .068). In subgroup analysis, TBI-based regimens were superior to busulfan-based regimens in terms of survival for acute lymphoblastic leukemia, but not for myeloid malignancies. Further investigation is warranted even for CBT.

Posttransplant Cyclophosphamide-Based Haploidentical Vs Matched Unrelated Donor Peripheral Blood Hematopoietic Stem Cell Transplantation Using Myeloablative Targeted Busulfan-Based Conditioning for Pediatric Acute Leukemia

Haploidentical related donor (HRD) is a common alternative donor strategy used when matched sibling or unrelated donors are not available for hematopoietic stem cell transplantation (HSCT). Post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis is an attractive option when performing a HRD HSCT because of its promising outcomes and easy application. However, there have been no studies comparing HRD HSCT with PTCy and MUD HSCT with antithymocyte globulin, using similar busulfan-based myeloablative conditioning regimen in pediatric acute leukemia. Herein, we compared the outcomes in children and adolescents with acute leukemia after HRD HSCT with PTCy (n=35) and matched unrelated donor (MUD) HSCT (n=45) after targeted busulfan-based myeloablative conditioning using intensive pharmacokinetic monitoring. The median follow-up times of the HRD and MUD groups were 3.7 and 4.6 years. No engraftment failure was observed. The cumulative incidence of GVHD grades II-IV (34.3% versus 48.9%, p=0.142), grades III-IV (2.9% vs. 8.9%, p=0.272), extensive chronic GVHD (11.4% vs. 18.3%, p=0.417), relapse (25.6% vs. 28.0%, p=0.832), and non-relapse mortality (0% vs. 2.2%, p=0.420) were not significantly different. The 3-year severe chronic GVHD-free/relapse-free, leukemia-free and overall survival rates in the HRD and MUD groups were 62.9±8.7% versus 49.8±7.6% (p=0.318), 74.4±8.0% versus 67.5±7.2% (p=0.585), and 88.6±5.4% versus 83.7±5.7% (p=0.968), respectively. In subgroup analyses of patients with acute lymphoblastic leukemia and acute myeloid leukemia, there were no significant differences in outcomes between the groups. Our results demonstrated that HRD HSCT with PTCy using a targeted busulfan-based myeloablative conditioning shows outcomes similar to those of MUD HSCT. HRD HSCT with PTCy could be considered for pediatric acute leukemia patients who lack an HLA-matched donor. DisclosuresKang: Cartexell: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Korea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen Korea: Membership on an entity's Board of Directors or advisory committees, Research Funding.

251 - Effects of Post-Transplant Cyclophosphamide on Early Donor Chimerism Outcomes after Allogeneic Stem Cell Transplant with Busulfan Based Myeloablative Conditioning

251 - Effects of Post-Transplant Cyclophosphamide on Early Donor Chimerism Outcomes after Allogeneic Stem Cell Transplant with Busulfan Based Myeloablative Conditioning

Haploidentical stem cell transplantation with post-transplant cyclophosphamide for osteopetrosis and other nonmalignant diseases.

Allogeneic hematopoietic stem cell transplantation (HSCT) is curative for a variety of nonmalignant disorders including osteopetrosis, bone marrow failures, and immune deficiencies. Haploidentical HSCT is a readily available option in the absence of a matched donor, but engraftment failure and other post-transplant complications are a concern. Post-transplant cyclophosphamide (PT-Cy) regimens are gaining popularity and recent reports show promising results. We report our experience with nine pediatric patients with nonmalignant diseases who were transplanted from a haploidentical donor with PT-Cy. From 2015 to 2019, nine children with nonmalignant diseases underwent haploidentical HSCT with PT-Cy, two as a second transplant and seven as primary grafts after upfront serotherapy and busulfan-based myeloablative conditioning. Patient’s diseases included osteopetrosis (n = 5), congenital amegakaryocytic thrombocytopenia (n = 2), hemophagocytic lymphohistiocytosis (n = 1), and Wiskott Aldrich syndrome (n = 1). Two patients failed to engraft following upfront PT-Cy transplants, one was salvaged with a second PT-Cy transplant, and the other with a CD34+ selected graft. None of the patients suffered from graft-versus-host disease. Three patients died from early posttransplant infectious complications and six patients are alive and well. In conclusion, haploidentical HSCT with PT-Cy is a feasible option for pediatric patients with nonmalignant diseases lacking a matched donor.

PF775 MONOSOMY 7 ALONE OR WITH OTHER CHROMOSOMAL ABNORMALITIES SIGNIFICANTLY AFFECT SURVIVAL OF SECONDARY AML PATIENTS TREATED WITH ALLOGENEIC- SCT

Background: T-cell replete Haploidentical stem cell transplantation (Haplo-SCT) with high dose post-transplant cyclophosphamide (PT-Cy) is being increasingly used for patients when a HLA identical sibling or a matched related donor is not available. With regard to inborn errors of metabolism (IEM) or primary immunodeficiency which need a hematopoietic stem cell transplantation (HSCT) for cure, haplo-SCT could be an alternative option. However, there is insufficient data on the efficiency and safety of the procedure of haplo-SCT with PT-Cy in patients with nonmalignant genetic diseases. Aims: The aim of the present study is to evaluate the feasibility and safety of haplo-SCT with PT-Cy in patients with nonmalignant genetic diseases compared with HLA matched donor transplantation. Methods: We retrospectively analyzed 16 patients (Haplo group) receiving Haplo-SCT with PT-Cy from peripheral blood graft source, and 20 patients (Matched group) receiving HSCT from related matched (n = 4), unrelated 9–10/10 matched donors (n = 16) between Jan 2014 and Feb 2018 at Seoul National University Children's Hospital. Three chronic granulomatous disease (CGD), 5 adrenoleukodystrophy (ALD), 4 Krabbe disease, and 4 others were included in Haplo group, whereas 11 CGD, 1 ALD, 1 Krabbe disease, 3 congenital neutropenia, and 4 other diseases in Matched group. We used an intensive daily pharmacokinetic monitoring method for busulfan dosing for effective myeloablation and to reduce toxicity. The total target area under the curve (AUC) of busulfan was set at 74,000 to 76,000 μg × h/L. Targeted busulfan, fludarabine were used in both groups for the conditioning regimen, while cyclophosphamide was included in Haplo group, and anti-thymocyte globulin in Matched group. Results: The outcomes of haplo group and Matched group, respectively, are discussed. The median follow-up time were 27.6 months (range, 11.9–60.8), and 34.2 months (range, 12.5–59.9), respectively. The cumulative incidence (CI) rates of neutrophil engraftment in haplo and control groups were 93.8% and 95.0%. The median days of neutrophil engraftment were 14 days and 11 days, and those of platelet engraftment were 34 days and 17 days, respectively. The both groups did not differ in terms of transplantation-associated complications (hepatic veno-occlusive disease, CMV reactivation, hepatic toxicity, hemorrhagic cystitis). For 13 patients with IEM, the post-HSCT brain MRI findings were reported as similar to the pre-HSCT one. In particular, 2 ALD patients in Haplo group who did not showed neurologic symptom before HSCT (pre-HSCT Loes scores were 0 and 2, respectively) are still normal with regard to neurologic status at median follow-up time 41 months and 18 months, respectively. The CI rates of grade II–IV, grade III-IV acute and extensive chronic graft versus host disease were 45.0% versus 40.0% (P = 0.68), 6.0% versus 20.0% (P = 0.263) and 13.3% versus 26.7% (P = 0.335), respectively. The event-free survival rates at 2 years (93.8% versus 95.0%, P = 0.856) were similar and the overall survival rates were 100% in both groups. Summary/Conclusion: The present study shows that haplo-SCT using PT-Cy, along with a targeted busulfan-based myeloablative conditioning regimen, is a safe and promising therapeutic option for patients with nonmalignant genetic diseases. In particular, it could be useful for patients in urgent need of HSCT who lack a sibling donor or do not have enough time to find a suitable unrelated donor.

Prophylaxis and Treatment Strategy for Endothelial Cell Damages after Hematopoietic Cell Transplantation in Children

Introduction Sinusoidal obstruction syndrome (hSOS) and thrombotic microangiopathy (TMA) are life-threatening complications caused by endothelial cell damage (ECD) associated with hematopoietic cell transplantation (HCT). Danaparoid sodium (DS) is a heparinoid comprising a mixture of low molecular weight glycosaminoglycans with anti-Xa and anti-IIa effects, which prevent fibrin formation. Recombinant thrombomodulin (rTM) comprises the active extracellular domain of thrombomodulin and inactivates coagulation by binding to thrombin. Both of them were expected to play crucial roles in the management of disseminated intravascular coagulation (DIC) and ECD after HCT. Objectives We aimed to evaluate the efficacy and feasibility of DS for prophylaxis and rTM for the treatment of hSOS and TMA after HCT in children. Methods Between January 2011 and December 2017, 91 children (median age 7.6 years, range 0.6–18.2; with hematologic malignancies [n = 54], solid tumors [n = 9], or benign diseases [n = 28]) underwent 118 consecutive HCTs (9 autologous and 109 allogeneic settings; busulfan-based myeloablative conditioning [n = 23], total body irradiation-based myeloablative conditioning [n = 35], or reduced intensity [n = 60]) at our institution. All of them were treated prophylactically with DS (intravenously injection, 30 international units [IU] per kg of body weight, twice a day from the initiation of the conditioning regimen to day 50 after HCT) to prevent ECD. Any patient who developed ECD despite prophylaxis were treated with rTM (intravenous drip infusion, 380 IU per kg, once a day). We reviewed their clinical records and evaluated the efficacy and feasibility of rTM for these children. Results Nine patients developed SOS (severe 5, moderate 1, and mild 3) at a median of 19 days after HCT (range, 6–173), and 6 patients developed TMA at median day 38 (range, 27–106). The cumulative incidences of SOS and TMA at 100 days were 6.8% and 4.4%, respectively. A total of 17 patients received 18 courses of rTM for complications after HCT. The median dose and duration of rTM treatments were 367 IU/kg/day (range, 189–404) and 7 days (range, 3–22), repectively. rTM treatments initiated at a median of 30 days after HCT (range, 6–173). The cause of rTM administration included SOS (n = 9), infection with DIC (n = 4), TMA (n = 3), or engraftment syndrome with DIC (n = 2). All these complications were resolved or improved by rTM treatment along with supportive care. Among the 17 patients receiving rTM treatment, no hemorrhagic events or deaths due to HCT-related toxicity were observed; however, 7 died of their underlying disease. Multivariate analysis revealed that neither SOS nor TMA had a negative impact for transplant outcome. Conclusion DS and rTM are effective and safe for the management of ECD after HCT in children. A larger multicenter prospective study is warranted to confirm these findings.

Comparison of Haploidentical Transplantation with Post-Transplantation Cyclophosphamide and Umbilical Cord Blood Transplantation in Children and Adolescents with Hematologic Malignancies after Targeted Busulfan-Based Myeloablative Conditioning Using Intensive Pharmacokinetic Monitoring

Introduction: Haploidentical related donor (Haplo) and umbilical cord blood (UCB) stem cell sources represent common alternative donor strategies used when a matched sibling donor or matched unrelated donor is not available for hematopoietic stem cell transplantation (HSCT). The aim of this study was to compare the results of graft source on outcome of children and adolescents with hematologic malignancies after Haplo and UCB transplantation in the setting of targeted busulfan-based myeloablative conditioning using intensive pharmacokinetic (PK) monitoring.Patients and methods: We retrospectively analyzed outcomes in 140 pediatric patients with hematologic malignancies who received allogeneic HSCT from Haplo donors (n=36), UCB (n=24), and unrelated donors (n=80) in Seoul National University Children's Hospital from January 2009 to February 2018. Because UCB transplantation had been conducted until 2016 while Haplo transplantation using posttransplantation cyclophosphamide (PTCy) was started from 2014 in our institution, differences over time of HSCT must be considered to compare them. Therefore, unrelated HSCT group was divided into Unrelated A group (n=51) who received HSCT from 2009 to 2013 and Unrelated B group (n=29) from 2014, which were compared first with the purpose of using them as a control to compare Haplo and UCB groups. Patients who received the first allogenic HSCT using an intensive PK monitoring, targeted busulfan-based myeloablative conditioning were included. The majority of UCB and unrelated groups received busulfan, fludarabine ± etoposide regimen with antithymocyte globulin. For graft-versus-host disease (GVHD) prophylaxis, cyclosporine and mycophenolate mofetil were used in UCB group while tacrolimus and methotrexate in unrelated groups. Busulfan, fludarabine and cyclophosphamide with PTCy, tacrolimus and methotrexate for GVHD prophylaxis were used in Haplo group.Results: First of all, Unrelated A group was compared to Unrelated B group. The median follow-up time were 5.7 years (0.2-9.5) and 1.8 years (0.3-4.5) in the Unrelated A and Unrelated B groups, respectively. The event-free survival (EFS) rates at 2 years (78.1±5.8% versus 72.3±9.1%, P=0.917) and overall survival (OS) rates at 2 years (83.7±5.3% versus 77.8±9.1%, P=0.874) in Unrelated A and B groups were similar. Under the assumption that there was no significant survival difference over time of HSCT from 2009 to 2013 and that from 2014 in our institution, the outcomes of Haplo and UCB groups were compared subsequently. The median follow-up time were 4.8 years (0.1-9.3) and 1.8 years (0.3-4.5), respectively. The median time to neutrophil and platelet recovery were 15 days (13-21) versus 14 days (12-40) (P=0.059), and 27 days (13-71) versus 46 days (21-77) (P<0.001) in Haplo and UCB groups, respectively. Engraftment failure occurred in 1 patient of UCB group. The cumulative incidence (CI) rates of acute GVHD grade II-IV, grade III-IV, and extensive chronic GVHD in Haplo and UCB groups were 38.9% versus 54.2% (P=0.479), 2.8% versus 29.2% (P=0.004), and 11.7% versus 12.5% (P=0.906), respectively. The CI rates of nonrelapse mortality were significantly lower in Haplo group (0% versus 33.6%, P<0.001), while the relapse incidences were not different (18.3% versus 8.6%, P=0.272). The event-free survival (EFS) rates at 2 years (79.3±7.0% versus 54.2±10.2% %, P=0.034) and overall survival (OS) rates at 2 years (85.8±6.7% versus 65.7±9.9%, P=0.029) in Haplo and UCB groups were significantly different.Conclusion: In this study, the CI rates of nonrelapse mortality and acute GVHD III-IV was lower in Haplo group than in UCB transplants, which translates into a better EFS and OS rate in Haplo group. Our results suggest that haploidentical HSCT with PTCy using intensive PK monitoring, targeted busulfan-based myeloablative conditioning regimen is a safe and promising alternative option for patients with hematological malignancies who lack an HLA-matched donor. DisclosuresNo relevant conflicts of interest to declare.

Cognitive Function and Quality of Life in Vorinostat-Treated Patients after Matched Unrelated Donor Myeloablative Conditioning Hematopoietic Cell Transplantation

Myeloablative conditioning allogeneic hematopoietic cell transplantation (HCT) puts patients at greater risk for significant cognitive and quality of life decline compared with recipients of reduced-intensity conditioning or autologous HCT. Vorinostat, a histone deacetylase inhibitor, has been shown to have neuroprotective and neurorestorative effects in preclinical models of neurologic diseases. Thus, within the context of a myeloablative conditioning phase II clinical trial of vorinostat combined with tacrolimus and methotrexate for graft-versus-host disease prophylaxis, we conducted an ancillary study to evaluate feasibility of assessing associations between vorinostat and neurocognitive function and quality of life (ClinicalTrials.gov NCT02409134). Nine patients (mean age, 53 years; range, 36 to 66) underwent computerized neuropsychological testing (Cogstate) and completed surveys of mood (Patient Health Questionnaire-9), anxiety (General Anxiety Disorder-7), and quality of life (Functional Assessment of Cancer Therapy–General). Control cohorts from a separate concurrent longitudinal study (19 autologous and 18 allogeneic HCT patients, who matched the vorinostat patients on relevant medical and demographic variables) completed the same test battery. All allogeneic patients received busulfan-based myeloablative conditioning and were transplanted with HLA-matched unrelated donors. The total neurocognitive performance score of vorinostat patients did not change significantly across the study duration (ie, baseline, day 30, day 100, and day 160). Depression, anxiety, and quality of life also did not differ significantly across time. In univariate analyses (analysis of variance), vorinostat-treated patients showed no difference in neurocognitive function or quality of life compared with autologous and allogeneic control subjects. However, when medical variables were accounted for in a linear mixed effects regression model, the total neurocognitive performance of vorinostat-treated patients was comparable with autologous control subjects. Notably, autologous control subjects performed significantly better than allogeneic control subjects (estimate, .64; standard error, .23; P ≤ .01). Moreover, a smaller percentage of vorinostat-treated patients were classified as mildly, moderately, or severely impaired across neurocognitive domains as well as time points compared with both control cohorts. Thus, vorinostat may have neurorestorative or neuroprotective effects in the HCT setting. Accordingly, we recognize the need for a future, full-scale randomized controlled trial to further examine this hypothesis.

Evaluation of a Test Dose Strategy for Pharmacokinetically-Guided Busulfan Dosing for Hematopoietic Stem Cell Transplantation

Targeted busulfan dosing helps limit chemotherapy-related toxicity and optimize disease outcomes in hematopoietic stem cell transplantation (HCT). The objective of this study was to evaluate busulfan exposure from a pharmacokinetic (PK)-guided dosing strategy using a test dose. This retrospective evaluation included adult patients who underwent HCT at our institution with busulfan-based myeloablative (>9 mg/kg) conditioning between January 2014 and October 2015. A weight-based test dose of 0.8 mg/kg was used with PK assessments to predict area under the curve (AUCpred) achieved with weight-based dosing, with a target AUC of 4800 µM*minute (AUCtarget). PK from the test dose was then used to calculate a PK-guided first myeloablative busulfan dose. PK assessments were also done after the first dose to assess if the goal area under the curve (AUC) had been achieved (AUCfirst). A PK-guided first dose resulted in achievement of target AUC with target ranges of ±10% in 50% of patients, ±15% in 75%, and ±20% in 94%. This was an improved rate of target achievement compared with the 33%, 44%, and 63% of patients who achieved the desired AUC for these respective target ranges when using weight-based dosing (P = .12, .004, and <.001, respectively). The PK-guided strategy also decreased the variability of AUC from 3.6-fold in AUCpred from the weight-based test doses (2700.8 to 9631 µM*minute; SD, 1211.6 µM*minute) to 1.8-fold in AUCfirst from the PK-guided first doses (3672.1 to 6609.8 µM*minute; SD, 574.7 µM*minute). This reflects a 2-fold improvement in AUC variability with a PK-guided dosing strategy. This is also improved from the 3-fold variability in AUC reported in other studies. Weight and body surface area were significantly associated with the likelihood of AUCfirst being within the ±10% target range (P = .04 for both associations). There was no significant association between AUCfirst and death, relapse, or a composite of the two. These results demonstrate a significant improvement in target AUC attainment and less interpatient variability with PK-guided dosing using a test dose strategy compared with weight-based dosing.

Favorable Outcome of Post-Transplantation Cyclophosphamide Haploidentical Peripheral Blood Stem Cell Transplantation with Targeted Busulfan-Based Myeloablative Conditioning Using Intensive Pharmacokinetic Monitoring in Pediatric Patients

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with post-transplantation cyclophosphamide (PTCy) was performed previously in adults using a nonmyeloablative conditioning regimen and bone marrow as a graft source. In an effort to reduce relapse rates, myeloablative conditioning regimens with higher intensities are now used. We used an intensive daily pharmacokinetic monitoring method for busulfan dosing in children for effective myeloablation and to reduce toxicity. Here, we report the retrospective results of 34 patients (median age 11.1 years) who underwent haplo-HSCT with PTCy using a targeted busulfan-based myeloablative conditioning regimen and peripheral blood as a stem cell source. The donor-type neutrophil engraftment rate was 97.1%, and the cumulative incidence rates of grade II to IV and grade III to IV acute and extensive chronic graft-versus-host disease were 38.2%, 5.9%, and 9.1%, respectively. The overall survival and event-free survival rates, and treatment-related mortality were 85.0%, 79.4%, and 2.9%, respectively. Based on the subgroup analysis of patients with malignancies (n = 23), the relapse incidence rate was 21.7%. Haplo-HSCT using PTCy with targeted busulfan-based myeloablative conditioning and peripheral blood as a stem cell source was a safe and promising therapeutic option for children.

Risk Score for the Development of Veno-Occlusive Disease after Allogeneic Hematopoietic Cell Transplant

A risk score identifying patients at high risk for veno-occlusive disease (VOD) may aid efforts to study preventive strategies for this uncommon complication of hematopoietic cell transplantation (HCT). Patients receiving a first allogeneic HCT between 2008 and 2013 as reported to the Center for International Blood and Marrow Transplant Research (N = 13,097) were randomly divided into training and validation sets. Independent prognostic factors for development of VOD by day +100 after HCT were identified with a multivariate logistic regression model. A risk score was constructed in the training set using the significant factors and confirmed in the validation set. Baseline characteristics of the training and validation sets were balanced. In total, 637 patients (4.9%) developed VOD by day +100. Younger age, positive hepatitis B/C serology, lower Karnofsky performance scale score, use of sirolimus, disease, disease status at transplant, and conditioning regimen were independent prognostic factors. Myeloablative conditioning regimens were associated with higher risk of VOD. Busulfan-based myeloablative conditioning regimens guided by pharmacokinetic monitoring were associated with higher risk than those without pharmacokinetic monitoring. Patients were stratified into 4 distinct, statistically significantly different groups by their risk score percentile. This pretransplant risk score successfully stratified allogeneic HCT patients by risk of developing VOD, was validated in an independent set, and demonstrated strong discriminatory ability to identify a high-risk cohort.

Pharmacokinetics-adapted Busulfan-based myeloablative conditioning before unrelated umbilical cord blood transplantation for myeloid malignancies in children.

Unrelated umbilical cord blood transplantation (UCBT) is an alternative to provide transplants in children with acute leukemia or myelodysplastic syndrome who lack a related donor. Intravenous Busulfan (Bu) combined with therapeutic drug monitoring-guided dosing has been increasingly used, with more predictable bioavailability and better outcomes comparing to oral Bu. There is still an important variation in Bu pharmacokinetic between patients that is associated with an increased risk of toxicity and graft failure. The objective of the study was to analyze the impact of first-dose pharmacokinetic adapted myeloablative conditioning regimen of intravenous Bu on the different outcomes after transplantation. Data of 36 children who underwent allogeneic HSCT with Bu plus a second alkylating agent at Sainte Justine Hospital in Montreal, Canada, between December 2000 and April 2012 were analyzed. For children with high risk myeloid malignancies receiving an UCBT, first dose Bu pharmacokinetic seems to be a significant prognostic factor, influencing neutrophil (100% vs 67.9%) and platelet recovery (95.5% vs 70.5%), non-relapse mortality (0% vs 18.6%), EFS (64% vs 28.6%) and OS (81.3% vs 37.5%) for a first-dose steady-state concentration (Css) <600ng/mL vs >600ng/mL, respectively. These data reinforce the importance of Busulfan therapeutic drug monitoring-guided dosing in pediatric HSCT patients, particularly in the context of UCBT.

Analysis of Real-world Data on Postremission Therapy for Acute Myeloid Leukemia With Intermediate Risk Cytogenetics in First Complete Remission

BackgroundWe retrospectively analyzed data from 310 patients with acute myeloid leukemia with intermediate-risk cytogenetics in first complete remission (CR1) to evaluate the usage and efficacy of various types of postremission therapy. Patients and MethodsCox regression with time-dependent covariates, landmark analysis, and competing risk models were used to estimate the outcomes and effects of treatment and patient- and disease-related risk factors. ResultsThe early relapse rate and early nonrelapse mortality (NRM) were 12.8% and 4.4%, respectively. In our study, 77.2% of patients completed postremission therapy: 44% received allogeneic hematopoietic cell transplantation (HCT), 20% completed treatment with high-dose cytarabine (HIDAC), and 13% completed treatment with intermediate-dose cytarabine. The 3-year overall survival rate was 67.5% for patients treated with HIDAC and 63.4% after HCT (P = .5876). The NRM and relapse rate at 3 years were 0% and 58.9% after HIDAC and 21.9% and 29.3% after HCT, respectively. HCT reduced the risk of relapse (hazard ratio, 0.6; 95% confidence interval, 0.36-0.98). Total body irradiation-based myeloablative conditioning increased NRM compared with busulfan-based conditioning (hazard ratio, 8.33; 95% confidence interval, 2.52-27.45). ConclusionMost patients with acute myeloid leukemia with intermediate-risk cytogenetics received allogeneic HCT, which decreased the risk of relapse but increased NRM, leading to a similar overall survival for patients who received HCT and HIDAC. Our data support the use of allogeneic transplantation for patients in CR1 from a human leukocyte antigen-matched related or unrelated donor after a busulfan-based myeloablative conditioning regimen as a primary strategy of postremission therapy for eligible younger patients.

Cost-Effectiveness of Defibrotide in the Prophylaxis of Veno-Occlusive Disease after Pediatric Allogeneic Stem Cell Transplantation

Veno-occlusive disease (VOD) remains a serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). Prophylactic use of defibrotide (DF) might further reduce VOD rates but has no impact on the incidence of severe VOD or VOD-associated mortality. We investigated the cost-effectiveness of prophylactic DF according to the British Committee for Standards in Haematology/British Society for Blood and Marrow Transplantation guidelines in 348 children who underwent transplantation between 2001 and 2014 in our hospital, 138 of whom were at risk for VOD. The VOD incidence was 7.4% for the total cohort. Patients at risk had a higher incidence of VOD compared with patients without risk factors (15.2% versus 2.4%, P < .0001). VOD occurred more often in patients after busulfan-based myeloablative conditioning than in patients after total body irradiation (11.2% versus 3.5%, P = .001). Donor types or the transplantation-related mortality (TRM) risk score did not correlate with VOD incidence. In 81% of patients who responded to therapeutic DF, VOD resolved completely. Overall VOD-associated mortality was .3% for the complete cohort, 3.7% for patients diagnosed with VOD, and 20% for patients with severe VOD. Neither the cumulative incidence of TRM (19% ± 8% versus 17% ± 2%, P = .706) nor the median length of hospitalization differed between patients with VOD and patients without. The median costs per HSCT in patients with VOD were about one-third higher than the overall median costs per transplantation at our institution. The calculated total costs of prophylactic DF treatment for 138 patients at risk was almost 6 times as high as the incremental costs for patients with VOD. We conclude that prophylactic DF for children at risk for VOD is not cost-effective with respect to TRM and length of hospital stay.

Early Post Transplant Organ Toxicity after Allogeneic One-Haplotype Mismatch (Haplo) Hematopoietic Stem Cell Transplant (HSCT)

T-replete Haplo-HSCT is presently a major evolution in the field of allo-HSCT. Despite we miss prospective evaluation, we are faced to a high pace of diffusion worldwide. We however need to collect informations on many aspects. In this abstract we report an analysis of the early events and organ toxicities in the first patients transplanted in our program. Between 2011 and 2015, 117 patients treated for hematologic malignancy, receiving a Haplo-HSCT and post-transplant high dose cyclophosphamide (PT-HDCY) with a minimal follow-up of 100 days were analyzed. All organ toxicities were graded according to WHO scale and only grade 3-4 toxicities were analyzed: impact of age, Hematopoietic transplant comorbidity index (HCT-CI) and conditioning regimen were analyzed in this first step evaluation. Median age was 56 (19-73) and 58% were males (M/M: 35%; M/F: 21%; F/M: 23%; F/F: 21%; Donor origin: Sibling: 43%; offspring: 45%; Mother: 9%; Father: 3%). Patients were transplanted for: Acute Leukemia (AL): 32%; Non-AL myeloid malignancies: 19%; Lymphoma: 36%; Non-lymphoma Lymphoid malignancies: 13%. Patients were at high risk of both relapse (48% of active disease at the time of Haplo-HSCT, Disease risk index: low: 8%; Intermediate: 59%; high/very high: 33%) and non-relapse mortality [NRM] (65% had HCT-CI of 3 or more). Conditioning regimens were non-myeloablative TBI-based (NMAC), busulfan-based reduced intensity (RIC) and busulfan-based myeloablative conditioning (MAC) in 68%, 10% and 22%, respectively. PBSC were infused in 89% of the patients. Graft CD34/CD3 cells: 5.2 (0,8-14,8) / 261 (27-629) x 10e6/kg. Seventeen (15%) pts received a previous allo-HSCT and 7 (6%) pts with AL were included in a sequential debulking-transplant strategy.One-year overall survival, PFS and GRFS were 85%, 78% and 55%.Graft failure occurred in 3 pts (all with positive donor specific antibodies). Others reached ANC>0.5 G/L and platelet count>20G/L in a median time of 20 (14-38) and 31 (10-395) days post Haplo-HSCT. Day-100 cumulative incidence of grade 2-4 and 3-4 acute GVHD were 24% and 7%, respectively. Grade 3-4 WHO toxicities within 100 days: Pulmonary: 31%; Cardiac: 23%; Liver: 20%; Cystitis: 14%; mucositis: 12%; renal: 8%.14 patients (12%) died within 100 days at a median of 40 (2-84) days (9 (9%) of the 100 patients with first and 5 (29%) of 17 patients with previous allo-HSCT). Causes of NRM were (n patients): infection: 6; Cardiac: 4; GVHD: 2; Neurologic: 2. In a multivariate analysis, grade 3-4 3-4 OMS cardiac toxicity occurred more frequently in pts older than 60 (HR: 0.42 (0.17-1.0), p=0.05, Figure 1A) and both oral mucositis (HR: 0.22 (0.06-0.72), p=0.01) and liver toxicity (HR: 0.32 (0.12-0.89), p=0.03) in patients treated with busulfan-based conditioning (Figure 1B). Seventy-nine (68%) patients experienced bacterial infection, 56 (48%) viral reactivation and 14 (12%) fungal infections. Pts older than 60 experienced more frequent bacterial infection than others (82% vs 58%: p=0.01, Figure 1A).In conclusion, this retrospective analysis suggests a higher incidence of peculiar organ toxicity as cardiac and bladder deserving further analysis. It also suggests that in a high-risk population (second allo-HSCT:15%; patients over 60 years: 38%; HCT-CI≥3: 65%; High/Very high DRI: 33%; transplanted with active disease: 48%early NRM is somehow limited allowing further development at the condition to take into account the main factors leading to these toxicities and to develop adapted care. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The Changing Patterns of Graft Failure in MPS1H, Hurler Syndrome: A Review of 30-Years Experience

Introduction: Hurler syndrome (HS), the most severe phenotype of mucopolysaccharidosis type I, is characterized by α-L-iduronidase (IDUA) deficiency. Without therapy, most affected children die of cardiac complications in the first decade. Haematopoietic stem cell transplantation (HSCT) is the standard of care in children with HS as it is the only therapy that can arrest disease progression. One of the challenges in HSCT for HS is graft failure. Here, we examined the evolving pattern of graft failure over the past three decades.Methods: Retrospective review of all children with HS undergoing first HSCT at the Royal Manchester Children’s Hospital or the University of Minnesota Children’s Hospital over a thirty-four-year period (1983 - 2016). The diagnosis of HS was confirmed by an increase in urinary GAG excretion, a deficiency or absence of IDUA in peripheral blood leukocytes, and the clinical phenotype. A full-intensity Busulfan-based myeloablative conditioning regimen (MAC) with pharmacokinetic-guided dosing was started from 2004 (post Bu-pK era). Conditioning regimen used prior to Bu-pK era was variable. Graft failure was classified into 4 types: 1. Primary aplasia, (no neutrophil engraftment by Day +42) 2. Primary autologous reconstitution (neutrophil engrafted by Day +42 but with <20% donor-derived hematopoiesis) 3. Secondary aplasia (cytopenia following neutrophil engraftment and fully donor-derived hematopoiesis) 4. Secondary autologous reconstitution (falling donor chimerism <20% following neutrophil engraftment and adequate donor-derived hematopoeisis)Results: A total of 240 children with HS were enrolled (131 pre-Bu-pK; 109 post-Bu-pK). The median age at HSCT was 16.3 months (range 4.9-72.2 months) in pre-Bu-pK era and 14.0 months (range 3.8-65.1 months) in post-Bu-pK era (p = 0.002) ). In pre-Bu-pK era, the graft source was predominately marrow/peripheral blood (n=109, 83.2%). The use of cord blood (CB) increased from 16.8% (n=22) in pre-Bu-pk era to 63.3% (n=69) in post-Bu-pK era (p<0.001). The 5-year overall survival (OS) improved from 60.8% to 85.2% (p<0.001) while the 5-year event-free survival increased from 41.2% to 76.3% (p<0.01) in the modern era. The proportion of patients with graft failure reduced significantly from 37.2% (49/113 patients) in pre-Bu-pK era to 10.1% (11/109 patients) in post-Bu-pK era (p<0.001). Of the 49 patients with graft failure in pre-Bu-pK era, 1 had primary aplasia, 19 had primary autologous reconstitution and 28 had secondary autologous reconstitution. In the post-Bu-pk era, all the graft failure occurred in CB recipients (10 had a busulfan based MAC; 1 had a non-MAC). Of these 11 patients, 7 patients had aplasia while 4 had autologous marrow reconstitution. On univariate analysis, neither pre-transplant factors (age and sex) nor transplant factors (graft-recipient HLA disparity, total nucleated cell dose, CD34+ cell dose, graft-recipient ABO compatibility, conditioning regimen, type of serotherapy and GVHD prophylaxis regimen) were correlated with graft failure in CB recipients receiving busulfan-based MAC in the post-Bu-pK era. Of 60 patients with graft failure, 48 (39 pre-Bu-pK; 9 post-Bu-pK) had a second transplant. Of the 39 patients undergoing second transplant in the early era, 13 died and 5 had repeat graft failure. Three patients underwent third transplant and all died of transplant-related complications (1 GVHD, 2 infection). Of the 9 patients undergoing second transplant in the modern era, 8 are alive and engrafted; the sole death was from adenoviral infection. For all patients undergoing second HSCT, the estimated 5-year OS 70.1% (pre-Bu-pK 66.7% vs. post-Bu-pK 85.7%, p=0.235). Of the 85 patients who were "alive-and-engrafted" after first transplant in post-Bu-pK era, 68 (80%) had full-donor chimerism while 17 (20%) had mixed-donor chimerism. CB was significantly associated with a higher rate of full-donor chimerism (p=0.01) among engrafted survivors.Conclusions: The transplant outcomes have improved. All deaths due to infection, graft failure and pulmonary failure have significantly reduced a better transplant care. The pattern of graft failure has changed from primarily marrow reconstitution likely secondary to inadequate myelosuppression in pre-Bu-pk era, to graft rejection likely secondary to inadequate immunosuppression in post-Bu-pk era. DisclosuresJones:Genzyme: Consultancy, Research Funding, Speakers Bureau; BioMarin: Consultancy, Research Funding, Speakers Bureau.