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Primate bone marrow cells were infected with a retroviral vector carrying the genes for human adenosine deaminase (h-ADA) and bacterial neomycin resistance (neor). The infected cells were infused back into the lethally irradiated donor animals. Several monkeys fully reconstituted and were shown to express the h-ADA and neor genes at low levels in their recirculating hematopoietic cells for short periods of time.

Background: The prognosis for patients with central nervous system (CNS) retinoblastoma (RB) (trilateral or stage 4b metastatic RB) treated with high-dose chemotherapy and autologous stem cell transplant (HDC-ASCT) remains poor. The impact of irradiation when administered as part of upfront therapy post HDC-ASCT on treatment outcomes and survival is unknown., Methods: We performed a retrospective review of all patients with CNS RB (seven stage 4b, eight trilateral, one pineal lesion belonging to methylation group RB) who underwent induction chemotherapy with an intent to proceed to HDC-ASCT at two institutions., Results: Twelve of 16 patients (n = 75%) achieved an objective response to induction chemotherapy, while four patients had progressive/refractory disease; two patients responded to subsequent therapy and proceeded to ASCT, and two patients did not. Seven of 14 patients who underwent HDC-ASCT, received radiotherapy as part of upfront therapy post HDC-ASCT in the form of craniospinal irradiation (CSI) (n = 3), intraventricular radioimmunotherapy (n = 3), or both CSI and intraventricular radioimmunotherapy (n = 1). The Kaplan-Meier estimate of overall survival for these patients was 62.5% at 5 years; no patients developed second malignant neoplasms within the radiation fields. For the seven patients who did not receive radiotherapy, the overall survival was 28.6% at 5 years., Conclusions: CSI (23.4 Gy) alone or in conjunction with intraventricular RIT may have clinical utility in eliminating persistent MRD post HDC-ASCT, contributing to improved disease-free survival in patients with CNS RB. This treatment strategy merits evaluation in a prospective, multicenter clinical trial for patients with CNS metastatic RB., (© 2024 Wiley Periodicals LLC.)

The clinical value of serial routine bone marrow aspirates (rBMAs) in the first year after allogeneic hematopoietic cell transplantation (alloHCT) to detect or predict relapse of acute leukemia (AL) and myelodysplastic syndrome (MDS) in pediatric and young adult patients is unclear. The purpose of this analysis was to determine if assessment of minimal residual disease (MRD) by multiparameter flow cytometry (MFC, MFC-MRD) or donor chimerism (DC) in rBMAs or serial complete blood counts (CBCs) done in the year after alloHCT predicted relapse of AL or MDS in pediatric and young adult patients. We completed a retrospective analysis of patients with AL or MDS who had rBMAs performed after alloHCT between January 2012 and June 2018. Bone marrow (BM) was evaluated at approximately 3, 6, and 12 months for disease recurrence by morphology, MFC-MRD, and percent DC by short tandem repeat molecular testing. CBCs were performed at every clinic visit. The main outcome of interest was an assessment of whether MFC-MRD or DC in rBMAs or serial CBCs done in the year after alloHCT predicted relapse in AL or MDS pediatric and young adult patients. A total of 121 recipients with a median age of 13 years (range 1 to 32) were included: 108 with AL and, 13 with MDS. A total of 423 rBMAs (median 3; 0 to 13) were performed. Relapse at 2 years was 23% (95% CI: 16% to 31%) and at 5 years 25% (95% CI: 18% to 33%). One hundred fifty-four of 157 (98%) rBMAs evaluated for MRD by MFC were negative and did not preclude subsequent relapse. Additionally, low DC (<95%) did not predict relapse and high DC (≥95%) did not preclude relapse. For patients alive without relapse at 1 year, BM DC (P = .74) and peripheral T-cell DC (P = .93) did not predict relapse. Six patients with low-level T-cell and/or BM DC had a total of 8 to 20 BM evaluations, none of these patients relapsed. However, CBC results were informative for relapse; 28 of 31 (90%) relapse patients presented with an abnormal CBC with peripheral blood (PB) blasts (16 patients), cytopenias (9 patients), or extramedullary disease (EMD, 3 patients). Two patients with BM blasts >5% on rBMA had circulating blasts within 5 weeks of rBMA. Neutropenia (ANC <1.5 K/mcl) at 1 year was predictive of relapse (P = .01). Neutropenia and thrombocytopenia (<160 K/mcl) were predictive of disease-free survival (DFS) with inferior DFS for ANC <1.5 K/mcl, P = .001, or platelet count <160 K/mcl (P = .04). These results demonstrate rBMAs after alloHCT assessed for MRD by MFC and/or for level of DC are poor predictors for relapse in pediatric and young adult patients with AL or MDS. Relapse in these patients presents with PB blasts, cytopenias, or EMD. ANC and platelet count at 1-year were highly predictive for DFS., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background Aims: Traditional weight-based dosing of rabbit anti-thymocyte globulin (rATG) used in allogeneic hematopoietic cell transplantation (HCT) to prevent graft-versus-host disease (GVHD) and graft rejection leads to variable exposures. High exposures induce delayed CD4+immune reconstitution (CD4+IR) and greater mortality. We sought to determine the impact of rATG exposure in children and young adults receiving various types of EX-VIVO T-cell-depleted (EX-VIVO-TCD) HCT., Methods: Patients receiving their first EX-VIVO-TCD HCT (CliniMACS CD34+, Isolex or soybean lectin agglutination), with removal of residual T cells by E-rosette depletion (E-) between 2008 and 2018 at Memorial Sloan Kettering Cancer Center were retrospectively analyzed. rATG exposure post-HCT was estimated (AU*d/L) using a validated population pharmacokinetic model. Previously defined rATG-exposures, <30, 30-55, ≥55 AU*d/L, were related with outcomes of interest. Cox proportional hazard and cause-specific models were used for analyses., Results: In total, 180 patients (median age 11 years; range 0.1-44 years) were included, malignant 124 (69%) and nonmalignant 56 (31%). Median post-HCT rATG exposure was 32 (0-104) AU*d/L. Exposure <30 AU*d/L was associated with a 3-fold greater probability of CD4+IR (P < 0.001); 2- to 4-fold lower risk of death (P = 0.002); and 3- to 4-fold lower risk of non-relapse mortality (NRM) (P = 0.02). Cumulative incidence of NRM was 8-fold lower in patients who attained CD4+IR compared with those who did not (P < 0.0001). There was no relation between rATG exposure and aGVHD (P = 0.33) or relapse (P = 0.23). Effect of rATG exposure on outcomes was similar in three EX-VIVO-TCD methods., Conclusions: Individualizing rATG dosing to target a low rATG exposure post-HCT while maintaining total cumulative exposure may better predict CD4+IR, reduce NRM and increase overall survival, independent of the EX-VIVO-TCD method., Competing Interests: Declaration of competing interest KJC: research support: Novartis, Celgene, Cellectis, Atara Bio; consultant: Novartis, Atara Bio. SEP: support for the conduct of clinical trials: AlloVir, Jasper Therapeutics, Atara Biotherapeutics; consultation (last 24 months) CellEvolve, ADMA, Regeneron; intellectual property related to the use of third-party VSTs licensed to Atara Biotherapeutics with all rights assigned to Memorial Sloan Kettering Cancer Center. RJO: royalties following licensure of EBV-specific T-cell bank by Atara Biotherapeutics, research support and consultant fees from Atara Biotherapeutics. JJB: consulting Sobi, Bluebird Bio, Avrobio, BlueRock, SmartImmune, Sanofi, Omeros, Advanced Clinical (DMC Chair). All other authors have no commercial, proprietary or financial interest in the products or companies described in this article., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

The only curative approach for myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) arising in patients with Fanconi anemia (FA) is allogeneic hematopoietic stem cell transplantation (HCT); however, HCT approaches are inconsistent and limited data on outcomes exist. We retrospectively evaluated outcomes of thirty patients with FA and MDS/AML who underwent first allogeneic HCT with a T-cell depleted (TCD) graft at our institution. Patients were transplanted on successive protocols with stepwise changes in cytoreduction and GVHD prophylaxis. All but two patients (93%) experienced durable hematopoietic engraftment. With median follow-up of 8.7 years, 5-year OS was 66.8% and DFS 53.8%. No significant differences in survival were found in patients with high-risk prognostic features (age ≥20 years, AML diagnosis, alternative donor graft) or when stratified by conditioning regimen. The 5-year cumulative incidences of relapse and NRM were 24.3% and 21.9%, respectively. NRM was higher in patients ≥20 years at HCT but did not otherwise differ. We herein demonstrate promising outcomes following allogeneic HCT for patients with FA and MDS/AML using TCD grafts, particularly in a cohort of high-risk patients with 50% ≥20 years and a majority receiving mismatched grafts. Future prospective studies are needed to compare this approach with other HCT platforms., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Busulfan is an alkylating drug routinely used in conditioning regimens for allogeneic hematopoietic cell transplantation (allo-HCT). A myeloablative conditioning regimen, including busulfan, is commonly used in patients undergoing T-cell depletion (TCD) and allo-HCT, but data on optimal busulfan pharmacokinetic (PK) exposure in this setting are limited. Between 2012 and 2019, busulfan PK was performed to target an area under the curve exposure between 55 and 66 mg × h/L over 3 days using a noncompartmental analysis model. We retrospectively re-estimated busulfan exposure following the published population PK (popPK) model (2021) and correlated it with outcomes. To define optimal exposure, univariable models were performed with P splines, wherein hazard ratio (HR) plots were drawn, and thresholds were found graphically as the points at which the confidence interval crossed 1. Cox proportional hazard and competing risk models were used for analyses. 176 patients were included, with a median age of 59 years (range, 2-71). Using the popPK model, the median cumulative busulfan exposure was 63.4 mg × h/L (range, 46.3-90.7). The optimal threshold was at the upper limit of the lowest quartile (59.5 mg × h/L). 5-year overall survival (OS) with busulfan exposure ≥59.5 vs <59.5 mg × h/L was 67% (95% CI, 59-76) vs 40% (95% CI, 53-68), respectively (P = .02), and this association remained in a multivariate analyses (HR, 0.5; 95% CI, 0.29; 0.88; P = .02). In patients undergoing TCD allo-HCT, busulfan exposure is significantly associated with OS. The use of a published popPK model to optimize exposure may significantly improve the OS., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Patients with leukemia relapse after allogeneic hematopoietic cell transplant (HCT) have poor survival due to toxicity and disease progression. A second HCT often offers the only curative treatment., Methods: We retrospectively reviewed our bi-institutional experience (MSKCC-USA; Utrecht-NL) with unrelated cord blood transplantation (CBT) for treatment of post-transplant relapse. Overall survival (OS) and event-free survival (EFS) were evaluated using the Kaplan-Meier method, treatment-related mortality (TRM) and relapse were evaluated using the competing risk method by Fine-Gray., Results: Twenty-six patients age < 21 years received a second (n=24) or third (n=2) HCT with CB grafts during the period 2009-2021. Median age at first HCT (HCT1) was 11.5 (range: 0.9-17.7) years and all patients received myeloablative cytoreduction. Median time from HCT1 to relapse was 12.8 (range 5.5-189) months. At CBT, median patient age was 13.5 (range 1.4-19.1) years. Diagnoses were AML: 13; ALL: 4, MDS: 5, JMML: 2; CML: 1; mixed phenotype acute leukemia: 1. Sixteen patients (62%) were in advanced stage, either CR>2 or with active disease. Median time from HCT1 to CBT was 22.2 (range 7-63.2) months. All patients engrafted after CBT. Thirteen patients developed acute GvHD; 7 had grade III or IV. With a median survivor follow-up of 46.6 (range 17.4-155) months, 3-year OS was 69.2% (95% CI 53.6-89.5%) and 3-year EFS was 64.9% (95% CI 48.8-86.4%). Eight patients died, 3 of AML relapse and 5 due to toxicity (respiratory failure [n=4], GvHD [n=1]) at a median time of 7.7 (range 5.9-14.4) months after CBT. Cumulative incidence of TRM at 3 years was 19.2% (95% CI 4.1-34.4%). Notably, all TRM events occurred in patients transplanted up to 2015; no toxicity-related deaths were seen in the 16 patients who received CBT after 2015. Cumulative incidence of relapse was 15.9% (95% CI 1.6-30.2%) at 3 years, remarkably low for these very high-risk patients., Conclusions: Survival was very encouraging following CB transplants in pediatric patients with recurrent leukemia after first HCT, and TRM has been low over the last decade. CBT needs to be strongly considered as a relatively safe salvage therapy option for post-transplant relapse., Competing Interests: SP receives support for the conduct of sponsored trials: Atara, AlloVir, Jasper. Consulting CellEvolve, Pierre Fabre. Honoraria: Regeneron. Advisor Board: Smartimmune. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2023 Troullioud Lucas, Boelens, Prockop, Curran, Bresters, Kollen, Versluys, Bierings, Archer, Davis, Klein, Kernan, Lindemans and Scaradavou.)

BackgroundRefractory CMV viremia and disease are associated with significant morbidity and mortality in recipients of hematopoietic stem cell transplant (HCT).MethodsIn phase I/II trials, we treated 67 subjects for CMV viremia or disease arising after HCT with adoptive transfer of banked, third-party, CMVpp65-sensitized T cells (CMVpp65-VSTs). All were evaluable for toxicity and 59 for response. Evaluable subjects had CMV disease or persisting viremia that had failed at least 2 weeks of induction therapy with a median of 3 antiviral drugs; 84.7% had more than 3 of 11 high-risk features. CMVpp65-VSTs were specific for 1 to 3 CMVpp65 epitopes, presented by a limited set of HLA class I or II alleles, and were selected based on high-resolution HLA matching at 2 of 10 HLA alleles and matching for subject and subject's HCT donor for 1 or more alleles through which the CMVpp65-VSTs were restricted.ResultsT cell infusions were well tolerated. Of 59 subjects evaluable for response, 38 (64%) achieved complete or durable partial responses.ConclusionsRecipients responding to CMVpp65VSTs experienced an improved overall survival. Of the risk factors evaluated, transplant type, recipient CD4+ and CD8+ T cell levels prior to adoptive therapy, and the HLA restriction of CMVpp65-VSTs infused each significantly affected responses. In addition, CMVpp65-specific T cells of HCT donor or recipient origin contributed to the durability of both complete and partial responses.Trial RegistrationNCT00674648; NCT01646645; NCT02136797 (NIH).FundingNIH (P01 CA23766, R21 CA162002 and P30 CA008748); Aubrey Fund; Claire Tow Foundation; Major Family Foundation; "Rick" Eisemann Pediatric Research Fund; Banbury Foundation; Edith Robertson Foundation; Larry Smead Foundation.

Poor graft function (PGF) is a life-threatening complication after allogeneic stem cell transplantation (alloSCT). Historically, outcomes of patients with PGF have been very poor, and there are no standardized approaches to treatment. Furthermore, few outcomes after CD34-selected stem cell boost (CD34+SCB) for PGF in pediatric alloSCT recipients have been reported. Here we report on a single center experience with CD34+SCB for PGF after alloSCT in patients treated on the Pediatric Transplant and Cellular Therapy Service at MSK Kids, Memorial Sloan Kettering Cancer Center. A retrospective analysis of patients transplanted for malignant and nonmalignant disorders who received a CD34+SCB between 2008 to 2020 for treatment of PGF defined as the need for granulocyte colony-stimulating factor (G-CSF) and/or packed red blood cell or platelet transfusion support with bone marrow donor chimerism ≥85%. Peripheral blood stem cells from the original donor were the source for CD34+SCB. Durable complete recovery (durable CR) was defined as recovery of peripheral blood counts without recurrent need for G-CSF or transfusion support. The main outcomes of interest were recovery of hematopoiesis and overall survival. Development of graft versus host disease (GVHD) was an additional outcome of interest. Fourteen patients with PGF received a boost. Six patients had no known infection, while 8 patients had PGF associated with an infection. The probability of CR at 60 days was 79% (95% confidence interval [CI], 57%-100%). The overall survival at both 2 and 5 years was 78% (95% CI, 56%-100%). One patient developed GVHD, which was fatal. No other CD34+SCB-related toxicities were observed. While including patients with PGF as recently defined by the American Society for Transplantation and Cellular Therapy, as well as PGF in patients with concomitant infections, we demonstrate that CD34+SCB is safe and can provide for durable trilineage hematopoietic recovery and long-term survival in pediatric patients after alloSCT., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Stage 4a metastatic retinoblastoma (RB) is curable with intensive multimodality therapy including myeloablative chemotherapy with autologous stem cell transplant (HDC-ASCT) and involved field radiation therapy (IFRT). To our knowledge, no data exist on the impact of (a) pre-ASCT disease status, and (b) IFRT to sites of metastatic disease post ASCT on survival., Procedure: We retrospectively reviewed patients with stage 4a metastatic RB who underwent induction chemotherapy followed by HDC-ASCT, with or without IFRT, to residual tumor sites at Memorial Sloan Kettering Cancer Center (MSKCC) (n = 24)., Results: The degree of postinduction response prior to ASCT did not affect outcome, with 5-year overall survival (OS) of 68% and 86% in patients who achieved complete response (CR) and very good partial response (VGPR)/partial response (PR) prior to ASCT, respectively. IFRT administered post ASCT in patients with possible residual bony metastatic disease increases the likelihood of developing osteosarcoma in the radiation field., Conclusion: OS for patients with stage 4a metastatic RB treated with ASCT with VGPR or PR to pretransplant chemotherapy was not significantly different from patients with CR. In addition, IFRT does not seem to be required for bony disease control and increased the likelihood of developing osteosarcoma., (© 2022 Wiley Periodicals LLC.)

There are limited data for letermovir as primary cytomegalovirus (CMV) prophylaxis in patients less than 18 years of age. We report 9 adolescent patients who received letermovir following hematopoietic cell transplantation. No patients developed clinically significant CMV while taking letermovir. Letermovir was well tolerated and efficacious in preventing CMV infections., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Hepatic sinusoidal obstruction syndrome (SOS) is a serious complication after allogeneic stem cell transplantation (allo-HCT). However, there is no uniform consensus on the optimal strategy for SOS prevention. Ursodeoxycholic acid is the most used regimen, even though its administration is challenging in recipients unable to tolerate oral medication. Defibrotide was recently studied in a phase 3 trial, but enrollment was stopped early due to futility. Low-dose unfractionated heparin (UFH) is an alternative strategy. However, its efficacy is reputed but unproven increased risk of bleeding has not been fully established. We evaluated 514 adult allo-HCT recipients who received SOS prophylaxis with low-dose UFH. Bleeding complications occurred in 12 patients 2.3% of patients of which only 2 (0.4%) had significant grade 3 bleeding. Only 14 patients were diagnosed with hepatic SOS. Univariate analysis showed that day 100 SOS was higher in recipients of unmodified grafts when compared to CD34+ selected ex vivo T-cell depleted grafts (p ≤ 0.001), and patients with hepatitis B and/or C exposure pre-HCT (p = 0.028). Overall, UFH was well tolerated and associated with a low incidence of subsequent hepatic SOS. Low-dose UFH prophylaxis can be considered in select patients who cannot tolerate oral ursodiol., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Effective reinduction regimens are needed for children with relapsed and refractory acute myeloid leukemia (AML), as outcomes remain poor. Therapeutic options are limited in this heavily pretreated patient population, many of whom have reached lifetime recommended doses of anthracycline chemotherapy. The development of effective non-anthracycline-based salvage regimens is crucial to these patients who are at significant risk of life-threatening cardiotoxicity. We previously reported results of a phase 2 trial of a clofarabine-based regimen with topotecan, vinorelbine, and thiotepa (TVTC) in patients with relapsed acute leukemias. Here we report on an expanded bicenter cohort of 33 patients, <25 years of age, with relapsed/refractory AML treated with up to 2 cycles of the TVTC reinduction regimen from 2007 to 2018. The overall response rate, defined as complete remission or complete remission with partial recovery of platelet count, was 71.4% (95% confidence interval [CI], 41.9-91.6) for those patients in first relapse (n = 14) and 47.4% (95% CI, 24.4-71.1) for patients in second or greater relapse or with refractory disease. Responses were seen across multiple high-risk cytogenetic and molecular subtypes, with 84% of responders successfully bridged to allogeneic stem cell transplantation. The 5-year overall survival for patients in first relapse was 46.2% (95% CI, 19.1-73.3) and 50.0% (95% CI, 26.9-73.1) for patients who responded to TVTC. For pediatric and young adult patients with relapsed/refractory AML, TVTC reinduction compares favorably with currently used salvage regimens and warrants further exploration., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background Aims: Cytomegalovirus (CMV) reactivation is a significant complication following allogeneic hematopoietic stem cell transplant (HSCT) and affects upwards of 40% of pediatric HSCT patients. Pre-emptive therapy remains the only effective treatment strategy available for pediatric patients following CMV reactivation. Little is known about how the timing of induction treatment following CMV reactivation impacts outcomes in pediatric patients, especially following ex vivo T-cell-depleted (TCD) HSCT., Methods: The authors evaluated how the timing of induction treatment after CMV reactivation impacts overall survival (OS) and CMV disease in pediatric patients undergoing TCD HSCT at a single institution. The authors retrospectively analyzed patients treated on the pediatric service who received an initial ex vivo TCD HSCT at Memorial Sloan Kettering Cancer Center (MSKCC) from January 2010 to June 2018. CMV reactivation was defined as ≥1 CMV polymerase chain reaction >500 copies/mL in whole blood or >137 IU/mL in plasma within the first 180 days after allogeneic HSCT. To analyze the impact of the timing of induction treatment, the authors' primary study outcome was OS and secondary outcome was CMV disease., Results: A total of 169 patients who underwent an initial allogeneic TCD HSCT on the pediatric service at MSKCC from January 2010 to June 2018 were included in the analysis. Thirty-seven (22%) patients reactivated CMV during the first 180 days following HSCT. Of those patients who reactivated CMV, CMV donor/recipient (D/R) serostatus was as follows: D+/R+ n = 28 (76%) and D-/R+ n = 9 (24%). There was no CMV reactivation observed among recipients who were CMV-seronegative irrespective of donor serostatus. In those patients who reactivated CMV, the median time from HSCT to CMV reactivation was 24 days (interquartile range, 20-31). Eleven patients ultimately developed CMV disease in addition to CMV viremia, whereas the remaining patients had only CMV viremia. The cumulative incidence of CMV reactivation at 60 days was 45.2% (95% confidence interval [CI], 32.8-57.5) in the D+/R+ subgroup and 31% (95% CI, 14.2-47.9) in the D-/R+ subgroup. For those patients who reactivated CMV, 30 (81%) received induction treatment with ganciclovir or foscarnet. To analyze the impact of the timing of induction treatment on clinical outcomes, the authors restricted the analysis to those patients who reactivated CMV and received induction treatment (n = 30). The timing of induction treatment was significantly associated with OS, with optimal timing of initiation within a week of CMV reactivation (P = 0.02). There was no significant impact on the timing of induction treatment and risk of CMV disease (P = 0.30)., Conclusions: In ex vivo TCD HSCT in pediatric patients, early initiation of induction treatment after CMV reactivation is associated with improved OS., (Copyright © 2021 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Traditional weight-based dosing results in variable rabbit antithymocyte globulin (rATG) clearance that can delay CD4+ T-cell immune reconstitution (CD4+ IR) leading to higher mortality. In a retrospective pharmacokinetic/pharmacodynamic (PK/PD) analysis of patients undergoing their first CD34+ T-cell-depleted (TCD) allogeneic hematopoietic cell transplantation (HCT) after myeloablative conditioning with rATG, we estimated post-HCT rATG exposure as area under the curve (arbitrary unit per day/milliliter [AU × day/mL]) using a validated population PK model. We related rATG exposure to nonrelapse mortality (NRM), CD4+ IR (CD4+ ≥50 cells per µL at 2 consecutive measures within 100 days after HCT), overall survival, relapse, and acute graft-versus-host disease (aGVHD) to define an optimal rATG exposure. We used Cox proportional hazard models and multistate competing risk models for analysis. In all, 554 patients were included (age range, 0.1-73 years). Median post-HCT rATG exposure was 47 AU × day/mL (range, 0-101 AU × day/mL). Low post-HCT area under the curve (<30 AU × day/mL) was associated with lower risk of NRM (P < .01) and higher probability of achieving CD4+ IR (P < .001). Patients who attained CD4+ IR had a sevenfold lower 5-year NRM (P < .0001). The probability of achieving CD4+ IR was 2.5-fold higher in the <30 AU × day/mL group compared with 30-55 AU × day/mL and threefold higher in the <30 AU × day/mL group compared with the ≥55 AU × day/mL group. In multivariable analyses, post-HCT rATG exposure ≥55 AU × day/mL was associated with an increased risk of NRM (hazard ratio, 3.42; 95% confidence interval, 1.26-9.30). In the malignancy subgroup (n = 515), a tenfold increased NRM was observed in the ≥55 AU × day/mL group, and a sevenfold increased NRM was observed in the 30-55 AU × day/mL group compared with the <30 AU × day/mL group. Post-HCT rATG exposure ≥55 AU × day/mL was associated with higher risk of a GVHD (hazard ratio, 2.28; 95% confidence interval, 1.01-5.16). High post-HCT rATG exposure is associated with higher NRM secondary to poor CD4+ IR after TCD HCT. Using personalized PK-directed rATG dosing to achieve optimal exposure may improve survival after HCT., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Chimeric antigen receptor (CAR) T cells achieve response and durable remission in patients with relapsed/refractory (R/R) B cell malignancies. Following collection of patient T cells, chemotherapy ("bridging chemotherapy") is utilized during the manufacture of CAR T cells. However, the optimal bridging chemotherapy has yet to be defined. Our objective in this study was to report clinical outcomes following bridging chemotherapy in a cohort of pediatric/young adult patients with R/R B cell acute lymphoblastic leukemia (B-ALL) treated with CAR T cell therapy. This retrospective study included patients enrolled on clinical trial NCT01860937 or referred to Memorial Sloan Kettering Cancer Center for commercial CAR T cell therapy (tisagenlecleucel). Bridging chemotherapy (given after T cell collection and before CAR T cell infusion) was defined as high intensity if myelosuppression was expected for >7 days. Outcome comparison analyses were performed in high-intensity versus low-intensity bridging chemotherapy, 1 cycle versus ≥2 cycles of bridging chemotherapy, disease burden at the start of bridging chemotherapy, disease burden at the start of bridging chemotherapy with chemotherapy intensity, tumor debulking by bridging chemotherapy, and disease burden pre-lymphodepleting chemotherapy (LDC) for CAR T cell treatment. The outcomes of this analysis showed that the incidence of grade ≥3 infection was significantly higher (94% versus 56%; P = .019) and overall survival (OS) was significantly lower (hazard ratio, 3.73; 95% confidence interval, 1.39 to 9.97; P = .006) in patients who received ≥2 cycles versus 1 cycle of bridging chemotherapy. No difference in incidence was found for cytokine release syndrome (P > .99) or neurotoxicity/immune effector cell-associated neurotoxicity syndrome (P = .70). Disease burden at the start of bridging chemotherapy, disease burden prior to LDC, and tumor debulking by bridging chemotherapy also did not significantly affect outcomes after CAR T cell therapy in this cohort. In this study, patients receiving ≥2 cycles of bridging chemotherapy had higher rates of infection and lower OS but no difference in CAR-specific toxicity. Clinicians should carefully consider the use of additional cycles of chemotherapy during the bridging period as it delays treatment with CAR T cells and increases the risk of infectious complications. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), a potentially life-threatening complication of hematopoietic cell transplantation (HCT), results from prolonged sinusoidal endothelial cell activation and profound endothelial cell damage, with sequelae. Defibrotide, the only drug approved in the United States and Europe for treating VOD/SOS post-HCT, has European Commission orphan drug designation for preventing graft-versus-host disease (GvHD), associated with endothelial dysfunction. This endothelial cell protector and stabilizing agent restores thrombo-fibrinolytic balance and preserves endothelial homeostasis through antithrombotic, fibrinolytic, anti-inflammatory, anti-oxidative, and anti-adhesive activity. Defibrotide also preserves endothelial cell structure by inhibiting heparanase activity. Evidence suggests that downregulating p38 mitogen-activated protein kinase (MAPK) and histone deacetylases (HDACs) is key to defibrotide's endothelial protective effects; phosphatidylinositol 3-kinase/Akt (PI3K/AKT) potentially links defibrotide interaction with the endothelial cell membrane and downstream effects. Despite defibrotide's being most extensively studied in VOD/SOS, emerging preclinical and clinical data support defibrotide for treating or preventing other conditions driven by endothelial cell activation, dysfunction, and/or damage, such as GvHD, transplant-associated thrombotic microangiopathy, or chimeric antigen receptor T-cell (CAR-T) therapy-associated neurotoxicity, underpinned by cytokine release syndrome and endotheliitis. Further preclinical and clinical studies will explore defibrotide's potential utility in a broader range of disorders resulting from endothelial cell activation and dysfunction., (© 2021. The Author(s).)

Long-term outcomes after allogeneic hematopoietic cell transplantation (HCT) for therapy-related myeloid neoplasms (tMNs) are dismal. There are few multicenter studies defining prognostic factors in pediatric patients with tMNs. We have accumulated the largest cohort of pediatric patients who have undergone HCT for a tMN to perform a multivariate analysis defining factors predictive of long-term survival. Sixty-eight percent of the 401 patients underwent HCT using a myeloablative conditioning (MAC) regimen, but there were no statistically significant differences in the overall survival (OS), event-free survival (EFS), or cumulative incidence of relapse and non-relapse mortality based on the conditioning intensity. Among the recipients of MAC regimens, 38.4% of deaths were from treatment-related causes, especially acute graft versus host disease (GVHD) and end-organ failure, as compared to only 20.9% of deaths in the reduced-intensity conditioning (RIC) cohort. Exposure to total body irradiation (TBI) during conditioning and experiencing grade III/IV acute GVHD was associated with worse OS. In addition, a diagnosis of therapy-related myelodysplastic syndrome and having a structurally complex karyotype at tMN diagnosis were associated with worse EFS. Reduced-toxicity (but not reduced-intensity) regimens might help to decrease relapse while limiting mortality associated with TBI-based HCT conditioning in pediatric patients with tMNs., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication that occurs after hematopoietic cell transplantation (HCT). The mortality associated with untreated VOD/SOS with multiorgan dysfunction (MOD) has been reported to be >80%. The recommended dose of defibrotide is 6.25 mg/kg every 6 hours, administered as a 2-hour i.v. infusion, for a minimum of 21 days or until resolution of VOD/SOS signs and symptoms. The objective of this analysis was to evaluate the time to complete response (CR) in patients with post-HCT VOD/SOS treated with defibrotide. The time to defibrotide discontinuation due to a CR served as a surrogate for time to CR in an expanded access study (T-IND; ClinicalTrials.gov NCT00628498; n = 1000), and was analyzed separately from the time to CR data pooled from a phase 2 randomized dose-finding study (NCT00003966; n = 74 patients who received 25 mg/kg/day) and a phase 3 historically controlled study (NCT00358501; n = 102). For all studies, a CR was defined as total serum bilirubin <2 mg/dL with resolution of VOD/SOS-related MOD (renal and/or pulmonary dysfunction); the phase 2 study also required resolution of central nervous system dysfunction. In the T-IND, 390 patients discontinued treatment due to a CR and had sufficient data for analysis. The median time to discontinuation was 22 days (range, 2 to 64 days). Discontinuation due to CR occurred beyond 21 days in 235 patients (60%) and beyond 28 days in 57 patients (15%). The pooled phase 2 and 3 studies included 60 patients who achieved a CR, with a median time to CR of 24.5 days (range, 7 to 123 days). A CR was achieved beyond 21 days in 32 patients (53%) and beyond 28 days in 24 patients (40%). The Kaplan-Meier estimate of day +100 survival rate was substantially higher in patients who discontinued due to a CR compared with those who did not (92.5% versus 37.3%). Treatment-emergent adverse events occurred in 185 of 390 patients (47%) who discontinued due to a CR in the T-IND and in 55 of 60 patients (92%) who achieved a CR in the pooled phase 2 and 3 studies, and rates did not differ according to duration of treatment (≤21 days versus >21 days). Taken together, these results highlight the importance of continued defibrotide therapy until resolution of VOD/SOS signs and symptoms, as currently indicated in the approved product labels, which may occur beyond the recommended minimum of 21 days., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

To define the tolerability and outcome of allogeneic hematopoietic stem cell transplant (allo-HSCT) following CAR T-cell therapy, we retrospectively reviewed pediatric/young adult patients with relapsed/refractory B-ALL who underwent this treatment. Fifteen patients (median age 13 years; range 1-20 years) with a median potential follow-up of 39 months demonstrated 24-month cumulative incidence of relapse, cumulative incidence of TRM, and OS of 16% (95% CI: 0-37%), 20% (95% CI: 0-40%), and 80% (95% CI: 60-100%), respectively. Severe toxicity following CAR T cells did not impact OS (p = 0.27), while greater time from CAR T cells to allo-HSCT (>80 days) was associated with a decrease in OS. In comparing CD34-selected T-cell depleted (TCD; n = 9) vs unmodified (n = 6) allo-HSCT, the cumulative incidence of relapse, TRM, and OS at 24 months was 22% (95% CI: 0-49%) vs 0% (p = 0.14), 0% vs 50% [95% CI: 10-90%] (p = 0.02) and 100% vs 50% [95% CI: 10-90%] (p = 0.02). In this small cohort of patients, CAR T cells followed by a CD34-selected TCD allo-HSCT appears to result in less TRM and favorable OS when compared with unmodified allo-HSCT. There was no evidence that disease control was impacted by the type of consolidative allo-HSCT, which demonstrates the feasibility of this approach.

Background: An association between early CD4+ T cell immune reconstitution (CD4+ IR) and survival after T-replete allogeneic hematopoietic cell transplantation (HCT) has been previously reported. Here we report validation of this relationship in a separate cohort that included recipients of ex vivo T-cell-depleted (TCD) HCT. We studied the relationship between CD4+ IR and clinical outcomes., Methods: A retrospective analysis of children/young adults receiving their first allogeneic HCT for any indication between January 2008 and December 2017 was performed. We related early CD4+ IR (defined as achieving >50 CD4+ T cells/µL on two consecutive measures within 100 days of HCT) to overall survival (OS), relapse, non-relapse mortality (NRM), event-free survival (EFS) and acute graft-versus-host disease (aGVHD). Fine and Gray competing risk models and Cox proportional hazard models were used., Results: In this analysis, 315 patients with a median age of 10.4 years (interquartile range 5.0-16.5 years) were included. The cumulative incidence of CD4+ IR at 100 days was 66.7% in the entire cohort, 54.7% in TCD (N = 208, hazard ratio [HR] 0.47, P < 0.001), 90.0% in uCB (N = 40) and 89.6% in T-replete (N = 47) HCT recipients. In multi-variate analyses, not achieving early CD4+ IR was a predictor of inferior OS (HR 2.35, 95% confidence interval [CI] 1.46-3.79, P < 0.001) and EFS (HR 1.80, 95% CI 1.20-2.69, P = 0.004) and increased NRM (HR 6.58, 95% CI 2.82-15.38, P < 0.001). No impact of CD4+ IR on relapse or aGVHD was found. Within the TCD group, similar associations were observed., Conclusion: In this HCT cohort, including recipients of TCD HCT, we confirmed that early CD4+ IR was an excellent predictor of outcomes. Finding strategies to predict or improve CD4+ IR may influence outcomes., (Copyright © 2020 International Society for Cell and Gene Therapy. Published by Elsevier Inc. All rights reserved.)

For patients with untreated hepatic veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) with multi-organ dysfunction (MOD), mortality is >80%. We conducted a pooled analysis of three studies that assessed Day 100 survival in relationship to MOD severity, with dialysis and/or ventilator dependence representing the most severe organ dysfunction. All patients in the analysis were diagnosed using Baltimore criteria/biopsy. This analysis of patients with VOD/SOS and MOD after haematopoietic cell transplantation (HCT; n = 651) demonstrated higher Day 100 survival rates amongst defibrotide-treated patients with VOD/SOS with less versus more severe forms of MOD. Even patients with severe forms of MOD post-HCT benefitted from defibrotide., (© 2020 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of hematopoietic cell transplantation (HCT) that is traditionally diagnosed using Baltimore or modified Seattle criteria. Whereas the Baltimore criteria require the presence of hyperbilirubinemia (bilirubin ≥2 mg/dL) for a diagnosis of VOD/SOS, the modified Seattle criteria do not. Before approval by the US Food and Drug Administration, defibrotide was available in the United States through an expanded-access study (T-IND). The T-IND protocol initially required post-HCT diagnosis of VOD/SOS by the Baltimore criteria or biopsy but was later amended to include patients diagnosed using the modified Seattle criteria. This post hoc analysis examined the incidence of VOD/SOS with a bilirubin level <2 mg/dL before and after Day 21 post-HCT in T-IND patients enrolled following the amendment allowing for diagnosis by the modified Seattle criteria. Survival of adult and pediatric patients with or without hyperbilirubinemia and with or without multiorgan dysfunction (MOD) was also evaluated. Of 803 post-HCT patients with VOD/SOS enrolled following the protocol amendment, 181 (23%) had a bilirubin level <2 mg/dL and would not have been diagnosed if hyperbilirubinemia was required. The bilirubin level at diagnosis was <2 mg/dL in 165 of 331 patients (50%) diagnosed by the modified Seattle criteria and in 16 of 23 patients (70%) diagnosed by biopsy. VOD/SOS with a bilirubin level <2 mg/dL was more common in pediatric patients (29%), although it also occurred in adult patients (15%). Patients with hyperbilirubinemia had lower Day 100 survival (54% versus 87% in patients with bilirubin <2 mg/dL) and a higher incidence of MOD (41% versus 26% in patients with bilirubin <2 mg/dL). The incidence of treatment-emergent adverse events and serious adverse events was lower in patients with a bilirubin level <2 mg/dL. These results indicate that anicteric VOD/SOS occurs in both adult and pediatric patients post-HCT and can be diagnosed before and after Day 21 in both groups. The worse survival in patients with bilirubin ≥2 mg/dL suggests that requiring hyperbilirubinemia may result in a progressed disease stage associated with worse outcomes. Taken together, these results highlight the importance of awareness and the possibility of VOD/SOS in the absence of elevated bilirubin level., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

BACKGROUNDAdoptive transfer of donor-derived EBV-specific cytotoxic T-lymphocytes (EBV-CTLs) can eradicate EBV-associated lymphomas (EBV-PTLD) after transplantation of hematopoietic cell (HCT) or solid organ (SOT) but is unavailable for most patients.METHODSWe developed a third-party, allogeneic, off-the-shelf bank of 330 GMP-grade EBV-CTL lines from specifically consented healthy HCT donors. We treated 46 recipients of HCT (n = 33) or SOT (n = 13) with established EBV-PTLD, who had failed rituximab therapy, with third-party EBV-CTLs. Treatment cycles consisted of 3 weekly infusions of EBV-CTLs and 3 weeks of observation.RESULTSEBV-CTLs did not induce significant toxicities. One patient developed grade I skin graft-versus-host disease. Complete remission (CR) or sustained partial remission (PR) was achieved in 68% of HCT recipients and 54% of SOT recipients. For patients who achieved CR/PR or stable disease after cycle 1, one year overall survival was 88.9% and 81.8%, respectively. In addition, 3 of 5 recipients with POD after a first cycle who received EBV-CTLs from a different donor achieved CR or durable PR (60%) and survived longer than 1 year. Maximal responses were achieved after a median of 2 cycles.CONCLUSIONThird-party EBV-CTLs of defined HLA restriction provide safe, immediately accessible treatment for EBV-PTLD. Secondary treatment with EBV-CTLs restricted by a different HLA allele (switch therapy) can also induce remissions if initial EBV-CTLs are ineffective. These results suggest a promising potential therapy for patients with rituximab-refractory EBV-associated lymphoma after transplantation.TRIAL REGISTRATIONPhase II protocols (NCT01498484 and NCT00002663) were approved by the Institutional Review Board at Memorial Sloan Kettering Cancer Center, the FDA, and the National Marrow Donor Program.FUNDINGThis work was supported by NIH grants CA23766 and R21CA162002, the Aubrey Fund, the Claire Tow Foundation, the Major Family Foundation, the Max Cure Foundation, the Richard "Rick" J. Eisemann Pediatric Research Fund, the Banbury Foundation, the Edith Robertson Foundation, and the Larry Smead Foundation. Atara Biotherapeutics licensed the bank of third-party EBV-CTLs from Memorial Sloan Kettering Cancer Center in June 2015.

Chimeric antigen receptor (CAR) T cells have demonstrated clinical benefit in patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We undertook a multicenter clinical trial to determine toxicity, feasibility, and response for this therapy. A total of 25 pediatric/young adult patients (age, 1-22.5 years) with R/R B-ALL were treated with 19-28z CAR T cells. Conditioning chemotherapy included high-dose (3 g/m2) cyclophosphamide (HD-Cy) for 17 patients and low-dose (≤1.5 g/m2) cyclophosphamide (LD-Cy) for 8 patients. Fifteen patients had pretreatment minimal residual disease (MRD; <5% blasts in bone marrow), and 10 patients had pretreatment morphologic evidence of disease (≥5% blasts in bone marrow). All toxicities were reversible, including severe cytokine release syndrome in 16% (4 of 25) and severe neurotoxicity in 28% (7 of 25) of patients. Treated patients were assessed for response, and, among the evaluable patients (n = 24), response and peak CAR T-cell expansion were superior in the HD-Cy/MRD cohorts, as compared with the LD-Cy/morphologic cohorts without an increase in toxicity. Our data support the safety of CD19-specific CAR T-cell therapy for R/R B-ALL. Our data also suggest that dose intensity of conditioning chemotherapy and minimal pretreatment disease burden have a positive impact on response without a negative effect on toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01860937., (© 2019 by The American Society of Hematology.)

Background: Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially fatal complication of conditioning for hematopoietic stem cell transplantation (HSCT) but can occur after nontransplant-associated chemotherapy. Following HSCT, VOD/SOS with multi-organ dysfunction (MOD) may be associated with >80% mortality. Defibrotide is approved to treat severe hepatic VOD/SOS post-HSCT in patients aged >1 month in the European Union and hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT in the United States. Prior to US approval, defibrotide was available to treat VOD/SOS through an expanded-access treatment (T-IND) program. A post hoc analysis of nontransplant-associated VOD/SOS patients treated with defibrotide initiated within 30 days of starting chemotherapy and followed for 70 days is presented., Procedure: Patients were diagnosed by Baltimore or modified Seattle criteria or biopsy, and received defibrotide 25 mg/kg/day in four divided doses (≥21 days recommended)., Results: Of the 1,154 patients in the T-IND, 137 had nontransplant-associated VOD/SOS, 82 of whom developed VOD/SOS within 30 days of starting chemotherapy. Of them, 66 (80.5%) were aged ≤16 years. Across all the 82 patients, Kaplan-Meier estimated day +70 survival was 74.1%, 65.8% in patients with MOD (n = 38), and 81.3% in patients without MOD (n = 44). By age group, Kaplan-Meier estimated day +70 survival was 80.1% in pediatric patients (n = 66) and 50.0% in adults (n = 16). Treatment-related adverse events occurred in 26.8%., Conclusions: In this post hoc analysis of 82 patients initiating defibrotide within 30 days of starting chemotherapy, Kaplan-Meier estimated survival was 74.1% at 70 days after defibrotide initiation. Safety profile was consistent with prior defibrotide studies., (© 2018 The Authors. Pediatric Blood & Cancer Published by Wiley Periodicals, Inc.)

To evaluate outcomes and prognostic markers among children with relapsed Hodgkin lymphoma (HL) treated with autologous stem cell transplant (ASCT), we conducted a retrospective analysis of 36 consecutive pediatric patients treated at Memorial Sloan Kettering Cancer Center from 1989 to 2013. With a median follow-up of 9.6 years, the 10-year overall survival (OS) and event-free survival (EFS) were 74.1 and 67.1% respectively. Absence of B-symptoms, chemotherapy-sensitive disease, and transplant date after 1997 were each associated with superior EFS [HR 0.12 (p = .0015), 0.18 (p = .0039), and 0.17 (p = .0208), respectively]. Childhood Hodgkin International Prognostic Score at relapse (R-CHIPS) was calculated in a subset of patients (n = 22) and a lower score was associated with improved OS (HR 0.29, p = .0352) and a trend toward improved EFS (HR 0.38, p = .0527). In summary, ASCT results in durable remission for the majority of pediatric patients with relapsed HL. R-CHIPS should be evaluated in larger cohorts as a potential predictive tool.

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of haematopoietic stem cell transplant (HSCT) conditioning and chemotherapy. Defibrotide is approved for treatment of hepatic VOD/SOS with pulmonary or renal dysfunction [i.e., multi-organ dysfunction (MOD)] after HSCT in the United States and severe VOD/SOS after HSCT in patients aged older than 1 month in the European Union. Defibrotide was available as an investigational drug by an expanded-access treatment programme (T-IND; NCT00628498). In the completed T-IND, the Kaplan-Meier estimated Day +100 survival for 1000 patients with documented defibrotide treatment after HSCT was 58·9% [95% confidence interval (CI), 55·7-61·9%]. Day +100 survival was also analysed by age and MOD status, and post hoc analyses were performed to determine Day +100 survival by transplant type, timing of VOD/SOS onset (≤21 or >21 days) and timing of defibrotide treatment initiation after VOD/SOS diagnosis. Day +100 survival in paediatric patients was 67·9% (95% CI, 63·8-71·6%) and 47·1% (95% CI, 42·3-51·8%) in adults. All patient subgroups without MOD had higher Day +100 survival than those with MOD; earlier defibrotide initiation was also associated with higher Day +100 survival. The safety profile of defibrotide in the completed T-IND study was similar to previous reports., (© 2018 The Authors. British Journal of Haematology published by John Wiley & Sons Ltd.)

Background: The combination of cyclophosphamide (CY) and antithymocyte globulin (ATG) has been used as a standard conditioning regimen for matched related donor transplantation in patients with severe aplastic anemia., Procedure: To decrease the regimen-related toxicity while maintaining appropriate engraftment and survival rates, fludarabine (FLU) was added to the regimen. Four pediatric patients received matched related donor bone marrow transplantation with CY (50 mg/kg×2) (instead of the 50 mg/kg×4 standard dosing), equine ATG (30 mg/kg×3), with the addition of FLU (30 mg/m×4). Graft versus host disease (GvHD) prophylaxis included a calcineurin inhibitor and methotrexate., Results: No grade 4 acute toxicities occurred during the first 30 days after transplant. All patients engrafted with normalization of peripheral blood counts and transfusion independence. One patient developed grade 1 to 2 acute GvHD, followed by chronic GvHD that resolved. With a median follow-up of 41.7 months, all 4 patients are alive and transfusion free, with complete donor chimerism. This combination of a low-dose CY/ATG+FLU regimen was overall very well tolerated and contributed toward a successful outcome including engraftment, chimerism, and survival., Conclusion: This small pilot study shows that this cytoreductive regimen could be considered as the standard of care for transplantation of pediatric patients with aplastic anemia from HLA-matched siblings.

A strategy to rapidly determine if a matched unrelated donor (URD) can be secured for allograft recipients is needed. We sought to validate the accuracy of (1) HapLogic match predictions and (2) a resultant novel Search Prognosis (SP) patient categorization that could predict 8/8 HLA-matched URD(s) likelihood at search initiation. Patient prognosis categories at search initiation were correlated with URD confirmatory typing results. HapLogic-based SP categorizations accurately predicted the likelihood of an 8/8 HLA-match in 830 patients (1530 donors tested). Sixty percent of patients had 8/8 URD(s) identified. Patient SP categories (217 very good, 104 good, 178 fair, 33 poor, 153 very poor, 145 futile) were associated with a marked progressive decrease in 8/8 URD identification and transplantation. Very good to good categories were highly predictive of identifying and receiving an 8/8 URD regardless of ancestry. Europeans in fair/poor categories were more likely to identify and receive an 8/8 URD compared with non-Europeans. In all ancestries very poor and futile categories predicted no 8/8 URDs. HapLogic permits URD search results to be predicted once patient HLA typing and ancestry is obtained, dramatically improving search efficiency. Poor, very poor, andfutile searches can be immediately recognized, thereby facilitating prompt pursuit of alternative donors., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

We sought to develop a myeloablative chemotherapeutic regimen to secure consistent engraftment of T-cell depleted (TCD) hematopoietic stem cell transplantations (HSCT) without the need for total body irradiation, thereby reducing toxicity while maintaining low rates of graft-versus-host disease (GVHD) and without increasing relapse. We investigated the myeloablative combination of busulfan (Bu) and melphalan (Mel), with the immunosuppressive agents fludarabine (Flu) and rabbit antithymocyte globulin (r-ATG) as cytoreduction before a TCD HSCT. No post-transplantation immunosuppression was administered. Between April 2001 and May 2008, 102 patients (median age, 55 years) with a diagnosis of primary or secondary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) underwent cytoreduction with Bu/Mel/Flu, followed by TCD grafts. TCD was accomplished by CD34 + -selection followed by E-rosette depletion for peripheral blood stem cell grafts and, for bone marrow grafts, by soybean agglutination followed by E-rosette depletion. Donors included matched and mismatched, related and unrelated donors. Risk stratification was by American Society for Blood and Marrow Transplantation risk categorization for patients with primary disease. For patients with secondary/treatment-related MDS/AML, those in complete remission (CR) 1 or with refractory anemia were classified as intermediate risk, and all other patients were considered high risk. Neutrophil engraftment occurred at a median of 11 days in 100 of 101 evaluable patients. The cumulative incidences of grades II to IV acute and chronic GVHD at 1 year were 8.8% and 5.9%, respectively. Overall- and disease-free survival (DFS) rates at 5 years were 50.0% and 46.1%, respectively, and the cumulative incidences of relapse and treatment-related mortality were 23.5% and 28.4%, respectively. Stratification by risk group demonstrated superior DFS for low-risk patients (61.5% at 5 years) compared with intermediate- or high-risk (34.2% and 40.0%, respectively, P = .021). For patients with AML, those in CR1 had superior 5-year DFS compared with those in ≥CR2 (60% and 30.6%, respectively, P = .01), without a significant difference in incidence of relapse (17.1% and 30.6%, respectively, P = .209). There were no differences in DFS for other patient, donor, or disease characteristics. In summary, cytoreduction with Bu/Mel/Flu and r-ATG secured consistent engraftment of TCD transplantations. The incidences of acute/chronic GVHD and disease relapse were low, with favorable outcomes in this patient population with high-risk myeloid malignancies., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)